Randomized, Phase II Study Evaluating Concurrent or Sequential Fixed-Dose Pembrolizumab in Combination With Cisplatin and Intensity Modulated Radiotherapy in Intermediate or High Risk, Previously Untreated, Locally Advanced Head and Neck Cancer
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Dan Zandberg

1 
 
TITLE: A Randomized, Phase II Study Evaluating Concurrent or Sequential Fixed-Dose 
Pembrolizumab in Combination with Cisplatin and Intensity Modulated Radiotherapy 
(IMRT) in Intermediate or High Risk, Previously Untreated, Locally Advanced Head and 
Neck Cancer 
HCC Study Number: 
15-132 
Phase: 
Randomized Phase II 
Version: 
2.0 
Version Date: 
05/22/2019 
Investigational Agent: 
Pembrolizumab 
Commercial Agent: 
Cisplatin 
Radiation Therapy: 
Intensity Modulated Radiotherapy (IMRT) 
 
 
SPONSOR-INVESTIGATOR: 
David Clump MD 
UPMC Hillman Cancer Center 
5230 Centre Avenue 
                    1st floor Posner Tower 
Pittsburgh, PA 15232 
                                                                 Phone: (412) 623-6720  (24 hours) 
 
 
CO-CHAIRS: 
Radiation Oncology: 
Jonathan J. Beitler, MD, MBA 
(Emory University) 
Medical Oncology: 
Julie E. Bauman, MD 
(University of Arizona) 
Translational Science: 
Robert Ferris, MD, PhD 
(UPMC) 
 
BIOSTATISTICIAN: 
Daniel P. Normolle, PhD 
Email: dpn7@pitt.edu 
 
Source(s) of Support: 
Merck, Inc. 

2 
 
STUDY SCHEMA 
 
 
 

3 
 
TABLE OF CONTENTS 
STUDY SCHEMA ....................................................................................................................................... 2 
1. 
BACKGROUND & RATIONALE .................................................................................................. 6 
1.1 
Disease Background .................................................................................................................. 6 
1.1.1 
Carcinogen-Induced HNSCC ............................................................................................................ 6 
1.1.2 
HPV-Associated HNSCC ................................................................................................................. 6 
1.2 
Pembrolizumab .......................................................................................................................... 6 
1.2.1 
Background ....................................................................................................................................... 7 
1.2.2 
Rationale for Dose Selection/Regimen/Modification ....................................................................... 8 
1.3 
Other Protocol-Specified Drug(s) Background: Cisplatin ......................................................... 9 
1.4 
Study Rationale .......................................................................................................................... 9 
1.4.1 
PD-1 in HNSCC ................................................................................................................................ 9 
1.4.2 
PD-1 and Radiation ......................................................................................................................... 10 
1.5 
Correlative Studies Background .............................................................................................. 10 
2. 
STUDY OBJECTIVES .................................................................................................................. 11 
2.1 
Primary .................................................................................................................................... 11 
2.2 
Secondary ................................................................................................................................ 11 
3. 
PATIENT SELECTION ................................................................................................................ 11 
3.1 
Inclusion Criteria ..................................................................................................................... 11 
3.2 
Exclusion Criteria .................................................................................................................... 13 
4. 
PATIENT REGISTRATION/RANDOMIZATION ...................................................................... 15 
5. 
TREATMENT PLAN .................................................................................................................... 16 
5.1 
Study Drug Administration: Pembrolizumab .......................................................................... 16 
5.1.1 
Route of Administration ................................................................................................................. 16 
5.1.2 
Doses to be Administered ............................................................................................................... 16 
5.1.3 
Dosing Schedule ............................................................................................................................. 17 
5.1.4 
Order of Administration .................................................................................................................. 17 
5.1.5 
Prohibited Concomitant Medications .............................................................................................. 17 
5.2 
Drug Administration – Cisplatin ............................................................................................. 17 
5.2.1 
Route of Administration ................................................................................................................. 17 
5.2.2 
Doses to be Administered ............................................................................................................... 18 
5.2.3 
Dosing Schedule ............................................................................................................................. 18 
5.2.4 
Concomitant Medications during Cisplatin Infusion ...................................................................... 18 
5.3 
Dose Modifications .................................................................................................................. 18 
5.3.1 
Pembrolizumab Dose Modifications ............................................................................................... 18 
5.3.2 
Cisplatin Dose Modifications.......................................................................................................... 23 
5.4 
Intensity Modulated Radiotherapy (IMRT) ............................................................................. 25 
5.4.1 
Dose specifications ......................................................................................................................... 25 
5.4.2 
Immobilization and Simulation ....................................................................................................... 25 
5.4.3 
Target Delineation .......................................................................................................................... 26 
5.4.4 
Treatment Planning and Delivery ................................................................................................... 27 
5.4.5 
Image Guidance for IGRT When Using Reduced Margins ............................................................ 27 
5.4.6 
Definition of Normal Tissues/Organs at Risk (OARs).................................................................... 29 
5.4.7 
Management of the Low Neck/Supraclavicular Region (Match versus No Match) ........................ 30 
5.4.8 
Dose Prescription ............................................................................................................................ 30 
5.4.9 
Planning Priorities and Goals .......................................................................................................... 32 
5.4.10 
Critical Structures ........................................................................................................................... 32 
5.4.11 
Image-Guided Radiotherapy ........................................................................................................... 33 
5.4.12 
Radiation Therapy Treatment Interruptions .................................................................................... 34 
5.4.13 
Radiation Therapy Adverse Events ................................................................................................. 34 
5.5 
Duration of Treatment and Follow-up ..................................................................................... 34 

4 
 
5.6 
Patient Discontinuation ............................................................................................................ 35 
5.7 
Dose Limiting Toxicity (DLT) ................................................................................................ 35 
5.7.1 
DLT................................................................................................................................................. 35 
6. 
RESPONSE ASSESSMENT ......................................................................................................... 36 
6.1 
Solid Tumor Response Criteria (modified RECIST Criteria version 1.1) ............................... 37 
6.1.1 
Malignant Disease Evaluation......................................................................................................... 37 
6.1.2 
Definitions of a Response ............................................................................................................... 38 
6.1.3 
Evaluation of Patient's Best Overall Response ................................................................................ 39 
6.2 
Methods of Measurement ........................................................................................................ 41 
6.2.1 
CT and MRI .................................................................................................................................... 41 
6.2.2 
Clinical Examination ...................................................................................................................... 41 
6.2.3 
Cytology and Histology .................................................................................................................. 41 
6.2.4 
FDG-PET Scan ............................................................................................................................... 41 
7. 
DRUG INFORMATION ................................................................................................................ 43 
7.1 
Pembrolizumab ........................................................................................................................ 43 
7.1.1 
Study Drug Materials ...................................................................................................................... 43 
7.1.2 
Pembrolizumab Study Drug Storage ............................................................................................... 44 
7.2 
Cisplatin ................................................................................................................................... 44 
8. 
CLINICAL AND LABORATORY EVALUATIONS .................................................................. 45 
8.1 
Pre-Registration Evaluations ................................................................................................... 45 
8.1.1 
Required Pre-Registration Evaluations ...................................................................................... 45 
8.1.2 
Required Pre-Treatment Evaluations ......................................................................................... 46 
8.1.3 
Recommended Pre-Treatment Evaluations ................................................................................ 46 
8.2 
Evaluations during treatment ................................................................................................... 47 
8.2.1 
Arm 1 (Cisplatin-IMRT followed by sequential pembrolizumab) .................................................. 47 
8.2.2 
Arm 2 (Concurrent pembrolizumab, cisplatin and IMRT) .............................................................. 49 
8.3 
Post-treatment Evaluations ...................................................................................................... 51 
8.3.1 
Response Assessment ..................................................................................................................... 51 
8.3.2 
End of Treatment Visit(s) 
8.3.3 
Surgical Consolidation .................................................................................................................... 52 
8.4 
Long Term Follow Up ............................................................................................................. 53 
9. 
BIOMARKER, CORRELATIVE, OR SPECIAL STUDIES ........................................................ 54 
9.1 
Biomarker sampling schedule .................................................................................................. 54 
9.2 
Research biopsies..................................................................................................................... 55 
9.2.1 
Research Biopsy Methodology ....................................................................................................... 56 
9.2.2 
Sample Preparation and Shipment Instructions ............................................................................... 56 
9.3 
Research Blood ........................................................................................................................ 58 
9.4 
Correlative Science Studies ..................................................................................................... 62 
9.4.1 
Tumor PD-L1 Expression ............................................................................................................... 62 
9.4.2 
Tumor Antigen (EGFR, p53, E6, E7) Seroreactivity ...................................................................... 63 
9.4.3 
Peripheral Blood CD69/137+ or ICOS+ Activated T cells ............................................................. 63 
9.4.4 
Tumor Cell Immune Escape, Extent of Tumor Infiltrating Lymphocytes (“Immunoscore”), and 
Activating/Suppressive Ligands...................................................................................................... 64 
9.4.5 
Whole Exome Sequencing and RNA-Seq Analysis ........................................................................ 64 
9.4.6 
Paired Analysis of TCR Clonality in Pre- and Post-Treatment Tumor Specimens ......................... 64 
9.4.7 
Germline DNA Analysis for SNPs ................................................................................................. 65 
10. 
STATISTICAL METHODS .......................................................................................................... 65 
10.1 
Primary Objective .................................................................................................................... 65 
10.2 
Sample Size Determination ..................................................................................................... 65 
10.3 
Early Stopping Rule ................................................................................................................. 67 

5 
 
10.4 
Analysis Plan ........................................................................................................................... 67 
10.5 
Secondary Endpoints ............................................................................................................... 68 
10.5.1 
Toxicity ........................................................................................................................................... 68 
10.5.2 
Preliminary efficacy data ................................................................................................................ 68 
10.5.3 
Biomarker endpoints ....................................................................................................................... 68 
11. 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ............... 69 
11.1 
Investigational Product ............................................................................................................ 69 
11.2 
Packaging and Labeling Information ....................................................................................... 69 
11.3 
Clinical Supplies Disclosure .................................................................................................... 69 
11.4 
Storage and Handling Requirements ....................................................................................... 69 
11.5 
Returns and Reconciliation ...................................................................................................... 69 
12. 
Assessing and Reporting Adverse Events ...................................................................................... 70 
12.1 
Definition of Adverse Event .................................................................................................... 70 
12.2 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor and to 
Merck ....................................................................................................................................... 72 
12.3 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ...................................... 72 
12.4 
Immediate Reporting of Adverse Events to the Sponsor, Institutional IRB, and to Merck ..... 73 
12.4.1 
Serious Adverse Events .................................................................................................................. 73 
12.4.2 
Events of Clinical Interest ............................................................................................................... 74 
12.4.3 
Evaluating Adverse Events ............................................................................................................. 75 
12.4.4 
Sponsor Responsibility for Reporting Adverse Events ............... Error! Bookmark not defined.73 
13. 
Data Safety and Monitoring Plan ................................................................................................... 78 
14. 
Administrative and Regulatory Details .......................................................................................... 79 
14.1 
Quality Control and Quality Assurance ................................................................................... 79 
14.2 
Data Handling and Record Keeping ........................................................................................ 79 
14.3 
Ethics ....................................................................................................................................... 79 
14.3.1 
Institutional Review Board (IRB) approval .................................................................................... 79 
14.3.2 
Ethical and scientific conduct of the clinical research study ........................................................... 80 
14.3.3 
Subject Informed Consent ............................................................................................................... 80 
14.4 
Compliance with Trial Registration and Results Posting Requirements ................................. 80 
15. 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ............... 81 
15.1 
Investigational Product ............................................................................................................ 81 
15.2 
Packaging and Labeling Information ....................................................................................... 81 
15.3 
Clinical Supplies Disclosure .................................................................................................... 81 
15.4 
Storage and Handling Requirements ....................................................................................... 81 
15.5 
Returns and Reconciliation ...................................................................................................... 81 
16. 
APPENDICES ................................................................................................................................ 82 
Appendix A: Tobacco Use Assessment Form.......................................................................................... 82 
Appendix B: Performance Status Criteria .............................................................................................. 84 
Appendix D: CTCAE v.4.0 ....................................................................................................................... 91 
Appendix E: Medwatch Form 3500A ...................................................................................................... 92 
17. 
REFERENCES ............................................................................................................................... 93 

6 
 
1. BACKGROUND & RATIONALE 
1.1 Disease Background 
Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the upper 
aerodigestive tract. HNSCC is the sixth leading cancer worldwide with 600,000 cases annually.1 Despite 
advances in multimodality therapy, 5-year overall survival (OS) is 40-60%, and has increased only 
incrementally in the past three decades.2 The current standard of care for nonsurgical management of 
previously untreated locally advanced (PULA) HNSCC is concurrent cisplatin-radiotherapy (RT), which 
improved overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) compared 
with RT alone in the landmark Intergroup 0126 trial.3,4 Although LRC and OS are improved with concurrent 
cisplatin-RT, a meta-analysis indicated disappointing local and distant failure rates of 50% and 15% 
respectively, and an absolute survival benefit of only 6.5% compared to conventionally fractionated RT 
alone.5 
1.1.1 Carcinogen-Induced HNSCC 
The classic environmental risk factors for HNSCC are tobacco and alcohol exposure. Even when treated 
with cisplatin-RT, patients with carcinogen-induced PULA HNSCC have poor OS, PFS and LRC. In RTOG 
01296 patients with human papillomavirus (HPV)(-) tumors had an absolute 25.1% reduction in OS at 3 
years (57.1% vs. 82.4%) vs. patients with HPV(+) tumors, with similar reductions in PFS and LRC. Poor 
outcomes persist despite intensification with altered fractionation,7 multi-drug induction,8 or EGFR-targeted 
monoclonal antibodies (mAb).9  For HPV(-) patients, new intensification approaches are a major unmet 
need. 
1.1.2 HPV-Associated HNSCC 
HPV(+) HNSCC is rapidly increasing in incidence.10 In the US, two-thirds of patients with oropharynx 
cancer have HPV(+) tumors. HPV status and pack-years of tobacco exposure are the major determinants of 
OS in HNSCC, followed by nodal stage.6 Based upon HPV status, pack-years and nodal stage, patients with 
HNSCC can be classified patients into three risk groups having low, intermediate, or high risk of death. This 
clinical risk classification has framed national clinical trial priorities in PULA HNSCC. Specifically, de- 
intensification strategies are being tested in patients with low-risk HPV(+) HNSCC whereas intensification 
strategies are the major unmet need for high-risk HPV(-) and intermediate-risk HPV(+) disease.11,12 
1.2 Pembrolizumab 
Pembrolizumab (formerly MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between programmed cell death 
protein 1 (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. 
 
Pembrolizumab was studied in a Phase Ib expansion cohort in patients with recurrent/metastatic HNSCC.13 
Preliminary clinical data were promising. Half of patients had a decrease in tumor burden and 20% met 
criteria for RECIST response, which was equivalently distributed between HPV(+) and HPV(-) patients. 
Striking activity in a heavily pre-treated HNSCC population, coupled to mechanistic insights regarding the 
importance of PD-1 in HNSCC immune escape, justify the investigation of pembrolizumab in PULA 
HNSCC. 

7 
 
Please refer to the pembrolizumab Investigator Brochure (IB) for descriptions of all preclinical and clinical 
available data. 
1.2.1 Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been 
known for decades.14 Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes 
(TILs) in cancer tissue and favorable prognosis in various malignancies.15-19 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).20,21 The 
structure of murine PD-1 has been resolved.22 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.20,23-25 The mechanism by which PD-1 down modulates T-cell responses is similar to, 
but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.26,27 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.28,29 Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells.30 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 tumors26,31-33 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.26 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).34 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. 

8 
 
1.2.2 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity of single 
agent pembrolizumab. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 
mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three 
dose levels were well tolerated, and no dose-limiting toxicities were observed. This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 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 pembrolizumab 
program has shown that a lower dose of pembrolizumab and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 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 pembrolizumab 
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. Pembrolizumab 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 pembrolizumab 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 

9 
 
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. 
 
1.3 Other Protocol-Specified Drug(s) Background: Cisplatin 
In PULA HNSCC, where cancer involves regional cervical lymph nodes, the cornerstone chemotherapeutic 
in the definitive radiotherapy setting has been cisplatin.4,35,36 This standard of care derives from the sentinel 
Intergroup trial 0126, a randomized phase III trial evaluating radiation alone, concurrent cisplatin-radiation, 
or split course radiation with sequential administration of cisplatin-5FU.4 The trial demonstrated a 
significant survival benefit for patients treated on the cisplatin-radiation arm compared to radiation alone 
resulting in the current, preferred standard of care for non-operative management as published in national 
guidelines.37 
Cisplatin [cis-diamminedichloroplatinum(II)] reacts with DNA to form single base adducts, intrastrand 
crosslinks between 2 bases, and the uniquely lethal interstrand crosslink (ICL).38 The considerable toxicities 
of cisplatin include nausea, hearing loss, nephrotoxicity, myelosuppression, and exacerbation of radiation 
effects such as mucositis and dysphagia.4,39,40 
In Intergroup trial 0126, as well as the adjuvant high risk trials RTOG 95-01 and EORTC 22931, cisplatin 
was administered at 100 mg/m2every 3 weeks for a total of three doses. High dose bolus cisplatin, as dosed 
in these studies, is clearly associated with greater ototoxicity, nephrotoxicity, and emetogenicity compared 
to daily or weekly cisplatin schedules.41-44 Moreover, compliance with three cycles of high dose cisplatin is 
limited; only 64-70% of patients completed three cycles in these studies. Recognition of the importance of 
the cumulative dose of cisplatin, greater than or equal to 200 mg/m2, rather than the dosing schedule per se, 
has resulted in increasing preference for weekly dosing schedules.4,42-45 The RTOG now accepts cisplatin 40 
mg/m2/week concurrent with radiation as the reference standard of care for the adjuvant management of 
high risk HNSCC (RTOG 1216). 
This protocol will use a cisplatin-IMRT backbone consisting of concurrent weekly cisplatin for a total of 7 
doses, rather than high-dose bolus cisplatin, in order to facilitate treatment intensification with 
pembrolizumab. The starting cohort will utilize 40 mg/m2; however if the fixed dose of pembrolizumab 
cannot be added to cisplatin-IMRT without dose-limiting toxicity, then the cisplatin dose will be de- 
escalated to 30 mg/m2 which still results in a cumulative dose of 210 mg/m2. 
1.4 Study Rationale 
1.4.1 PD-1 in HNSCC 
Immunotherapy may be the “fourth modality” in HNSCC, long recognized as an immunosuppressive 
disease. Patients display tumor-permissive cytokine profiles, defective antigen presenting cells (APC), and 
quantitative and qualitative T lymphocyte deficiencies.46-56 HNSCC tumor-infiltrating lymphocytes (TILs) 
are characterized by high expression of the co-inhibitory receptors CTLA-4 and PD-1, so-called “immune 
checkpoints.”54,57 Following activation of the T cell receptor (TCR), PD-1 is expressed by multiple immune 
cells including cytotoxic T lymphocytes (CTLs), natural killer cells and dendritic cells. The PD-1 ligands, 

10 
 
PD-L1 and PD-L2, are expressed broadly on non-hematopoietic tissue in response to IFN-γ; PD-1 ligation 
protects against autoimmunity.58 However, in the case of HNSCC, PD-1 promotes tolerance and immune 
escape. PD-L1 is expressed in the majority of HNSCC, and is explicitly linked to the immune-privileged, 
invasive front of HPV-transformed HNSCC.15,59,60 Moreover, PD-L1 is dynamically upregulated in 
response to RT. 
1.4.2 PD-1 and Radiation 
Ionizing RT is understood to induce adaptive immune responses via three broad mechanisms, which could 
be synergistic with immunotherapy: 1) RT-induced tumor cell death releases tumor antigens (TA) for 
processing and presentation by APCs; 2) RT upregulates chemokines within the tumor microenvironment 
(TME), recruiting TILs and 3) non-lethal RT modulates the tumor phenotype, increasing expression of TA 
and MHC, rendering it more vulnerable to CTL killing.61 However, RT also induces local immune 
suppression by upregulation of PD-L1 on both tumor and myeloid-derived suppressor cells (MDSC), 
reducing the adaptive response and theoretically facilitating future relapse. In two preclinical models, 
concurrent PD-L1 blockade and RT were synergistic in controlling tumor growth, and generated prolonged 
protective T cell immunity as demonstrated by subsequent abscopal effect.62 
2. STUDY OBJECTIVES 
2.1 Primary 
To evaluate two schedules of fixed-dose pembrolizumab (concurrent vs. sequential) added to 
standard, concurrent cisplatin-IMRT in patients with PULA HNSCC, in order to 
recommend  the schedule to be tested in a subsequent definitive, randomized study. 
 (please see Section 9.2 for Statistical Methods). 
2.2 Secondary 
Secondary objectives for this study include: 
• 
To evaluate the toxicity of two sequences of the combination of pembrolizumab and 
concurrent cisplatin-IMRT in patients with PULA HNSCC. 
 
3. PATIENT SELECTION 
3.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
• 
Patients must have histologically-confirmed head and neck squamous cell carcinoma with no 
evidence of distant metastasis. The primary site may be the oral cavity, oropharynx, larynx, or 
hypopharynx. Patients with squamous cell carcinoma of unknown primary, metastatic to cervical 
lymph nodes, are permitted to enroll. 
• 
Patients must have high risk or intermediate risk disease, defined below. Staging evaluation should 
be determined by imaging studies and complete head and neck exam in accordance with the 
American Joint committee on Cancer Staging Manual, 7th edition. 
o 
High risk patient must meet one of the following criteria: 
• 
Surgically unresectable oral cavity. Patients who are technically resectable but 
refuse surgery due to morbidity (eg. total glossectomy) are also eligible. Medically 
inoperable patients are not eligible. 
• 
Larynx: T4 any N; T2-3 and ≥ N2a. 

11 
 
• 
Hypopharynx: T1-2N1-3 or T3-4N0-3. 
• 
Oropharynx: p16(-) AND T3-4 or ≥ N2a. 
• 
Unknown primary: p16(-) AND ≥ N2a. 

12 
 
o 
Intermediate risk patients must meet one of the following criteria: 
• 
Oropharynx: p16(+) AND one of the following 
• 
T3 or ≥ N2a AND ≥ 10 pack-years tobacco exposure (see Tobacco 
Assessment Form, Appendix A). 
• 
T4 or N3 disease irrespective of tobacco exposure. 
• 
Unknown primary: p16(+) AND one of the following 
• 
≥ N2a AND ≥ 10 pack-years tobacco exposure. 
• 
N3 disease irrespective of tobacco exposure. 
Note: for patients with oropharyngeal or unknown primary tumors, p16 status must 
be known, and can be performed at the local site. p16-positive disease is defined as 
≥70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 
immunohistochemistry (IHC). A positive test for HPV-16 by in-situ hybridization 
(ISH), if this is the local site preference for assessing HPV status, may substitute for 
p16 IHC testing. p16 staining is not required for non-oropharyngeal sites. 
• 
Patients must be untreated with curative-intent surgery for current diagnosis of Stage III, IVa, or 
IVb disease. Diagnostic biopsy of primary tumor and/or nodal sites is permitted. 
o 
Diagnostic simple tonsillectomy is permitted, provided patient has RECIST-measurable nodal 
disease. 
o 
Patients with a second HNSCC primary tumor are eligible for this study, provided more than 
2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed 
with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred. 
• 
Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients 
with bilateral tonsil cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma 
(resected or management deferred), who are eligible. 
• 
No prior systemic (chemotherapy or biologic/molecular targeted therapy) or radiation treatment for 
head and neck cancer. 
o 
Patients may have received chemotherapy or radiation for a previous, curatively treated non- 
HNSCC malignancy, provided at least 2 years have elapsed. 
o 
Patients must be untreated with radiation above the clavicles. 
• 
Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at 
least 2 years except for excised and cured: carcinoma-in-situ of breast or cervix; non-melanomatous 
skin cancer; T1-2, N0, M0 resected differentiated thyroid carcinoma; superficial bladder cancer; T1a 
or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen 
(PSA) since resection. 

13 
 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (See Appendix B) 
• 
Age ≥ 18 
• 
Patients must have measurable disease according to RECIST 1.1 (See Section 6.1) 
• 
Patients must demonstrate adequate organ function as defined in; all screening labs should be 
performed within 14 days of treatment initiation. 
Table 1. Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mm3 
Platelets 
≥100,000 / mm3 
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 
Creatinine clearance ≥60 mL/min (for subject with creatinine 
levels > 1.5 X institutional ULN) determined by 24-hour 
collection or estimated by Cockcroft-Gault formula: 
Calculated creatinine clearance = [(140-age) X (actual body 
weight in kg) X (0.85 if female)]/(72 X serum creatinine) 
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 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
• 
Written informed consent must be obtained from all patients prior to study registration. Patients 
should have the ability to understand and the willingness to sign a written informed consent 
document. 
• 
If a woman of childbearing potential, documentation of negative pregnancy. 
• 
Within 14 days prior to first dose (see section 8.1.1). Sexually active patients must agree to use 
adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. 
All fertile female subjects (and their partners) must agree to use a highly effective method of 
contraception. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; 
or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and 
spermicides (creams or gels that contain a chemical to kill sperm). Should a woman become 
pregnant or suspect she is pregnant while in this study, she should inform her treating physician 
immediately. 
3.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
• 
Nasopharyngeal primary site. 
• 
Current participation in or previous participation in a study of an investigational agent or using an 
investigational device within 4 weeks of the first dose of study treatment. 

14 
 
• 
History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or 
excipients in the investigational agent. 
• 
Distant metastatic disease including CNS or leptomeningeal metastases is not allowed. 
• 
History 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. 
• 
Received prior monoclonal antibody (for cancer) 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. 
• 
History of second malignancy within 2 years prior to Study Day 1 (except for excised and cured 
non-melanoma skin cancer, carcinoma in situ of breast or cervix, superficial bladder cancer, or T1a 
or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen 
(PSA) since resection). 
• 
Active autoimmune disease requiring systemic treatment within the past 3 months or a documented 
history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or 
immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study. Subjects with known hypothyroidism stable on 
hormone replacement, subclinical hypothyroidism, or Sjogren’s syndrome will not be excluded 
from the study. 
• 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note: HIV 
testing is not required for entry into this protocol. The need to exclude patients with AIDS from this 
protocol is necessary because the cisplatin and IMRT involved in this protocol may be significantly 
immunosuppressive. Patients with known HIV, CD4 counts ≥ 250/μL, and undetectable viral loads 
who are stable on an antiretroviral regimen may be included. 
• 
Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
• 
Received a live vaccine within 30 days prior to the first dose of trial treatment. 
• 
Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
• 
Significant pulmonary disease, including pulmonary hypertension, interstitial lung disease, or 
active, non-infectious pneumonitis. 
• 
History or current evidence of any other medical or psychiatric 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. 
• 
Peripheral neuropathy ≥ Grade 2 
• 
Significant cardiovascular disease, including: 
o 
Cardiac failure New York Heart Association (NYHA) class III or IV. 
o 
Myocardial infarction, severe or unstable angina within 6 months prior to Study Day 1. 
o 
History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation). 

15 
 
o 
Ventricular cardiac arrhythmias requiring anti-arrhythmic medications. 
o 
Known left ventricular ejection fraction (LVEF) ≤ 50%. 
• 
Significant thrombotic or embolic events within 3 months prior to Study Day 1. Significant 
thrombotic or embolic events include but are not limited to stroke or transient ischemic attack 
(TIA). Catheter-related thrombosis is not a cause for exclusion. Diagnosis of deep vein thrombosis 
or pulmonary embolism is allowed if the patient is clinically stable and has completed or is on stable 
anti-coagulation therapy. 
• 
Major surgery within 6 weeks prior to Study Day 1 (subjects must have completely recovered from 
any previous surgery prior to Study Day 1). Biopsy, diagnostic tonsillectomy, airway tumor 
debulking or excisional lymph node biopsy do not constitute major surgery. 
• 
Active infection requiring antibiotics or antifungals within 7 days prior to first dose of study drug. 
• 
Significant electrolyte imbalance prior to enrollment (note that patients may be supplemented to 
achieve acceptable electrolyte values): 
o 
Hypomagnesemia < 1.2 mg/dL or 0.5 mmol/L. 
o 
Hypokalemia < 3.0 mmol/L. 
• 
Women must not be pregnant or breastfeeding because chemotherapy and/or pembrolizumab may 
be harmful to the fetus or the nursing infant. Pregnant women are excluded from this study because 
chemotherapy and/or pembrolizumab have the potential for teratogenic or abortifacient effects. 
4. PATIENT REGISTRATION/RANDOMIZATION 
Note: All patients can be registered following eligibility confirmation by calling the coordinating center 
study liaison, Carrie Muniz, RN, BSN: 
5150 Centre Avenue 
Suite 301 
Pittsburgh, PA 15232 
Phone:  (412) 623-6121 
Fax: 
(412) 648-6650 
E-mail: munizca@upmc.edu 
 
For questions regarding the eligibility of subjects, please contact the study doctor, David Clump, MD, at 
(412) 623-6720. 
Registration will require the following information: 1) your name, telephone and email; 2) protocol name 
and number; 3) date treatment begins; 4) subject name; 5) date of birth; 6) subject hospital medical record 
number; 7) primary study physician; 8) primary treatment institution; 9) confirmation of eligibility; 10) 
copies of the informed consent signature page and 11) verification that the informed consent was signed. 
Randomization will occur at the UPCI Biostatistics Core once consent and eligibility are verified. 

16 
 
5. TREATMENT PLAN 
Arm 1 (Table 2): Pembrolizumab will be initiated 2 weeks after the completion of cisplatin-IMRT (week 9 
of protocol treatment) and administered at the fixed dose of 200 mg IV q 3 weeks (+/- 3 days) for a total of 
24 weeks (8 doses; 6 months). NOTE: Per discretion of the treating investigator, the week 9 dose of 
pembrolizumab may be delayed up to 3 weeks for recovery of acute toxicities from chemoradiotherapy. This 
dose would be considered delayed, and all subsequent doses would be administered at a q 3 week interval 
(+/- 3 days) from first pembrolizumab dose. 
Arm 2 (Table 3): Pembrolizumab will be initiated 1 week prior to cisplatin-IMRT (the “window”) at the 
dose of 200 mg IV q 3 weeks (+/- 3 days). Pembrolizumab will be continued concurrently through cisplatin- 
IMRT (weeks 3, 6), and continued for a 15 week maintenance period after completion of cisplatin-IMRT for 
a total pembrolizumab treatment period of 24 weeks (8 doses; 6 months). NOTE: Per discretion of the 
treating investigator, the week 9 dose of pembrolizumab may be delayed up to 3 weeks for recovery of acute 
toxicities from chemoradiotherapy. This dose would be considered delayed, and all subsequent doses would 
be administered at a q 3 week interval (+/- 3 days) until completion. 
 
 
Table 2. Arm 1 Treatment Plan 
 
 
ARM 1 
Week of Treatment 
1 
2 
3 
4 
5 
6 
7 
9 
12 
15 
18 
21 
24 
25 
30 
IMRT 
X 
X 
X 
X 
X 
X 
X 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Table 3. Arm 2 Treatment Plan 
 
 
ARM 2 
Week of Treatment 
-1 
1 
2 
3 
4 
5 
6 
7 
9 
12 
15 
18 
21 
IMRT 
X 
X 
X 
X 
X 
X 
X 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
5.1 Study Drug Administration: Pembrolizumab 
5.1.1 Route of Administration 
Pembrolizumab will be administered as an IV infusion. 
5.1.2 Doses to be Administered 
The dose of pembrolizumab will be 200 mg (fixed dose) IV every 3 weeks (+/- 3 days), beginning on week 
9 of treatment (Arm 1) or beginning one week (week -1) prior to concurrent cisplatin-IMRT (in Arm 2). 

17 
 
5.1.3 Dosing Schedule 
Subjects will receive pembrolizumab once every 3 weeks (+/- 3 days) in an IV infusion over 30 minutes. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion fluid 
and administration of infusion solution. 
 
5.1.4 Order of Administration 
When cisplatin and pembrolizumab are administered on the same day in Arm 2, pembrolizumab should 
follow cisplatin. Pembrolizumab may be given either before or after the radiation therapy fraction that is 
given the same day. 
5.1.5 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment phases of 
this trial: 
 
• 
Colony stimulating factors, including G-CSF, pegylated G-CSF, and erythropoietin analogs. 
• 
Immunotherapy not specified in this protocol. 
• 
Chemotherapy not specified in this protocol. 
• 
Radiation not specified in this protocol. 
• 
Investigational agents other than pembrolizumab. 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines 
(e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
• 
Glucocorticoids for any purpose other than the following two clinical situations: 
o To control cisplatin-related nausea, if viewed as absolutely necessary for symptom control by 
the treating medical oncologist. NOTE: every effort will be made to minimize glucocorticoid 
administration either as premedication or as prophylaxis/treatment of delayed nausea from 
cisplatin. 
o To modulate symptoms from an event of clinical interest of suspected immunologic etiology. 
Subjects who, in the assessment of the treating 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. 
 
There are no prohibited therapies during the Post-Treatment or Follow-up phases of this trial. 
 
5.2 Drug Administration – Cisplatin 
5.2.1 Route of Administration 
Cisplatin will be administered as an IV infusion. 

18 
 
5.2.2 Doses to be Administered 
The starting dose of cisplatin will be 40 mg/m2 weekly (+/- 3 days), beginning concurrent with IMRT during 
week 1 of study treatment in both Arms (see Tables 2 and 3). The actual body weight will be used for all 
patients. There should be no dose modifications because of obesity. 
5.2.3 Dosing Schedule 
Patients will receive cisplatin once weekly as an IV infusion over 60 minutes, for a total of 7 doses. 
Cisplatin should be administered on Monday, Tuesday, or Wednesday of each treatment week and may be 
given either before or after the radiation therapy fraction that is given on the same day. When cisplatin and 
pembrolizumab are administered on the same day, pembrolizumab should follow cisplatin. 
5.2.4 Concomitant Medications during Cisplatin Infusion 
5.2.4.1 Nausea 
Cisplatin, 30-40 mg/m2, is a moderately emetogenic drug. For acute nausea and vomiting, premedication 
should include a 5-HT3 antagonist, such as granisetron 1 mg iv; ondansetron, up to 16 mg iv; or 
palonosetron, 0.25 mg iv. Palonosetron has a longer half-life (40h) than the first generation 5HT3 
antagonists. NOTE: The use of a corticosteroid premedication, such as dexamethasone 10 mg IV, is 
typically combined with a 5-HT3 antagonist when administering weekly cisplatin. In this protocol, omitting 
scheduled corticosteroid premedication, due to the immunosuppressive properties, is strongly encouraged on 
both study arms. However, if necessary in the judgment of the treating investigator, a corticosteroid may be 
administered as a premedication for acute nausea/vomiting. Fosaprepitant may be administered in 
accordance with institutional guidelines or investigator judgment. 
Breakthrough nausea and vomiting may be managed at the discretion of the treating investigator. Delayed 
nausea and vomiting (greater than 24 hours after chemotherapy administration) may be managed per 
investigator discretion, including use of the following potential nausea regimens: oral metoclopramide 10 
mg qid x 2-4 days; prochlorperazine 10 mg qid x 2-4 days; a 5HT3 antagonist (e.g. granisetron, 
ondansetron) may also be given for up to 3 days (only if palonosetron was not given prior to chemotherapy). 
Aprepitant may also be used for delayed nausea. NOTE: Although dexamethasone and other corticosteroids 
are discouraged for delayed cisplatin-induced nausea in this protocol, corticosteroids may be used if viewed 
as necessary by the treating investigator (e.g. 8 mg bid for 2 days, followed by 4 mg bid for 2 days). 
5.2.4.2 Hydration and Electrolyte Support 
Patients must receive vigorous hydration and diuresis. Recommendations are to administer cisplatin, 40 
mg/m2, in NS 1000 ml. Additional IV fluid, potassium chloride, and/or magnesium sulfate may be 
administered at the discretion of the medical oncologist. Mannitol may be administered at the discretion of 
the medical oncologist. 
5.3 Dose Modifications 
5.3.1 Pembrolizumab Dose Modifications 
Retreatment criteria for pembrolizumab and cisplatin are independent (retreatment criteria for cisplatin are 
specified in section 5.3.2 below). There are no dose reductions for pembrolizumab. If the subject meets 
retreatment criteria, the full dose of 200 mg will be administered. If subjects do not meet retreatment 
criteria, then the dose of pembrolizumab will be SKIPPED. The sole exception to this rule is the first dose of 
pembrolizumab following completion of chemoradiotherapy, on both Arms 1 and 2. Although scheduled for 

19 
 
Week 10 of protocol treatment, the first post-chemoradiotherapy dose of pembrolizumab may be 
DELAYED up to 3 weeks to allow for recovery from acute toxicities, in accordance with the treating 
investigator’s judgment. In the case of such delay, the following three doses of pembrolizumab will then be 
scheduled every 3 weeks (+/- 3 days) from the first post-chemoradiotherapy dose. 
 
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 in Table 4 below and in greater detail below. 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 to pembrolizumab, the investigator is 
instructed to follow the Events of Clinical Interest (ECI) reporting guidance but does not need to follow the 
treatment guidance (as outlined in the ECI guidance document). Please see section 12.4.2 for ECI reporting 
guidance. 
 
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. 
 
Table 4. Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold  
Pembrolizumab 
For NCI 
CTCAE Grade 
Timing for Restarting Treatment 
Discontinue Pembrolizumab Permanently 
Out-of-field Rash 
(skin rash outside 
of the radiation 
field) 
3 
Toxicity resolves to Grade 0-1 and 
the patient has tapered off of or did 
not require systemic 
corticosteroids. (Ongoing 
management with topical steroids 
is acceptable.) 
Toxicity does not resolve within 12 weeks of last 
dose or inability to taper off of corticosteroids within 
12 weeks. 
In-field radiation 
dermatitis (skin 
rash within the 
radiation field) – 
Arm 2 
4a 
Toxicity resolves to Grade 3 or 
less. 
NOTE: systemic and topical 
steroids should be avoided in the 
case of radiation dermatitis that is 
restricted to in-field. 
Toxicity does not resolve to Grade 3 or better within 
6 weeks of completing IMRT 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 and 
the patient has successfully tapered 
off of corticosteroids. 
Toxicity does not resolve within 12 weeks of last 
dose or inability to taper off of corticosteroids within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 and 
the patient has tapered off of 
corticosteroids. 
Toxicity does not resolve within 12 weeks of last 
dose. 
3-4 
Permanently discontinue 
Permanently discontinue 

20 
 
Toxicity 
Hold  
Pembrolizumab 
For NCI 
CTCAE Grade 
Timing for Restarting Treatment 
Discontinue Pembrolizumab Permanently 
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 taper corticosteroids to a dose of 
prednisone 10 mg or less 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 taper off corticosteroids 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 taper off corticosteroid within 12 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritisb – 
Serum/Whole 
Creatinine 
2c 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to taper off corticosteroid within 12 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug- 
Related Toxicityd 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability taper off of corticosteroids within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue pembrolizumab for any severe or Grade 3 drug-related AE that recurs or any life- 
threatening event. 
a Per investigator discretion, pembrolizumab may be held for grade 3 in-field radiation dermatitis. If pembrolizumab is held for grade 
3 in-field radiation dermatitis, no specific grade of resolution is required to restart pembrolizumab; restart would also be per 
investigator discretion. 
bNOTE: Dose modification of cisplatin in the setting of renal insufficiency is addressed separately in Section 5.3.2. 
c NOTE: if event is considered clinically unrelated or unlikely to be related to pembrolizumab, and an alternate clinical explanation 
is likely, probable, or definite in the judgment of the investigator (example, attributable to cisplatin and/or prerenal azotemia in the 
setting of nausea, and responding to hydration), then corticosteroids may be omitted and pembrolizumab may be administered. 
d Patients with intolerable or persistent Grade 2 drug-related AE may hold pembrolizumab at physician discretion. Permanently 
discontinue pembrolizumab for persistent Grade 2 adverse reactions for which treatment with study drug has been held, and that do 
not recover to Grade 0-1 within 12 weeks of the last dose of pembrolizumab. Note: Pembrolizumab does not need to be held for 
grade 3 dysphagia, grade 3 pain, grade 3 weight loss, or grade 3 fatigue, which are expected toxicities for chemoradiation of 
HNSCC and will be managed aggressively by treating investigators per standards of care. 
 
• 
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. 

21 
 
• 
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 (or to administer liberal quantities of clear fluids via PEG tube if present). If 
sufficient oral of PEG-tube fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA): 
 
o For T1DM or Grade 3 – 4 Hyperglycemia: 
▪ 
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. NOTE: 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 with pembrolizumab. Of note, patients 
with HNSCC undergoing cisplatin-IMRT may experience subclinical mild hyperthyroidism or 
euthyroid sick syndrome during IMRT, and commonly develop late hypothyroidism as a 
consequence of radiation dose to the thyroid. Monitor patients for changes in thyroid function (TSH 
and free T4 every 3 weeks on Arms 1 and 2, and as indicated based on clinical evaluation) and for 
clinical signs and symptoms of thyroid disorders. No intervention is required for Grade 1 
hyperthyroidism or hypothyroidism events. 
 
o Grade 2 hyperthyroidism events: 
▪ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
o Grade 3-4 hyperthyroidism events: 
▪ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 

22 
 
o Grade 2-4 hypothyroidism 
▪ 
Hypothyroidism is a common consequence of chemoradiotherapy for HNSCC, and 
is likely permanent. In Grade 2-4 hypothyroidism, thyroid hormone replacement 
therapy, with levothyroxine or liothyroinine, is indicated per standard of care. 
 
• 
Hepatic: 
 
o For Grade 2 events, monitor liver function tests weekly until returned to baseline values 
▪ 
Treat with IV or oral corticosteroids. 
o For Grade 3-4 events, hospitalization is indicated. Treat with intravenous corticosteroids for 
24 to 48 hours. Monitor liver function tests frequently. 
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: 
Mild to moderate renal insufficiency can occur in the context of cisplatin chemotherapy. Dose 
modification of cisplatin in the setting of renal insufficiency is addressed separately in Section 5.3.2. 
o For Grade 2 events at least possibly related to pembrolizumab, hold pembrolizumab and treat 
with vigorous hydration and oral corticosteroids. Monitor renal function weekly until returned 
to baseline values. NOTE: if event is considered clinically unrelated or unlikely to be related 
to pembrolizumab, and an alternate clinical explanation is likely, probable, or definite in the 
judgment of the investigator (example, attributable to cisplatin and/or prerenal azotemia in 
the setting of nausea, and responding to hydration), then corticosteroids may be omitted and 
pembrolizumab may be administered. 
o For Grade 3-4 events, hospitalization is indicated. Treat with vigorous hydration and IV 
corticosteroids for 24 to 48 hours. Monitor renal function frequently. Consultation with 
nephrology is recommended. 
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 5 below shows 
treatment guidelines for subjects who experience an infusion reaction associated with administration of 
pembrolizumab. 
 
 
Table 5. 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 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 

23 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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 pembrolizumab 
administration. 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further pembrolizumab 
administration. 
No subsequent dosing of 
pembrolizumab 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
 
5.3.2 Cisplatin Dose Modifications 
There is one level of dose reduction for cisplatin (dose level -1): when dose reduction is required, cisplatin 
will be reduced to 30 mg/m2/week. There is no dose level below 30 mg/m2. Retreatment criteria for 
pembrolizumab and cisplatin are independent. Dose modifications for cisplatin are specified for hematologic 
and non-hematologic toxicity in Tables 6 and 7 below. 

24 
 
Table 6. Cisplatin Dose Modifications for Hematologic Toxicity 
 
NCI CTCAE Toxicity 
Grade (CTCAE v. 4) 
Cisplatin Dosec,d at Start of Subsequent Cycles of 
Therapy 
Neutropenia 
1 (1500-1999/mm3) 
Maintain cisplatin dose level 
2 (1000-1499/mm3) 
Maintain cisplatin dose level 
3 (500-999/mm3) 
Hold cisplatin dose for the week; check CBCD weekly. 
Resume cisplatin at dose level -1 (30 mg/m2/week) when 
neutropenia recovers to Grade 2 or better. 
4 (<500/mm3) 
Hold cisplatin dose for the week; check CBCD weekly. 
Resume cisplatin at dose level -1 (30 mg/m2/week) when 
neutropenia recovers to Grade 2 or better. 
Second incident, grade 3-4 
neutropenia 
Hold cisplatin and recheck CBCD weekly. Resume cisplatin 
at 30 mg/m2/week when neutropenia reaches Grade 2 or 
better. 
Neutropenic Fevere 
Hold cisplatin and initiate standard treatment. Resume 
cisplatin at 30 mg/m2/week when neutropenia has recovered 
to Grade 2 or better, neutropenic fever has resolved, and 
patient is stable. 
Thrombocytopenia 
1 (75,000/mm3-LLN) 
Maintain cisplatin dose level 
2 (50,000- 74,999/mm3) 
Hold cisplatin dose for the week; check CBCD weekly. 
Resume cisplatin at dose level -1 (30 mg/m2/week) when 
thrombocytopenia recovers to Grade 1 or better. 
3 (25,000- 49,999/mm3) 
Hold cisplatin dose for the week; check CBCD weekly. 
Resume cisplatin at dose level -1 (30 mg/m2/week) when 
thrombocytopenia recovers to Grade 1 or better. 
4 <25,000/mm3) 
Hold cisplatin dose for the week; check CBCD weekly. 
Resume cisplatin at dose level -1 (30 mg/m2/week) when 
thrombocytopenia recovers to Grade 1 or better. 
Second incident, grade 2-4 
thrombocytopenia 
Hold cisplatin and recheck CBCD weekly. Resume cisplatin 
at 30 mg/m2/week when thrombocytopenia reaches Grade 1 
or better. 
 
 
 
Table 7. Cisplatin Dose Modifications for Non-hematologic Toxicity 
 
NCI CTCAE Toxicitya 
Grade (CTCAE v. 4) 
Cisplatin Doseb 
Renal-serum Creatinine 
≤ Grade 1 (ULN-1.5 x ULN) 
Maintain cisplatin dose level 
Grade 2 (> 1.5-3.0 x ULN) 
Hold cisplatin. Check serum creatinine weekly. Resume 
cisplatin at dose level -1 (30 mg/m2/week) when recovered to 
Grade 1 or baseline. 
≥ Grade 3 (>3.0-6.0 x ULN)c 
Discontinue cisplatin. Per investigator discretion, the patient 
may be changed to carboplatin AUC 2 weekly. 
Fatigue 
Grade 3 
Decrease cisplatin to dose level -1 (30 mg/m2/week) 
Nausea/Vomiting 
≤ Grade 2 with maximal 
medical management 
Maintain dose level 
≥ Grade 3 with maximal 
medical management 
Hold cisplatin until ≤ grade 2, then resume cisplatin at dose 
level -1 (30 mg/m2/week) 
Other non-hematologic 
Toxicitiesd 

25 
 
Neuropathy 
Grade 2 
Grade 3-4 
Decrease cisplatin to dose level -1 (30 mg/m2/week) 
Discontinue cisplatin. Per investigator discretion, the patient 
may be changed to carboplatin AUC 2 weekly. 
Ototoxicity 
Grade 2 
Grade 3-4 
Decrease cisplatin to dose level -1 (30 mg/m2/week) 
Discontinue cisplatin 
Other: Mucositis in RT field 
Grade 0-3 
Grade 4 
Maintain cisplatin dose level 
Hold cisplatin until ≤ grade 3, then resume at dose level -1 
(30 mg/m2/week) 
Rash, in RT field (inclusive 
of radiation dermatitis) 
Grade 2-3 
Grade 4 
Maintain dose leveld 
Hold cisplatin until ≤ grade 3, then resume at dose level -1 
(30 mg/m2/week) 
Rash, out of RT field 
Grade 1-4 
Maintain cisplatin dose level 
Grade 3-4/Othere 
Hold cisplatin until baseline or ≤ grade 1; per investigator 
judgment,may resume cisplatin at dose level -1. Note 
exceptions in footnote.f 
aFor CTCAE Grade ≤ 2 non-hematologic toxicity not described above, attributed to cisplatin, maintain dose level of 
cisplatin. 
bDose levels are relative to the previous dose. Dose reductions of cisplatin below the –1 dose level will not be allowed. 
For a second incident of non-hematologic toxicity of sufficient severity to requires dose modification, hold cisplatin 
until toxicity resolves to Grade 1 or baseline, then resume at 30 mg/m2/week. 
cIf Grade ≥ 3 nephrotoxicity occurs, 
dDose modification of cisplatin is not required in the setting of asymptomatic electrolyte abnormalities. For depressed 
K or Mg, administer replacement therapy per local standard. Cisplatin may continue at full dose, at the discretion of the 
treating physician. 
dPer investigator discretion, cisplatin may be dose-reduced to dose level -1 or held for grade 3 radiation dermatitis. 
e For CTCAE Grade 3-4 non-hematologic toxicity not described above, attributed to cisplatin, hold cisplatin until 
baseline or ≤ Grade 1. Per investigator judgment, may resume cisplatin at dose level -1. 
f Cisplatin does not need to be held or dose-reduced for grade 3 dysphagia, grade 3 pain, grade 3 weight loss, or grade 3 
fatigue, which are expected toxicities for chemoradiation of HNSCC and will be managed aggressively by treating 
investigators per standards of care. 
 
If ototoxicity or nephrotoxicity occurs, treatment can be changed to carboplatin with AUC (area under 
curve) of 2 for remainder of concurrent radiotherapy. 
5.4 Intensity Modulated Radiotherapy (IMRT) 
5.4.1 
Dose specifications 
IMRT will be delivered in 35 fractions over 7 weeks (five fractions per non-holiday week) in one plan 
(SIB). Concomitant boost using separate IMRT plans is not allowed. 
Missed treatments due to holidays or logistic reasons can be compensated for by delivering an additional 
BID treatment during the week, OR treating on the Saturday or Sunday of that week, OR adding to the 
end of treatment. 
 
5.4.2 Immobilization and Simulation 
Patients must have an immobilization device (e.g. Aquaplast mask) made prior to treatment planning    
CT scan. Use of an immobilizing mouthpiece is strongly encouraged for all patients, especially those with 
cancers of the oral cavity and oropharynx. 

26 
 
The treatment planning CT scan should be performed with IV contrast so that the major vessels of the neck 
are easily visualized. The treatment planning CT scan must be performed with the immobilization device 
and in the treatment position. Slice thickness should be 0.3 cm or thinner. 
 
5.4.3 Target Delineation 
The Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT, PET/CT, 
clinical information, endoscopic findings and/or potentially MRI. 
The Clinical Target Volume (CTV) is defined as the GTV plus areas considered to contain potential 
microscopic disease, delineated by the treating physician. The margin between each GTV and its CTV will 
typically be a minimum of 0.5 cm except in those areas where the GTV is immediately adjacent to structures 
known to be uninvolved such as bone and adjacent muscle. In this instance, the CTV should be modified to 
exclude structures that serve as a boundary that prevents the natural spread of disease (bone, muscle, etc). 
The Planning Target Volume (PTV) will provide a margin around each CTV (i.e. both the primary tumor 
and the lymph nodes containing clinical or radiographic evidence of metastases) to compensate for the 
variation of treatment set up and internal organ motion. Studies should be implemented by each institution 
to define the appropriate magnitude of the uncertainty components of the PTV; however, an unedited 
expansion of 0.3 - 0.5 cm is recommended. 
In general, the PTV should not go outside of the skin surface; if it does exceed the skin surface, the 
application of bolus material over this portion of the PTV may be considered if it is judged clinically that the 
skin is at risk but is generally not recommended. 
 
For those institutions that are using daily IGRT for margin reduction, the minimum CTV-to-PTV 
expansion is 3.0 mm (a larger expansion may be necessary for a target volume subject to significant intra- 
fraction variability, such as the non-immobilized oral tongue). In general, the CTV-to-PTV expansion (with 
IGRT) should not exceed 5 mm. 
 
The primary tumor and involved nodes (CTV1) will typically consist of a 0.5 - 1.5 cm expansion of the 
gross tumor volume (GTV) to cover potential local invasion and will be prescribed 2 Gy/fraction, total     
70 Gy (see Section 5.4.8. for details of prescription for PTV1). 
 
High-risk sub-clinical disease sites, which include possible local subclinical infiltration at the primary 
site (primary site CTV2) and first echelon nodes, which are not clinically or radiographically involved 
(nodal CTV2), should be expanded by 3 - 5 mm to create PTV2. PTV2 should receive a total dose of 60 
Gy/35 fractions. 
 
Lower-risk targets (PTV3) (such as neck nodal levels which are not first echelon nodes and are not adjacent 
to levels containing grossly involved nodes) will be prescribed 54 Gy/35 fractions 
 
Treatment of the low neck: see details in Section 5.4.7. If the low neck is treated, the preferred technique is 
to treat with isocentric matching AP or AP-PA fields with larynx block, matched to the IMRT portals just 
above the arytenoids. The dose  will  be 2 Gy per  fraction  prescribed to 3 cm depth to a total dose of  50 
Gy in 25 daily fractions. Whole-neck IMRT is allowed. Involved low neck nodes will receive total 70 Gy 

27 
 
in 35 fractions. This can be achieved by either boosting the low neck field with an additional 16 Gy in 8 
fractions, by an AP or AP-PA fields, or by planning the whole neck using IMRT. In cases of gross 
involvement of the vallecula or low neck, whole-neck IMRT should be considered. Whole-neck IMRT 
may also be considered if level VI is considered to be at risk due to gross involvement of level IV nodes. 
 
All plans must be  normalized  such  that  95%  of  the  volume  of  the  PTV1  is  covered  with 
prescription dose of 70 Gy. Additionally: At 1 cc PTV1 volume  on  the  DVH  curve,  the  dose  should 
not be >  110%  of  the prescribed dose. At a volume of 0.03 cc within the PTV1 volume on the DVH 
curve, the dose should not be < 95% of the prescribed dose. For any volume of tissue outside the PTVs that 
has a size of 1 cc, the dose should not be > 74 Gy. 
 
Lymph Node Regions 
 
a. Submental nodes (level IA): In cases where the floor of mouth, oral tongue, or level IB are involved. 
 
b. Submandibular nodes (level IB): To be covered when the ipsilateral level II has nodal disease of at least 3 
cm or the oral cavity is involved. 
c. Upper deep jugular (junctional, parapharyngeal) nodes: all cases (at the neck side ipsilateral to the 
primary tumor). 
d. Subdigastric (jugulodigastric) nodes, midjugular, lower neck, and supraclavicular nodes (levels II through 
IV): all cases, bilaterally; unilateral neck treatment can be considered for well lateralized T1/2 primary 
tumors. 
e. Posterior cervical nodes (level V): all cases, at the neck side where there is evidence of jugular nodal 
metastases. 
f. Medial retropharyngeal nodes: all cases involving the pharyngeal axis (i.e. not required for oral cavity and 
larynx cancers not involving pharyngeal structures) should be contoured from the level of C1 through the 
superior border of the hyoid body. 
Critical Normal Structures 
 
The normal tissue volume to be contoured will include the skin surface, brainstem, spinal cord, mandible, 
glottic larynx, supraglottis, esophagus, trachea, oral cavity, lips and parotid and submandibular salivary 
glands. The PRV (planning risk volume) spinal cord contours will be defined at least 0.5 cm larger in the 
radial dimension than the spinal cord (i.e. the cord diameter on any given slice will be 1.0 cm larger than the 
cord itself). The normal tissues will be contoured and considered as solid organs. The tissue within the skin 
surface and outside all other critical normal structures and PTVs is designated as unspecified tissue 
5.4.4 Treatment Planning and Delivery 
Megavoltage energy photon beam irradiation is required. Any treatment planning and delivery system 
that has been credentialed for head and neck IMRT for previous RTOG trials is acceptable. 
5.4.5 Image Guidance for IGRT When Using Reduced Margins 
Daily image guidance of IMRT may be achieved using any one or more of the following techniques: 
• 
Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 

28 
 
• 
Linear-accelerator mounted kV and MV helical conebeam CT images; 
• 
Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
• 
Other mechanism, after discussion with the Radiation Oncology Co-Chair, Jonathan J. Beitler, 
MD. 
 
The institution’s procedure for registering daily treatment imaging datasets with a reference dataset should 
comply with the following recommendations: 
 
Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high dose PTV and 
adjacent spinal cord; if the supraclavicular region is a part of the target volume the ROI should extend to the 
C6 level; If the fusion software allows the user to create an  irregular  ROI  (e.g.,  ExacTrac), treatment 
room objects  seen  on  in-room  x-rays  should  be  excluded  from  the registration; manual  (e.g.,  based  
on bony anatomy) and automatic (e.g., based on mutual information) types of registration can be used; the 
result of the fusion must be visually checked for the alignment of the bony anatomy, such as vertebral bodies 
and applicable soft tissue structures (e.g., optic nerves and/or optic chiasm). 
 
Following the registration, the translational and (if the appropriate technology is available) rotational 
corrections should be applied to the treatment couch. If all the variances  are less than 2.5 mm (this 
typically corresponds to one half of the usual PRV margin), the treatment can proceed without correction 
(however, the physician/team may elect to perform adjustments even for a variance < 2.5 mm). If one or 
more corrections are 2.5-5 mm, adjustment is necessary prior to treatment; however, re-imaging is not 
mandatory. If one or more of the corrections are larger than 5 mm, the imaging must be repeated in addition 
to performing table/positioning adjustments. However, the use of numerous repeat IGRT studies should be 
avoided (see next section). 
 
Management of Radiation Dose to the Patient from IGRT 
Estimates of patient doses per imaging study for various imaging systems vary considerably. The doses are 
in the range of 1 mGy for Cyberknife’s and BrainLab’s ExacTrac planar kV- systems. The doses from 
helical MV CT scan on a tomotherapy unit were estimated to be in the range of 1 to 3 cGy for head and 
neck studies, similar to doses reported for kV cone beam CT on the Elekta Synergy machine. The doses for 
MV cone beam CT are in the range of 10 cGy for a pelvis study to 6 cGy for a head and neck study. Thus, 
the doses for 3D imaging systems are in the range from 1 to 6 cGy for head and neck imaging and can 
contribute from 0.5 to 3% to the daily dose of 2.0 Gy. These dose estimates apply to a single imaging 
procedure, and the 2 cGy dose is used as a typical fraction size for comparison purposes within the treated 
region. It is important to point out that the imaging dose typically covers parts of the patient’s anatomy that 
are outside the high-dose region that is treated therapeutically, and that it  is  sometimes  necessary  to 
repeat the procedure  a  number  of times during, before, or after a single fraction delivery. The imaging 
dose to nearby critical structures may become significant when repeated IGRT procedures are performed for 
patients with severe set up problems (e.g., requiring frequent corrections of more than 5 mm). It is 
recommended that patients demonstrating severe set up problems during the first week of treatment be 
moved to a treatment with larger margins. 

29 
 
5.4.6 Definition of Normal Tissues/Organs at Risk (OARs) 
NOTE: Only the parts of the normal tissues/organs at risk outside the PTVs will be considered 
for dose optimization purposes. 
 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e. the top of the C1 vertebral body). 
Superior to this is brainstem and inferior to this is cord. The inferior border of the spinal cord is at 
approximately T3-4 (i.e., just below the lowest slice level that has PTV on it). The spinal cord shall be 
defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) 
spinal cord shall be defined. The PRVcord = cord + 5 mm in each dimension. This is irrespective of 
whether or not IGRT is used. 
 
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where it meets 
the spinal cord. For the purposes of this study, the superior most portion of the brainstem is 
approximately at the level of the top of the posterior clinoid. The brainstem shall be defined based on the 
treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) brainstem shall be 
defined. The PRVbrainstem = brainstem + 3 mm in each dimension. 
 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to keep the lip 
dose much lower than the oral cavity dose. The definition of lips is self-explanatory. The oral cavity 
will be defined as a  composite  structure  consisting  of  the anterior ½ to 2/3 of the oral tongue/floor 
of mouth, buccal mucosa, and palate. 
 
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan. 
 
OARpharynx: This will be defined as the “uninvolved” posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior pterygoid plates level) 
to the cricopharyngeal inlet (posterior cricoid cartilage level). 
 
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
OARpharynx and extends to the thoracic inlet. 
 
Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular prism shaped” volume that 
begins just inferior to the hyoid bone and extends to the cricoid cartilage inferiorly and extends from the 
anterior commissure to include the arytenoids. This includes the infrahyoid but not suprahyoid epiglottis. 
 
Mandible: This includes the entire boney structure of the mandible from TMJ through the symphysis. 
 
Unspecified Tissue Outside the Targets: This will be defined as tissue located between the skull base and 
thoracic inlet that is not included in either the target volumes or the normal tissues described above. 
 
In cases of weight loss > 10% or significant shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask will be adjusted or re-made in order t o preserve 

30 
 
adequate immobilization, and that a repeated simulation CT be performed to assess the dose distributions 
in the current anatomy. Whether or not a new IMRT plan will be generated is at the discretion of the 
treating physician. If a new plan is made, the targets should be the same as those used for the initial plan. 
The new CT dataset should be used for IGRT image registration when the patient’s shape changes 
significantly. 
 
5.4.7 Management of the Low Neck/Supraclavicular Region (Match versus No Match) 
It is recognized that comprehensive head and neck irradiation incorporating IMRT can be done in several 
ways, any of which is permitted for this study. Patient-specific QA measurements are required for all IMRT 
treatments. When a field “match” technique is used for treating the lower neck, patient-specific 
measurements should include a verification of the dose coverage in the gap region for each patient. 
 
1. Match: The upper cervical lymphatics and primary tumor bed are treated with IMRT. The lower 
cervical lymphatics and supraclavicular region are treated with a single AP (or occasionally APPA for 
larger patients with posterior neck at high risk) non-IMRT technique. The latter non-IMRT field(s) is 
matched to the upper neck IMRT fields.  This  technique requires comprehe nsive mid-line spinal 
cord blocking in the lower neck fields. This technique also allows for a simultaneous blocking  of 
portions of the larynx, hypopharynx, and cervical esophagus in the lower neck fields. Matching 2 IMRT 
plans is allowed. 
2. No Match: The entire clinical target volume (CTV) [upper and lower neck and primary tumor bed] is 
irradiated with IMRT. There is no match line between upper and lower portions of the regions at risk. In 
this technique, limiting radiotherapy dose to organs at risk (OARs), e.g., the cervical esophagus, is 
entirely achieved by inverse treatment planning via IMRT algorithms. 
 
5.4.8 Dose Prescription 
Doses to PTVs 
See Sections above for definitions of CTVs and PTVs and their prescribed doses. The goal is for 95% of   
the PTV70 to receive ≥ 2 Gy with a minimum dose (cold spot) of no less than 66.5 Gy. It is recognized that 
portions of the PTV70 close to the skin may receive significantly less than 66.5 Gy. This is acceptable as 
long as cold spots within PTV1 do not exist at a depth deeper than 8 mm beneath the skin. 
 
For planning prioritization and priorities in dose coverage, in the final plan, PTV1 will be the highest 
priority target structure. PTV2 and PTV3, if applicable, will be ranked in the IMRT planning as lower 
priority than PTV1 although usually at a higher priority than normal structures other than spinal cord and 
brain stem. 
 
Doses to Normal Structures 
Spinal Cord: The PRVcord (as defined in Section 5.3.6.) should not exceed ≤ 50 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the spinal cord PRV 
should be given the highest priority. 

31 
 
Brainstem: The PRVbrainstem (as defined in Section 5.3.6.) should not exceed 52 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRVbrainstem 
should be given less priority than the PRVcord but more priority than the other critical structures listed 
below. 
 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. This may be 
exceeded in oral cavity cancers. 
 
Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy for the non-  
involved oral cavity. Efforts should also be made to avoid hot spots (> 60 Gy) within the non-involved oral 
cavity. 
 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The treatment planning 
goal will be for this individual parotid gland to receive a mean dose of < 26 Gy. Taking  into  account  
new data suggesting monotonous improvement in saliva as dose is reduced, without  a  threshold 
(Dijkema 2010), the objective will be to reduce the 
mean doses to both parotid glands as much as possible. 
 
Contralateral submandibular gland: If contralateral level I is not a target, aim to reduce mean contralateral 
submandibular gland to < 39 Gy. 
 
OARpharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) treatment 
goals include: 1) No more than 33% of the OARpharynx exceeds 50 
Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy. 
 
Cervical Esophagus: Reduce the dose as much as possible. Some recommended (but not required) 
treatment goals include: Mean dose < 30 Gy. 
 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. The glottic larynx me a n dose 
is recommended to be < 20 Gy. If whole-neck IMRT is used, under- dosage of PTV2/PTV3 adjacent to the 
glottic larynx will be limited to < 10% receiving 
< 95% prescribed dose (this under-dosage is similar to that caused by the laryngeal block inserted in the 
split-field IMRT; Webster 2009). 
 
Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be avoided. It is 
recommended that maximum dose within the mandible be < 66 Gy, except in areas overlapping PTV. 
 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside the targets can 
receive 74 Gy or more 

 
 
5.4.9 Planning Priorities and Goals 
1. Spinal Cord 
2. Brainstem 
3. PTV1 
4. PTV2 (if applicable) 
5. PTV3 (if applicable) 
6. a. OARpharynx 
b. Parotid gland contralateral to primary tumor site 
7. a. GSL 
b. Esophagus 
8. a. Lips 
b. Oral Cavity 
9. a. Parotid gland ipsilateral to primary tumor site 
b. Mandible 
10. Unspecified tissue outside the targets 
 
5.4.10 Critical Structures 
Note: All required structures must be labeled as listed in the table below for digital RT data submission. 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed. 
 
Table 8 outlines the naming of the various normal and critical structures for submission to TRIAD. 
 
Table 8. Standard Nomenclature for Normal and Critical Structures 
 
Standard Name 
Description 
Reference Dose (Gy) 
GTV 
Primary tumor and involved 
70 
CTV70 
Primary tumor and involved 
70 
PTV70 
CTV to PTV expansion should be 
5 
mm minimal margin without 
70 
CTV_60 
First Echelon nodal regions 
60 

 
 
 
PTV60 
CTV to PTV expansion should be 
5 
mm minimal margin without 
60 
CTV50 
Lower risk nodal regions 
50 
PTV50 
CTV to PTV expansion 
should be 5 mm minimal 
margin without IGRT+ 
50 
CTV54 
Lower risk nodal regions 
54 
PTV54 
CTV to PTV expansion 
should be 5 mm minimal 
margin without IGRT; 3 mm 
54 
SpinalCord 
Spinal Cord 
≤ 48 
SpinalCord_05 
Planning risk Volume of 5 mm 
≤ 50 
BrainStem 
Brain Stem 
≤ 50 
BrainStem_03 
Planning Risk Volume of 3 mm 
≤ 52 
Parotid 
Mean doses to one Parotid 
≤ 26 
OralCavity (excluding PTV’s) 
Oral Cavity 
Mean dose ≤ 32 
Mandible (excluding PTV’s) 
Mandible 
D0.03cc < 66 
OARPharynx 
Uninvolved posterior pharyngeal 
wall 
plus adjacent constrictor muscles; 
Mean dose ≤ 40 
Esophagus_Up 
Cervical Esophagus 
Mean dose ≤ 30 
Larynx 
Glottic/Supraglottic Larynx 
Mean dose ≤ 35 
NonPTV_7000 
Maximum dose (hot spot > 1cc 
outside the PTVs) 
D1cc < 63 
 
 
 
5.4.11 Image-Guided Radiotherapy 
Daily image guidance of IMRT may be achieved using any one or more of the following techniques: 
• 
Orthogonal kilovoltage (KV) images. 
• 
Linear-accelerator mounted kV and MV cone-beam CT images (CBCT). 

 
 
5.4.12 Radiation Therapy Treatment Interruptions 
Treatment interruptions are strongly discouraged. Treatment breaks must be clearly indicated in the treatment record 
when they occur. Patients who have treatment interruptions for > 3 weeks will be taken off study. The interruption of 
radiation therapy for grade 4 mucositis / dermatitis / dysphagia is at the discretion of the treating radiation oncologist. 
Treatment breaks, if necessary, ideally should not exceed five treatment days at a time and ten treatment days total. 
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for intercurrent illness and not 
for social or logistical reasons. Cisplatin and pembrolizumab will not be administered during radiotherapy treatment 
breaks. 
5.4.13 Radiation Therapy Adverse Events 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 4 will be utilized for grading all adverse events. All appropriate treatment areas should have access 
to a copy of the CTCAE, v. 4. A copy of the CTCAE, v. 4 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
Grade 3 therapy-induced mucositis and/or dysphagia are expected to develop in about one third to one half of patients. 
Nutritional evaluation prior to the initiation of therapy for a prophylactic gastrostomy (PEG) tube placement is highly 
recommended. Placement of a feeding tube should be recorded on the appropriate case report form, as should use of a 
feeding tube during and after treatment (e.g., greater than or less than 50% of nutrition by tube). Other common 
radiation adverse events include: fatigue, weight loss, regional alopecia, loss of teeth or cavities, xerostomia, 
hoarseness, transient ear discomfort, dysgeusia, increased sensitivity of the skin to hot and cold temperature as well as 
the sun and skin erythema and desquamation within the treatment fields. 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, chronic swallowing 
dysfunction requiring permanent feeding tube, brachial plexopathy, and cervical fibrosis. Much less common radiation 
adverse events include: mandibular osteoradionecrosis (< 5% incidence with attention to dental recommendations), 
and cervical myelopathy (< 1% with restriction of spinal cord dose to ≤ 45 Gy). 
Rare but serious side effects that may develop including fibrotic tissue formation, soft tissue ulceration and/or irritation 
or damage to the skin within the neck that may result in bleeding. Blindness and the development of secondary (new) 
cancers and tumors is very rare but also possible. 
5.5 Duration of Treatment and Follow-up 
Complete treatment includes the course of definitive radiotherapy with concurrent chemotherapy and a total of 8 doses 
of pembrolizumab. In the absence of treatment delays due to adverse event(s), treatment may continue until disease 
progression or until one of the following criteria applies: 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 

 
 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
 
Patients will be followed for progression and survival every 3 months for two years, then every 6 months for one year, 
then annually for two years after removal from study or until death, whichever occurs first. Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event. 
5.6 Patient Discontinuation 
Subjects who meet the following criteria should be discontinued from study treatment: 
• 
Inability of subject to comply with study requirements. 
• 
The patient elects to withdraw from the study for any reason. 
• 
Determination by the investigator that it is no longer safe for the subject to continue therapy. 
• 
Disease progression - patients who undergo surgical consolidation and are found to have residual disease 
are not considered to have disease progression. 
 
5.7 Dose Limiting Toxicity (DLT) 
Dose Limiting Toxicity will be continuously monitored in both treatment arms, and is explicitly 
intended for the purposes of safety monitoring of the concurrent combination of pembrolizumab 
and cisplatin-IMRT (Arm 2). As defined, excess DLT is not expected during standard of care 
cisplatin-IMRT. Excess DLT in either arm, however, would trigger the early stopping rule. Please 
see Section 10.3 for details of the early stopping rule. 
 
5.7.1 DLT 
DLT is defined as the occurrence of a severe adverse event (AE) listed below that is at least possibly 
related to pembrolizumab and occurs within 24 weeks of the initiation of pembrolizumab on either 
treatment arm. AEs will be graded according to NCI CTCAE version 4.0. 
DLT Definition: 
Since autoimmune/inflammatory events may occur at any time during the course of treatment, and may occur with 
evidence of clinical benefit, the following criteria will be used to define DLT: 

 
 
• 
Any ≥ Grade 4 non-hematologic toxicity except: 
o Grade 4 in-field radiation dermatitis for which IMRT is held ≤ 1 week (5 fractions). 
o Grade 4 mucositis for which IMRT is held ≤ 1 week (5 fractions). 
o Asymptomatic Grade 4 hypomagnesemia or hypokalemia, which corrects to Grade 
≤ 2 with replacement therapy. 
• 
An alanine or aspartate amino transaminase elevation of greater than three times the upper limit of normal 
with concurrent elevation of bilirubin two times the upper limit of normal attributable to pembrolizumab 
should be considered a DLT. Patients meeting this criterion should be permanently discontinued from 
pembrolizumab. 
• 
Autoimmune toxicity of any grade requiring systemic corticosteroids or other anti-inflammatory that cannot 
be tapered off in less than 12 weeks. 
• 
Delay in completion of radiation therapy >10 fractions, or inability to complete prescribed IMRT course, due 
to immune toxicity at least possibly attributed to pembrolizumab. 
• 
Grade ≥ 3 neutropenia with fever (oral temperature > 39°C). 
• 
Grade ≥ 3 thrombocytopenia with bleeding. 
 
Patients who experience a DLT will receive no additional doses of pembrolizumab and will be withdrawn from the 
protocol. Patients may complete cisplatin and radiation per standard of care. 
 
6. RESPONSE ASSESSMENT 
Patients will undergo clinical head and neck exam and post-treatment CT scan with IV contrast 12-14 +/- 2 weeks 
following completion of IMRT. Note, an integrated PET/CT with contrasted diagnostic CT scan is recommended if 
feasible at the participating site; however, only a diagnostic CT scan is required. Rare patients may require an MRI for 
tumor measurements, due to allergy to iodinated contrast despite premedication. In these patients, MRI of the neck 
should be performed at baseline and at first response assessment. 
Responses will be coded for: 
• 
Clinical examination response, primary and nodes. 
• 
CT response, primary and nodes (see modified RECIST criteria version 1.1, Section 6.1). 

 
 
• 
If applicable: Integrated PET/CT response, primary and nodes (see Integrated PET/CT 
response criteria, Section 6.2.4). Solid Tumor Response Criteria (modified RECIST Criteria version 
1.1) 
6.1.1 Malignant Disease Evaluation 
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent 
measurements will be compared. Measurable disease is defined by the presence of at least one measurable lesion. 
All measurements should be recorded in metric notation by use of a ruler or calipers. The same method of assessment 
and the same technique should be used to characterize each identified lesion at baseline and during follow-up. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 
four weeks before registration. 
The term unevaluable in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. At baseline, the primary tumor and pathologic neck lymph nodes 
will be characterized as either measurable or non-measurable. 
6.1.1.1 Measurable Disease 
6.1.1.1.1 
Primary Tumor 
Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm 
(2.0 cm) with conventional techniques or as ≥ 10 mm (1.0 cm) with spiral CT scan. 
6.1.1.1.2 
Neck Lymph Nodes 
Neck lymph nodes are considered pathologic and measurable if short axis ≥ 15 mm. 
Neck lymph nodes are considered pathologic but non-measurable if short axis ≥ 
10 mm but < 15 mm. Neck lymph nodes are considered non-pathologic and 
non-measurable if short axis < 10 mm. 
6.1.1.2 Non-measurable disease 
All other lesions, including small lesions [longest diameter < 20 mm (2.0 cm) with conventional techniques or < 10 
mm (1.0 cm) with spiral CT scan] are truly non-measurable lesions. 
Lesions considered to be truly non-measurable include the following: bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, 

 
 
inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed 
by imaging techniques, and cystic lesions. 
6.1.2 
Definitions of a Response 
6.1.2.1 Target Lesions 
All measurable lesions, including the primary tumor, and up to a maximum of five neck lymph nodes, should be 
measured at baseline. 
The sum of the longest diameter of the primary tumor, and the short axis diameter of target pathologic lymph nodes, 
will be calculated at baseline and reported as the baseline sum diameter. 
6.1.2.1.1 
Complete Response (CR) 
The disappearance of the primary tumor and the resolution of pathologic neck adenopathy. For the definition of 
radiographic complete response in the neck, the resolution of neck lymph nodes to < 10 mm in short axis diameter with 
non-pathologic appearance is sufficient. 
6.1.2.1.2 
Partial Response (PR) 
At least a 30% decrease in the sum of target lesion diameters (longest diameter of the primary tumor; short axis 
diameter of the target lymph nodes), taking as reference the baseline sum diameter. 
6.1.2.1.3 
Progressive Disease (PD) 
At least a 20% increase in the sum of target lesion diameters (longest diameter of the primary tumor; short axis 
diameter of the target lymph nodes), taking as reference the smallest sum diameter recorded since the baseline sum 
diameter measurements, or the appearance of one or more new lesion(s). 
6.1.2.1.4 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. 
6.1.2.2 Non-target Lesions 
All other lesions or sites of disease. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
6.1.2.2.1 
Complete Response (CR) 
The disappearance of all nontarget lesions and normalization of tumor marker levels, if applicable. 

 
 
6.1.2.2.2 
Partial Response (PR)/Stable Disease (SD) 
The persistence of one or more nontarget lesion(s). 
6.1.2.2.3 
Progressive Disease (PD) 
The appearance of one or more new lesion(s) and / or unequivocal progression of existing non target lesions. 
6.1.2.3 Symptomatic Deterioration 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be classified as having symptomatic deterioration. 
6.1.3 
Evaluation of Patient's Best Overall Response 
The best overall response is the best response recorded from registration until disease progression/recurrence, taking 
as reference for progressive disease the smallest measurements recorded since registration. Table 9 below provides 
overall responses for all possible combinations of tumor responses in target and nontarget lesions, with or without 
new lesions. 
To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once 
after study entry at a minimum interval of eight weeks. 
Table 9. Overall Response for all Possible Combinations of Tumor Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 
NOTE: BOTH CLINICAL (by ENT examination) AND RADIOGRAPHIC RESPONSE (by CT or MRI scan) 
will be recorded. Response in the primary and the neck will be reported separately. 

 
 
6.1.3.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
6.1.3.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for response are first met. 
6.1.3.3 Duration of Response 
Duration of overall response - the period measured from the time that measurement criteria are met for complete or 
partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded since treatment started. 
6.1.3.4 Duration of Overall Complete Response 
The period measured from the time measurement criteria are met for complete response until the first date that recurrent 
disease is objectively documented. 
6.1.3.5 Duration of Stable Disease 
A measurement from registration until the criteria for disease progression is met, taking as reference the smallest 
measurements recorded since registration. To be assigned a status of stable disease, measurements must have met the 
stable disease criteria at least once after study entry at a minimum interval of six weeks. 
6.1.3.6 Survival 
Survival will be measured from the date of entry on study. 
6.1.3.7 Time to Progression and Progression-free survival 
This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or 
objective tumor progression. Progression-free survival (PFS) will be calculated from treatment initiation to disease 
progression or death from any cause or last follow up. 

 
 
6.2 Methods of Measurement 
Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging modality must be 
used throughout the study to measure disease. 
6.2.1 CT and MRI 
CT and magnetic resonance imaging (MRI) are the best currently available and most reproducible methods for 
measuring target lesions. Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice 
thickness. Spiral CT should be performed by use of a 5 mm contiguous reconstruction algorithm. This specification 
applies to tumors of the chest, abdomen, and pelvis, while head and neck tumors, and those of the extremities require 
specific procedures. 
6.2.2 Clinical Examination 
Evaluation of measurable disease in the primary site as well as nodal sites by ENT examination should be recorded at 
baseline. Determination of complete response will occur through radiologic imaging as well as the post-protocol 
endoscopic examination. 
6.2.3 Cytology and Histology 
Cytologic and histologic techniques can be used to differentiate between complete and partial response in rare cases 
(e.g., after treatment to differentiate residual benign lesions and residual malignant lesions in germ cell tumors). 
Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required 
when the measurable tumor has met response or stable disease criteria. 
Should primary site biopsy, primary site salvage, and/or neck dissection be conducted, the pathologic response will be 
recorded. 
6.2.4 FDG-PET Scan 
The ideal post-chemoradiotherapy response assessment method would accomplish two goals: 1) accurately detect viable 
residual disease amenable to surgical consolidation and 2) be prognostic for longer term clinical outcomes including 
PFS. Head and neck clinical examination alone has an accuracy of less than 50% for residual neck nodal disease,63 
while post-radiation diagnostic CT has higher sensitivity than clinical exam but unsatisfactory specificity.64,65 An 
increasing body of literature suggests that post-chemoradiotherapy positron emission tomography (PET), performed 8-
12 weeks following completion of radiotherapy has improved accuracy relative to CT for classification of complete 
response in PULA HNSCC. The negative predictive value (NPV) for determination of residual neck disease, in 
particular, ranges from 92-100%.66-69 The University of Pittsburgh institutional experience indicates that serial PET/CT 
scans permit safe deferral of planned neck dissection following chemoradiotherapy. Moreover, a PET scan added to a 
diagnostic contrasted CT is superior to clinical examination or diagnostic CT alone 

 
 
(utilizing RECIST criteria 1.0) with regard to correlation with PFS.70 However, RECIST 1.0 criteria were developed 
primarily for response assessment in the metastatic solid tumor setting, where patients are treated with palliative 
systemic therapy. RECIST 1.0 criteria inadequately address the post-chemoradiotherapy setting. Specifically, a CR in 
accordance with RECIST 1.0 requires disappearance of all target lesions, including pathologic lymph nodes. However, 
non-pathologic, subcentimeter lymphadenopathy can persist after chemoradiotherapy. RECIST 1.1 now incorporates 
new guidelines for the measurement of nodal disease, and for determination of CR, a short axis of < 1 cm is no longer 
considered residual disease. The accuracy of the RECIST 1.1 criteria for assessment of residual disease or as a 
predictor of PFS following chemoradiotherapy for PULA HNSCC is not reported. 
To date, the majority of PET/CT literature conducted has been retrospective. The sole prospective study of PET/CT 
versus CT for first response assessment following chemoradiotherapy was performed at MDACC.66 This study found 
that PET/CT was not superior to diagnostic CT alone for the accuracy of response assessment in unselected PULA 
HNSCC patients. However, in high risk patients defined as HPV-negative, non- oropharynx, and/or tobacco-exposed, 
PET/CT outperformed CT. The study has been criticized for lack of integration of a diagnostic contrasted CT into the 
PET/CT acquisition algorithm, although PET/CT results were interpreted with knowledge of a separate contrasted 
diagnostic CT; such integration enhances per-lesion sensitivity and specificity in head and neck cancer staging71 and is 
of theoretical utility in the post-treatment patient. The CT criteria used in the MDACC study to classify nodal disease 
were clinical and related to RECIST. However, long axis nodal measurements were utilized with the following 
categorization: 
• 
Pathologic (residual disease) nodes: > 15 mm in longest diameter and/or necrotic appearance. 
• 
Indeterminate nodes: 10-15 mm in longest diameter and non-specific CT findings. 
• 
Non-pathologic nodes: < 10 mm in longest diameter and non-necrotic (CR). 
 
At the University of Pittsburgh, the standard of care following definitive chemoradiotherapy for PULA HNSCC has 
been integrated PET/CT. Following PET/CT patients are placed into four clinical categories: Negative PET/CT 
(Complete Response); Probably Negative PET/CT (Low clinical concern; follow up indicated); Probably Positive 
PET/CT (Clinical concern; tissue sampling indicated); Positive PET/CT (Definite residual disease). This 
categorization has been found to correlate with clinical outcomes, specifically PFS.72 
Definition of CR following chemoradiotherapy therefore has two relevant, literature-based definitions which may be of 
clinical utility: 1) Quantitative anatomic criteria (RECIST 1.1); 2) Integrated PET/CT criteria. 

 
 
Complete Response: Modified RECIST 1.1 (see section 6.1) 
 
• 
Disappearance of primary tumor. Irregular contour of the tumor bed is consistent with -radiation change. 
• 
Decrease in measurable pathologic neck lymph nodes to short axis measurement < 10 mm and 
non-necrotic appearance with normalization of nodal configuration. Increased enhancement may 
be attributable to radiation change. 
• 
No new pathologic lesions. 
 
7. DRUG INFORMATION 
7.1 Pembrolizumab 
7.1.1 Study Drug Materials 
Pembrolizumab drug substance is produced at two locations to yield: 1) a partially formulated aqueous solution 
stored under refridgerated conditions (2-8˚C) at a concentration of 40-50 mg/mL in 10 mM histidine buffer, pH 5.2-
6.8, and 2) a fully formulated aqueous solution stored frozen (-40˚C) at a concentration of 22.5-27.5 mg/mL in 10 
mM histidine buffer, pH 5.2-5.8 containing 7% sucrose and 0.02% polysorbate 80. The drug products are sterile 
filtered into Type I glass vials intended for single use. 
Two drug product dosage forms are available for pembrolizumab: 1) a white to off-white lyophilized powder, 50 
mg/vial, and 2) a liquid, 100 mg/vial. 
• 
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial (manufactured using the partially formulated 
drug substance), is reconstituted with sterile water for injection prior to use. It is formuated with L-histidine 
as buffering agent, polysorbate 80 (surfactant), sucrose as stabilizer/tonicity modifier, and hydrochloric acid 
(HCl) and/or sodium hydroxide (NaOH) for pH adjustment (if necessary). 
• 
Pembrolizumab Solution for Infusion, 100 mg/vial is a liquid drug product (manufactured using the fully 
formulated drug substance), and has the identical formulation as that of the reconstituted lyophilized vial. 
The product after reconstitution with sterile water and the liquid drug product are a clear to opalescent solution which 
may contain proteinaceous and extraneous particulates. 
Both the pembrolizumab reconstituted product and the liquid product are intended for IV administration and both 
can be further diluted with normal saline in IV containers made of polyvinyl chloride (PVC) or non-PVC 
material. 

 
 
7.1.2 Pembrolizumab Study Drug Storage 
Both pembrolizumab drug product dosage forms are to be stored 
under refrigerated conditions (2o C– 8oC) and in a secure location. 
Note: No other use of pembrolizumab study drug intended for use in this trial is authorized by the sponsor. The 
investigator (or designee) will be responsible for the appropriate handling and disposition of residual study drug in 
partially used vials. 
Vial Labels: Pembrolizumab vial labels will bear the appropriate label text for investigational agents, as 
required by governing regulatory agencies. 
Complete study drug information (including packaging, labeling, storage and disposition) is provided in the 
Pembroliuzumab Investigator’s Brochure (IB). 
7.2 Cisplatin 
Refer to the package insert for additional information. 
Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric acid 
for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range will be 3.5 to 4.5. Cisplatin 
injection also is available from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 9 mg 
NaCl and HCL or NaOH to adjust pH. 
Mechanism of Action: The dominant mode of action of cisplatin appears to be inhibition of the incorporation of DNA 
precursors, although protein and RNA synthesis are also inhibited. Although this drug seems to act as an alkylating agent, 
there are data to indicate that its mode and sites of action are different from those of nitrogen mustard and the standard 
alkylating agents. 
Administration: Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate hydration and anti-
emetics. 
Storage and Stability: Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be 
protected from light if not used within 6 hours. The vials and injection should not be refrigerated. Cisplatin has been 
shown to react with aluminum needles, producing a black precipitate within 30 minutes. 
Adverse Events: Human toxicity includes nausea, vomiting, renal toxicity (with an elevation of BUN and creatinine 
and impairment of endogenous creatinine clearance, as well as renal tubular damage, which appears to be transient), 
ototoxicity (with hearing loss that initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. 
Much more severe and prolonged toxicity has been observed in patients with 

 
 
abnormal or obstructed urinary excretory tracts. Myelosuppression, often with delayed erythrosuppression, is expected. 
Supply: Cisplatin is commercially available. The use of drug(s) or combination of drugs in this protocol meets the 
criteria described under Title 21 CFR 312.2(b) for IND exemption. 
8. CLINICAL AND LABORATORY EVALUATIONS 
Schedule of Assessments. See Appendix C for Study Calendar. 
8.1 Pre-Registration Evaluations 
NOTE: This section lists baseline evaluations that are required for registration. Evaluations should be 
performed within 4 weeks of registration unless otherwise indicated. 
8.1.1 Required Pre-Registration Evaluations 
• 
History and physical examination, including vital signs, weight, height and ECOG performance status 
determination. 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistry studies (may be obtained from whole blood or serum/plasma samples), including BUN, 
creatinine, electrolytes (K+, Na+, CI-, CO2), glucose, calcium, Mg++ and liver function tests (total protein, 
albumin, total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase), uric acid, and lactate 
dehydrogenase. 
• 
Coagulation studies, including prothrombin time (PT), international normalized ratio (INR), and activated 
partial thromboplastin time (aPTT). 
• 
Thyroid function tests, including thyroid stimulating hormone (TSH), free thyroxine, (FT4), anti-thyroglobulin 
antibody, thyroid peroxidase antibody, thyroid stimulating immunoglobulin, and ANA. Establishing baseline 
thyroid function and pre-existing thyroid auto- immunity is required, as an appropriate clinical standard prior to 
chemoradiotherapy for HNSCC as well as anti-PD1 therapy for HNSCC. However, normal thyroid function 
and absence of subclinical thyroid auto-immunity (example detectable anti-thyroglobulin antibody or 
detectable thyroid peroxidase antibody) are not eligibility criteria. If subclinical hypothyroidism is detected, 
treatment should be initiated according to standard practice. If subclinical thyroid auto-immunity is detected, 
the patient is still eligible. 
• 
For women of child bearing potential: Urine or blood pregnancy test within 2 weeks of registration to 
rule out pregnancy. (Note, pregnancy test will be repeated within 3 days of initiating protocol 
treatment.) 
• 
Baseline tumor measurements within 4-6 weeks prior to registration. Contrasted diagnostic CT scan for 
staging and baseline tumor measurements. In the rare case that a patient is not a candidate for contrasted 
diagnostic CT scan (e.g. history of allergic reaction to iodinated contrast despite premedication), MRI of the 
neck may be conducted for baseline tumor measurements. Note: when feasible, a baseline integrated 
PET/CT with diagnostic contrasted CT scan is preferred. Any scans or x-rays used to document measurable 
disease should be done as close to study entry as possible and within 4 weeks prior to registration. 

 
 
• 
Evaluation by an otolaryngologist with endoscopy as indicated, within 8 weeks prior to registration. 
Endoscopy for oropharyngeal carcinoma may be performed as clinically indicated. Endoscopy is 
required for hypopharyngeal and laryngeal carcinoma. 
• 
For oropharyngeal or unknown primary cases: HPV status must be known or established and recorded at 
baseline. 
• 
Tobacco history assessment form (See Appendix A). 
 
 
8.1.2 Recommended Pre-Treatment Evaluations 
Note: This section lists baseline evaluations recommended but not required before the initiation of 
protocol treatment. These evaluations do not affect eligibility. 
• 
An audiogram within 12 weeks prior to start of protocol treatment and 8 to 12 weeks after IMRT is complete 
• 
Dental evaluation and if applicable, prophylaxis, within 12 weeks prior to the start of protocol treatment. Prior 
to treatment, patients should be evaluated by a dental professional and receive clearance to initiate 
radiotherapy. A delay of at least 10 calendar days from major oral surgery, including dental extractions, is 
recommended prior to first radiotherapy treatment. 
• 
Patients should be provided with dental education including the risk for radiation-induced dental decay, 
methods for maintaining good oral hygiene, and use of prescription fluoride treatment. Appropriate oral 
hygiene includes the following: brushing teeth after each meal, flossing daily, the frequent use of oral rinses 
with Salt and/or Baking Soda (every two to four hours), and the daily use of prescription fluoride therapy. 
• 
Nutritional Evaluation. It is strongly encouraged that all patients undergo an initial dietary assessment by a 
trained dietician, prior to start of protocol treatment. Patients with weight loss and inadequate oral intake 
should be strongly considered for a feeding tube prior to initiation of therapy. For patients with adequate oral 
intake, the prophylactic placement of a feeding tube is at the discretion of the treating physician. Patients 
should be followed by dieticians routinely throughout the course of treatment. Dietary recommendations 
should include: recommended total caloric intake, recommended intake of protein, daily requirement for free 
water, and the appropriate use of 

 
 
supplements. Should it become evident at any time during therapy that oral intake is inadequate, a feeding tube 
should be placed. Close monitoring by dieticians is important for patients with feeding tubes, particularly 
immediately after tube placement as patients often experience problems with enteral feeding or formulations. 
All patients who have a feeding tube placed should be referred to Speech and Language Pathology (SLP) for 
swallowing exercises to minimize disuse atrophy. In addition, post-treatment, it is critical to work with the 
SLP and dietician to identify when it is safe and appropriate for patients to return to oral intake. Patients should 
be encouraged to wean themselves off their feeding tubes as soon as possible in order to maximize swallowing 
outcomes. 
• 
Speech and Language Pathology (SLP). It is strongly encouraged that all patients undergo swallowing 
assessment and therapy prior to the start of protocol treatment. Swallowing assessment and therapy should be 
considered a critical component of care for all head and neck cancer patients undergoing concurrent therapy. 
Assessments should be done by a trained Speech-Language Pathologist. SLP should be consulted during 
treatment planning and should provide routine follow-up throughout the trajectory of the patient’s treatment 
and recovery. The treating physician should communicate with SLP in order to coordinate care in those 
patients found to have significant swallowing abnormalities. Critical component of the swallowing evaluation 
should include: 1) identification of any swallowing abnormalities, 2) recommendations for further testing, 3) 
formation of a treatment plan, 4) dietary recommendations and 5) clear identifications of patients at risk for 
aspiration. Patients should be referred immediately for evaluation if any of the following “trigger symptoms” 
are identified: coughing or clear the throat before, during or after eating, inability to control food, liquids or 
saliva in the oral cavity, complaint of difficulty swallowing or food “sticking” in the throat, nasal regurgitation 
of food, or pocketing of food in the cheek. 
 
8.2 Evaluations during treatment 
8.2.1 
Arm 1 (Cisplatin-IMRT followed by sequential pembrolizumab) 
ARM 1, WEEKS 1-7 (During 
concurrent cisplatin-IMRT) 
Weekly: 
Note: The following assessments will be performed weekly and may be performed on the day of or 
the day prior to cisplatin administration. 
 
• 
History and physical examination. 
• 
Vital signs, including weight. 
• 
Toxicity assessment with attribution. 
• 
Update of concomitant medications. 

 
 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests [bilirubin, AST (SGOT), 
ALT (SGPT), and alkaline phosphatase, total protein, albumin]. 
 
Every 3 weeks (Week 3 and Week 6): 
 
Note: The following assessments will be performed every 3 weeks during concurrent cisplatin-IMRT 
and may be performed on the day of or the day prior to cisplatin administration. It is recommended 
that research blood should be coupled to the standard of care blood draw, to minimize needle sticks 
to the patient. 
 
• 
Thyroid function tests (TSH, FT4). 
 
 
Once (Week 6): 
 
• 
Anti-thyroglobulin antibody, thyroid peroxidase antibody, thyroid stimulating immunoglobulin, and 
ANA. 
 
ARM 1, WEEKS 8-31 (During sequential 
pembrolizumab treatment): Every 3 
weeks (Week 9, 12, 15, 18, 21, 24, 25, 
30): 
Note: The following assessments will be performed every 3 weeks, and may be performed on the day of or the 
day prior to pembrolizumab administration. 

 
 
• 
History and physical examination. 
• 
Vital signs, including weight. 
• 
Toxicity assessment with attribution, including irAE assessment. 
• 
Update of concomitant medications. 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests [bilirubin, AST (SGOT), 
ALT (SGPT), and alkaline phosphatase, total protein, albumin] . 
• 
Thyroid function tests (TSH, FT4). 
 
Twice (Week 18, Week 30; these will be performed at the 4th and 8th doses of pembrolizumab, respectively): 
 
• 
Anti-thyroglobulin antibody, thyroid peroxidase antibody, thyroid stimulating immunoglobulin, and 
ANA. 
 
8.2.2 
Arm 2 (Concurrent pembrolizumab, cisplatin and IMRT) 
ARM 2, WEEKS -1 to +7 (During concurrent 
pembrolizumab, cisplatin-IMRT) Weekly: 
Note: The following assessments will be performed weekly starting Week -1, and may be performed 
on the day of or the day prior to pembrolizumab and/or cisplatin administration. 
 
• 
History and physical examination. 
• 
Vital signs, including weight. 
• 
Toxicity assessment with attribution, including irAE assessment. 
• 
Update of concomitant medications. 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests [bilirubin, AST (SGOT), 
ALT (SGPT), and alkaline phosphatase, total protein, albumin]. 

 
 
Every 3 weeks (Week 3 and Week 6): 
 
Note: The following assessments will be performed every 3 weeks during concurrent pembrolizumab, 
cisplatin-IMRT, and may be performed on the day of or the day prior to cisplatin/pembrolizumab 
administration. It is recommended that research blood should be coupled to the standard of care blood 
draw, to minimize needle sticks to the patient. 
 
• 
Thyroid function tests (TSH, FT4). 
 
 
 
Once (Week 6): 
 
• 
Anti-thyroglobulin antibody, thyroid peroxidase antibody, thyroid stimulating immunoglobulin, and 
ANA. 
 
ARM 2, WEEKS 8-25 (During sequential 
pembrolizumab treatment): Every 3 
weeks (Week 9, 12, 15, 18, 21): 
Note: The following assessments will be performed every 3 weeks, and may be performed on the day of or the 
day prior to pembrolizumab administration. 
 
• 
History and physical examination. 
• 
Vital signs, including weight. 
• 
Toxicity assessment with attribution, including irAE assessment. 
• 
Update of concomitant medications. 

 
 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests [bilirubin, AST (SGOT), 
ALT (SGPT), and alkaline phosphatase, total protein, albumin]. 
• 
Thyroid function tests (TSH, FT4). 
 
Twice (Week 9, Week 21; these will be performed at the 4th and 8th doses of pembrolizumab, respectively): 
 
• 
Anti-thyroglobulin antibody, thyroid peroxidase antibody, thyroid stimulating immunoglobulin, and 
ANA. 
 
8.3 Post-treatment Evaluations 
8.3.1 
Response Assessment 
8.3.1.1 RECIST 1.1. Response assessment by RECIST 1.1 is required; integrated PET/CT 
interpretation is strongly recommended where available. 
Twelve to 14 weeks following completion of cisplatin-IMRT (week 20-22 of protocol 
treatment), patients on both treatment arms will undergo diagnostic contrasted CT 
scan of the neck and chest, to assess treatment response according to RECIST 1.1. In 
the case where MRI of the neck was required for baseline tumor measurements, 
MRI of the neck should be repeated for response assessment, with non-contrasted 
diagnostic CT of the chest. Note: where available, an integrated PET/CT with 
contrasted diagnostic CT scans of the neck and chest is strongly preferred for 
response assessment. 
8.3.1.2 Evaluation by an otolaryngologist with endoscopy as indicated. 
8.3.1.3 The patient will be evaluated by the otolaryngologist 12-14 weeks following completion of 
cisplatin-IMRT (during weeks 20-22). Endoscopy for oropharyngeal or unknown primary carcinoma 
will be performed for response assessment as clinically indicated, and is at the discretion of the 
surgeon. Endoscopy is required for hypopharyngeal and laryngeal carcinoma. The surgeon will 
evaluate the need for primary site biopsy and/or neck dissection. 

 
 
8.3.2 End of Treatment Visit(s): Week 33 (+/- 2 weeks) for Arm 1; Week 24 (+/- 2 weeks) for Arm 
2. Patients will undergo the following procedures at the end of treatment visit: 
 
• 
History and physical examination and performance status. 
• 
Assessment for resolution of toxicities, including irAE, with attribution. 
• 
Thyroid function testing (TSH, T3, FT4). 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including BUN, creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests (bilirubin, AST (SGOT), ALT 
(SGPT), and alkaline phosphatase, total protein, albumin). 
• 
Audiogram assessment as indicated. 
 
8.3.3 Surgical Consolidation 
The necessity for and the timing of surgical consolidation will be determined by the surgeon. If patients undergo 
surgical consolidation, tumor tissue should be submitted for correlative study. 
Primary Site 
Surgery will be performed in the setting of resectable residual disease if the patient is considered a surgical candidate 
and: 
1) Definitive radiotherapy was not completed, and radiographic or clinical evidence of persistent or progressive disease 
is established. 
2) Biopsy-proven disease is demonstrated at the primary site and/or neck at least 8-12 weeks after completion of 
IMRT. In cases of residual disease at the primary site, the neck will always be dissected at the time of surgical 
salvage (if neck dissection was not previously conducted at post-protocol biopsy). 
Surgical Management of the Neck 
Neck dissection will be performed, if there is concern for residual disease. The extent of neck dissection will be 
determined by the surgeon. The consideration to perform less than radical procedures is strongly encouraged if 
oncologically safe. Note: the presence of residual disease at surgical consolidation, if performed within 24 weeks of 
completion of IMRT, will not constitute a progression event. 

 
 
8.4 Long Term Follow Up 
After the end of treatment visit, patients will be evaluated every 3 months for 21 months (+/- 2 weeks), then every 6 
months (+/- 1 month) for one year, then annually (+/- 1 month) for two years, which will represent a total of 5 years 
from completion of IMRT. Thus, long-term follow-up evaluations will start approximately 6 months after completion 
of IMRT, and will include the following: 
• 
History and physical examination and performance status. 
• 
Vitals signs, including weight. 
• 
Assessment for late toxicity, including dysphagia, xerostomia, gastrostomy tube dependence, pain, fibrosis 
and lymphedema within the head and neck, hypothyroidism, late autoimmune events. 
• 
Thyroid function testing (TSH, FT4). 
• 
Complete blood count, including platelets and differential. 
• 
Blood chemistries (may be obtained from whole blood or serum/plasma sample), including BUN, creatinine, 
electrolytes (K+, Na+, CI-, CO2), calcium, Mg++ and liver function tests (bilirubin, AST (SGOT), ALT 
(SGPT), and alkaline phosphatase, total protein, albumin) 
• 
During the long term follow-up period, tumor assessments will be performed 6, 9, 12, 18, 24, 36, 48, and 60 
months after completion of radiotherapy (+/- one month). The minimum protocol imaging requirement is: 
contrasted, diagnostic neck and chest CT at intervals specified above. More intensive imaging may be 
conducted per local practice. 
• 
Swallowing assessments per local practice and as indicated by post-radiotherapy evaluation and patient-reported 
symptoms. 
• 
Note: patients who have documented progression may discontinue scheduled study assessments and will be 
followed only for survival. Survival assessments will be performed every 6 months (+/- 2 months) by 
telephone contact and/or by evaluation of the Social Security Death Index or other public records. 
 
 
9. STATISTICAL METHODS 
This is a randomized, parallel group, non-comparative phase II trial evaluating the safety and efficacy of two schedules of 
fixed-dose pembrolizumab combined with standard cisplatin-IMRT in intermediate or high risk, PULA HNSCC: 
sequential and concurrent. This study is being performed in order to provide: a) necessary safety experience; b) 
preliminary efficacy estimates; c) characterization of the PD-L1 biomarker in the context of definitive chemoradiation; d) 
the recommended schedule for definitive testing. 
 Primary Objective 
To evaluate two schedules of fixed-dose pembrolizumab (concurrent vs. sequential) added to standard, concurrent 
cisplatin-IMRT in patients with PULA HNSCC, in order to recommend  the schedule to be tested in a subsequent 
definitive, randomized study. 
 Sample Size Determination 
The target sample size is 40 evaluable patients per arm. Assuming 10% drop out or ineligibility, 90 patients will be 
randomized (all evaluable patients will be analyzed). The sample size is determined based upon the following 
assumptions: 1) the 1-year PFS in the high risk population treated with conventional cisplatin-radiotherapy is 60%;6 2) As 
defined, DLTs occurring in more than 20% of the study population are unacceptable and would constitute an unsafe 
regimen; 3) The study requires adequate power to detect a signal of antagonism, defined as a 1-year local failure rate 

exceeding 60%. To advance to Phase II/III testing, a treatment arm must meet all of the following criteria:  
• 
DLT occurs in ≤ 20%  
• 
1-year local failure rate is < 60% 
• 
1-year PFS is ≥ 60% 
If both arms meet the above criteria, then the treatment arm demonstrating numerically superior 1-year PFS will advance 
for definitive testing, as in a so-called “pick-the-winner” trial model. An early phase trial cannot provide the statistical 
power required for a formal statistical comparison between arms. 
The graphic in Figure 1 below demonstrates the probability of accepting either treatment (that is, based on n = 40 
evaluable patients per arm) by means of 90% one-sided exact confidence intervals (CI) for DLT, 1-year failure rate, and 1-
year PFS.  If the upper bound of the DLT CI is less than 0.20, the upper bound of the failure CI is less than 0.60, and the 
lower bound of the 1-year PFS CI is greater than 0.60, the treatment will be accepted. 
 
Figure 1: Probability of accepting the treatment according to the three primary metrics 
 
 
 
 Early Stopping Rule 
Dose Limiting Toxicity (DLT; see Section 5.8 for DLT definition) will be continuously monitored in both treatment arms, 
and is explicitly intended for the purposes of safety monitoring of the concurrent combination of pembrolizumab and 
cisplatin-IMRT (Arm 2). As defined, excess DLT is not expected during standard of care cisplatin-IMRT. Excess DLT in 
either arm, however, would trigger the early stopping rule. A continuous Bayesian stopping rule will be adopted, once 4 
patients have accrued to either treatment arm. For either arm, if p(p(DLT)>0.2) ≥ 0.6, then the stopping rule would be 
triggered.  Table 11 describes the number of DLTs per number of treated patients required to trigger the early stopping 
rule, which will require a suspension of accrual to that Arm and evaluation of toxicity data by the H&N Program DSMC to 
determine further action.  
Table 11. Boundaries for the Early Stopping Rule for Excess DLT 
 
Number of patients treated on that Arm 
0.05
0.10
0.15
0.20
0.0
0.2
0.4
0.6
0.8
1.0
True P(DLT)
P(Accept Treatment)
0.3
0.4
0.5
0.6
0.7
0.0
0.2
0.4
0.6
0.8
1.0
True P(Local Failure)
P(Accept Treatment)
0.50
0.60
0.70
0.80
0.0
0.2
0.4
0.6
0.8
1.0
True P(1−Year PFS)
P(Accept Treatment)

 
4 
8 
12 
16 
20 
24 
28 
32 
36 
Accrual to the arm 
is halted if the 
number of DLTs 
is greater than or 
equal to 
2 
3 
4 
4 
5 
6 
7 
8 
9 
 
 
Analysis Plan 
The proportions of patients experiencing DLT, local failure at 1 year, or are progression-free at one year will be calculated 
with exact (Klopper-Pearson) 90% confidence intervals.  Adverse events will be tabulated by category and grade.  The 
relationship between the three primary metrics and baseline PD-L1 expression will be assessed using logistic regression.   
 
 Secondary Endpoints 
Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with pembrolizumab. The proportion of 
DLTs in each dosing arm (concurrent vs. sequential) will be reported, as will the proportion of AEs in accordance with 
NCI CTCAE v.4 grading criteria. 
Preliminary efficacy data 
Overall and progression-free survival in both arms will be characterized by product-limit (Kaplan-Meier) survival function 
estimates with appropriate confidence intervals.  The study is not adequately powered for a formal test comparing PFS 
between arms. 
 
 

 
 
10. LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 10.1Investigational 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 the investigational product, pembrolizumab, in 
accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck 
as summarized in Table 7. Table 12. Product 
Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded 
to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or 
lists are not provided. 
10.3Storage 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. 
10.4 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. 
11 ASSESSING AND REPORTING ADVERSE EVENTS 
11.1Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of the drug in humans, whether or not 
considered drug related. 
Suspected adverse reaction. Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event (considered “possibly related”). For the purposes of safety reporting, "reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
Adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of suspected adverse 
reactions where there is reason to conclude that the drug caused the event. 
 
 
Serious Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. Specifically, results in death, is life-threatening, requires inpatient hospitalization or causes 
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect, or is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes 
listed in the definition above.) Any subject death within 30 days of the last dose of study drug, regardless of the causality 
or a secondary malignancy should also be recorded as a serious adverse event. 
Life-threatening, suspected adverse reaction. A suspected adverse reaction is considered “life-threatening” if, in the view 
of either the Investigator (i.e., the study site principal investigator), its occurrence places the patient or research subject at 
immediate risk of death. It does not include a suspected adverse reaction that had it occurred in a more severe form, 
might have caused death. 

 
 
Unexpected, suspected adverse reaction. A suspected adverse reaction is considered “unexpected” if it is not listed in 
the general investigational plan or clinical protocol; or is not listed at the specificity or severity that has been previously 
observed and/or specified. If an investigator brochure is not required or available, suspected adverse reaction is not 
consistent with the risk information described in the general investigational plan or elsewhere in the current application, 
as amended. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that 
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. Any 
clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or 
investigator brochure can also be considered unexpected. An aggregate analysis of specific events observed in a clinical 
trial (such as known consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently 
in the drug treatment group than in a concurrent or historical control group. 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless of study 
group or suspected causal relationship to the study drug(s) will be recorded in the subjects’ case histories. For all 
adverse events, sufficient information will be pursued and/or obtained so as to permit 1) an adequate determination of 
the outcome of the event (i.e., whether the event should be classified as a serious adverse event) and; 2) an assessment 
of the casual relationship between the adverse event and the study drug(s). All toxicities encountered during the study 
will be evaluated on an ongoing basis according to the NCI Common Toxicity Criteria version 4.0. 
Adverse events or abnormal test findings felt to be associated with the study drug(s) will be followed until the 
event (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the Principal 
Investigator. 
 
 
In the event of an adverse event the first concern will be for the safety of the subject. 
 
 
11.2 Review of safety information. The principal investigator / sponsor must promptly review all 
information relevant to the safety of the drug obtained or otherwise received from foreign or 
domestic sources, including information derived from any clinical or epidemiological 
investigations, animal or in vitro studies, reports in the scientific literature, and unpublished 
scientific papers, as well as reports from foreign regulatory authorities and reports of foreign 
commercial marketing experience for drugs that are not marketed in the United States. The 
study sponsor must notify all 

 
 
participating investigators of potential serious risks, from clinical trials or any other source, as 
soon as possible. Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck. 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times 
the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. Appropriate 
supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the adverse event(s) is 
reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated clinical 
symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest (ECI), 
using the terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) using the departmental 
SAE form or on a Form FDA 3500 MedWatch. 
 
11.3 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their 
designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of 
a male subject's female partner that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All 
subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety (Attn: 
Worldwide Product Safety; FAX 215 993-1220) using the departmental SAE form or on a Form FDA 3500 
MedWatch. 

 
 
11.4 Immediate Reporting of Adverse Events to the Sponsor, Institutional IRB, and to Merck 
12.4.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any time during protocol treatment with 
pembrolizumab, cisplatin and IMRT that: 
 
• Results in death. 
• Is life threatening. 
• Results in persistent or significant disability/incapacity. 
• Results in or prolongs an existing inpatient hospitalization (NOTE: Elective outpatient procedures for 
feeding tube placement do not constitute SAEs in this protocol.) 
• 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 13 below for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment allocation/randomization, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause that occurs to 
any subject must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety 
using the departmental SAE form or on a Form FDA 3500 MedWatch if it causes the subject to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier, any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
whether or not related to pembrolizumab, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety using the departmental SAE form or on a Form FDA 3500 MedWatch. Elective 
outpatient procedures for feeding tube placement do not require expedited Adverse Event Reporting. 
 
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 pembrolizumab that is brought to the attention of the investigator at any time following consent through the 
end of the specified safety follow-up period specified in the paragraph above, or at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor and to Merck 
Global Safety using the departmental SAE form or on a Form FDA 3500 MedWatch. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety 
facsimile number: +1-215- 993-1220 
 
12.4.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must 
be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX 215 993-1220) using the departmental SAE form or on a Form FDA 3500 MedWatch. 
 
For the time period beginning when the consent form is signed until treatment allocation/randomization, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or placebo treatment. 
For the time period beginning at treatment allocation/randomization through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 24 hours to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
 
1. An overdose of pembrolizumab, as defined in Section 12.2 - Definition of an Overdose for This Protocol 
and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or abnormal 
laboratory results. 
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same 
time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 

 
 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria 
is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. 
 
12.4.3 Evaluating Adverse Events 
Table 13. 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 pembrolizumab 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.. Moreover, Elective hospitalization for feeding tube 
placement 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 
pembrolizumab, 
cisplatin, and/or 
IMRT 
Did the pembrolizumab cause the adverse event? The determination of the likelihood that pembrolizumab caused the adverse event 
will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. 
This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship between the pembrolizumab and the adverse event 
based upon the available information. The physician will also take into consideration the relationship of the adverse event to the 
standard study treatments, cisplatin and IMRT. 
The following components are to be used to assess the relationship between pembrolizumab and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the pembrolizumab 
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 pembrolizumab? 
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)//cisplatin/IMRT, or other host or environmental factors 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to 
pembrolizumabm 
cisplatin, and/or 
IMRT 
(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 pembrolizumab 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 the initial AE resulted in death or permanent disability. 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY PEMBROLIZUMAB, OR IF REEXPOSURE TO 
PEMBROLIZUMAB POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
PRINCIPAL INVESTIGATOR 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 pembrolizumab 
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 
pembrolizumab relationship). 
Yes, there is a reasonable 
possibility of pembrolizumab 
relationship. 
There is evidence of exposure to pembrolizumab. The temporal sequence of the AE onset relative to the 
administration of pembrolizumab is reasonable. The AE is more likely explained by pembrolizumab than by 
another cause. 
No, there is not a reasonable 
possibility of 
pembrolizumab relationship 
Subject did not receive pembrolizumab OR temporal sequence of the AE onset relative to administration of 
pembrolizumab is not reasonable OR there is another obvious cause of the AE. (Also entered for a subject with 
overdose without an associated AE.) 

77 
 
Timelines for Reporting of Suspected Adverse Events 
In the event of a serious adverse event, the principal investigator, the University of Pittsburgh Institutional 
Review Board, and as applicable the local institutional review board (per institutional reporting 
requirements), and Merck will be notified using the the departmental SAE form or FDA Form 3500 
MedWatch. 
All events meeting the definition of a serious adverse event should be recorded on the departmental SAE 
form or on a Form FDA 3500 MedWatch 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and 
submitted to: 
Sponsor-Investigator (Principal Investigator) – within 24 hours of the Investigator learning of th event 
 
 
David Clump MD 
c/o UPCI Clinical Research Services 
UPMC Cancer Pavilion 
5150 Centre Ave., Suite 301 
Pittsburgh, PA 15232-1305 
Phone 412-623-6096 
Fax 412-623-0004 
crssafetysubmissions@upmc.edu 
 
 
Local Institutional Review Board – timeline per institutional reporting requirements 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) – within 2 working days of 
the Investigator learning of the event 
 
 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include as applicable the following information that is available at the time of report within the 
Narrative (Section C) on the departmental SAE form or the Event Description (section 5) of the 
Form FDA 3500 MedWatch: 
• 
CTCAE term(s) and grade(s). 
• 
current status of study drug. 
• 
all interventions to address the AE (testing and result, treatment and response). 
• 
hospitalization and/or discharge dates. 
• 
event relationship to study drug. 

78 
 
Follow-up reports: 
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form or the Form FDA 3500 MedWatch and submitting it as follow-up or 
creating supplemental summary information and submitting it as follow-up with the original MedWatch 
3500 form. Data Safety and Monitoring Plan 
The study will be monitored by the UPCI/UPMC Data Safety and Monitoring Committee (DSMC). In 
addition, Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet monthly in the head and neck cancer 
disease center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
• 
serious adverse events 
• 
subject safety issues 
• 
recruitment issues 
• 
accrual 
• 
protocol deviations 
• 
unanticipated problems 
• 
breaches of confidentiality 
 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are serious, at 
least possibly related and unexpected will be reported to the IRB. Any modifications necessary to ensure 
subject safety and decisions to continue, or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated Problem 
submission and the study may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPCI DSMC which also meets monthly following 
a designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed semi-annually. 

79 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend 
accrual or further investigate treatment on any trial based on information discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
13. ADMINISTRATIVE AND REGULATORY DETAILS 
13.1 Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically (i.e., at a minimum of annually) by qualified staff of the Education and Compliance Office – 
Human Subject Research, Research Conduct and Compliance Office, University of Pittsburgh. 
The Sponsor-Investigator and the University of Pittsburgh and UPMC will permit direct access of the 
study monitors and appropriate regulatory authorities to the study data and to the corresponding source 
data and documents to verify the accuracy of this data. 
13.2 Data Handling and Record Keeping 
The Sponsor-Investigator will maintain records in accordance with Good Clinical Practice guidelines. 
The Sponsor-Investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not submitted or 
approved for the investigational drug, until 2 years after investigations under the IND have been 
discontinued and the FDA so notified. 
13.3 Ethics 
13.3.1 Institutional Review Board (IRB) approval 
The Sponsor-Investigator will obtain, from the University of Pittsburgh Institutional Review Board (IRB), 
prospective approval of the clinical protocol and corresponding informed consent form(s); modifications 
to the clinical protocol and corresponding informed consent forms, and advertisements (i.e., directed at 
potential research subjects) for study recruitment. 
The only circumstance in which a deviation from the current IRB-approved clinical protocol/consent 
form(s) may be initiated in the absence of prospective IRB approval is to eliminate an apparent immediate 
hazard to the research subject(s). In such circumstances, the Sponsor-Investigator will promptly notify the 
University of Pittsburgh IRB of the deviation. 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 50 and 
21 CFR 56, and in conformance with applicable International Conference on Harmonization (ICH) 
Guidelines on Good Clinical Practice (CGP). 
In the event of the Sponsor-Investigator’s decision to modify the previously accepted clinical protocol: 
• 
For Phase 2 and 3 clinical studies: The Sponsor-Investigator will submit (i.e., in advance of 
implementing the change) a Protocol Amendment to the IRB describing any change to a Phase 2 
or Phase 3 protocol that significantly affects the safety of subjects, the scope of the investigation, 

80 
 
or the scientific quality of the study. Examples of Phase 2 and 3 clinical protocol changes 
requiring the submission of a Protocol Amendment include: 
o 
Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
o 
Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
o 
The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or adverse event; or the dropping of a test intended to 
monitor the safety of the investigational drug. 
13.3.2 Ethical and scientific conduct of the clinical research study 
The clinical research study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH GCP Guidelines adopted by the FDA; and relevant policies, requirements, and regulations 
of the University of Pittsburgh IRB, University of Pittsburgh and UPMC, Commonwealth of 
Pennsylvania, and applicable federal agencies. 
13.3.3 Subject Informed Consent 
The Sponsor-Investigator will make certain that an appropriate informed consent process is in place to 
ensure that potential research subjects, or their authorized representatives, are fully informed about the 
nature and objectives of the clinical study, the potential risks and benefits of study participation, and their 
rights as research subjects. The Sponsor-Investigator, or a sub-investigator(s) designated by the Sponsor- 
Investigator, will obtain the written, signed informed consent of each subject, or the subject’s authorized 
representative, prior to performing any study-specific procedures on the subject. The date and time that 
the subject, or the subject’s authorized representative, signs the informed consent form and a narrative of 
the issues discussed during the informed consent process will be documented in the subject’s case history. 
The Sponsor-Investigator will retain the original copy of the signed informed consent form, and a copy 
will be provided to the subject, or to the subject’s authorized representative. 
The Sponsor-Investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and that the 
subjects are informed of any new information that may affect their decision to continue participation in 
the clinical study. In the event of substantial changes to the clinical study or the risk-to-benefit ratio of 
study participation, the Sponsor-Investigator will obtain the informed consent of enrolled subjects for 
continued participation in the clinical study. 
13.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the Clinical 
Trials Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact information. 

81 
 
14. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
14.1Investigational 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 the investigational product, 
pembrolizumab, in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 12. 
14.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
14.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not 
blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure 
envelopes or lists are not provided. 
14.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
14.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the subjects and the amount remaining at the 
conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational product will 
be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. 

82 
 
15. APPENDICES 
APPENDIX A: TOBACCO USE ASSESSMENT FORM 
 
1. Have you ever smoked a total of 100 cigarettes (approximately 5 packs) or more over 
your life-time? 
 
 Yes  
 No 
 
2. Have you ever smoked cigarettes regularly, that is, at least one cigarette per day for six 
months or longer? 
 
 Yes  
 No 
 
3. How old were you when you first started smoking at least one cigarette per day? 
 
  
years old 
 
4. Do you currently smoke cigarettes? 
 
 Yes  
 No 
 
If no, how old were you when you last smoked a cigarette? 
 
  
years old 
 
 
5. Thinking about all the years that you have smoked, how many cigarettes do you (or did 
you) usually smoke in a day? 
 1-9 cigarettes per day 
 10 to 19 cigarettes per day 
 20 to 29 cigarettes per day 
 30 to 39 cigarettes per day 
 40 to 49 cigarettes per day 
 
 
6. Have you ever smoked cigars regularly, that is, at least one cigar per day for six months 
or longer? 
 
 Yes  
 No 

83 
 
 
7. How old were you when you first started smoking at least one cigar per day? 
 
  
years old 
 
8. Do you currently smoke cigars? 
 
 Yes  
 No 
 
If no, how old were you when you last smoked a cigar? 
 
  
years old 
 
 
9. How many cigars did you usually smoke in a day? 
 
  
cigars per day 
 
10. Have you ever smoked a pipe regularly, that is, at least one pipe per day for six months or 
longer? 
 
 Yes  
 No 
 
11. How old were you when you first started smoking at least one pipe per day? 
 
  
years old 
 
12. Do you currently smoke a pipe? 
 
 Yes  
 No 
 
If no, how old were you when you last smoked a pipe? 
 
  
years old 
 
 
13. Thinking about all the years that you have smoked, how many pipes do you (or did you) 
usually smoke in a day? 
  
pipes per day 

84 
 
APPENDIX B: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
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). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
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. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

85 
 
APPENDIX C: Study Calendars 
Arm 1: 
Study Treatment (weeks) 
Post 
-tx 
Long 
Term 
Follow 
Upm 
Pre 
- 
stu 
dya 
1 
2 
3 
4 
5 
6 
7 
9 
12 
15 
18 
21 
24 
27 
30 
33 +/- 
2 
(at 6, 9, 
12, 18, 
24, 36, 
48, 60 
months) 
Medical 
History, 
PE, Vital 
Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG 
PS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC 
with 
Different 
ial b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood 
chemistr 
yc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Liver 
functiond 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomi 
tant meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnanc 
y testn 
x 
Orophary 
ngeal 
cases, 
p16 
status0 
x 
Thyroid 
functione 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANA, 
anti-Tg 
Ab, TPO, 
TSIr 
x 
x 
x 
x 

86 
 
ENT/end 
o-scopy 
evaluatio 
np 
x 
x 
Tobacco 
history 
x 
Tumor 
measure 
ments, 
RECISTf 
x 
x 
x 
x 
PET/CTg 
x 
x 
x 
x 
CT neckh 
x 
x 
x 
x 
CT chesti 
x 
x 
x 
x 
Dental 
evaluatio 
nj 
x 
Nutrition 
consultj 
x 
SLP 
consultj 
x 
x 
x 
Audiogra 
mj 
x 
x 
x 
Cisplatin 
q 
x 
x 
x 
x 
x 
x 
x 
Pembroli 
zumab 
x 
x 
x 
x 
x 
x 
x 
x 
IMRT 
x 
x 
x 
x 
x 
x 
x 
Adverse 
event 
evaluatio 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

87 
 
Arm 2: 
 
Study Treatment (weeks) 
Post-tx 
Long Term 
Follow Upm 
Pre 
- 
stu 
dy 
-1 
1 
2 
3 
4 
5 
6 
7 
9 
12 
15 
18 
21 
24 +/- 2 
(at 6, 9, 12, 18, 
24, 36, 48, 60 
months) 
Medical 
History, 
PE, Vital 
Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG PS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC with 
Differenti 
al b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood 
chemistry 
c 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Liver 
functiond 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomit 
ant meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnanc 
y testn 
x 
Orophary 
ngeal 
cases, 
p16 
status0 
x 
Thyroid 
functione 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANA, 
anti-Tg 
Ab, TPO, 
TSIr 
x 
x 
x 
x 
ENT/end 
o-scopy 
evaluatio 
np 
x 
Tobacco 
x 

88 
 
history 
Tumor 
measure 
ments, 
RECISTf 
x 
x 
PET/CTg 
x 
x 
CT neckh 
x 
x 
CT chesti 
x 
x 
Dental 
evaluatio 
nj 
x 
Nutrition 
consultj 
x 
SLP 
consultj 
x 
x 
Audiogra 
mj 
x 
x 
Cisplatinq 
x 
x 
x 
x 
x 
x 
x 
Pembroli 
zumab 
x 
x 
x 
x 
x 
x 
x 
x 
IMRT 
x 
x 
x 
x 
x 
x 
x 
Adverse 
event 
evaluatio 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a. 
Pre-treatment evaluations will be performed within 4 weeks prior to registration, unless otherwise 
specified. 
b. 
Complete blood count with differential (CBCDs) should include WBC, ANC, PLT, Hb, Hct. 
CBCDs required for protocol therapy may be performed on the day of or the day prior to 
cisplatin/pembrolizumab administration. 

89 
 
c. 
Blood chemistry should include Na, K, Cl, CO2, BUN, Cr, Glucose, Ca and Magnesium and be 
either Serum or Whole blood based on institutional practices/policies. 
d. 
Liver function tests should include SGOT (AST), SGPT (ALT), total bilirubin, total protein, 
albumin, alkaline phosphatase. 
e. 
Thyroid function studies (TSH, FT4) are required at baseline, and at weeks 3, 6, 9, 12, 15, 18, 21, 
24, 27, 30, and recommended at week 33 f/u (Arm 1); TSH, FT4 is required at baseline, and at weeks 3, 6, 
9, 12, 15, 18, and 21 and recommended at week 24 f/u (Arm 2). TSH and FT4 are required at 6, 9, 12, 18, 
24, 36, 48, and 60 month follow-up in both Arms. 
f. 
A diagnostic contrast CT of the neck and chest will be conducted for staging and tumor 
measurements at baseline, and 12-14 weeks after completing IMRT. If feasible at participating sites, an 
integrated PET/CT with diagnostic contrasted CT is recommended at both time points. Tumor 
measurements will be conducted in accordance with RECIST 1.1. Rare patients may require an MRI for 
tumor measurements, due to allergy to iodinated contrast despite premedication. In these patients, MRI of 
the neck should be performed at baseline and at first response assessment. During long term f/u, neck 
MRI should continue to be performed in the place of neck CT. 
g. 
Integrated PET/CT with diagnostic contrasted neck CT is strongly recommended at pre-study 
baseline and 12-14 weeks after completing IMRT. However, PET/CT is not required for study 
participation. 
h. 
CT of the neck (or MRI in those with iodinated contrast allergy) will be conducted at the 
following intervals post IMRT: 6 mos, 9 mos, 12 mos, 18 mos, 24 mos. More intensive imaging may be 
conducted per local practice. 
i. 
Chest CT (without contrast in those with iodinated contrast allergy) will be conducted at the 
following intervals post IMRT: 6 mos, 9 mos, 12 mos, 18 mos, 24 mos. 
j. 
These evaluations are strongly encouraged, but not mandatory. See section 5.4.13 for guidelines. 
k. 
Long term follow up assessments (examination, non-thyroid laboratories, adverse event/late 
toxicity assessments) should occur every 3 months for 2 years, then every 6 months for 3 years, for a total 
of 5 years from completion of IMRT. No specific requirements if patient is more than 5 years from study 
entry. If patient dies during follow-up, cause of death should be recorded. 
l. 
Women of child bearing potential are required to have a pregnancy test within 2 weeks of 1st 
study treatment to rule out pregnancy 

90 
 
m. 
For oropharyngeal cases, p16 status must be established at the participating site, if not previously 
known before the screening process. 
n. 
Evaluation by an otolaryngologist with endoscopy. Endoscopy is not required for oral cavity 
carcinoma. Endoscopy for oropharyngeal carcinoma may be performed as clinically indicated. 
Endoscopy is required for hypopharyngeal and laryngeal carcinoma. 
o. 
Cisplatin should be administered on Monday, Tuesday, or Wednesday of each treatment week 
and may be given either before or after the radiation therapy fraction that is given on the same day. When 
cisplatin and pembrolizumab are administered on the same day in Arm 2, pembrolizumab should follow 
cisplatin. 
p. 
Thyroid auto-immunity will be monitored as specified in section 8.2. 

91 
 
APPENDIX D: CTCAE v.4.0 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 

92 
 
APPENDIX E: MEDWATCH FORM 3500A 
 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/ucm082728.pdf 

93 
 
16. 
REFERENCES 
1. 
Kamangar F, Dores GM, Anderson WF. Patterns of Cancer Incidence, Mortality, and 
Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in Different 
Geographic Regions of the World. Journal of Clinical Oncology 2006;24:2137-50. 
2. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a cancer journal for 
clinicians 2010;60:277-300. 
3. 
Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 
2008;371:1695-709. 
4. 
Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard 
radiation therapy and two schedules of concurrent chemoradiotherapy in patients with 
unresectable squamous cell head and neck cancer. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2003;21:92-8. 
5. 
Pignon JP, le Maitre A, Maillard E, Bourhis J, Group M-NC. Meta-analysis of 
chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 
17,346 patients. Radiotherapy and oncology : journal of the European Society for Therapeutic 
Radiology and Oncology 2009;92:4-14. 
6. 
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. The New England journal of medicine 2010;363:24-35. 
7. 
Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without 
concurrent chemotherapy for locally advanced head and neck cancer. The New England journal 
of medicine 1998;338:1798-804. 
8. 
Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with 
docetaxel in head and neck cancer. The New England journal of medicine 2007;357:1705-15. 
9. 
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell 
carcinoma of the head and neck. The New England journal of medicine 2006;354:567-78. 
10. 
Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human 
papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2008;26:612-9. 
11. 
O'Sullivan B, Huang SH, Perez-Ordonez B, et al. Outcomes of HPV-related 
oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 
Oncology 2012;103:49-56. 
12. 
Marur S, Li S, Cmelak A, et al. E 1308: A phase II trial of induction chemotherapy 
followed by cetuximab with low dose versus standard dose IMRT in patients with human 
papilloma virus-associated resectable squamous cell carcinoma of the oropharynx. J Clin Oncol 
(suppl; abstr 6005) 2013. 
13. 
Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with 
human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014 
(suppl; abstr 6011);32:5s. 
14. 
Disis ML. Immune regulation of cancer. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2010;28:4531-8. 
15. 
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion. Nature medicine 2002;8:793-800. 

94 
 
16. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature reviews Immunology 
2002;2:116-26. 
17. 
Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on 
dendritic cells enhances T cell activation and cytokine production. Journal of immunology 
2003;170:1257-66. 
18. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunological reviews 2010;236:219-42. 
19. 
Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating 
immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
2007;13:1757-61. 
20. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer metastasis reviews 2007;26:373-400. 
21. 
Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. Journal of experimental & clinical cancer research : CR 1998;17:77-81. 
22. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
2008;14:5220-7. 
23. 
Deschoolmeester V, Baay M, Van Marck E, et al. Tumor infiltrating lymphocytes: an 
intriguing player in the survival of colorectal cancer patients. BMC immunology 2010;11:19. 
24. 
Diez M, Pollan M, Enriquez JM, et al. Histopathologic prognostic score in colorectal 
adenocarcinomas. Anticancer research 1998;18:689-94. 
25. 
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells 
within human colorectal tumors predict clinical outcome. Science 2006;313:1960-4. 
26. 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. International journal of clinical oncology 2010;15:544-51. 
27. 
Nobili C, Degrate L, Caprotti R, et al. Prolonged survival of a patient affected by 
pancreatic adenocarcinoma with massive lymphocyte and dendritic cell infiltration after 
interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30. 
28. 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. Journal 
of cutaneous pathology 2010;37 Suppl 1:48-53. 
29. 
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. The Lancet 
Oncology 2009;10:840-1. 
30. 
Hillen F, Baeten CI, van de Winkel A, et al. Leukocyte infiltration and tumor cell 
plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer 
immunology, immunotherapy : CII 2008;57:97-106. 
31. 
Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of tumour- 
infiltrating lymphocytes in gastric cancer. British journal of cancer 2008;99:1704-11. 
32. 
Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-infiltrating T- 
lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer 
immunology, immunotherapy : CII 2009;58:449-59. 
33. 
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. The Journal of experimental medicine 
2000;191:891-8. 

95 
 
34. 
Liotta F, Gacci M, Frosali F, et al. Frequency of regulatory T cells in peripheral blood 
and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. 
BJU international 2011;107:1500-6. 
35. 
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and 
chemotherapy for high-risk squamous-cell carcinoma of the head and neck. The New England 
journal of medicine 2004;350:1937-44. 
36. 
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without 
concomitant chemotherapy for locally advanced head and neck cancer. The New England journal 
of medicine 2004;350:1945-52. 
37. 
Niedernhofer LJ, Garinis GA, Raams A, et al. A new progeroid syndrome reveals that 
genotoxic stress suppresses the somatotroph axis. Nature 2006;444:1038-43. 
38. 
Palom Y, Suresh Kumar G, Tang LQ, et al. Relative toxicities of DNA cross-links and 
monoadducts: new insights from studies of decarbamoyl mitomycin C and mitomycin C. 
Chemical research in toxicology 2002;15:1398-406. 
39. 
Henk JM. Controlled trials of synchronous chemotherapy with radiotherapy in head and 
neck cancer: overview of radiation morbidity. Clinical oncology 1997;9:308-12. 
40. 
Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated 
outcomes in patients with head and neck cancer receiving radiotherapy with or without 
chemotherapy: a systematic literature review. Radiotherapy and oncology : journal of the 
European Society for Therapeutic Radiology and Oncology 2003;66:253-62. 
41. 
Vermorken JB, Kapteijn TS, Hart AA, Pinedo HM. Ototoxicity of cis- 
diamminedichloroplatinum (II): influence of dose, schedule and mode of administration. 
European journal of cancer & clinical oncology 1983;19:53-8. 
42. 
Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin- 
radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal 
carcinoma. Journal of the National Cancer Institute 2005;97:536-9. 
43. 
Chiu TJ, Chen CH, Chien CY, Li SH, Tsai HT, Chen YJ. High ERCC1 expression 
predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous 
cell carcinoma of head and neck in a betel-chewing area. Journal of translational medicine 
2011;9:31. 
44. 
Jeremic B, Milicic B, Dagovic A, Vaskovic Z, Tadic L. Radiation therapy with or 
without concurrent low-dose daily chemotherapy in locally advanced, nonmetastatic squamous 
cell carcinoma of the head and neck. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2004;22:3540-8. 
45. 
Quon H, Leong T, Haselow R, Leipzig B, Cooper J, Forastiere A. Phase III study of 
radiation therapy with or without cis-platinum in patients with unresectable squamous or 
undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative 
Oncology Group (E2382). International journal of radiation oncology, biology, physics 
2011;81:719-25. 
46. 
Allen C, Duffy S, Teknos T, et al. Nuclear factor-kappaB-related serum factors as 
longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
2007;13:3182-90. 
47. 
Leibowitz MS, Andrade Filho PA, Ferrone S, Ferris RL. Deficiency of activated STAT1 
in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. 
Cancer immunology, immunotherapy : CII 2011;60:525-35. 

96 
 
48. 
Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL. Decreased absolute counts of 
T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and 
neck. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2004;10:3755-62. 
49. 
Whiteside TL. Immunobiology of head and neck cancer. Cancer metastasis reviews 
2005;24:95-105. 
50. 
Hoffmann TK, Dworacki G, Tsukihiro T, et al. Spontaneous apoptosis of circulating T 
lymphocytes in patients with head and neck cancer and its clinical importance. Clinical cancer 
research : an official journal of the American Association for Cancer Research 2002;8:2553-62. 
51. 
Dasgupta S, Bhattacharya-Chatterjee M, O'Malley BW, Jr., Chatterjee SK. Inhibition of 
NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head 
and neck cancer. Journal of immunology 2005;175:5541-50. 
52. 
Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL. Preferential apoptosis of 
CD56dim natural killer cell subset in patients with cancer. European journal of immunology 
2003;33:119-24. 
53. 
Young MR, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM. Mechanisms 
of immune suppression in patients with head and neck cancer: influence on the immune infiltrate 
of the cancer. Int J Cancer 1996;67:333-8. 
54. 
Baruah P, Lee M, Odutoye T, et al. Decreased levels of alternative co-stimulatory 
receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients. 
Immunobiology 2012;217:669-75. 
55. 
Lopez-Albaitero A, Nayak JV, Ogino T, et al. Role of antigen-processing machinery in 
the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by 
CTL. Journal of immunology 2006;176:3402-9. 
56. 
Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in 
antigen-processing machinery in head and neck cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research 2006;12:3890-5. 
57. 
Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a 
favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer research 
2013;73:128-38. 
58. 
Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host 
immune response against cancer. British journal of cancer 2013;108:1560-5. 
59. 
Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of 
PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral oncology 
2011;47:1148-53. 
60. 
Lyford-Pike S, Peng S, Young GD, et al. Evidence for a Role of the PD-1:PD-L1 
Pathway in Immune Resistance of HPV-Associated Head and Neck Squamous Cell Carcinoma. 
Cancer research 2013;73:1733-41. 
61. 
Hodge JW, Guha C, Neefjes J, Gulley JL. Synergizing radiation therapy and 
immunotherapy for curing incurable cancers. Opportunities and challenges. Oncology 
2008;22:1064-70; discussion 75, 80-1, 84. 
62. 
Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically 
promote antitumor immunity in mice. The Journal of clinical investigation 2014;124:687-95. 
63. 
Peters LJ, Weber RS, Morrison WH, Byers RM, Garden AS, Goepfert H. Neck surgery in 
patients with primary oropharyngeal cancer treated by radiotherapy. Head & neck 1996;18:552- 
9. 

97 
 
64. 
Velazquez RA, McGuff HS, Sycamore D, Miller FR. The role of computed tomographic 
scans in the management of the N-positive neck in head and neck squamous cell carcinoma after 
chemoradiotherapy. Archives of otolaryngology--head & neck surgery 2004;130:74-7. 
65. 
Ojiri H, Mendenhall WM, Stringer SP, Johnson PL, Mancuso AA. Post-RT CT results as 
a predictive model for the necessity of planned post-RT neck dissection in patients with cervical 
metastatic disease from squamous cell carcinoma. International journal of radiation oncology, 
biology, physics 2002;52:420-8. 
66. 
Moeller BJ, Rana V, Cannon BA, et al. Prospective risk-adjusted 
[18F]Fluorodeoxyglucose positron emission tomography and computed tomography assessment 
of radiation response in head and neck cancer. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2009;27:2509-15. 
67. 
Brkovich VS, Miller FR, Karnad AB, Hussey DH, McGuff HS, Otto RA. The role of 
positron emission tomography scans in the management of the N-positive neck in head and neck 
squamous cell carcinoma after chemoradiotherapy. The Laryngoscope 2006;116:855-8. 
68. 
Porceddu SV, Pryor DI, Burmeister E, et al. Results of a prospective study of positron 
emission tomography-directed management of residual nodal abnormalities in node-positive 
head and neck cancer after definitive radiotherapy with or without systemic therapy. Head & 
neck 2011;33:1675-82. 
69. 
Zimmer LA, Snyderman C, Fukui MB, et al. The use of combined PET/CT for localizing 
recurrent head and neck cancer: the Pittsburgh experience. Ear, nose, & throat journal 
2005;84:104, 6, 8-10. 
70. 
Passero VA, Branstetter BF, Shuai Y, et al. Response assessment by combined PET-CT 
scan versus CT scan alone using RECIST in patients with locally advanced head and neck cancer 
treated with chemoradiotherapy. Annals of oncology : official journal of the European Society 
for Medical Oncology / ESMO 2010;21:2278-83. 
71. 
Branstetter BFt, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT 
more accurate than PET or CT alone? Radiology 2005;235:580-6. 
72. 
Zhang I, Branstetter BFt, Beswick DM, Maxwell JH, Gooding WE, Ferris RL. The 
benefit of early PET/CT surveillance in HPV-associated head and neck squamous cell 
carcinoma. Archives of otolaryngology--head & neck surgery 2011;137:1106-11. 
73. 
Postow MA, Callahan MK, Wolchok JD. The antitumor immunity of ipilimumab: (T- 
cell) memories to last a lifetime? Clinical cancer research : an official journal of the American 
Association for Cancer Research 2012;18:1821-3. 
74. 
Jie HB, Gildener-Leapman N, Li J, et al. Intratumoral regulatory T cells upregulate 
immunosuppressive molecules in head and neck cancer patients. British journal of cancer 
2013;109:2629-35. 
75. 
Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7- 
specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer 
research 2005;65:11146-55. 
76. 
Jie HB, Schuler PJ, Lee SC, et al. CTLA-4+ Regulatory T Cells are Increased in 
Cetuximab Treated Head and Neck Cancer Patients, Suppress NK Cell Cytotoxicity and 
Correlate with Poor Prognosis. Cancer research 2015. 
77. 
Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck 
squamous cell carcinomas. Nature 2015;517:576-82. 
78. 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. 

98 
 
79. 
Snyder A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 
blockade. The New England journal of medicine 2015;372:783.