Immunotherapy With MK-3475 in Locoregionally Advanced, Surgically Resectable Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Cancer of Head and Neck, Head and Neck Cancer, Neoplasms, Head and Neck, Carcinoma, Squamous Cell of Head and Neck, Squamous Cell Carcinoma of the Head and Neck, Squamous Cell Carcinoma, Head and Neck
Sponsor: Washington University School of Medicine

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Immunotherapy with MK-3475 in locoregionally advanced, surgically resectable head and neck 
squamous cell carcinoma 
 
Washington University School of Medicine 
Department of Otolaryngology 
660 South Euclid Avenue, Campus Box 8115 
St. Louis, MO  63110 
 
Protocol #: 201412118 
Version Date: 10/28/2024  
 
Coordinating Center: 
 
Washington University School of Medicine 
 
Principal Investigator: 
 
Douglas R. Adkins, M.D. 
Phone: (314) 362-4471 
E-mail: dadkins@wustl.edu   
 
Sub-Investigators 
 
Institution 
 
 
Modality 
Ravindra Uppaluri, M.D., Ph.D. Dana Farber Cancer Institute 
Otolaryngology 
Max Artyomov, Ph.D.  
Washington University  
Pathology/Immunology 
Rebecca Chernock, M.D. 
Washington University  
Head & Neck Pathology 
Hiram Gay, M.D. 
 
Washington University  
Radiation Oncology 
Nsangou Ghogomu, M.D. 
Washington University  
Otolaryngology 
Dorina Kallogjeri, M.D., MPH Washington University  
Biostatistics 
Brian Nussenbaum, M.D. 
Washington University  
Otolaryngology 
Randal Paniello, M.D.  
Washington University  
Otolaryngology 
Jay Piccirillo, M.D. 
 
Washington University  
Otolaryngology/Biostatistics 
Jason Rich, M.D. 
 
Washington University  
Otolaryngology 
Robert D. Schreiber, Ph.D. 
Washington University  
Pathology/Immunology 
Wade Thorstad, M.D. 
 
Washington University  
Radiation Oncology 
Tanya M. Wildes, M.D.  
Washington University  
Medical Oncology 
Gavin P. Dunn, M.D., Ph.D. 
Washington University  
Neurosurgery 
  
Study Drug:  
 
MK-3475 (pembrolizumab, Keytruda) 
 
IND #: 
124877 
Clinical Trials.gov #: 
NCT02296684 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons 
to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them 
 
 

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Immunotherapy with MK-3475 in locoregionally advanced, surgically resectable HPV-negative 
head and neck squamous cell carcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
12/12/2014 
Amendment #1 Version 
 
 
 
 
 
 
02/06/2015 
Amendment #2 Version 
 
 
 
 
 
 
08/07/2015 
Amendment #3 Version 
 
 
 
 
 
 
04/26/2016 
Amendment #4 Version – PRMC only 
 
 
 
 
09/09/2016 
Amendment #4 Version 
 
 
 
 
 
 
09/30/2016 
Amendment #5 Version 
 
 
 
 
 
 
12/29/2016 
Amendment #6 Version 
 
 
 
 
 
 
12/11/2017 
Amendment #7 Version 
 
 
 
 
 
 
10/28/2024 
 
 
 

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Immunotherapy with MK-3475 in locoregionally advanced, surgically resectable HPV-negative 
head and neck squamous cell carcinoma 
 
Principal Investigator Signature Page 
 
 
Principal Investigator (printed):       
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States 
Code of Federal Regulations or local regulations governing the conduct of 
clinical studies. 
 
 
 

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Immunotherapy with MK-3475 in locoregionally advanced, surgically resectable HPV-negative 
head and neck squamous cell carcinoma 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 

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Glossary of Abbreviations 
AE/irAE 
Adverse event/immune-related adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
CBC 
Complete blood count 
CMP 
Complete metabolic panel 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DM 
Distant metastases 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECI/irECI 
Event of clinical interest/immune-related event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papilloma virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
LRR 
Locoregional recurrence 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
OPSCC 
Oropharyngeal squamous cell carcinoma 
PBMC 
Peripheral blood mononuclear cell 
PI 
Principal investigator 
PT 
Prothrombin time 
PTT/aPTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SUSAR 
Suspected unexpected serious adverse reaction 
UPN 
Unique patient number 

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Table of Contents 
SCHEMA ............................................................................................................................................. 4 
1.0 
BACKGROUND AND RATIONALE ............................................................................... 8 
1.1 
HPV-negative Head and Neck Squamous Cell Carcinoma .................................................. 8 
1.2 
MK-3475 ........................................................................................................................... 8 
1.3 
Study Rationale ................................................................................................................ 10 
1.4 
Correlative Studies Background ....................................................................................... 11 
1.5 
Rationale for Retrospective Review of OCSCC Surgical Data .......................................... 12 
1.6 
Rationale for Interim Analysis of All Pembrolizumab-Treated Patients ............................ 12 
1.7 
Rationale for Performing CT Scan after Neoadjuvant Dose Prior to Surgery .................... 13 
1.8 
Rationale for Addition of Cohort 2 ................................................................................... 13 
2.0 
OBJECTIVES .................................................................................................................. 14 
2.1 
Primary Objectives ........................................................................................................... 14 
2.2 
Secondary Objectives ....................................................................................................... 14 
 
Exploratory Objective ...................................................................................................... 15 
2.3 
15 
3.0 
PATIENT SELECTION................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................. 15 
3.2 
Exclusion Criteria ............................................................................................................ 16 
3.3 
Inclusion of Women and Minorities ................................................................................. 17 
4.0 
REGISTRATION PROCEDURES................................................................................... 17 
4.1 
Confirmation of Patient Eligibility ................................................................................... 18 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ................................ 19 
4.3 
Assignment of UPN ......................................................................................................... 19 
5.0 
TREATMENT PLAN ...................................................................................................... 19 
5.1 
Premedication Administration .......................................................................................... 19 
5.2 
Agent Administration ....................................................................................................... 20 
5.3 
Adjuvant Treatment ......................................................................................................... 20 
5.4 
Definition of Evaluability ................................................................................................. 27 
5.5 
General Concomitant Medication and Supportive Care Guidelines ................................... 27 
5.6 
Women of Childbearing Potential .................................................................................... 28 
5.7 
Duration of Therapy ......................................................................................................... 31 
5.8 
Duration of Follow-up ...................................................................................................... 31 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 31 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ................................................ 34 
7.1 
Definitions ....................................................................................................................... 34 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University .. 36 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .................................................................................................................... 37 
7.4 
Reporting Requirements for Secondary Sites .................................................................... 37 
7.5 
Reporting to Secondary Sites ........................................................................................... 37 
7.6 
Reporting to the FDA ....................................................................................................... 37 
7.7 
Reporting to Merck & Co., Inc. ........................................................................................ 38 
7.8 
Timeframe for Reporting Required Events ....................................................................... 40 
8.0 
PHARMACEUTICAL INFORMATION ......................................................................... 40 
8.1 
MK-3475 ......................................................................................................................... 40 
9.0 
CORRELATIVE STUDIES ............................................................................................. 41 

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9.1 
Tumor Biopsy .................................................................................................................. 41 
9.2 
Archival Tissue ................................................................................................................ 41 
9.3 
Peripheral Blood for Biomarkers ...................................................................................... 41 
10.0 
STUDY CALENDAR ...................................................................................................... 43 
10.1 
Calendar for Cohort 1 ....................................................................................................... 43 
10.2 
Calendar for Cohort 2 ....................................................................................................... 44 
10.3 
Post-CRT Calendar for Cohort 1 Participants Who Receive Adjuvant MK-3475 .............. 45 
11.0 
DATA SUBMISSION SCHEDULE ................................................................................ 45 
12.0 
MEASUREMENT OF EFFECT ...................................................................................... 45 
12.1 
Methods for Evaluation of LRR/DM ................................................................................ 45 
12.2 
RECIST Analysis of Post-Neoadjuvant Dose CT Scan for Treatment Response ............... 47 
13.0 
DATA AND SAFETY MONITORING ........................................................................... 48 
14.0 
AUDITING ...................................................................................................................... 49 
15.0 
STATISTICAL CONSIDERATIONS .............................................................................. 50 
15.1 
Sample Size Justification .................................................................................................. 50 
15.2 
Analysis ........................................................................................................................... 50 
15.3 
Stopping Rule .................................................................................................................. 51 
16.0 
INTERIM ANALYSIS .................................................................................................... 52 
16.1 
Implication of Interim Analysis ........................................................................................ 52 
17.0 
RETROSPECTIVE REVIEW .......................................................................................... 52 
18.0 
MULTICENTER REGULATORY REQUIREMENTS .................................................... 53 
19.0 
REFERENCES ................................................................................................................ 54 
APPENDIX A: ECOG Performance Status Scale ................................................................................ 56 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
HPV-negative Head and Neck Squamous Cell Carcinoma 
 
Current therapies for the treatment of stage III/IV locally advanced human papillomavirus (HPV)-
negative head and neck squamous cell carcinomas (HNSCC) result in cure in 40-50% of patients, 
with many of the remaining suffering from locoregional recurrences (LRR) and distant metastases 
(DM) resulting in patient demise.  Although the last decade has seen a near epidemic growth of 
HPV-induced oropharyngeal squamous cell carcinomas (OPSCC), the “classical” carcinogen-
induced HNSCCs still represent the major subtype that causes the greatest patient mortality.  
Whereas current treatment of HPV-induced OPSCC results in 80-90% cure rates, multimodality 
approaches in non-HPV-related HNSCC are not nearly as successful.  Thus, there is a pressing 
need for development of novel therapeutics in carcinogen-induced HNSCC. 
 
Standard of care treatment for loco-regionally advanced disease includes definitive combined 
chemotherapy and radiation or surgical extirpation followed by adjuvant radiation without or with 
chemotherapy.  In the latter approach, post-operative adjuvant treatment is dictated by pathologic 
findings where patients either receive radiation alone or more intensive combined chemotherapy 
and radiation.  Despite the addition of these modalities, these “high risk” radiation- and 
chemotherapy-treated subgroup of patients (those with positive margins or lymph node 
extracapsular extension) suffer disease-specific mortality and could most benefit from novel 
therapeutic intensification approaches such as adjuvant immunotherapy.  This fact is illustrated in 
clinical trials that first demonstrated superiority of combined postoperative chemoradiation 
regimens where LRR/DM was still observed in 35% of patients within 2 years after surgery and 
chemoradiation (1, 2). 
 
1.2 
MK-3475 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (3).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies (4-8) .  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) (9, 10).  The structure of murine PD-1 has 
been resolved (11).  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 

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tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade (10, 12-14).  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 (6, 15).  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 (16, 17).  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells (18).  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors (3-7).  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 (17).  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) (19) .  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. 
 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.   
 
Please refer to the IB for preclinical and clinical data. 
 
1.2.1 Rationale for Dosing 
 
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer 
trials. Available PK results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in PK exposures obtained at a given dose 
among tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being 
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 maximum tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.  For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to 
receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate 

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(ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full 
analysis set (FAS)).  The proportion of subjects with drug-related adverse events (AEs), 
grade 3-5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an 
AE was comparable between groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at a given dose among tumor types.  Population PK analysis has been performed 
and has confirmed the expectation that intrinsic factors do not affect exposure to 
pembrolizumab to a clinically meaningful extent.  Taken together, these data support the 
use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumor 
indications.  2 mg/kg Q3W is being evaluated in NSCLC in PN001, Cohort F30 and 
PN010, and 200 mg Q3W is being evaluated in head and neck cancer in PN012, which are 
expected to provide additional data supporting the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.  A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using available 
data from 476 subjects from PN001.   The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with 
some tendency for individual values to range slightly higher with the 200 mg fixed 
dose.   The slight increase in PK variability predicted for the fixed dose relative to weight-
based dosing is not expected to be clinically important given that the range of individual 
exposures is well contained within the range of exposures shown in the melanoma studies 
of 2 and 10 mg/kg to provide similar efficacy and safety.  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 tumor types and indication settings. 
 
1.3 
Study Rationale 
 
From a therapeutic standpoint, HNSCC genomics-driven oncologic approaches have identified 
potential targets but may be limited by inter- and intratumoral heterogeneity.  With this 
background, HNSCC has several features that make it ideal for checkpoint blockade-based 
immunotherapeutic approaches.  First, supporting a role for immune surveillance, epidemiologic 
evidence suggests that immunodeficient states increase HNSCC (reviewed in (20)).  Second, 
although there is some mixed data, analysis of immune infiltrates suggests that an ongoing 
immune response occurs in HNSCC patients.  Finally, as a carcinogen-related malignancy, the 
genomic landscape of these cancers bears a rich repertoire of mutations that represent an array of 
antigenic targets for immune-based therapeutics.  These three points parallel features of patients 
with NSCLC where MK-3475 has successfully achieved clinically meaningful responses and thus 
serves as a critical rationale for a similar approach in HNSCC.  
 
In support of this approach, data presented at ASCO 2014 in HNSCC patients with recurrent 
metastatic disease showed encouraging results with 20% of patients achieving best overall 

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response (Seiwert et al, ASCO 2014, Abstract 6011).  In this study, 78% of patients were classified 
as PD-L1 positive (>= 1% of tumor cells staining for PD-L1) and there was a trend towards better 
response in the PD-L1 positive patients. Data from other studies shows that expression of PD-L1 
on HNSCC tissues varies between 46-100% (reviewed in (21)). The variability in expression is 
likely due to a combination of factors including the specific antibody used for staining and head 
and neck subsite. In summary, there is a strong foundation for MK-3475 immunotherapy based 
treatment intensification in patients with locally advanced HNSCC. 
 
1.3.1 Rationale for MK-3475-based treatment intensification in the neoadjuvant 
and post-operative setting 
 
The key problem in the management of locally advanced HNSCC is the 35% LRR/DM 
rate despite aggressive surgical and post-operative chemoradiation regimens. Importantly, 
the rationale for combined chemoradiation in the post-operative setting is that cisplatin-
based therapy acts as a radiosensitizer.  Previous intensification studies with additional 
chemotherapy have not shown a survival benefit in this group of patients, and these studies 
have been complicated by toxicity and patient compliance issues. Thus, no other adjuvant 
therapies have been identified to reduce the 35% LRR/DM rate. 
 
MK-3475 immunotherapy as an intensification approach is well justified in the high-risk 
HNSCC population because (1) PD-L1 expression is common in HNSCC, (2) MK-3475 
displays activity in the recurrent/metastatic setting, and (3) immunotherapy may be ideally 
suited for the minimal residual disease post-operative setting. Our novel trial design aims 
to define whether MK-3475 immunotherapy can improve outcomes in the initial treatment 
of advanced stage HNSCC patients using a combined neoadjuvant with post-operative 
adjuvant approach. The neoadjuvant portion will allow us to analyze patient tissue pre- 
and post-treatment. Here, the patient serves as their own control, which allows for 
important treatment effect comparisons.  Importantly, although speculative, this pre-
operative dose coupled with surgery may enhance tumor specific immune responses. 
Surgical extirpation likely releases significant tumor antigens and stimulates wound 
healing inflammation that combined with checkpoint blockade may prime antigen specific 
T cell responses. At present, it is unclear which advanced stage patients benefit from 
combined treatment but clearly 35% of them fail this therapy. Thus, MK-3475 will be 
continued in this high-risk group after completion of and recovery from chemoradiation. 
Although we considered combining MK-3475 with the post-operative chemoradiation, 
concerns about toxicity that will alter standard of care treatments precluded this option. In 
addition, there is no data on the combination of MK-3475, cisplatin, and radiation 
treatment. In summary, there is a strong foundation for MK-3475 immunotherapy based 
treatment intensification in patients with locally advanced HNSCC. 
   
1.4 
Correlative Studies Background 
 
The goal of the correlative work will be to determine if there is any correlation between the 
primary endpoint and biomarkers within peripheral blood or in the tumor specimens. The key 
advantage of this study is the availability of not only matched pre- and post-treatment peripheral 
blood but also pre- and post-treatment tumor tissue from treatment naïve patients. Existing data 
suggest that tumor expression of PD-L1 correlates with patient responses.  However, the 
understanding of predictive biomarkers is incomplete.  Thus, we propose to not only incorporate 

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PD-L1 tumor staining on the neoadjuvant biopsies of pre- and post-treatment tumors, but to also 
analyze molecular signatures in peripheral blood and tumor tissues. Together, these data will lead 
to an improved understanding of those patients who may benefit most from MK-3475 therapy.  
 
We hypothesize that MK-3475 will result in increased T cell responses in peripheral blood as 
detected by multiparameter analysis and will define a unique biomarker molecular signature of 
MK-3475 activity and (2) MK-3475 treatment will reveal an intratumoral signature of an immune 
response to HNSCC. The goal will be to determine if there is any correlation between the primary 
endpoint and biomarkers within peripheral blood or in the tumor specimens. The key advantage 
of this study is the availability of not only matched pre- and post-treatment peripheral blood but 
also pre- and post-treatment tumor tissue from treatment naïve patients.  In addition to standard 
IHC methodology, we will aim to generate biomarkers that will be linked to patient outcomes 
identified in the primary endpoint. We will apply a novel machine learning algorithm to 
histopathologic slides to identify predictive biomarkers of treatment response using computational 
analysis of the spatial organization of tumor infiltrating lymphocytes in relation to tumor cells. 
Using our immunomonitoring core, we will apply CyTOF or FACS based multiparameter analysis 
of PBMCs pre- and post- MK-3475 treatment to delineate immune cell subsets and cell surface 
activation markers.  If sufficient pre-treatment tumor tissue is available, FACS or CyTOF will 
also be applied to tumor infiltrating immune cells.  We will deconvolute RNA-Seq data from pre- 
and post-treatment blood and tumor tissue to identify not only immune cell populations but also 
markers of immune cell activation. Finally, conventional genomics-based analysis of the tumor 
cells themselves may provide insight into intrinsic mediators of responsiveness or resistance. 
 
1.5 
Rationale for Retrospective Review of OCSCC Surgical Data 
 
An early unexpected observation noted after treating 18 patients on this prospective trial (as of 
September 2016) is the very low rate of patients with high-risk pathologic features after one dose 
of MK-3475 followed by surgery.  The impact of this observation is that the fraction of patients 
undergoing surgery on this study who prove to have high risk pathologic features is much lower 
than expected, meaning that a lower number of patients than expected go on to receive adjuvant 
chemotherapy or chemoradiation followed by adjuvant MK-3475.  We expected that 85% of 
patients on this trial would have these high-risk features.  The reason for this observation is unclear 
but could include stage decrease due to the neoadjuvant MK-3475, or it could be that our original 
assumption that 85% of patient would have high risk features was too high.  Therefore, we are 
amending this protocol to include a retrospective review of Washington University’s experience 
with patients with clinically locally advanced oral cavity SCCs who undergo surgery to determine 
the historical percentage of these patients that have high risk pathologic features and then compare 
these data to this endpoint in this prospective trial.  Please refer to Section 16.0 for a description 
of this embedded retrospective review. 
 
1.6 
Rationale for Interim Analysis of All Pembrolizumab-Treated Patients 
 
As described in Section 1.5, we have observed a low rate of patients with high-risk pathologic 
features with neoadjuvant pembrolizumab treatment. These findings are unexpected and may have 
significant impact for clinical outcomes in these patients.  Given these findings, we are amending 
this protocol to perform an interim analysis of all 20 patients enrolled so far with the intent to 
present this data at upcoming scientific meetings. We will review clinical and pathologic staging, 
rates of locoregional recurrence and distant metastasis since neoadjuvant pembrolizumab 

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treatment and correlative data that are available to date. The latter include genomic information 
completed on a subset of the 20 patients, PD-L1 staining and serum cytokine responses.  
 
1.7 
Rationale for Performing CT Scan after Neoadjuvant Dose Prior to Surgery 
 
We are amending this protocol to include a study CT scan of the head and neck with contrast to 
assess whether RECIST criteria can be used to identify responder patients after the neoadjuvant 
dose.  As described above several responses have been observed with the neoadjuvant dose. 
However, definition of “response” is based on a combination of observed tumor specific clinical 
changes, patient subjective reports and evaluation of pathology specimens after definitive surgical 
resection. To better define objective responses, we will also perform a dedicated head and neck 
study CT scan in the pre-surgery period to compare to the baseline, standard of care CT. 
 
1.8 
Rationale for Addition of Cohort 2  
 
Patients enrolled to cohort 2 will be treated with two (vs. one) neoadjuvant doses of MK-3475, 
but will not receive adjuvant MK-3475. 
 
The interim analysis of the first 25 patients (Section 1.6) showed the following observations: 
 
1. No serious drug-related AEs or unexpected surgical delays/complications. 
2. No LRR/DM events in the first 14 patients with > 1 year of follow-up. 
3. Rate of high risk pathologic features 42%, much lower than the expected rate of 85% and the 
historical institutional rate of 71%.   
4. Pathologic evidence of treatment effect was noted in 42% of patients. Twenty-five percent of 
patients had tumor samples with a major (> 50%) treatment effect. Treatment effect was 
defined as tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris distinct 
from growing tumor and only seen with therapy.  
5. Patient 15 underwent staged neck dissections. The first neck dissection (right side) showed no 
treatment effect. The second neck dissection (left side) showed extensive treatment effect. In 
this case, the additional time between the neoadjuvant dose of MK-3475 and the second 
surgery is one possible explanation for the presence of treatment effect in the tissue removed 
at the second surgery but lack of treatment effect in the tissue removed at the first surgery. 
This case suggests that additional time between administration of neoadjuvant MK-3475 and 
surgery is needed to fully deploy the immunologic therapeutic effect of MK-3475. 
 
Clinical-to-pathologic tumor down-staging, pathologic treatment effect, and lack of LRR/DM 
events in the first 14 patients with one year of follow-up are impressive evidence of the anti-tumor 
activity of MK-3475. Down-staging and treatment effect can only be related to the neoadjuvant 
pembrolizumab, and since most patients did not have high risk features and thus did not receive 
adjuvant MK-3475.  The lack of relapse events to date may be primarily due to the single dose of 
neoadjuvant MK-3475.  
 
The original hypothesis of the protocol was that adjuvant MK-3475 would reduce the LRR/DM 
rate in patients with high risk pathology features; however, the unexpectedly low rate of patients 
with high risk pathology features and thus low number of patients given adjuvant MK-3475 
coupled with the absence of LRR/DM events to date make it impossible to prove the original 
hypothesis in such a small study.  

Protocol Version: 10/28/2024, Amendment 7 
 
Page 14 of 56 
 
Beginning with Amendment #6, we plan to focus on pathologic treatment effect as an important 
endpoint. In other cancers, this endpoint has proven to be an excellent early surrogate of later 
relapse events. Steps taken to increase pathologic treatment effect correlated with lower relapse  
events in osteosarcoma, and breast and anorectal cancers. The primary objectives for Cohort 1 
(one dose of neoadjuvant MK-3475) and Cohort 2 (two doses of neoadjuvant MK-3475) will be 
to determine the major pathologic treatment effect. To collect additional data on this endpoint for 
one dose of neoadjuvant MK-3475, accrual to Cohort 1 will continue until Cohort 2 opens.     
 
Cohort 2 will be treated with two doses of neoadjuvant MK-3475: dose 2 given 21 days (+/- 3) 
after dose 1 and 14-24 days before surgery. We hypothesize that two doses of neoadjuvant MK-
3475 will result in a major pathologic treatment effect in 50% of patients compared to the rate of 
25% seen in Cohort 1 treated with one neoadjuvant dose of MK-3475. We estimate that a sample 
size of 26 patients in Cohort 2 is needed to allow us to detect with 80% power at the one sided 
alpha level of 0.05 a major pathologic treatment rate of 50%, as a significant improvement over 
the 25% rate in the single dose use cohort. Considering a 15% drop out rate, we plan to enroll 31 
patients in Cohort 2. 
 
  
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. Cohorts 1 and 2: To determine the locoregional recurrence rates in patients with stage III/IV 
HNSCC being treated with surgical therapy followed by indicated adjuvant therapy intensified 
by MK3475. 
 
2. Cohorts 1 and 2: To determine the distant failure rate in patients with stage III/IV HNSCC 
being treated with surgical therapy followed by indicated adjuvant therapy intensified by MK-
3475 
 
3. Cohort 1 only: To determine the rate of major pathologic treatment effect after one dose of 
neoadjuvant MK-3475. 
 
4. Cohort 2 only: To determine the rate of major pathologic treatment effect after two doses of 
neoadjuvant MK-3475. 
 
2.2 
Secondary Objectives 
 
1. Cohorts 1 and 2: To evaluate the safety of treatment with MK-3475 as measured by occurrence 
of adverse events. 
 
2. Cohorts 1 and 2: To evaluate the safety of treatment with MK-3475 as measured by surgical 
complications or delays. 
 
3. Cohorts 1 and 2: To determine the LRR/DM rates. 
 

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4. Cohorts 1 and 2: To evaluate overall survival and event-free survival rates. Overall survival will 
be defined as time from surgery to death from any cause. Event free survival will be defined as 
time from surgery to time to disease recurrence, distant metastasis, new primary, or death due to 
any cause, whichever occurred first. 
 
5. Cohorts 1 and 2: To evaluate overall survival and event-free survival rates differences by presence 
versus absence of recurrent genomic alterations.    
 
 
2.3 
Exploratory Objective 
 
To compare the anti-HNSCC immune response before and after MK-3475 including assessment 
of PD-L1 expression, immune function, and molecular signatures of activation in the pre- and 
post-treatment blood and tumor tissue.  
 
To apply a machine learning algorithm to hematoxylin and eosin-stained slides of tumor from 
baseline and surgically-resected specimens to characterize the spatial organization of tumor-
infiltrating lymphocytes and identify spatial architectures associated with treatment response and 
survival outcomes. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed stage III or IV HNSCC oral cavity, hypopharynx, 
oropharynx, larynx (excluding p16 or HPV-positive oropharynx primaries and sinonasal 
primaries). 
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest x-
ray, or >10 mm with calipers by clinical exam by RECIST 1.1. 
 
3. At least 18 years of age. 
 
4. ECOG performance status ≤ 1 (see Appendix A). 
 
5. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcl 
b. Platelets ≥ 100,000/mcl 
c. Hemoglobin ≥ 9 g/dL  
d. Total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin 
> 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases) 
f. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 30 
mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN 
g. INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT 
is within therapeutic range of intended use of anticoagulants 

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Page 16 of 56 
h. aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or 
PTT is within therapeutic range of intended use of anticoagulants 
 
6. Sexually active women of childbearing potential and men must agree to use 2 methods of 
contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, 
for the duration of study participation, and for 120 days after last dose of MK-3475.  Should 
a woman become pregnant or suspect she is pregnant while participating in this study, she 
must inform her treating physician immediately. 
 
7. Ability to understand and willingness to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Prior treatment for head and neck cancer.  
 
2. Patients with HPV-positive or p16-positive oropharyngeal SCCA.  
 
3. Patients with sinonasal SCCAs 
 
4. Patients with metastatic SCCA neck disease with an unknown primary tumor site 
 
5. Prior treatment 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). 
 
6. Received a live vaccine within 30 days prior to the first dose of MK-3475.  Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated 
viruses and are not allowed. 
 
7. A history of other malignancy ≤ 3 years previous with the exception of previous head and 
neck cancer treated only by surgery, basal cell or squamous cell carcinoma of the skin which 
were treated with local resection only, or carcinoma in situ of the cervix. 
 
Note: patients with synchronous head and neck cancer primaries are an exception to this 
criterion and may qualify for the study.  
 
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of MK-3475. 
 
9. Currently receiving any other investigational agents or has participated in a study of an 
investigational agent or using an investigational device within 4 weeks of the first dose of 
MK-3475. 
 

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10. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475 or other agents used in the study. 
 
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary 
disease, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
12. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
13. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
 
14. Pregnant and/or breastfeeding.  Patient must have a negative serum or urine pregnancy test 
within 72 hours of study entry. 
 
15. Known history of active TB (bacillus tuberculosis). 
 
16. Known history of hepatitis B (defined as hepatitis B survace antigen [HBsAg] reactive) or 
known active hepatitis C (defined as HCV RNA [qualitative] is detected) infection.  Note: 
know testing for hepatitis B and hepatitis C is required unless mandated by local health 
authority. 
 
17. Known history of HIV (HIV 1/2 antibodies). 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman Cancer 
Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center Oncore database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 

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4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and emailing 
it to the research coordinator listed in the Siteman Cancer Center Clinical Trials Core Protocol 
Procedures for Secondary Sites packet at least one business day prior to registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
 

Protocol Version: 10/28/2024, Amendment 7 
 
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4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent late 
afternoon or early morning enrollments should be planned in advance and coordinated with the 
Washington University research coordinator.  Registration will be confirmed by the research 
coordinator or his/her delegate by email within one business day. Verification of eligibility and 
registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore database at 
Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients will 
also be identified by first, middle, and last initials.  If the patient has no middle initial, a dash will 
be used on the case report forms (CRFs).  All data will be recorded with this identification number 
on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
This is a phase II trial of neoadjuvant MK-3475 in locally advanced, surgically resectable HPV-negative 
HNSCC.  After registration, tumor biopsy and peripheral blood will be obtained and then patients will 
receive preoperative MK-3475.  Patients in Cohort 1 will receive a single dose of MK-3475 and will 
undergo surgery two to three weeks later.  Blood and tissue will again be collected at the time of surgery, 
and paired pre-and post-treatment blood will be analyzed for changes in immune populations.  Molecular 
approaches will be used to define alterations in peripheral blood immune populations and define a 
molecular signature of MK-3475 activity.  Patients in Cohort 2 will receive two doses of neoadjuvant 
MK-3475 21 days apart (+/- 3 days).  The second dose will be 14 to 24 days prior to surgery.  Research 
blood and tissue will be collected at the time of surgery for Cohort 2 patients as well.  
 
Patients will then proceed with postoperative adjuvant treatment (Section 5.3). After completing adjuvant 
treatment, patients in Cohort 1 with high-risk features per pathology (i.e. positive involved surgical 
margins or extracapsular extension, defined as extension of metastatic cancer cells beyond the lymph 
node capsule, including soft tissue metastasis which obliterates the entire lymph node or is present as 
small extranodal deposits of tumor in the neck soft tissues) will receive MK-3475 every 3 weeks for a 
maximum of 6 postoperative doses.  MK-3475 will be started once the acute toxicities of post-operative 
chemotherapy and radiation have resolved to ≤ grade 1. Cohort 2 patients will be treated with standard 
adjuvant therapy but will not receive adjuvant MK-3475.  
 
NOTE: Enrollment to Cohort 1 will continue until enrollment to Cohort 2 opens (or enrollment to Cohort 
1 has been completed, whichever occurs first). 
 
5.1 
Premedication Administration 
 
No premedications are required, but antiemetics may be given as per institutional practice if 
needed. 

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Page 20 of 56 
 
5.2 
Agent Administration 
 
MK-3475 will be given intravenously over the course of 30 minutes (-5 min/+10 min) on an 
outpatient basis at a dose of 200 mg.  In Cohort 1, it will be given once prior to surgery 
(approximately 2 to 3 weeks pre-op).  In cohort 2, a second dose of MK-3475 will be given 21 
days (+/- 3) after dose 1 and 14-24 days before surgery. For patients in cohort 1 whose pathology 
displays high-risk features, MK-3475 will be given every 3 weeks after completion of standard of 
care adjuvant treatment (and after AEs resulting from adjuvant treatment have resolved to ≤ grade 
1) for a maximum of 6 doses after surgery.  The decision to administer chemotherapy or 
chemoradiation in the adjuvant setting is not dictated by this protocol, but should the treating 
physician choose to give adjuvant chemotherapy or chemoradiation, it will be given as described 
in Section 5.3.  Patients in Cohort 2 will not be given adjuvant MK-3475. 
 
5.3 
Adjuvant Treatment 
 
Intensity modulated radiation therapy (IMRT) is mandatory, and image-guided radiation therapy 
(IGRT) is recommended but optional.  Chemotherapy will be high-dose bolus cisplatin.  Non-
local patients may receive adjuvant therapy at their local hospital provided a medical oncologist 
(if applicable) and radiation oncologist from the study team sign off on the treatment plan. 
 
5.3.1 Radiation Therapy 
 
5.3.1.1 Dose Specifications 
 
The prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size 
(total of 30 fractions).  Radiotherapy should begin on a Monday, Tuesday, or 
Wednesday.  The daily dose of 2 Gy will be prescribed such that 95% of the PTV60 
volume receives at least 60 Gy.  As described below, PTV56 is also used, and 
PTV66 (given as an integrated boost) may be optionally defined.  3D-CRT 
followed by a 6 Gy boost is not permitted.  Dose-limiting normal tissue constraints 
are listed below 
 
5.3.1.2 Treatment Planning/Target Volumes 
 
CTV60: This volume will receive 2 Gy per day.  CTV60 will include the primary 
tumor 
bed 
(based 
on 
preoperative 
imaging, 
preoperative 
physical 
exam/endoscopy, operative findings, pathologic findings) plus regions of grossly 
involved lymphadenopathy.  CTV60 may include the broader operative resection 
bed in the region of gross primary and nodal disease.  The entire nodal regions in 
the involved hemi-neck may be included in CTV60 at the discretion of the 
investigator for perceived higher-risk cancers. 
 
CTV60 will include the ipsilateral pathologically positive hemi-neck (if both sides 
of the neck are proven pathologically positive, CTV60 will include both sides).  
This generally means encompassing nodal levels 2a, 3, and 4 for most cases.  Nodal 
levels 1, 2b, 5a, and 5b are included in CTV60 in selected circumstances.  For 
example, level 1 should be included for oral cavity cancer but is not mandatory for 

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Page 21 of 56 
larynx cancer. 
 
CTV56: This will include all other lesser risk regions in the operative bed (that 
were involved with surgery in any way) but felt to be at risk for harboring 
microscopic cancer that do not meet the criteria for CTV60.  For example, this 
could apply to the broad operative bed, the contralateral hemi-neck being irradiated 
electively.  This volume should not directly approach the skin < 5 mm.  This 
volume will receive 1.85 Gy per day. 
 
CTV66 (optional): This volume may be defined at the discretion of the treating 
radiation oncologist.  This would include regions felt to be at particularly high risk 
for recurrence (e.g., an area of the ECS or positive margin of resection).  Note: this 
area will be receiving a daily fraction size of 2.2 Gy and thus, the volume of CTV66 
should be kept as small as possible. 
 
Planning Target Volumes (PTVs): In general, the PTV should not extend beyond 
the skin surface, except if the skin was involved with tumor.  If it does extend 
beyond the skin surface, the application of bolus material over this portion of the 
PTV may be considered.  It is also allowable to define 2 PTVs for a given CTV: 
1) PTV for planning, which extends beyond the skin surface and is used for 
planning treatment segments; and 2) PTV Evaluation (PTV_Eval), which does not 
reach the skin surface within 2 mm and is used for evaluation of the dose volume 
histogram to determine if treatment goals have been met. 
 
PTV Expansion with and without Daily IGRT: The minimum CTV-to-PTV 
expansion should be 5 mm (a larger expansion may be necessary for a target 
volume subject to significant inter-fraction variability such as the tongue).  In 
general, the CTV-to-PTV expansion should not exceed 10 mm. 
 
Management of the Low Neck/Supraclavicular Region (Match vs. No Match for 
IMRT Treatment Modality): It is recognized that comprehensive head and neck 
irradiation incorporating IMRT can be done in 1 of 2 ways, either of which is 
permitted for this study. 
 
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 the upper neck IMRT fields.  This technique also allows 
for a simultaneous blocking of portions of the larynx, hypopharynx, and 
cervical esophagus in the lower neck fields.  In general, this technique is 
appropriate for irradiation of cancers of the oral cavity or oropharynx. 
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.  This technique in general is appropriate for irradiation of 

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Page 22 of 56 
cancers of the larynx and/or oral/pharyngeal cancers that involve the 
hypopharynx. 
 
Dose to Supraclavicular Nodal Region: Regardless of whether technique 1 (Match) 
or technique 2 (No Match) is used, the dose to the supraclavicular nodal region 
may be limited to 56 Gy for the non-operated, node negative hemi-neck, and for 
an involved hemi-neck if level 4 nodes were dissected and found to be negative. 
 
IMRT Dose Prescription to PTVs: The prescribed radiotherapy dose will be 60 Gy 
in 2 Gy once-daily fraction size 5 days a week.  For inverse planning IMRT, the 
goal is for 95% of the PTV60 to receive ≥ 2 Gy with a minimum dose (cold spot) 
of no less than 56 Gy.  It is recognized that portions of the PTV close to the skin 
may receive significantly less than 56 Gy. 
 
Prioritization for IMRT Planning 
1. Spinal cord 
2. Brainstem 
3. PTV60 
4. PTV56 (required if applicable) 
5. PTV66 (if applicable) 
6. OARpharynx 
7. Parotid gland contralateral to primary tumor site 
8. GSL 
9. Esophagus 
10. Lips 
11. Oral Cavity 
12. Parotid gland ipsilateral to primary tumor site 
13. Unspecified tissue outside the targets 
 
5.3.1.3 Definitions and Constraints for Normal Tissues / Organs at Risk 
(OARs) 
 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 
vertebral body).  Superior to this is brainstem and inferior to this is cord.  The 
inferior border of the spinal cord is at approximately T3-4 (i.e., just below the 
lowest slice level that has PTV on it).  The spinal cord shall be 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 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 

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Page 23 of 56 
goal is to keep the lip dose much lower than the oral cavity dose.  The definition 
of lips is self-explanatory.  For non-oral cavity cancers, the oral cavity will be 
defined as a composite structure consisting of the anterior half to two-thirds of the 
oral tongue/floor of mouth, buccal mucosa, and palate.  For oral cavity cancers, the 
oral cavity will be defined as the subset of this composite structure that does not 
overlap with PTV. 
 
Parotid Glands: Parotid glands will be defined in their entirety (superficial and 
deep lobes) based on the treatment planning CT scan.  Parotid gland volume may 
include portions of any of the CTVs if the primary or nodal volumes involved or 
closely approached the parotid, although they can overlap the PTVs. 
 
OARpharynx: This will be defined as the “uninvolved” posterior pharyngeal wall 
plus adjacent constrictor muscles.  This extends from the superior constrictor 
region (the inferior pterygoid plates level) to the cricopharyngeal inlet (posterior 
cricoid cartilage level).  This should not overlap the PTVs. 
 
Cervical Esophagus: This will be defined as a tubular structure that starts at the 
bottom of OARpharynx and extends to the thoracic inlet. 
 
Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had a total 
laryngectomy, this structure is not applicable.  This will be defined as a “triangular 
prism-shaped” volume that begins just inferior to the hyoid bone and extends to 
the cricoid cartilage inferiorly and extends from the anterior commissure to include 
the arytenoids.  This includes the infrahyoid but not suprahyoid epiglottis. 
 
Mandible: This includes the entire boney structure of the mandible from TMJ 
through the symphysis.  It is recognized that for oral cavity cancers, this may 
overlap with CTVs and PTVs. 
 
Unspecified Tissue outside the Targets: This will be defined as tissue located 
between the skull base and thoracic inlet. 
 
IMRT Dose Constraints to Normal Structures 
All of the following structures are to be contoured: 
• Spinal cord: the PRVcord should not exceed 48 Gy to any volume in excess 
of 0.03 cc (approximately 3 mm x 3 mm x 3 mm).  The spinal cord PRV 
should not exceed 50 Gy to any volume in excess of 0.01 cc.  In treatment 
planning, the spinal cord PRV should be given the highest priority. 
• Brainstem: the PRVbrainstem should not exceed 52 Gy to any volume in 
excess of 0.03 cc.  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.  For non-oral cavity cancers, the maximum dose will be < 30 Gy.  For 
oral cavity cancers, the maximum dose will be < 50 Gy. 
• Oral cavity: reduce the dose as much as possible.  For non-oral cavity 
cancers, the mean dose should be 30 Gy.  Efforts should be made to avoid 

Protocol Version: 10/28/2024, Amendment 7 
 
Page 24 of 56 
hot spots (> 60 Gy) within the oral cavity, particularly for non-oral cavity 
cancers. 
• Parotid glands: in many cases, it may 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 up to 30 Gy. 
• OARpharynx: reduce the dose as much as possible.  Some recommended 
(but not mandatory) treatment goals include: 1) no more than 33% of the 
OARpharynx exceeds 50 Gy; 2) mean dose < 45 Gy; 3) no more than 15% 
of the OARpharynx exceeds 60 Gy. 
• Cervical esophagus: reduce the dose as much as possible.  For oral or 
oropharyngeal cancer, some recommended (but not mandatory) treatment 
goals include: 1) no more than 33% of the esophagus exceeds 45 Gy; 2) 
mean dose < 35 Gy; 3) no more than 15% of the esophagus exceeds 54 Gy.  
For larynx cancer, higher doses are expected and permitted.  Some 
recommended (but not mandatory) treatment goals include: 1) no more 
than 33% of the esophagus exceeds 50 Gy; 2) mean dose < 45 Gy; 3) no 
more than 15% of the esophagus exceeds 60 Gy. 
• Glottic and supraglottic larynx: reduce the dose as much as possible.  In 
patients with resected oral or oropharyngeal carcinoma, it is recommended 
that the dose to the larynx should be kept < 45 Gy whenever feasible. 
• Mandible: reduce the dose as much as possible.  It is recognized that 
particularly for oral cavity cancers, significant portions of the mandible will 
overlap the CTVs and/or PTVs; however, hot spots within the mandible 
should be avoided.  It is recommended that maximum dose within the 
mandible be < 66 Gy. 
• Unspecified tissue outside the targets: for the typical case in which there is 
no CTV66, no more than 0.03 cc can receive 66 Gy or more.  When a boost 
is used to increase the dose to high-risk regions to as much as 66 Gy, these 
numbers can be increased.  In this case, no more than 0.03 cc of the 
unspecified dose should exceed the boost dose value plus 10% or 72.6 Gy. 
 
5.3.1.4 Compliance Criteria 
 
Treatment breaks must be clearly indicated in the treatment record, along with 
the reasons for the breaks.  Treatment breaks, if necessary, ideally should not 
exceed five treatment days at a time and ten treatment days total.  Treatment 
breaks should only be allowed for resolution of severe acute toxicity and/or for 
intercurrent illness and not for social or logistical reasons.  Any treatment breaks 
exceeding two treatment days for reasons other than toxicity/illness will be 
considered a protocol deviation. 
 
It is recommended that patients receive BID treatments with minimum 6-hour 
inter-fraction interval to compensate for missed days included holidays and those 
for toxicity or illness once sufficiently recovered with the goal of keeping the 
overall treatment time confined to 6 weeks or 45 consecutive days. 
 
 

Protocol Version: 10/28/2024, Amendment 7 
 
Page 25 of 56 
 
 
Per Protocol 
Variation Acceptable 
Total RT dose to PTV60 (to 95% 
of PTV60) 
60-64 Gy 
< 60 and ≥ 58 Gy or > 
64 and ≤ 66 Gy 
Minimum dose for a volume of 
0.03 cc (“cold spot” within 
PTV60, not including portion of 
PTV near (<8 mm) skin) 
≥ 56 Gy 
≥ 54 and < 56 Gy 
Maximum dose (hot spot) within 
PTV60* for a volume of 0.03 cc 
≤ 69 Gy 
> 69 and ≤ 72 Gy 
Maximum dose (hot spot) outside 
of PTV60 for a volume of 0.03 cc 
≤ 66 Gy 
> 66 and ≤ 70 Gy 
Total RT dose to PTV 56 (to 95% 
of PTV56) 
56-58 Gy 
< 56 and ≥ 53.2 Gy or 
> 58 and ≤ 60 Gy 
Minimum dose (cold spot) within 
PTV56 for a volume of 0.03 cc 
45 Gy 
40 Gy 
Total RT dose to PTV 66 (to 95% 
of PTV66) 
66-68 Gy 
< 66 and ≥ 62.7 Gy or 
> 68 and ≤ 70.6 Gy 
Minimum dose (cold spot) within 
PTV 66 for a volume of 0.03 cc 
61.4 Gy 
59 Gy 
Maximum dose (hot spot) within 
PTV66 
1. No more than 
20% of PTV66 is 
at or above 72.6 
Gy 
2. No more than 
0.03 cc of PTV66 
can go above 75.9 
Gy 
1. No more than 40% 
of PTV66 is at or 
above 72.6 Gy 
2. No more than 0.03 
cc of PTV66 can 
go above 78 Gy 
Total RT dose to spinal cord PRV 
(0.03 cc) 
< 48 Gy 
≥ 48 but ≤ 50 Gy 
Total RT dose to brainstem PRV 
(0.03 cc) 
≤ 50 Gy 
> 50 Gy and < 52 Gy 
Lips maximum dose to 0.03 cc for 
non-oral cavity cancers 
≤ 25 Gy 
≤ 30 Gy 
Lips maximum dose to 0.03 cc for 
oral cavity cancers 
≤ 45 Gy 
≤ 50 Gy 
Oral cavity (for non-oral cavity 
cancers) mean dose 
≤ 30 Gy 
> 30 but ≤ 35 Gy 
Parotid gland: mean dose to 
individual parotid gland 
< 26 Gy 
> 26 Gy and < 30 Gy 
Overall RT treatment time 
< 45 days 
≥ 45 and ≤ 50 days** 
Non-medically indicated treatment 
interruptions 
0-2 
3-4 
* Not including the region of PTV60 that falls within PTV66 (if applicable) 
** Deviation unacceptable: > 50 days (without a medially appropriate indication for delay) 
 
5.3.2 Chemotherapy 
 
Patients will receive cisplatin, 100 mg/m2, administered intravenously on Days 1,22, and 
43 of the treatment course (Note: cisplatin given within 24 hours of Days 1, 22, and 43 
due to holidays, for example, is acceptable).  

Protocol Version: 10/28/2024, Amendment 7 
 
Page 26 of 56 
 
Use the actual body weight as long as the BSA is ≤ 2.0. If the BSA is > 2.0, recalculate 
using the ideal weight, and use the recalculated BSA to determine the dose with no 
cap or use a cap with a BSA of 2.0, whichever is higher. Use the formulas below: 
Males (kg): 51.65 + (1.85 x (height [inches] – 60)) 
Females (kg): 48.67 + (1.85 x (height [inches] – 60)) 
 
High dose cisplatin is a highly emetogenic regimen with significant incidence of delayed 
nausea and vomiting. Institutional guidelines for highly emetogenic regimens should be 
followed.  
 
Patients must receive vigorous hydration and diuresis. A suggested regimen is 
prehydration with a 1 liter of D5N S over 2-4 hours and mannitol, 12.5 g i.v. bolus 
immediately prior to cisplatin. Then cisplatin, 100 mg/m2, in 500 ml NS is administered 
over 1-2 hours with an additional 1 to 1.5 liters of fluid given post-hydration. Any pre-
existing dehydration must be corrected prior to cisplatin administration. Should 
extravasation occur, the treating physician should follow institutional guidelines for 
management. 
 
5.3.2.1 Dose Modifications for Cisplatin, Day 22 and Day 43 
 
Neutropenia: If on the day of scheduled treatment with cisplatin the absolute 
neutrophil count (ANC) is < 1000, hold treatment until ANC ≥ 1000, then treat at 
100% dose.  Neutropenic fever will require permanent 25% dose reduction.  
Neulasta may be used in the instance of neutropenia or neutropenic fever.  
 
Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet 
count is < 75,000, hold treatment until platelets are > 75,000, then treat at 100% 
dose.  Thrombocytopenia that results in bleeding will require a 25% dose 
reduction. 
 
Neurotoxicity: If any signs of grade 3 or greater neurotoxicity occur, discontinue 
cisplatin. Continue RT. 
 
Renal Adverse Events: Cisplatin should be administered on the scheduled day of 
treatment using the following guidelines: 
 
Note: If creatinine is > 1.5 mg/dl, clearance must be done in order to make dose 
adjustment. 
 
Creatinine Clearance Cisplatin Dose 
> 50 ml/min. 100 mg/m2 
40-50 ml/min. 50 mg/m2 
< 40 ml/min. Discontinue 
 
Other Adverse Events: 
• Mucositis: Grade 4 will require a 25% dose reduction 
• Ototoxicity: For new clinical hearing loss not requiring a hearing aid or for 

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tinnitus that interferes with activities of daily living, treat at 50% dose 
reduction. For hearing loss requiring a hearing aid, discontinue cisplatin. 
Continue RT. 
 
If the second or third dose of cisplatin is delayed more than 7 days because of 
hematologic or renal adverse events, that dose will be omitted. 
 
If a weight change of ≥ 10% occurs, the cisplatin dose should be adjusted. 
 
5.4 
Definition of Evaluability 
 
Patients must receive at least one postoperative dose of MK-3475 in order to be considered 
evaluable for the primary objective. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
 
Patients are prohibited from receiving the following therapies while in screening for and enrolled 
in this trial: 
• Anti-cancer systemic chemotherapy other than as dictated in the post-operative setting or 
biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Radiation therapy other than as dictated in the post-operative setting 
• Live vaccines within 30 days prior to the first dose of treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  Steroids may be used as anti-
emetics around the time of chemotherapy delivery, which may occur more than 10 weeks 
after the pre-operative single dose MK-3475 and 4 weeks before post-operative dosing. In 
the immediate perioperative period patients receive steroids to help with wound edema 
from surgery. The use of physiologic doses of corticosteroids may be approved. 
 
5.5.1 Supportive Care Guidelines for Infusion Reactions 
 
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. The table below shows treatment guidelines for patients who experience an 
infusion reaction associated with MK-3475. 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and 
the subject should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of MK-3475 with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that precludes 
withdrawal bleeding, and women who have had a tubal ligation) are required to have a negative 
serum or urine pregnancy test within 72 hours prior to the first dose of MK-3475.   
 
Pembrolizumab may have adverse effects on a fetus in utero. 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   

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A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).  Women in the following categories are not considered of 
childbearing potential: 
 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
• Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
 A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Requirements 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
below) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined timeframe:  
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in the table below when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
o Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration. 
 
 

Protocol Version: 10/28/2024, Amendment 7 
 
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Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below during 
the protocol-defined timeframe.  
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen-containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency 
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be used.
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study
treatment.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment,
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study treatments 
with genotoxic potential] after the last dose of study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable
hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test.  
 
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected, after the last dose of study 
treatment, and as required locally. 
 

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Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s 
health and/or the patient no longer wishes to continue protocol therapy, the protocol therapy 
should be discontinued and the reason(s) for discontinuation documented in the case report forms.  
In the absence of treatment delays due to adverse events, treatment may continue for up to 6 doses 
of MK-3475 following surgery or until one of the following criteria applies: 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or permanent 
harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
Patients who prematurely discontinue treatment for any reason will be followed as indicated in 
the study calendar. 
 
5.8 
Duration of Follow-up 
 
All patients will be followed for at least 4 years for cancer surveillance following completion of 
postoperative treatment with MK-3475 (i.e. up to 5 years after surgery) or for 5 years after surgery 
for patients who did not receive post-op MK-3475 or until death, whichever occurs first. Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event or up to 5 years as dictated by the treating physician. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications.  Based on existing clinical study 
data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity 
of irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in the table below. 

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General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg 
prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and symptoms of 
pneumonitis 
• 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics for opportunistic infections 
Grade 3 or 4, or 
recurrent grade 2 
Permanently discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (i.e. peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
• 
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids.  If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. 
Grade 4 
Permanently discontinue 
AST / ALT 
elevation or 
Increased Bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently discontinue 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 

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Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
 
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic 
in participants with 
hyperglycemia  
• 
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)  
Grade 3 or 4  
Withhold or permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g. propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g. levothyroxine 
or liothyroinine) per standard 
of care 
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis and renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently discontinue 
All Other immune-
related AEs 
Intolerable/ persistent 
Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm etiology or 
exclude other causes 
 
Grade 3 
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis 
Grade 4 or recurrent 
Grade 3  
Permanently discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ 
Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 

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Page 34 of 56 
 
Please also refer to Section 5.5 for information regarding supportive care and possible dose adjustments. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events meeting 
the definition of unanticipated problem or serious noncompliance be reported as outlined in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 7.6.  
In addition, any fatal or life-threatening adverse experiences where there is a reasonable possibility of 
relationship to study intervention must be reported. 
 
Merck requires that any SAE and SUSAR information be reported as outlined in Section 7.7, as well as 
events of clinical interest (Section 7.7.2). 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
For Merck’s purposes, an adverse event (or “AE”) shall mean any untoward medical 
occurrence in a Study subject who is administered the Study Drug regardless of whether 
or not a causal relationship with the Study Drug exists.  By way of example and without 
limitation, an AE can be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the Study 
Drug. 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 

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o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
For Merck’s purposes, a serious adverse event (or “SAE”) shall mean any untoward 
medical occurrence in a Study subject who is administered the Study Drug that results in 
death, a life-threatening drug experience, requires inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect, cancer, or is a new cancer if the cancer is the condition 
of the study, or overdose.  Other important medical events that may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed previously should also 
be considered “serious.” 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 

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(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
7.1.6 Suspected Unexpected Serious Adverse Reaction 
 
Suspected Unexpected Serious Adverse Reaction (or “SUSAR”) shall mean any serious 
adverse event (defined in Section 7.1.2), the nature, severity or frequency of which is not 
consistent with information in the most current investigator’s brochure, or with respect to 
a marketed product the most current Summary of Product Characteristics (SPC) or 
Package Insert. 
 
7.1.7 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.8 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
7.1.9 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the event.  For 
secondary sites, the Washington University PI will issue approval of the exception, but it 
must also be submitted to the local IRB with documentation of approval forwarded to 
Washington University.  Washington University IRB approval is not required for protocol 
exceptions occurring at secondary sites. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur at WU, 
any BJH or SLCH institution, or that impacts participants or the conduct of the study. 
• Noncompliance with federal regulations or the requirements or determinations of the IRB. 
• Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.  The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 

Protocol Version: 10/28/2024, Amendment 7 
 
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notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) 
at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any 
BJH or SLCH institution that has been reported to and acknowledged by HRPO as reportable.  
(Unanticipated problems reported to HRPO and withdrawn during the review process need not be 
reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a 
QASMC auditor. 
 
7.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington University 
PI and research coordinator of all reportable events (as described in Section 7.6) within 1 working 
day of the occurrence of the event or notification of the secondary site’s PI of the event.  This 
notification may take place via email if there is not yet enough information for a formal written 
report (using either an FDA MedWatch form if required or an institutional SAE reporting form if 
not).  A formal written report must be sent to the Washington University PI and research 
coordinator within 10 working days of the occurrence of the event or notification of the secondary 
site’s PI of the event.  The death of a research participant that qualifies as a reportable event should 
be reported within 1 working day of the occurrence of the event or notification of the secondary 
site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for reporting 
applicable events to its site’s IRB according to its own institutional guidelines.  The research team 
at Washington University is responsible for reporting all applicable events to the FDA. 
 
7.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary site 
of all reportable events that have occurred at other sites within 10 working days of the occurrence 
of the event or notification of the PI of the event.  This includes events that take place both at 
Washington University and at other secondary sites, if applicable. 
 
7.6 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  PLEASE 
NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM 
REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the responsibility of the 
Washington University principal investigator to report any unanticipated problem to the FDA as 
follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug (i.e., there is a reasonable possibility that the experience 
may have been caused by the drug) by telephone or fax no later than 7 calendar days after 

Protocol Version: 10/28/2024, Amendment 7 
 
Page 38 of 56 
initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), as well as results from 
animal studies that suggest significant clinical risk within 15 calendar days after initial 
receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at the 
following address or by fax: 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
Secondary sites must submit a completed MedWatch form to the Washington University PI and 
research coordinator within 4 calendar days (for fatal or life-threatening adverse experiences) or 
11 calendar days (for serious, unexpected adverse experiences).  The Washington University PI 
will be responsible for submitting all MedWatch forms from secondary sites to the FDA within 
the timeframes specified above. 
 
7.7 
Reporting to Merck & Co., Inc. 
 
The PI shall forward to Merck’s Global Safety group (FAX 215-661-6229) any SAE and SUSAR 
information, including, but not limited to, all initial and follow-up information involving any 
study subject in the study within 2 business days or 3 calendar days (whichever comes first) of 
learning of the SAE or SUSAR. Only SAEs that are believed to be related to the use of MK-3475 
will be reported to Merck. 
 
7.7.1 Reporting Overdose 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide 

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Product Safety; FAX 215 661-6229) 
 
7.7.2 Reporting Pregnancy and Lactation 
 
Although pregnancy and infant exposure during breastfeeding 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) that occurs during the trial. 
 
Pregnancies and infant exposures during breastfeeding that occur after the consent form 
is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of MK-3475, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must 
be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229). 
 
7.7.3 Reporting 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 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 661-6229) 
 
Events of clinical interest for this trial include: 
1. an overdose of Merck product that is not associated with clinical symptoms or 
abnormal laboratory results.  
2. an elevated AST or ALT lab value that is ≥ 3 x IULN and an elevated total bilirubin 
lab value that is ≥ 2 x IULN and, at the same time, an alkaline phosphatase lab 
value that is < 2 x IULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.  
 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported to Merck Global Safety 
within 2 working days. 
 
 

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7.8 
Timeframe for Reporting Required Events  
 
For patients who do not receive adjuvant pembrolizumab, adverse events will be tracked for 30 
days following date of surgery.  For patients who do receive adjuvant MK-3475, adverse events 
will be tracked for 30 days after the last dose of MK-3475.  For the purposes of this protocol, 
reportable adverse events are events thought to be possibly, probably, or definitely related to MK-
3475.  Events thought to be probably or definitely related to surgery, adjuvant chemotherapy, or 
radiotherapy need not be recorded.  Please note that patients must be followed for events of 
clinical interest for 90 days following the last dose of MK-3475 for all patients. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
MK-3475 
 
8.1.1 MK-3475 Description 
 
MK-3475 is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 
receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, MK-3475 has high affinity and potent receptor blocking activity for PD-1. MK-
3475 has an acceptable preclinical safety profile and is being advanced for clinical 
development as an IV immunotherapy for advanced malignancies. 
 
8.1.2 Clinical Pharmacology 
 
Refer to Section 5.2 of the IB. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Refer to Section 5.2 of the IB. 
 
8.1.4 Supplier 
 
MK-3475 will be provided free of charge by Merck & Co., Inc. 
 
8.1.5 Dosage Form and Preparation 
 
Merck will provide MK-3475 as a liquid drug product. 
 
8.1.6 Storage and Stability 
 
MK-3475 should be stored under refrigerated conditions (2°C - 8°C). 
 
If not used immediately, vials and/or IV bags may be stored at 2-8 °C for up to a 
cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be allowed to 
equilibrate to room temperature prior to subsequent use. MK-3475 solutions may be stored 
at room temperature for a cumulative time of up to 4 hours. 

Protocol Version: 10/28/2024, Amendment 7 
 
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8.1.7 Administration 
 
MK-3475 will be given intravenously over the course of 30 minutes (-5 min/+10 min) on 
an outpatient basis.   
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tumor Biopsy 
 
9.1.1 Collection of Specimens 
 
Two 3.5 mm punch biopsies of the primary site will be taken at baseline.  If the participant 
is enrolled in Washington University’s TAP protocol (the head & neck bank, HRPO# 
201102323), tissue that has been banked may be accessed in lieu of fresh biopsy at 
baseline.  Tissue from the surgical resection (preferred sometime between Day 14-17 
inclusive but may occur up to Day 24 depending on timing of surgery) will also be 
harvested for analysis of intratumoral changes. 
 
9.1.2 Handling of Specimens  
 
Specimens collected at WUSM will be transported fresh to the Immunomonitoring Lab 
on the 7th floor of the BJC Institute of Health, WUSM for lymphocyte extraction on the 
samples. Additionally, some samples will be sent to the Tissue Procurement Core on the 
5th floor of the BJC Institute of Health, WUSM.  Samples collected at DFCI will be 
transported fresh to Dr. Uppaluri’s lab.  The samples will be used for genomic 
(RNA/DNA) analysis and will be transplanted into immunodeficient NSG mice 
(NOD/scid/gamma chain knockout) and engraftment will be monitored.  Tumors 
established in mice will be used to generate cell lines and divided into ones that were 
responsive or unresponsive to MK-3475 treatment.  Specimens from WUSM may be 
shipped to DFCI, and specimens from DFCI may be shipped to WUSM.  Shipping 
instructions will be provided at a later date. 
 
9.2 
Archival Tissue 
 
Access to paraffin blocks from all patients enrolled to this study will be requested.  Blocks may 
be analyzed at WUSM or at DFCI. 
 
Hematoxylin and eosin-stained slides of formalin-fixed paraffin-embedded (FFPE) tissues will be 
digitized to apply a machine learning algorithm to quantify tumor infiltrating lymphocyte 
infiltration as a potential predictor of response.  FFPE blocks may be used to create tissue 
microarrays (TMAs) for multiplex histological analysis.  
 
9.3 
Peripheral Blood for Biomarkers 
 
9.3.1 Collection of Specimens 
 

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Blood (30 mL) will be collected in 3 purple top EDTA tubes at the following time points, 
for both Cohort 1 and Cohort 2: 
• Baseline 
• Time of surgery (between Day 14 and Day 24 inclusive) 
• 3 months post-surgery6 months post-surgery  
• 9 months post-surgery  
• 12 months post-surgery  
 
9.3.2 Handling of Specimens 
 
A portion of each sample will be stored as buffy coat peripheral blood mononuclear cells 
(PBMC) or DNA/RNA for future studies. This will take place in the BJC Institute of 
Health at WUSM and Dr. Uppaluri’s lab at DFCI.  Specimens from WUSM may be 
shipped to DFCI, and specimens from DFCI may be shipped to WUSM.  Shipping 
instructions will be provided at a later date. 
 

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Page 43 of 56 
 
10.0 
STUDY CALENDAR 
 
10.1 
Calendar for Cohort 1 
 
NOTE: Enrollment to Cohort 1 will continue until enrollment to Cohort 2 opens (or enrollment to Cohort 1 has been completed, 
whichever occurs first). 
 
Screening9 
Baseline 
Day 
1 
Days 14-24 
(Surgery) 
Adjuvant 
CRT5 
3 Mos after 
Surgery 
6 Mos after 
Surgery 
9 Mos after 
Surgery 
12 Mos after 
Surgery 
Follow-
Up4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
H&P, ECOG PS, wt 
X 
 
X 
 
 
 
 
 
 
 
CBC 
X 
 
X 
 
 
 
 
 
 
 
CMP 
X 
 
X 
 
 
 
 
 
 
 
Coagulation panel1 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X3 
 
 
 
 
 
 
 
 
 
T3, FT4, and TSH 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
 
X 
 
X 
 
 
 
 
 
 
Research blood 
 
X 
 
X 
 
X8 
X8 
X8 
X8 
 
MK-3475 
 
 
X 
 
 
 
 
 
 
 
RT 
 
 
 
 
X6 
 
 
 
 
 
Cisplatin 
 
 
 
 
X7 
 
 
 
 
 
Neck CT 
X 
 
 
X10 
 
Following completion of adjuvant treatment, routine imaging will take place 
approximately every 3 months for the first 15 months then approximately 
every 6 months thereafter. 
Chest CT or PET/CT 
X 
 
 
 
 
AE assessment 
 
X 
Patients will be followed for AEs for 30 days after surgery or last dose of adjuvant MK-3475, and for 
Events of Clinical Interest for 90 days following the last dose of MK-3475 
 
1. 
Consisting of a PTT and PT/INR  
2. 
Women of childbearing potential only 
3. 
No more than 72 hours prior to start of treatment 
4. 
Follow-up will be performed as per routine care (every 2-3 months for 15 months, then every 5-6 months) and data on recurrence and survival will be recorded. 
5. 
Adjuvant therapy should typically begin between 4 and 6 weeks following surgery.  Laboratory assessments will be performed as per routine care and will not be dictated by this 
research protocol. 
6. 
RT will be given as 30 daily fractions and should start on a Monday, Tuesday, or Wednesday.  Refer to Section 5.3.1 for guidelines. 
7. 
High-dose cisplatin will be given on Days 1, 22, and 43 (+/- 1 day). 
8. 
+/- 7 days, or drawn with standard labs 
9. 
Screening exams must take place within 14 days prior to registration with the exception of imaging, which must take place within 30 days prior to registration. 
10. After neoadjuvant pembrolizumab but before surgery. 

Protocol Version: 10/28/2024, Amendment 7 
 
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10.2 
Calendar for Cohort 2 
 
Screening9 
Baseline 
Day 
1 
Day 
22 
(+/-3) 
14-24 Days 
Post Day 
22 
(Surgery) 
Adjuvant 
CRT5 
3 Mos after 
Surgery 
6 Mos 
after 
Surgery 
9 Mos 
after 
Surgery 
12 Mos 
after 
Surgery 
Follow
-Up4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
H&P, ECOG PS, wt 
X 
 
X 
 
 
 
 
 
 
 
 
CBC 
X 
 
X 
 
 
 
 
 
 
 
 
CMP 
X 
 
X 
 
 
 
 
 
 
 
 
Coagulation panel1 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X3 
 
 
 
 
 
 
 
 
 
 
T3, FT4, and TSH 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
 
X 
 
 
X 
 
 
 
 
 
 
Research blood 
 
X 
 
 
X 
 
X8 
X8 
X8 
X8 
 
MK-3475 
 
 
X 
X 
 
 
 
 
 
 
 
RT 
 
 
 
 
 
X6 
 
 
 
 
 
Cisplatin 
 
 
 
 
 
X7 
 
 
 
 
 
Neck CT 
X 
 
 
 
X10 
 
Following completion of adjuvant treatment, routine imaging 
will take place approximately every 3 months for the first 15 
months then approximately every 6 months thereafter. 
Chest CT or PET/CT 
X 
 
 
 
 
 
AE assessment 
 
X 
 
Patients will be followed for AEs for 30 days after surgery or last dose of adjuvant MK-3475, and for 
Events of Clinical Interest for 90 days following the last dose of MK-3475 
1. 
Consisting of a PTT and PT/INR  
2. 
Women of childbearing potential only 
3. 
No more than 72 hours prior to start of treatment 
4. 
Follow-up will be performed as per routine care (every 2-3 months for 15 months, then every 5-6 months) and data on recurrence and survival will be recorded. 
5. 
Adjuvant therapy should typically begin between 4 and 6 weeks following surgery.  Laboratory assessments will be performed as per routine care and will not be dictated by this 
research protocol. 
6. 
RT will be given as 30 daily fractions and should start on a Monday, Tuesday, or Wednesday.  Refer to Section 5.3.1 for guidelines. 
7. 
High-dose cisplatin will be given on Days 1, 22, and 43 (+/- 1 day). 
8. 
+/- 7 days, or drawn with standard labs 
9. 
Screening exams must take place within 14 days prior to registration with the exception of imaging, which must take place within 30 days prior to registration. 
10. After second dose of neoadjuvant pembrolizumab but before surgery. 
 
 

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10.3 
Post-CRT Calendar for Cohort 1 Participants Who Receive Adjuvant MK-3475 
 
Only patients whose pathology shows high risk features will receive further treatment with MK-
3475.  This treatment will start 1-3 months after the end of standard of care adjuvant treatment.  
Each visit has a window of +/- 3 days. 
 
 
Dose #1 
Dose #2 
Dose #3 
Dose #4 
Dose #5 
Dose #6 
CBC 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
T3, FT4, and TSH 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
MK-34751 
X 
X 
X 
X 
X 
X 
Neck CT 
Routine imaging will take place approximately every 3 months for the first 15 
months following completion of adjuvant treatment, and approximately every 
6 months thereafter. 
Chest CT or PET/CT 
AE assessment 
X ------------------------------------------------------------------ X 
1. MK-3475 is given Q3W in the adjuvant setting. 
 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the schedule 
listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Tumor Biopsy Form 
Research Blood Form 
Archival Tissue form 
Prior to starting treatment 
Study Drug Form 
Every dose of MK-3475 
Tumor Biopsy Form 
Research Blood Form 
Time of surgery 
Chemoradiation Form 
End of CRT  
Research Blood Form 
3, 6, 9, and 12 months post-surgery (as applicable per 
cohort and adjuvant treatment eligibility) 
Adverse Events Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
5 years after end of treatment 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Methods for Evaluation of LRR/DM 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 

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baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans should 
be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality 
to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 

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Endoscopy:  There is a strong likelihood of utilization of endoscopic techniques in this head and 
neck cancer clinical trial.  Again as the head and neck region is easily accessible, endoscopic 
measurements may be used. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 
2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: FDG-PET is part of the post-operative surveillance for advanced head and neck 
cancers.  The measurement of SUVmax in pre-treatment and post-treatment scans will be used as 
the secondary endpoint. 
 
12.2 
RECIST Analysis of Post-Neoadjuvant Dose CT Scan for Treatment Response   
 
For new patients recruited to this study beginning with Amendment #5, we will also perform a 
study supported head and neck dedicated CT with contrast.  
 
12.2.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for response on Day 14-24 
after the infusion of study drug just prior to surgery. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2.2 Disease Parameters 
 
Measurable disease:  By definition, all patients will have measurable lesions (at least 20 
mm in the longest diameter) as measured by calipers on clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).. 

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Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Any distant metastatic disease would exclude 
patient enrollment and by definition as also considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the Data 
and Safety Monitoring Committee (DSMC) will be specifically convened for this trial to review toxicity 
data at least every 6 months following the activation of the first secondary site.  A DSMC will consist of 
no fewer than 3 members including 2 clinical investigators and a biostatistician.  Like investigators, 
DSMC members are subject to the Washington University School of Medicine policies regarding 
standards of conduct. Individuals invited to serve on the DSMC will disclose any potential conflicts of 
interest to the trial principal investigator and/or appropriate university officials, in accordance with 
institution policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMC must 
also be disclosed.  
 
The DSM report will be prepared by the study statistician with assistance from the study team, will be 
reviewed by the DSMC, and will be submitted to the Washington University Quality Assurance and 
Safety Monitoring Committee (QASMC). This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of 
HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from participating 
sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each participating site 
• Expected accrual end date and accrual by site 
• Objectives of protocol with supporting data and list the number of participants who have met each 
objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 

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• Summary of toxicities at all participating sites 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMC responsibilities are described in the DSMC charter. 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to be 
prepared by the study team will be submitted to the QASM Committee beginning 6 months after study 
activation at Washington University. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing basis. 
Once the principal investigator or coordinator becomes aware of an adverse event, the AE will be reported 
to the HRPO and QASMC according to institutional guidelines (please refer to Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee Policies 
and Procedures for full details on the responsibilities of the DSMC at https://siteman.wustl.edu/wp-
content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf 
 
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best practices 
for patient safety and data collection are being followed per protocol.  Participating sites will be asked to 
send copies of all audit materials, including source documentation.  The audit notification will be sent to 
the Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. Once 
accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the cases selected 
for review (up to 10 for each site) will be sent to the research team. However, if during the audit the need 
arises to review cases not initially selected, the research team will be asked to provide the additional 
charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Completeness of participant documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional 
details 
regarding 
the 
auditing 
policies 
and 
procedures 
can 
be 
found 
at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf  

Protocol Version: 10/28/2024, Amendment 7 
 
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15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Sample Size Justification 
 
15.1.1 Original (Cohort 1) 
 
Historical clinical trial data from the Cooper et al. and Bernier et al. studies (1, 2) showed 
that 35% of patients undergoing multimodality treatment for locally advanced “high risk” 
HNSCC suffer from LRR and DM at one year.  Our primary endpoint in the proposed 
single arm trial is to reduce LRR/DM to 15%.  We estimate that 31 patients will be needed 
to allow us to detect with 80% power (α = 0.05) a difference of at least 20% in the one-
year LRR/DM rate.  Since 80% of the patients are classified as high-risk post-surgery, and 
taking into account a 15% drop-out rate observed in most of our studies, we estimate that 
we will need to recruit 46 patients for this study to be able to achieve the goal of 31 
evaluable subjects successfully completing the study. As stated earlier in Section 1.8, the 
original hypothesis of the protocol was that adjuvant MK-3475 would reduce the LRR/DM 
rate in patients with high risk pathology features; however, the unexpectedly low rate of 
patients with high risk pathology features and thus low number of patients given adjuvant 
MK-3475 coupled with the absence of LRR/DM events to date make it impossible to prove 
the original hypothesis in such a small study.  
 
15.1.2 Amendment #6 (Addition of Cohort 2) 
 
In Cohort 2, we hypothesize that two doses of neoadjuvant MK-3475 will result in a major 
pathologic treatment effect in 50% of patients compared to the rate of 25%  seen in Cohort 
1 treated with one neoadjuvant dose of MK-3475. We estimate that a sample size of 26 
patients in Cohort 2 is needed to allow us to detect with 80% power at the one-sided alpha 
level of 0.05 a major pathologic treatment rate of 50%, as a significant improvement over 
the 25% rate in Cohort 1. Considering a 15% drop out rate, we plan to enroll 31 patients 
in Cohort 2. 
 
NOTE: Enrollment to Cohort 1 will continue until enrollment to Cohort 2 opens (or 
enrollment to Cohort 1 has been completed, whichever occurs first). 
 
15.2 
Analysis 
 
15.2.1 Relapse Rates and Adverse Events 
 
Relative frequency will be used to report the one-year rate of LRR/DM.  A one sample 
binomial test will be used to test the null hypothesis that LRR/DM rate is significantly 
different from 0.35.  Confidence intervals of 95% around the point estimate for the 
proportion rate of LRR/DM will be calculated and the upper limit will be compared to 
0.35. 
 
We will record and report all side effects and adverse events observed in the study as 
described above.  Paired samples t-test will be used to compare the anti-HNSCC immune 
response before and after MK-3475. 

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15.2.2 Long Term Relapse Rates and Survival Outcomes 
 
On long-term follow-up analysis, two-year rates of LRR/DM will be assessed, and 
LRR/DM rates will be compared between Cohorts 1 and Cohorts 2 and between patients 
who experienced pathologic treatment response (pTR) to those who did not. Fisher’s exact 
and chi-square testing will be used to test the null hypothesis that LRR/DM rates are not 
significantly different between cohorts and between patients with versus without pTR 
following neoadjuvant MK-3475. 
  
Overall and event-free survival will be analyzed using Kaplan Meier methods in our 
overall patient population. Kaplan Meier survival curves will then be stratified (1) by 
cohort, (2) by pTR status or (3) by presence of recurrent genomic alterations to assess 
differences in overall and event-free survival. Log-rank tests will be used to compare 
survival between groups at a significance level of 0.05. 
 
We will assess pathologic responses in lymph nodes versus in the primary tumor in 
isolation as a predictor of overall and event-free survival. There is evidence from 
neoadjuvant immunotherapy trials in lung cancer that pathologic response in lymph nodes 
may be an independent predictor of survival (34). 
 
15.2.3 Machine Learning Histopathologic Spatial Analysis 
 
Utilizing a previously developed machine-learning classifier trained on pathologist-
labeled samples that identifies tumor cells and tumor-infiltrating lymphocytes (TIL) across 
digitized slides, we will quantify the extent of TIL infiltration by measuring multitype 
nearest neighbor distances (G-cross function) comparing the coordinates of lymphocytes 
to tumor cells. Levels of spatial infiltration within tumor biopsy slides are then outputted 
as G-cross(r) curves, and the area-under-the-curve is used as a metric for measuring TIL 
spatial infiltration (G-score). A higher G-score is representative of a higher degree of TIL 
infiltration. 
  
For this study, we aim to use our computational spatial analysis algorithm to calculate the 
G-score of baseline biopsy samples. G-score will be modeled as both a continuous variable 
and categorized into tertiles for analysis. G-scores will be correlated to patient 
characteristics, pathologic risk categories and pathologic response rates using Kruskal-
Wallis and Wilcoxon rank-sum tests with a significance level of 0.05. Baseline G-scores 
categorized in tertiles will be correlated with survival outcomes using Kaplan Meier 
methods and compared with log rank tests with a significance level of 0.05. 
 
 
15.3 
Stopping Rule 
 
In the event of excessive MK-3475-related toxicity leading to substantial delays in surgery 
(defined as more than 14 days’ delay in 1 of the first 15 patients, 2 of the first 30 patients, 3 of the 
first 45 patients, or 5 of all patients enrolled) or in the event of excessive severe adverse events 
thought to be possibly, probably, or definitely related to study treatment (defined as grade 3-4 
events occurring in 1 of the first 10 patients, 2 of the first 20 patients, 3 of the first 30 patients, 4 

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of the first 40 patients, 5 of the first 50 patients, or 7 of all patients enrolled) or in the event of any 
deaths on study thought to be possibly, probably, or definitely related to study treatment, the study 
will be stopped, AEs assessed, and the study will be considered for revision or closure. 
 
 
16.0 
INTERIM ANALYSIS 
 
The goals of interim analysis of patients treated so far on this protocol are to (1) assess the clinical and 
pathologic responses in all patients who have received neoadjuvant pembrolizumab and (2) to assess 
correlative biomarkers including tumor cell PD-L1 staining and serum cytokine responses in relation to 
clinical and pathologic responses. To assess clinical and pathologic responses in these patients, we will 
compare clinical to pathologic staging in all patients who received the neoadjuvant dose comparing 
clinical staging established at initial diagnosis and assess any locoregional recurrence or distant 
metastases events in all 20 patients. Although, the 1-year post-treatment time point has been reached in 
about half the patients, we will describe the LRR/DM rates to current time points. For correlative studies, 
the pathology slides from the surgical resection will also be reviewed for immune infiltration and tumor 
cell status including in lymphadenectomy specimens.  Tumor cell PD-L1 staining will be completed and 
analyzed on baseline and post-treatment specimens. We will assess exome and RNA-Seq data on a subset 
of the treated cohort that has completed data available at the McDonnell Genome Institute. Finally, 
multiplex serum cytokine assays will be completed to profile for any changes detectable in blood after 
neoadjuvant dosing.    
 
16.1 
Implication of Interim Analysis 
 
Our primary motivation for performing the interim analysis is to assess whether the observed 
reduced rate of high-risk patients is related to the neoadjuvant dosing. Note that the retrospective 
analysis of the Washington University experience to identify the proportion of high risk patients 
in our population proposed in the previous amendment will complement the interim analysis of 
patients treated to date. Together, these data will show whether neoadjuvant pembrolizumab is 
downstaging patients (defined as a change in the clinical to pathologic stage) or is consistent with 
Washington University historical data.  
 
Note that we are aware and have considered the implications of a downstaging effect of 
pembrolizumab. If we do find that neoadjuvant pembrolizumab is downstaging patients, we will 
submit a new amendment addressing this issue and how it may impact the study going forward. 
 
 
17.0 
RETROSPECTIVE REVIEW 
 
The retrospective review of Washington University’s experience with patients with clinically locally 
advanced oral cavity SCCs who have undergone surgery will be performed as follows: 
 
Data from Washington University patients with clinically locally advanced oral cavity SCC who 
underwent surgery as initial therapy between 01/01/2010 and 12/31/2015 will be collected from an 
existing H&N registry titled “IMRT Treatment Outcome / Pattern of Failure Analysis” (HRPO# 
201013031 / 04-0454).  The following data points will be collected: name, date of birth, gender, oral 
cavity subsite, clinical T and N classification, pathologic T and N classification, ECE present/absent, 
margin positive/negative.  Descriptive statistics will be used to describe patient and tumor characteristics.  

Protocol Version: 10/28/2024, Amendment 7 
 
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These data will be compared to those from the prospective trial to test for differences in proportions 
between these two groups. 
  
 
18.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document to be 
reviewed and approved by the Washington University Regulatory Coordinator (or designee) prior to 
IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation from the 
coordinating center that the site has been approved to begin enrollment.  At a minimum, each participating 
institution must have the following documents on file at Washington University prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official document 
from the participating institution’s IRB.  This documentation must show which version of the 
protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality Assurance 
and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and the Washington 
University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all participating 
investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 weeks of 
obtaining Washington University IRB approval.  Activated secondary sites are expected to submit 
protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless otherwise noted.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol amendments 
or revisions, all SAE reports, and all protocol violations/deviations/exceptions must be kept on file at 
Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call to 
update and inform regarding the progress of the trial. 
 

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19.0 
REFERENCES 
 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead.