Clinical trial NCT02609503
Conditions: Head and Neck Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2016-05-16; Completion date: 2023-11-20
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to evaluate the efficacy of Pembrolizumab, concomitant with and following standard of care definitive radiation, for locally advanced squamous cell carcinoma of the head and neck patients who are not good candidates for Cisplatin.

Detailed description:
This open label, phase II trial will enroll 29 subjects in order to evaluate the efficacy of Pembrolizumab, concomitant with and following standard of care definitive radiation for locally advanced squamous cell carcinoma head and neck patients who are not good candidates for Cisplatin. Objectives include estimating progression free survival and overall survival, response rates, safety and toxicity, and quality of life in these patients. Correlative studies, based on serial blood collections and tumor samples, may be done under a separate protocol based on availability of archival diagnostic tissue.

Arms: arm 1: Pembrolizumab arm 2: Intensity Modulated Radiation Therapy (IMRT)
Interventions: intervention 1: Pembrolizumab intervention 2: Intensity Modulated Radiation Therapy
Intervention descriptions: intervention 1: Pembrolizumab, 200 mg IV during cycle visits every 3-weeks for up to 6 cycles, or until toxicities are no longer tolerable intervention 2: Eligible participants will receive Intensity Modulated Radiation Therapy daily x 7 weeks

Protocol documents:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 2 
 
 
LCCC 1509: Pembrolizumab and Radiation for Locally Advanced Squamous 
Cell Carcinoma of the Head and Neck (SCCHN) not Eligible for Cisplatin 
Therapy 
 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X    Scientific changes (IRB approval)         
        Therapy changes (IRB approval) 
X      Eligibility Changes (IRB approval)  
        Other 
 
 
Summary of Changes 
• 
Updated the following sections of the protocol to align with the most recent dose 
modification and guidelines recommended for Merck protocols: Inclusion criteria 
3.1.9 and 3.1.10; Added section 5.1.8 – Contraception which provides details on 
acceptable methods of birth control for WOCBP and males on the study; also 
updated sections 4.3.3, 4.3.4, 4.4.1, 4.4.2, 5.1.11, 7.1.1, 7.1.4, and 7.3.3. Section 
7.1.5 was deleted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
The attached version dated September 02, 2016 incorporates the above revisions  


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 1 
 
 
LCCC 1509: Pembrolizumab and Radiation for Locally Advanced Squamous 
Cell Carcinoma of the Head and Neck (SCCHN) not Eligible for Cisplatin 
Therapy 
 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X    Scientific changes (IRB approval)         
        Therapy changes (IRB approval) 
X      Eligibility Changes (IRB approval)  
        Other 
 
 
Summary of Changes 
• Added 3.2.17 criterion to exclude subjects with a history of non-infectious 
pneumonitis because pneumonitis is an identified risk of pembrolizumab therapy.  
• Checks for respiratory signs/symptoms + respiratory history were added to 
Evaluations and Assessments in section 6.0 of the protocol.  Ongoing patients are 
to be evaluated for active pneumonitis. Patients with a history of pneumonitis 
should be re-consented for this trial to consider if they should continue 
pembrolizumab or discontinue treatment based on the risk of fatal pneumonitis 
reported in recent safety findings. 
• Updated protocol in sections 1.1 and 1.9 to allow subjects in LCCC1509 to co-
enroll in LCCC1108 
 
The attached version dated July 29, 2016 incorporates the above revisions 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1509: Pembrolizumab and Radiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (SCCHN) not Eligible for Cisplatin Therapy 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
919-966-3856 (PHONE)    919-966-6735 (FAX) 
Email: Jared_Weiss@med.unc.edu 
 
Co-Investigator(s) 
Bhishamjit Chera, MD 
D. Neil Hayes, MD, MPH 
Juneko Grilley-Olson, MD 
Mary Fleming, NP 
Jennifer Paul, PA 
 
Biostatistician  
Allison Deal, MS 
Allison_Deal@med.unc.edu 
Phone: 919-966-1387    
Fax: 919-966-4244 
 
Clinical Protocol Office (CPO) 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
 
CPO UNC Cancer Network (UNCCN) Project Manager 
Phone: 919-966-7359 
Fax: 919-966-4300 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source: Merck & CO., INC. 
IND#: 127701 
Version: September 02, 2016


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1509: Pembrolizumab and Radiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (SCCHN) not Eligible for Cisplatin Therapy 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
919-966-3856 (PHONE)    919-966-6735 (FAX) 
Email: Jared_Weiss@med.unc.edu 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:______________________ 
 
PI Signature: ___________________ 
 
Date:  
 
 
 
 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Locally Advanced SCCHN: Cisplatin and Radiation as Standard of Care 
(SOC)  ...............................................................................................................................1 
1.3 
Locally Advanced SCCHN: Alternative Regimens ..............................................2 
1.4 
Pembrolizumab (MK-3475) ..................................................................................3 
1.5 
Clinical Efficacy of PD1 Inhibition in Human SCCHN .......................................5 
1.6 
Radiation and Immunology ...................................................................................6 
1.7 
Safety of Pembrolizumab Combined with Radiation ............................................7 
1.8 
Rationale................................................................................................................8 
1.9 
Correlative Studies ..............................................................................................10 
2.0 
STUDY OBJECTIVES .........................................................................................10 
2.1 
Primary Objective ...............................................................................................10 
2.2 
Secondary Objectives ..........................................................................................10 
2.3 
Exploratory Objectives ........................................................................................11 
2.4 
Endpoints .............................................................................................................11 
3.0 
PATIENT ELIGIBILITY ....................................................................................12 
3.1 
Inclusion Criteria .................................................................................................12 
3.2 
Exclusion Criteria ................................................................................................14 
4.0 
TREATMENT PLAN ...........................................................................................15 
4.1 
Study Schema ......................................................................................................16 
4.2 
Radiation Therapy ...............................................................................................16 
4.3 
Pembrolizumab....................................................................................................20 


LCCC1509 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
ii 
4.4 
Concomitant Medications/ Vaccinations (allowed & prohibited).......................27 
4.5 
Duration of Therapy ............................................................................................28 
4.6 
Duration of Follow-Up ........................................................................................28 
4.7 
Removal of Patients from Protocol Therapy .......................................................28 
4.8 
Study Withdrawal ................................................................................................28 
5.0 
DRUG INFORMATION ......................................................................................29 
5.1 
Pembrolizumab....................................................................................................29 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................35 
6.1 
Time and Events Table ........................................................................................35 
6.2 
Pre-Study Assessments .......................................................................................38 
6.3 
Treatment Assessments .......................................................................................38 
6.4 
Follow-Up ...........................................................................................................40 
6.5 
Patient Reported Outcomes version of the CTCAE ............................................41 
6.6 
Correlative Studies Procedures ...........................................................................42 
6.7 
Assessment of Safety ..........................................................................................42 
6.8 
Assessment of Efficacy .......................................................................................42 
7.0 
ADVERSE EVENTS ............................................................................................44 
7.1 
Definitions ...........................................................................................................45 
7.2 
Documentation of non-serious AEs or SARs ......................................................48 
7.3 
SAEs or Serious SARs and Events of Clinical Interest ......................................48 
7.4 
Data and Safety Monitoring Plan ........................................................................52 
8.0 
STATISTICAL CONSIDERATIONS ................................................................53 
8.1 
Study Design .......................................................................................................53 
8.2 
Sample Size and Accrual.....................................................................................53 


LCCC1509 
 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
iii 
8.3 
Data Analysis Plans .............................................................................................53 
9.0 
STUDY MANAGEMENT ....................................................................................54 
9.1 
Institutional Review Board (IRB) Approval and Consent ..................................54 
9.2 
Required Documentation.....................................................................................55 
9.3 
Registration Procedures.......................................................................................55 
9.4 
Data Management and Monitoring/Auditing ......................................................55 
9.5 
Adherence to the Protocol ...................................................................................56 
9.6 
Amendments to the Protocol ...............................................................................58 
9.7 
Record Retention .................................................................................................58 
9.8 
Obligations of Investigators ................................................................................59 
10.0 REFERENCES ......................................................................................................60 
11.0 APPENDICES .......................................................................................................63 
11.1 
Appendix A Cockcroft-Gault Formula ...............................................................63 
11.2 
Appendix B FACT-Head and Neck Version 4....................................................64 
11.3 
Appendix C Charlson Comorbidity Index Scoring System ................................69 
 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
1 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
We plan to enroll 29 patients in this open label, single arm, phase II study of the 
humanized monoclonal antibody (mAB) targeted against cell surface receptor 
programmed cell death-1 (PD-1), pembrolizumab, concomitant with and 
following standard of care definitive radiation for locally advanced SCCHN 
patients who are not good candidates for cisplatin.  We hypothesize that treatment 
with pembrolizumab and standard definitive radiation will result in a median 
progression free survival (PFS) of 16 months, superior to a historic control of 10 
months. Secondary endpoints include PFS at 20 weeks, 1 year and 2 years, 
objective response rate (ORR: complete response (CR)+ partial response (PR)), 
rate of CR, overall survival (OS), time to locoregional recurrence and time to 
distant metastases. We will also characterize the toxicity profile of the treatment 
and describe quality of life over the course of therapy.  
 
We may perform Multiplex next generation sequencing of DNA and RNA for 
expression profiling and protein-level analysis for expression level of checkpoints 
that could influence the efficacy of pembrolizumab via co-enrollment of 
LCCC1509 patients into a separate tissue procurement study LCCC1108. These 
studies may allow us to explore associations between these immuno-based 
correlatives with clinical outcome. 
 
It is standard of care to evaluate Human Papillomavirus (HPV) status in all 
oropharynx SCCHN patients, and we will also explore association between HPV 
status and outcome.   
1.2 
Locally Advanced SCCHN: Cisplatin and Radiation as Standard of Care 
(SOC) 
The most common treatment of locally advanced SCCHN is the concomitant use 
of cisplatin and radiation.  This “bolus” or “high dose” regimen consists of daily 
(Mon-Fri) radiation for 7 weeks, and cisplatin 100mg/m2 IV given every three 
weeks for a total of 3 doses starting day 1 of radiation.  This combination is 
highly accepted both in the United States and internationally as a result of several 
studies.  Two such studies were particularly important.  The meta-analysis of 
chemotherapy in head and neck cancer (MACH-NC) [1] included all trials 
completed at the time of analysis that compared loco-regional treatment alone to 
loco-regional treatment plus chemotherapy (n >16,000 patients), whether 
chemotherapy was given prior to (induction), concomitant with, or post local 
treatment. The greatest benefit was seen when chemotherapy was given 
concomitantly with radiation with a hazard ratio (HR) of 0.81 compared to loco-
regional treatment alone.  High dose single agent cisplatin was the most active 
chemotherapy agent, and the only drug recommended to be used alone when 
combined with definitive (i.e., curative intent) radiation.  The second study, 
RTOG 91-11[2] was designed as a larynx-preservation trial, but its findings have 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
2 
been widely applied to other SCCHN anatomic sites as well.  In this study, 
patients with locally advanced larynx cancer were randomized to induction 
chemotherapy followed by radiation, to concurrent chemoradiation or to 
radiotherapy alone.  The chemotherapy used in the chemoradiation arm of this 
trial was high dose cisplatin.  Five-year disease free survival (DFS) improved 
from 27% with radiation alone to 36% with the addition of cisplatin, while overall 
survival (OS) at 5 years was unchanged.  These results are inadequate on an 
absolute basis, but are particularly unimpressive when toxicity is accounted for—
82% of patients on RTOG91-11 experienced severe toxicity. 
 
1.2.1 High-dose bolus Cisplatin with Radiation Therapy: A Standard of Care that 
roughly half of patients cannot receive 
Despite being the “standard” regimen, a large proportion of patients are not 
eligible for high-dose bolus cisplatin.  Cisplatin is very ototoxic, and therefore 
poses increased risks to patients with any pre-existing high-frequency hearing loss 
or tinnitus.  Its high degree of nephrotoxicity is of particular concern for patients 
with any pre-existing renal insufficiency, diabetes, or other risk factors for renal 
problems.  Cisplatin is highly neuropathic and therefore contraindicated in 
patients with pre-existing neuropathy and considered high risk in patients with 
diabetes.  Cisplatin is highly emetogenic; therefore, after appropriate counseling, 
many patients refuse it and many clinicians prefer to avoid it for patients with 
borderline performance status (PS). 
1.3 
Locally Advanced SCCHN: Alternative Regimens 
Given the many problems with high dose cisplatin, it is surprising that there is no 
well-accepted, well-validated alternative.  The most frequently used alternative to 
high-dose cisplatin is weekly cisplatin. At a dose of 20mg/m2, the existing data 
indicates a lack of efficacy[3].  At a dose of 40mg/m2, limited data suggest 
efficacy, but the toxicity starts to approach that of high dose cisplatin[4].  A mid-
range dose of 30mg/m2 weekly is very commonly used, but data on efficacy are 
very limited and it is not clear if this regimen is better than radiation alone or as 
good as bolus cisplatin[5, 6].  None of these weekly regimens have ever been 
compared head to head with either radiation alone or with bolus cisplatin in a 
phase III randomized study. 
 
Perhaps the best-validated alternative regimen is weekly cetuximab combined 
with radiation, approved for this indication by the FDA in 2006.  Cetuximab is a 
monoclonal antibody against the epidermal growth factor receptor (EGFR).  A 
single randomized study comparing radiation combined with cetuximab to 
radiation alone [7, 8] demonstrated superior locoregional control, PFS and OS for 
the combination arm; the rate of distant metastases was not improved.  
Cetuximab, however, is not widely used for a variety of reasons: concerns that it 
may be less effective than cisplatin, risk of anaphylaxis and controversy regarding 
subgroup analyses from the Bonner trial. Subgroup analysis from the Bonner 
study demonstrated that benefit was driven by patients with characteristics that 
describe the HPV+ population: young male patients with good performance status 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
3 
(PS) and oropharynx primary site [7, 8].  However, HPV+ tumors tend to be low 
expressers of EGFR [9] and, when final HPV data became available, there was no 
preferential effect by HPV [10].  Novel agents for the treatment of locally 
advanced SCCHN are needed. Anticancer immunotherapeutics represent one 
exciting new class of novel agents worthy of further study in SCCHN. 
1.4 
Pembrolizumab (MK-3475) 
Pembrolizumab (MK-3475) is a potent and highly selective intravenous 
humanized mAb of the immunoglobulin (Ig) G4/kappa isotype that directly 
blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This 
blockade enhances functional activity of the target lymphocytes to facilitate an 
antitumor immune response, leading to tumor regression and immune rejection of 
the tumor. Indications currently under investigation by the manufacturer of 
pembrolizumab include non-small cell lung cancer and glioblastoma. 
KeytrudaTM (Pembrolizumab) has recently been approved (at a dose of 2 mg/kg 
IV every 3 weeks) in the United Stated for the treatment of patients with 
unresectable or metastatic melanoma with disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Further 
development of pembrolizumab in non-metastatic melanoma is ongoing.[11] 
1.4.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades [12].  Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in 
cancer tissue and favorable prognosis in various malignancies [13-17].  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 that has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) [18, 19].  The structure of 
murine PD-1 has been resolved [9].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-
based signaling motifs, an immunoreceptor tyrosine-based inhibition motif 
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).   
 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, all of 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
4 
which are involved in the CD3 T-cell signaling cascade [18, 20-22].  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 [13; 14].  PD-1 is expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells [23, 24].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [25].   
 
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 [25-28].  Both ligands are type I transmembrane receptors 
containing both IgV- and Ig (constant) C-like domains in the extracellular region 
and 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 [29].  Although healthy organs express little (if 
any) PD-L1, a variety of cancers are known 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) [30].  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. 
1.4.2 Pre-clinical Findings  
Pembrolizumab strongly enhances T-lymphocyte immune responses in 
cultured blood cells from healthy human donors, cancer patients, and primates.   
In T-cell activation assays using human donor blood cells, the EC50 
(concentration where 50% of the maximum effect is achieved) has been 
reported to be ~0.1 to 0.3 nM.  Levels of interleukin-2 (IL-2), tumor 
necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines 
are modulated by MK-3475.   The antibody potentiates existing immune 
responses only in the presence of antigen and does not nonspecifically activate T-
cells.[11] 
 
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor 
models.   In these experiments in mice, anti-PD-1 therapy is synergistic with 
chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) and 
combination therapy results in increased complete tumor regression rates in 
vivo.[11] 
 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
5 
The safety of MK-3475 was characterized in the 1-month repeat-dose toxicity 
study in cynomolgus monkeys when administered as intravenous (IV) doses of 6, 
40 or 200 mg/kg once a week (a total of five doses) and in the 6-month repeat-
dose toxicity study in the same species when administered as IV doses of 6, 40 
or 200 mg/kg every other week (a total of 12 doses).  MK-3475 was well-
tolerated with a systemic exposure (area under the curve (AUC)) of up to 
~170,000 μg/day/mL over the course of the 1-month study, and with an AUC of 
up to approximately 67,500 μg.day/mL over the course of the 6-month study. No 
findings of toxicological significance were observed in either study and the No 
Observed Adverse Event Level (NOAEL) was ≥200 mg/kg.   In addition, no 
findings of toxicological relevance were observed in the in vitro tissue cross-
reactivity study using human and cynomolgus monkey tissues.[11]    
1.5 
Clinical Efficacy of PD1 Inhibition in Human SCCHN 
Pembrolizumab is very active against human SCCHN.  In a Phase Ib study of 
recurrent/metastatic SCCHN, pembrolizumab demonstrated a 20% response rate 
in both HPV+ and HPV- patients [31], as evidenced in the water-fall plot below. 
 
 
 
 
 
 
 
 
 
 
 
Subjects
-100
-80
-60
-40
-20
0
20
40
60
80
100
Percent Change from Baseline
HPV Positive
HPV Negative


LCCC1509 
 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
6 
Some of these responses seemed durable: 
 
Additional experience in other cancers confirms the activity and tolerability of 
pembrolizumab [32, 33]  
1.5.1 Clinical Safety of Pembrolizumab in SCCHN 
For the average patient, pembrolizumab is quite nontoxic as the adverse event 
data (AEs: table summarizes those with a ≥ 5% incidence) from the head/neck 
phase Ib expansion cohort as shown below [31]:   
 
 
 
 
Adverse Event 
All Grades Drug-related  
Grade 3-5 Drug-related  
n 
(%) 
n 
(%) 
Any Adverse Event 
35 
(58.3) 
10 
(16.7) 
Fatigue 
10 
(16.7) 
0 
(0.0) 
Pruritus 
6 
(10.0) 
0 
(0.0) 
Rash 
4 
(6.7) 
1 
(1.7) 
Nausea 
4 
(6.7) 
0 
(0.0) 
Decreased appetite 
3 
(5.0) 
0 
(0.0) 
Myalgia 
3 
(5.0) 
0 
(0.0) 
 
1.6 
Radiation and Immunology 
Radiation therapy may act, at least in part, through immunologic mechanisms.  
0
4
8
12
16
20
24
28
32
36
40
44
48
Treatment Exposure (Weeks)
Subject
Complete Response
Partial Response
Treatment On-going


LCCC1509 
 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
7 
Radiation can lead to tumor cell death and subsequent antigen exposure.  It has 
long been hypothesized that the abscopal effect (when one tumor location is 
treated with radiotherapy and tumor at a separate location regresses) is caused 
through an immunotherapeutic mechanism.  Recently, this hypothesis was tested 
in a mouse model in which tumor was injected into both flanks of the mice.  
When only one flank was irradiated, there was no growth inhibition of the 
contralateral flank but when PD-L1 inhibition was added, there was growth 
inhibition. [34] 
 
In vitro data also suggest that fractionated radiation increases tumoral PD-L1 
expression. [34, 35] Inhibition of PD-1 or PD-L1 concurrently with radiation 
enhances radiation sensitivity and increases the cure rate in mice treated with 
radiotherapy[34].  Treatment with radiotherapy and PD-L1 inhibition leads to 
tumor antigen specific memory T cell responses that are protective against repeat 
tumor challenge.  Given the high rates of recurrence and second primary 
head/neck cancer, these results are potentially important to the treatment of 
human cancer. 
1.6.1 Radiation Safety in SCCHN 
In the Bonner trial cited earlier, the adverse events that occurred in at least 10% of 
patients (any grade) in the radiotherapy treatment arm alone included the 
following: mucositis (94%); rash (10%); radiation dermatitis (90%); weight loss 
(72%); xerostomia (71%); dysphagia (63%); asthenia (49%); nausea (37%); 
constipation (30%); taste perversion (28%); vomiting (23%); pain (28%); 
anorexia (23%); fever (13%); pharyngitis (19%); dehydration (19%); oral 
candidiasis (22%); coughing (19%); voice alteration (22%); diarrhea (13%); 
insomnia (14%); increased sputum (15%); and anemia (13%).  The potential 
overlapping toxicities with pembrolizumab (nausea, diarrhea and rash) were, with 
rare exception, ≤ Grade 2.  The ≥ Grade 3 adverse events that occurred in at least 
10% of patients in the same arm included: mucositis (52%); radiation dermatitis 
(18%); and dysphagia (30%). 
1.7 
Safety of Pembrolizumab Combined with Radiation 
Several patients in ongoing clinical trials have been treated with pembrolizumab 
and radiation.  The first (NCT02305186), a Phase I/II study,  randomizes patients 
with borderline resectable pancreatic cancer to fixed dose radiation (50.4 Gy total 
over 28 daily fractions) and capecitabine (825mg/m2 twice daily on the days 
radiation is due) with or without concomitant pembrolizumab 200mg IV every 3 
weeks. A second Phase II trial (NCT02289209) is enrolling locoregional 
inoperable recurrent or second primary SCCHN patients to pembrolizumab 
200mg IV every 3 weeks concomitant with 1.2 Gy radiation twice daily, 5 days a 
week for 5 weeks.    
 
Safety data is pending from these studies. However, the most frequent toxicities 
associated with pembrolizumab including low grade nausea, cough, pruritis, 
diarrhea and rash should not overlap with the major toxicities of radiation, and the 


LCCC1509 
 
CONFIDENTIAL 
PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
8 
mechanisms of action are distinct (meaning we expect no more than additive 
toxicity). Therefore, no serious safety issues are anticipated as a result of this 
combination. Any unexpected toxicities from the ongoing studies just summarized 
will be shared with the PI of LCCC1509 by the manufacturer of pembrolizumab 
and can be used to supplement toxicity monitoring if needed. 
 
In this trial, toxicity will be monitored continuously, with sequential boundaries 
employed to suspend the trial if excessive numbers of patients fail to receive at 
least 95% of the intended dose of radiation (8.3). If the study reaches a stopping 
boundary, it may be terminated by the PI, or submitted to the DSMC with a 
description of the toxicities and a rationale for why the study should be continued. 
1.8 
Rationale 
 
In summary, there is no accepted standard of care agent to be given together with 
radiation for patients who are not eligible for cisplatin.   As a result, the clinical 
research community has accepted the appropriateness of conducting trials of 
novel agents with radiotherapy. NCT01540682, NCT 00736619, NCT 01386632, 
NCT 01946867 and NCT 00206752 serve as examples of the acceptability of 
clinical trials in this setting.  Further, surgical salvage has always been a standard 
part of treatment for locally advanced head/neck cancer and would remain so in 
any novel paradigm.  In RTOG91-11 referenced above, a high proportion of 
patients in each arm had residual or recurrent disease, but had salvage surgery for 
cure.  This surgical salvage option further enhances the safety of novel combined 
modality radiation strategies. 
1.8.1 Rationale for Pembrolizumab Schedule 
When chemotherapy is given together with radiation therapy for locally advanced 
head and neck cancer, the standard sequencing is concurrent treatment [1, 2, 36].  
As reviewed in section 1.2, the standard regimen for chemotherapy when 
administered concurrent with radiation is high-dose cisplatin administered every 
three weeks.  The standard schedule of pembrolizumab is also every three weeks 
(see section 1.8.2 for additional data) and this has therefore been maintained. 
 
Historically, adjuvant therapy has not been efficacious, although it has never been 
studied with modern agents. Studies of neo-adjuvant treatment have focused on 
TPF (docetaxel, cisplatin and 5FU) where results have been negative [37-39] 
although the question is being re-asked with more modern agents (for example 
NCT01412229). Because existing data on pembrolizumab indicate that efficacy 
can be delayed, it would be reasonable to utilize neo-adjuvant pembrolizumab or 
to at least to start pembrolizumab before radiation.  Such an approach might 
improve efficacy, but would also delay the initiation of radiation.  This approach 
is worthy of study, but is outside the context of this study of concurrent therapy.  
 
Cell death from radiation is known to continue for weeks after the conclusion of 
active therapy; for this reason, we chose to administer additional pembrolizumab 
cycles after the conclusion of radiation.  Given the lack of overlap between 


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9 
pembrolizumab toxicity and the typical side effects of radiation that patients will 
be recovering from at this time point, we believe that the relative ratio of potential 
benefit of this approach vastly exceeds the risk of harm. 
 
1.8.2 Rationale for Dose Selection of Pembrolizumab  
An open-label Merck-sponsored Phase I trial (Protocol 001) evaluated 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 
dose levels were well tolerated and no dose-limiting toxicities (DLTs) 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.  No 
maximally tolerated dose (MTD) has been identified to date. Recent data from 
other clinical studies within the pembrolizumab program have shown that a lower 
dose of pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of pembrolizumab administered Q2W and 
Q3W showed slow systemic clearance, limited volume of distribution, and a long 
half-life. [11]  Pharmacodynamic (PD) data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days).  This early PK and PD data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population PK analysis of pembrolizumab has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK 
model, clearance and volume parameters of pembrolizumab were found to be 
dependent on body weight. The relationship between clearance and body weight, 
with an allometric exponent of 0.59, is within the range observed for other 
antibodies and supports both body weight normalized dosing or a fixed dose 
across all body weights (Merck, written communication).   
 
The choice of the 200 mg every 3 weeks as an appropriate dose for the switch to 
fixed dosing of pembrolizumab (which is pending FDA approval, and which is 
incorporated into this study) is based on simulations performed using the 
population PK model of pembrolizumab showing that the fixed dose of 200 mg 
every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks (the current FDA approved dose), 
2) will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe (Merck, written communication). A fixed dose regimen 
will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities and reduce wastage. 


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10 
1.9 
Correlative Studies 
It is standard of care to evaluate HPV status in all oropharynx SCCHN patients 
seen at UNC and sites recruited to participate will be required to obtain HPV 
status, and we will explore association between HPV status and outcome.   
 
Exploratory objectives based on serial blood collections and tumor samples may 
include some or all of the following (depending on availability of archival 
diagnostic tissue): an evaluation of the predictive capacity of PD-L1 expression, 
immune gene signatures, and a characterization of the change in phenotype in 
tumor-infiltrating lymphocytes (TILs) before and after therapy.  We may also 
explore whether T cell and B cell repertoires (TCRs and BCRs respectively; 
discovered via DNA and RNA sequencing) are enriched in tumors and/or blood at 
baseline and whether any change is seen in blood post treatment. We hypothesize 
that each of the following (increased PD-L1 mRNA expression, effector immune 
infiltrate, clonality in TILs and decreased regulatory cell populations) will be 
associated with a longer PFS. Collection of samples for correlative studies will be 
an option provided to patients in LCCC1509 and will involve co-enrollment into 
the tissue procurement study LCCC1108.  We will also collect serum for 
exploration of a proteomic immune signature under development, and its possible 
association with OR, PFS and OS. This proteomic immune signature is under 
development by Biodesix. 
 
Additional details regarding correlative studies can be found in the laboratory 
manual. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Estimate PFS after initiation of pembrolizumab (to be administered both 
concurrent with and following treatment with standard radiation) in locally 
advanced SCCHN patients not eligible for high-dose bolus cisplatin. 
2.2 
Secondary Objectives  
2.2.1 Evaluate the safety of the proposed regimen by:  
• Estimating the proportion of patients who receive <95% of the intended 
dose of radiation (i.e., <67 Gy)[2]   
• Documenting any clinically relevant toxicity (both observer related and 
patient reported) related to concurrent radiation plus pembrolizumab  
2.2.2 Estimate ORR after initiation of pembrolizumab concurrent with and following 
standard radiation  
2.2.3 Estimate rate of CR after initiation of pembrolizumab concurrent with and 
following standard radiation in locally advanced SCCHN 


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11 
2.2.4 Estimate OS after initiation of pembrolizumab (to be administered concurrent 
with and following standard radiation) in locally advanced SCCHN 
2.2.5 Estimate time to locoregional recurrence after initiation of pembrolizumab (to be 
administered concurrent with and post standard radiation)  
2.2.6 Estimate time to distant metastases after initiation of pembrolizumab (to be 
administered concurrent with and post standard radiation) 
2.2.7 Describe quality of life over the course of therapy 
 
2.3 
Exploratory Objectives 
2.3.1 Explore association between HPV status with OR, OS and PFS  
2.3.2 To explore the association of biological markers at baseline including PD-L1 
expression and immune gene expression and proteomic immune signatures with 
OR, OS and PFS 
2.3.3 To characterize the change in phenotype of TILs, including delineation of effector 
and regulatory T cells, before and after pembrolizumab treatment 
2.3.4 To define T cell receptor (TCR) and B cell receptor (BCR) repertoire profiles that 
are associated with OR, OS and PFS  
 
2.4 
Endpoints 
2.4.1 Primary Endpoint 
PFS is defined as the time from D1 of treatment to progression or death from any 
cause.  The primary endpoint will be median PFS, but we plan to also report 20 
weeks, 1 year and 2 year PFS, each respectively defined as the proportion of 
patients who are alive and free of progression from disease at the defined time 
points. 
2.4.2 Secondary Endpoints 
• Clinician assessed toxicity will be classified and graded according to the 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE, version 4.0) 
• Patient assessed toxicity will classified based on the Patient-Reported 
Outcome version of the CTCAE (PRO-CTCAE) 
• OR and CR are defined as per RECIST1.1 
• OS is defined as the time from D1 of treatment to death from any cause 
• Time to locoregional recurrence is defined from D1 of treatment until the 
first locoregional progression 


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12 
• Time to distant metastasis is defined as the time from D1 of treatment to 
progression of disease at a distant site; deaths or other progressions will be 
censored 
• QOL will be evaluated via the FACT-HN 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to participate in this 
study: 
3.1.1 Be willing and able to provide written informed consent/assent for the trial 
3.1.2 Be ≥ 18 years of age on day of signing informed consent 
3.1.3 ECOG Performance Status ≤ 1 
3.1.4 Histologically or cytologically confirmed stage III-IV (non-metastatic) SCCHN as 
defined by American Joint Committee on Cancer (AJCC).  Nasopharyngeal 
cancer patients will be excluded.  Note that in rare instances, a cancer may be 
clearly invasive on imaging, but pathology may not be definitive (e.g. in-situ 
carcinoma); in such cases, the patient will be eligible if the unanimous opinion of 
the institutional tumor board is that the situation is definitive for invasive SCCHN  
3.1.5 Ineligible for high dose cisplatin therapy; the reason for ineligibility must be 
defined.  Acceptable reasons for ineligibility include the following: 
• Abnormal renal function (GFR<lower limit of institutional normal 
(<LLN)) 
• Abnormal hearing (patient or audiology defined) 
• Pre-existing tinnitus 
• Neuropathy (bilateral parasthesias or loss of deep tendon reflexes in upper 
and/or lower extremities) 
• Diabetes Mellitus 
• Oncologist-certification that patient would not be considered eligible for 
high dose cisplatin when given as standard of care (for example, due to 
age or another medical problem); reason should be documented 
• Patient refusal for high dose cisplatin 
 
 
 
 
 


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13 
3.1.6 Demonstrate adequate organ function as defined in the table below. All screening 
labs should be performed within 14 days of treatment initiation. 
 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 /mcL 
Hemoglobin 
≥10 g/dL (acceptable to reach this via transfusion) 
Renal 
Measured or calculated creatinine 
clearance (CrCl; GFR can also be 
used in place of CrCl); see section 
11.1 Appendix A for Cockcroft-Gault 
formula for CrCl) 
    
 
       ≥30 mL/min  
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN (≤ 3 X ULN if Gilbert’s Syndrome) OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
 
 
 
3.1.7 No prior curative attempts for this cancer, (i.e., surgery, radiation and/or other)  
3.1.8 Female patients of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
3.1.9 Female patients of childbearing potential must be willing to use adequate method 
of contraception as outlined in Section 5.1.8 – Contraception, for the course of the 
study through 120 days after the last dose of study medication. Patients of 
childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 


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14 
3.1.10 Male patients must agree to use an adequate method of contraception as outlined 
in Section 5.1.8 - Contraception starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. 
3.1.11 As determined by the enrolling physician or protocol designee, ability of the 
patient to understand and comply with study procedures for the entire length of 
the study 
3.1.12 Consent for the use of any residual material from biopsy (archival tissue) and 
serial blood draws will be required for enrollment.  Patients without adequate 
tissue for bio-correlates will not be excluded or required to have a repeat biopsy. 
 
3.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be able to 
participate in this study: 
3.2.1 Is currently participating in or has participated in a study of an investigational 
agent or using an investigational device within 4 weeks of the first dose of 
treatment. 
3.2.2 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
(other than oral contraceptives) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment. 
3.2.3 Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier.  
3.2.4 Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting therapy.  Note: Toxicities that specifically define eligibility for this 
protocol (nephropathy, otopathy, neuropathy, or other as allowed by PI) are 
exceptions. 
3.2.5 Has a known additional malignancy that is metastatic, progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.   
3.2.6 Has an active automimmune disease requiring systemic treatment within the past 
3 months or a documented history of clinically severe autoimmune disease even if 
resolved; patients with vitiligo or resolved childhood asthma/atopy would be an 


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15 
exception to this rule.  Patients that require intermittent use of bronchodilators or 
local steroid injections would not be excluded from the study.  Patients with 
hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be 
excluded from the study. 
3.2.7 Has clinical or radiologic evidence of interstitial lung disease or active, non-
infectious pneumonitis. 
3.2.8 Has an active infection requiring systemic therapy. 
3.2.9 Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.   
3.2.10 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.2.11 Has inadequate home environment or social support to safely complete the trial 
procedures. 
3.2.12 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
3.2.13 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways) 
3.2.14 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
3.2.15 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
3.2.16 Has received a live vaccine within 30 days prior to the first dose of trial treatment.  
3.2.17 Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
4.0 
TREATMENT PLAN 


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16 
4.1 
Study Schema 
 
 
 
Also see section 6.1 for schedule of serial blood draws for biocorrelative studies. 
4.2 
Radiation Therapy 
All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT) as 
per standard of care (details of which are outlined below).  One IMRT plan with 2 
to 3 planning target volumes (PTVs) will be created.  Dose painting is required.  
The total dose will be 70 Gy at 2Gy/fx, 35 fractions, Monday to Friday, for 7 
weeks.   
4.2.1 CT Simulation   
CT simulation will be obtained preferably with IV contrast for treatment planning 
purposes for all patients. The head and neck area will be immobilized with an 
aquaplast mask. Patients will be positioned in the neck extended position. 
4.2.2 Target and Organ at Risk Volumes 
4.2.2.1 Gross Tumor Volume (GTV): is defined as all known gross disease determined 
on the CT simulation scan. 
4.2.2.2 High Risk Clinical Target Volumes (CTV-HR) is defined as the GTV plus a 
non-uniformly expanded 5 to 10 mm to account for high risk areas of 
microscopic spread. For situations where the primary tumor was removed with 
the biopsy (e.g. tonsillectomy) and the primary tumor cannot be seen on 
radiographic imaging the biopsy site will be included in the CTV-HR.  A CTV-
HR is required for all patients. 
4.2.2.3 Intermediate Risk Clinical Target Volume (CTV-IR) is optional except for 
patients with an unknown primary.  For patients with an unknown primary (T0) 
the ipsilateral oropharynx (base of tongue, tonsil, soft palate) will be included in 
the CTV-IR volume.  Other potential (but not required) indications for 
contouring a CTV-IR is to include the entirety of nodal level that contains a 
positive node or to include adjacent nodal levels.  For example if there is a node 
positive in Level 2, the node will be encompassed in the CTV-HR and a CTV-
IR may be used to cover the remainder of Level 2 and adjacent Level 3.   The 
purpose in using a CTV-IR is to cover intermediate risk areas of microscopic 
spread.   


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4.2.2.4 Standard Risk Clinical Target Volume (CTV-SR) is defined as the elective 
nodal regions. The consensus guidelines for the node negative and node positive 
necks published by Gregoire et al. will be used as a guide to define the CTV-
SR.[40, 41] For the situation of the unknown primary (i.e. T0), the nasopharynx 
will be included in the CTV-SR. The following guidelines will be used in 
delineating the CTV-SR. 
• Node positive hemi-neck (ipsilateral or contralateral to the primary site) 
[40]: The following elective nodal regions should be included in the CTV-
SR: Levels Ib-V.  The retropharyngeal region should also be included in 
oropharyngeal and hypopharyngeal primary tumors. The cranial extent to 
the base of skull of Level II and retropharyngeal nodes should be 
electively irradiated for oropharyngeal and hypopharyngeal primary 
tumors. 
• Ipsilateral node negative hemi-neck [41] The following elective nodal 
regions should be included in the CTV-SR: Levels II –IV. The 
retropharyngeal region should also be included in oropharyngeal and 
hypopharyngeal primary tumors. The cranial extent to the base of skull of 
Level II and retropharyngeal nodes should be electively irradiated for 
oropharyngeal and hypopharyngeal primary tumors.   
• Contralateral node negative hemi-neck[41, 42]: The contralateral parotid 
may be spared by omitting irradiation of the cranial portion of Level II and 
retropharyngeal region, defined as the Level II, retropharyngeal region 
above the transverse process of the C1 vertebrae and/or where the 
posterior belly of the digastric muscle crosses over the jugular vein.  
• Omission of Contralateral neck negative hemi-neck irradiation:  
Contralateral neck irradiation may be completely omitted for well 
lateralized tonsil cancers, defined as having no invasion of the base of 
tongue, and minimal invasion of the soft palate (i.e. > 1 cm from the 
uvula).  Bilateral neck radiation is required for larynx and hypopharyngeal 
primary tumors.  The contralateral node negative neck may be omitted in a 
well lateralized T1-T2 oral cavity cancer (i.e. oral tongue, alveolar ridge, 
buccal cavity).   
• Unknown Primary: The above elective nodal irradiation guidelines will be 
used. Furthermore the nasopharynx will be included in the CTV-SR. 
4.2.2.5 Planning Target Volumes (PTV): To account for daily setup errors, the CTV’s 
will be expanded uniformly by 3 mm to create a High Risk Planning Target 
Volume (PTV-HR), Intermediate Risk Planning Target Volume (PTV-IR), and 


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a Standard Risk Planning Target Volume (PTV-SR).  The PTV-IR is optional 
except for unknown primary tumors (see above section 4.2.2.3) 
4.2.2.6 Organs at Risk (OAR): The following normal tissues will be segmented on CT 
simulation scan: spinal cord, brainstem, parotids, cochleae, and larynx. 
4.2.2.7 Planning Risk Volumes (PRV): OAR(s) will be uniformly expanded 3mm to 
create individual Planning Risk Volumes (PRV) 
4.2.3 Dose Specification  
Dose painting IMRT will be used and all doses will be specified to the PTV. The 
PTV-HR, PTV-IR, and PTV-SR will be treated to the following respective total 
doses: 70 Gy, 63 Gy, and 54 Gy. The dose per fraction to the PTV-HR, PTV-IR, 
and PTV-SR will be 2 Gy per day, 1.8 Gy per day, and 1.54 Gy respectively. 
Thus the total number of fractions will be 35. All fields will be treated once a day 
Monday through Friday. 
4.2.4 IMRT Treatment Planning 
PTV’s and PRV will be included in the IMRT optimization. Seven to nine 
equidistant fields will be placed around the PTV. None of the beams will directly 
oppose one another. Tomotherapy® and other arc-based IMRT technologies 
(VMAT®, RapidArc®) are allowed.  Dose objectives will be chosen for the 
IMRT optimization based on previous institutional experience. Dose painting (i.e. 
simultaneous integrated boost) will be used to create one IMRT plan. The PTV-
SR contours will encompass the PTV-IR and PTV-HR contours. IMRT to treat 
the entire neck is preferred, however a matched low anterior neck field technique 
may be used only if it does not result in significant dose heterogeneity for the 
PTV-HR. 
4.2.5 Regimen 
Radiation continues for 35 consecutive weekdays. Patient will receive 2 Gy daily 
fractions of radiotherapy without a break except for weekends and holidays. 


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4.2.6 Dose Constraints  
 PTV-HR and PTV-SR  
o 100% of the prescription should cover 95% of the PTV  
o No more than 20% of the PTV should receive ≥ 110% of the 
prescribed dose. 
o No more than 1% of the PTV should receive ≤ 93% of the 
prescribed dose  
 Non-target Tissue  
o No more than 1% of the tissue outside the PTV should receive ≥ 
110% of the prescribed dose  
 PRV  
o Spinal Cord: 0.1cc ≤ 50 Gy  
o Brainstem: 0.1cc ≤ 54 Gy  
o Parotid: Mean dose < 26 Gy and/or 50% < 30 Gy  
o Cochlea: Mean dose < 45 Gy  
o Larynx: Mean dose < 41 Gy and/or 60 Gy to < 20%  
PTV coverage should not be compromised to meet the dose constraints of the 
parotid, cochlea, or larynx. Sparing of these structures is left at the discretion of 
the treating radiation oncologists. The dose constraints for the spinal cord and 
brainstem must be satisfied. This may be done at the cost of altering the PTV. 
4.2.7 Treatment Verification  
Weekly orthogonal films or cone beam CT’s should be performed to verify 
patient setup (at least) 
4.2.8 Rests and Interruptions 
For acute radiation toxicities, treatment breaks should be kept to a minimum. An 
effort will be made to complete the radiotherapy on schedule without significant 
treatment breaks, as prolongation of treatment is known to contribute to treatment 
failure.  The need for radiotherapy breaks due to severe acute toxicity will be 
determined by the treating radiation oncologist. If radiation therapy is held, 
pembrolizumab therapy may continue as per the discretion of the investigator, and 
based on the nature of the toxicity.    
 
The specific reason(s) for any treatment interruption must be recorded in the 
treatment chart and the electronic case report form (e-CRF). Treatment 
interruptions exceeding fourteen (14) days for reasons other than protocol-
mandated interruptions for adverse events will be considered a major protocol 
deviation. No modifications in dose will be made for interruptions in therapy. 
4.2.9 Patient Monitoring During Treatment 
During radiation therapy, all patients will be seen by a healthcare provider for 
radiation therapy management visits per institutional standard of care, typically at 
least weekly.  


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4.2.10 Supportive care during radiation therapy 
Routine management of toxicities during radiation therapy is allowed. 
Interventions may include, but are not limited to, the following: 
 
Toxicity 
Management 
Skin reactions: 
Topical agents such as Aquaphor® or Biofene® 
Dehydration: 
IV fluids as needed 
 
4.3 
Pembrolizumab 
4.3.1 Dosing Administration 
Starting on the first day of radiotherapy, patients will be treated with 
pembrolizumab 200mg IV every 3 weeks for 6 doses. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min). The Pharmacy Manual contains specific instructions 
for the preparation of the pembrolizumab infusion fluid and administration of 
infusion solution. This manual is provided as a document separate from the 
protocol. 
 
NOTE: Subjects should be assessed for possible Events of Clinical Interest (ECI; 
see the document provided separate from this protocol) prior to each dose.  Lab 
results should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic 
causes. If no other cause is found, then it is assumed to be immune-related. 
4.3.2 Management of Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Refer to 
the table below for infusion reaction treatment guidelines associated with 
administration of pembrolizumab. 
 
 
 
 
 
 
 
 
 
 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. If symptoms resolve 
within one hour of stopping drug 
infusion, the infusion may be restarted 
at 50% of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab 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. 


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UNIVERSITY OF NORTH CAROLINA 
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22 
4.3.3 Other Dose Modifications 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may 
occur shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table below. Also see section 4.3.4 for supportive care 
guidelines of drug-related events. See Section, including use of corticosteroids. 
 
Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects should be placed back 
on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
If a dose of pembrolizumab is delayed, then the subsequent dose should be 
administered 3 weeks later.  When pembrolizumab is delayed or held, radiation 
may and should continue if clinically appropriate.  Patients may receive up to 6 
total doses of pembrolizumab, even if doses are delayed to the point that they do 
not overlap with radiation. If radiation therapy is held, pembrolizumab therapy 
may continue as per the discretion of the investigator, and based on the nature of 
the toxicity.    
 
Hematological Toxicity Dose Delays or Discontinuation for Pembrolizumab 
Toxicity 
Hold Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab* 
Discontinue Subject** 
Autoimmune hemolytic 
anemia, aplastic 
anemia, disseminated 
intravascular 
coagulation, Hemolytic 
Uremic Syndrome 
(HUS-Idiopathic or 
immune), 
Thrombocytopenia 
Purpura (ITP), 
Thrombotic 
Thrombocytopenic 
Purpura (TTP) or Any 
Grade 4 anemia 
regardless of 
underlying mechanism 
2-3 
 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or 
equivalent per day within 12 
weeks. 
4 
Permanently 
discontinue** 
Permanently discontinue** 
**Whenever pembrolizumab is permanently discontinued, patient should still  be followed-up per protocol. 
 
 


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UNIVERSITY OF NORTH CAROLINA 
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23 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
old pembrolizumab for new onset Type 1 
diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2b 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; Refer to Table 2 – Infusion 
Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 


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UNIVERSITY OF NORTH CAROLINA 
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24 
4.3.4 Rescue Medications & Supportive Care 
Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary 
by the treating investigator.  Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined 
below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that 
several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, 
which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance as outlined below. 
Refer to Section 4.3.3 for dose modifications.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 
Hematologic (see table in Section 4.3.3 for what is considered hematologic ECI) 
 
All attempts should be made to rule out other causes such as metastases, sepsis 
and/or infection. Relevant diagnostic studies such as peripheral blood smear, 
reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., 
should be considered to confirm the diagnosis.  
 
For Grade 2 events: 
• Hold pembrolizumab 
• Prednisone 1-2 mg/kg daily may be indicated 
• Consider Hematology consultation 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 
mg or less of prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
• Hematology consultation 
• Hold pembrolizumab  
• Discontinuation should be considered at discretion of investigator 
• Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 
mg or less of prednisone or equivalent per day within 12 weeks. 


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September 02, 2016 
 
 
 
 
25 
 
Grade 4 events: 
• Hematology consultation 
• Discontinue pembrolizumab 
• Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) 
and of bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus (TIDM) (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) 
 
 
For T1DM or Grade 3-4 Hyperglycemia 
• . 
• Insulin replacement therapy is recommended for TIDM and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 
• Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
 


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UNIVERSITY OF NORTH CAROLINA 
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26 
o Hypophysitis: For Grade 2 events, treat with corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment; monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
• . 
• In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
• In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
Hepatic:  
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
 


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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
27 
 
 
 
Infusion Reaction 
See section 4.3.2 
 
4.4 
Concomitant Medications/ Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing trial.  If there is a clinical indication for one of 
these or other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The 
investigator should discuss any questions regarding this with the Merck Clinical 
team.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.   
4.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care.  All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
4.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase  
 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab  
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor. 
• Radiation therapy  


LCCC1509 
 
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28 
o Note:  Radiation therapy to a symptomatic solitary lesion may be allowed 
at the investigator’s discretion.   
Subjects who are removed from study treatment per above guidelines should be 
treated per standard of care.  
4.5 
Duration of Therapy 
In the absence of treatment delays due to AEs, treatment may continue until the 
end of study-defined treatment or until: 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable toxicity  
• Pregnancy 
• Patient decides to withdraw from study treatment, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
4.6 
Duration of Follow-Up 
Patients will be followed for up to 5 years after removal from study treatment 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.  After two years of follow-up as described in the time and events table, 
subsequent follow-up will be per standard of care and the study will follow only 
for progression and for survival for up to 3 additional years, for a total of 5 years 
of follow-up after completion of treatment. 
4.7 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.5 apply.  The reason for discontinuation of protocol 
therapy will be documented on the eCRF.   
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
4.8 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. The investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as 
completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the patient’s study withdrawal should be made with an 
explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an adverse event, the principal specific 
event will be recorded on the eCRF. Excessive patient withdrawals from protocol 


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UNIVERSITY OF NORTH CAROLINA 
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29 
therapy or from the study can render the study un-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
 
5.0 
DRUG INFORMATION 
5.1 
Pembrolizumab 
5.1.1 Description 
Clinical Supplies will be provided by Merck as summarized in the table below. 
 
Product Name & Potency 
Dosage Form 
pembrolizumab 50 mg 
Lyophilized Powder for Injection 
pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
5.1.2 Supplier/How Supplied 
Pembrolizumab will be provided at no cost to the study patient by Merck, the 
manufacturer of the drug. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not 
provided. 
5.1.3 Handling and Dispensing 
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
5.1.4 Storage and Stability 
As per the pharmacy manual, which will be provided as a document separate from 
the protocol. 
5.1.5 Return and Retention 
The investigator is responsible for keeping accurate records of the clinical 
supplies received from Merck or designee, the amount dispensed to and returned 
by the subjects and the amount remaining at the conclusion of the trial.  
 


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30 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per UNC IDS drug destruction 
policy. It is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
5.1.6 Adverse Events Associated with Pembrolizumab 
The most common adverse reactions (reported in ≥20% of patients in clinical 
trials of pembrolizumab) included fatigue, cough, nausea, pruritus, rash, 
decreased appetite, constipation, arthralgia, and diarrhea. The following warnings 
are associated with the use of pembrolizumab:  
 
 
 
Immune-Mediated Pneumonitis 
Pneumonitis occurred in ~3% of melanoma patients treated in clinical trials of 
pembrolizumab. The median time to development of pneumonitis was 5 months 
with a median duration of 4.9 months.  The one patient with Grade 3 pneumonitis 
required initial treatment with high-dose systemic corticosteroids (greater than or 
equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid 
taper. Pneumonitis completely resolved in seven of the nine patients with 
Grade 2-3 pneumonitis. 
 
Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred 1% of melanoma patients treated 
in clinical trials of pembrolizumab. The median time to onset of was 6.5 months 
with a median duration of 2.6 months. All three patients with Grade 2 or 3 colitis 
were treated with high-dose corticosteroids (greater than or equal to 40 mg 
prednisone or equivalent per day). 
 
Immune-Mediated Hepatitis  
Hepatitis (including autoimmune hepatitis) occurred in 0.5% of melanoma 
patients treated in clinical trials of pembrolizumab. The time to onset was 22 days 
for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 
4 hepatitis permanently discontinued pembrolizumab and was treated with high-
dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic 
corticosteroids followed by a corticosteroid taper. Both patients with hepatitis 
experienced complete resolution of the event.  
 
 
 
Immune-Mediated Hypophysitis  
Hypophysitis occurred in 0.5% of melanoma patients treated in clinical trials of 
pembrolizumab. The time to onset was 1.7 months for the patient with Grade 4 
hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both 
patients were treated with high-dose (greater than or equal to 40 mg prednisone or 


LCCC1509 
 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
31 
equivalent per day) corticosteroids followed by a corticosteroid taper and 
remained on a physiologic replacement dose.  
 
Renal Failure and Immune-Mediated Nephritis  
Nephritis occurred in 3 (0.7%) patients of melanoma patients treated in clinical 
trials of pembrolizumab, consisting of one case of Grade 2 autoimmune nephritis 
(0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 
3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months 
after the first dose of pembrolizumab (5 months after the last dose) and lasted 3.2 
months; this patient did not have a biopsy. Acute interstitial nephritis was 
confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three 
patients fully recovered renal function with treatment with high-dose 
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) 
followed by a corticosteroid taper. 
 
Immune-Mediated Hyperthyroidism  
Hyperthyroidism occurred in 5 (1.2%) of 411 melanoma patients treated in 
clinical trials of pembrolizumab. The median time to onset was 1.5 months and 
the median duration was 2.8 months (range 0.9 to 6.1). One of two patients 
with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial 
treatment with high-dose corticosteroids (greater than or equal to 40 mg 
prednisone or equivalent per day) followed by a corticosteroid taper. One patient 
(0.2%) required permanent discontinuation of pembrolizumab due to 
hyperthyroidism. All five patients with hyperthyroidism experienced complete 
resolution of the event. 
 
Immune-Mediated Hypothyroidism  
Hypothyroidism occurred in 34 (8.3%) of 411 melanoma patients treated in 
clinical trials of pembrolizumab. The median time to onset of hypothyroidism was 
3.5 months. All but two of the patients with hypothyroidism were treated with 
long-term thyroidhormone replacement therapy. The other two patients only 
required short-term thyroid hormone replacement therapy. No patient received 
corticosteroids or discontinued pembrolizumab for management of 
hypothyroidism. Thyroid disorders can occur at any time during treatment.  
 
Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated adverse reactions can occur. The 
following clinically significant, immune-mediated adverse reactions occurred in 
less than 1% of patients treated with pembrolizumab, including exfoliative 
dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial 
seizures arising in a patient with inflammatory foci in brain parenchyma, and 
adrenal insufficiency. 
 
Across clinical studies with pembrolizumab in approximately 2000 patients, the 
following additional clinically significant, immune-mediated adverse reactions 


LCCC1509 
 
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UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
32 
were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, 
and rhabdomyolysis. 
 
Embryofetal Toxicity 
Based on its mechanism of action, pembrolizumab may cause fetal harm when 
administered to a pregnant woman. Animal models link the PD-1/PD-L1 
signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue.  
5.1.7 Contraindications 
There are no reported contraindications associated with the use of 
pembrolizumab. 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm.   
5.1.8 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm.   
 
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).   
 
Female subjects will be considered of non-reproductive potential if they are 
either:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. In the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.);  
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening;  
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and 
for 120 days after the last dose of study drug by complying with one of the 
following:   
(1) practice abstinence† from heterosexual activity;  


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33 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection. 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
 
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region. 
 
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 above) 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. 
 
5.1.9 Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with 
pembrolizumab, the patient will immediately be removed from the study.  The site 
will contact the patient at least monthly and document the patient’s status until the 


LCCC1509 
 
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PI: Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
September 02, 2016 
 
 
 
 
34 
pregnancy has been completed or terminated.  The outcome of the pregnancy will 
be reported to the UNCCN Project Manager who will report the event to Merck 
without delay and within 24 hours if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the UNCCN Project Manager and Merck as 
described above.    
 
If a male patient impregnates his female partner the study personnel at the site 
must be informed immediately and the pregnancy reported to the UNCCN Project 
Manager and to Merck and followed as described above and in Section 7.3.3. 
5.1.10 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. 
5.1.11 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 UNCCN Project Manager who will report the event within 2 
working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) (see section 7.3.3). 
 
 


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6.0 
EVALUATIONS AND ASSESSMENTS  
6.1 
Time and Events Table 
Procedure 
Screening1 
D1 cycle 
12 
D1 cycle 
22 
D1 cycle 
32 
D1 cycle 
42 
D1 cycle 
52 
D1 cycle 
62 
D1 Week 
203,4 
Long-Term 
Follow-up5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Dental exam 
X1 
 
 
 
 
 
 
 
 
Charleson Comorbidity Index (CCMI) 
X 
 
 
 
 
 
 
 
 
Physical Exam & Medical History 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/differential  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries7 and LFTs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine or serum pregnancy  
X9 
 
 
 
 
 
 
 
 
Coagulation, urinalysis10 
X10 
 
 
X10 
 
 
 
X10 
 
Thyroid Panel 
X11 
 
 
X11 
 
 
 
X11 
X11 
Uric acid 
X 
 
 
 
 
 
 
 
 
Radiographic tumor evaluation 
X1 
 
 
 
 
 
 
X4 
X5 
Clinician toxicity assessment12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRO-CTCAE and Quality of Life13 
 
X13 
 
 
X13 
 
 
X13 
 
Pembrolizumab 200mg IV 
 
X 
X 
X 
X 
X 
X 
 
 
Radiation 
 
M-F daily IMRT x 7 weeks  
 
 
 
 
 
Concomitant Med Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Progression/Survival 
 
 
 
 
 
 
 
 
X 
Request archival tissue 
X1,14 
 
 
 
 
 
 
 
 
Blood draw for correlates (required) 
 
X15 
 
 
 
 
 
X15 
X15 
Respiratory signs/symptoms 
X16 
Check respiratory signs/symptoms16 
 


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36 
Key to Time and Events Table Footnotes 
1Unless otherwise noted, screening evaluations to take place within 2 weeks of day 1 (D1) of study 
treatment.  Archival tissue, if available, may be obtained at any point during conduct of the study. Dental 
exam must take place within 6 weeks of D1 of treatment. Baseline imaging will require neck CT or MRI 
(either with contrast) as well as chest imaging (either chest CT (recommended) or chest x-ray).  If PET-CT 
(or PET-MRI) is clinically indicated additional chest and neck CT will not be necessary. Baseline imaging 
must be acquired within 4 weeks of the start of treatment.  Dental evaluation is as required per standard of 
care evaluation (eg, a patient with clearly healthy dentition who would not be formally evaluated by a 
dentist as part of standard of care is not required to do so as part of this study). 
 
2Each cycle (total of 6 cycles) is defined by pembrolizumab infusion (every 3 weeks unless delayed, so 
lasting ~18 weeks), and the duration of XRT is typically 7 weeks; a window of +/-3 days will apply to all 
study visits. Laboratory evaluations on day 1 of cycle 1 need be repeated only if >7 days have elapsed 
between screening laboratory tests and day 1.   Typical radiation schema is shown here, but radiation is to 
be IMRT given per protocol. 
 
3 30 days (+/- 4 days) post last dose of pembrolizumab, whether treatment was discontinued because all 
doses were completed, or due to toxicity, progression etc., patients will be evaluated for 30 day post 
pembrolizumab safety. In patients who complete all doses on time, this visit should occur at week 20. 
Patients who are still experiencing a treatment-related ≥ Grade 2 adverse event will be contacted every 2 
weeks until the event is resolved to Grade 0 or 1, determined to be irreversible by the investigator, or until 
the patient begins an alternate form of treatment.   
 
4At week 20 of the study, (~12 weeks (+/- 7 days) after the last dose of radiation), a PET scan is required. If 
PET was done at baseline, remain consistent with the type of PET scan (either PET-CT or PET-MRI).  If a 
PET scan is refused by insurance, a neck CT or MRI (consistent with the test ordered at baseline whether 
associated with PET or not) will be acceptable.  
 
5 Serious adverse events (SAEs) or any grade of Events of Clinical Interest (see section 7.3 and the ECI 
Guidance Document that is provided as a document separate from this protocol) that occur within 90 days 
of the end of pembrolizumab (or prior to start of new anti-cancer therapy) must be recorded.  If all cycles 
occur on schedule, this should correspond to approximately week 28. Long-term follow-up visits will start 
at this week 28 visit, and then take place every 3 months (+/- 30 days) thereafter for one year, then every 6 
months (+/- 45 days) for a year.  Imaging will consist of a neck CT or MRI (consistent with the test ordered 
at baseline) during each of these visits (PET is not required).  Indeterminate pulmonary nodules should be 
followed per institutional standard of care.  Screening chest CT is recommended at least annually for 
patients with a smoking history.  After two years, follow up is per institutional care and documentation for 
study purposes will be limited to first subsequent anti-cancer treatment, and PFS and OS only for a 
maximum of five years. 
 
6Complete history at baseline only (including smoking history), thereafter focused history on 
symptoms/toxicity.   
 
7Serum chemistries and electrolytes to include sodium, potassium, phosphorus, chloride, bicarbonate, BUN, 
serum creatinine, glucose, calcium, magnesium, albumin   
 
8LFTs (liver function tests) include total bilirubin, alkaline phosphatase, AST, ALT  
 
9Urine or serum β-HCG to be done within 72 hours of day 1 of treatment in women of childbearing 
potential; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
 
 
 


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10Coagulation includes PT/INR and PTT; Urinalysis includes blood, glucose, protein, specific gravity, and 
microscopic exam if abnormal results are noted 
 
11Thyroid panel includes TSH, T3 and free T4.  If consistent with institutional standard of care, it is 
acceptable to obtain TSH alone and only obtain T3 and free T4 if clinically useful. 
 
12Via NCI CTCAEv4.0 
 
13See section 6.5  for tools and schedule of these assessments during follow-up; Quality of life will be 
measured by the FACT-HN (see Section11.2, Appendix B). 
 
14Tissue from diagnostic biopsy, when available, will be requested for correlative studies.  Further details to 
be provided in a laboratory manual. 
 
15Blood draw (see section 6.6.2; 3x 8mLs whole blood in ACD tubes and one serum separator tube (gel 
barrier) required at each scheduled draw) will be to evaluate for clonally restricted circulating B and T cells 
and for proteomics.  The draws will be on C1 (pre-pembrolizumab), 4 weeks following the last dose of 
pembrolizumab, and at the second long-term follow-up visit (approximately week 40 from start of 
treatment) 
 
16Perform baseline assessment and check for history of pneumonitis, monitor for 
respiratory signs/symptoms while patients are on pembrolizumab and manage toxicity 
for pneumonitis as outlined in section 4.3.4 
a) If applicable: ongoing patients are to be evaluated for active pneumonitis. 
Patients with a history of pneumonitis should be re-consented for this trial to 
consider if they should discontinue pembrolizumab or continue treatment 
based on the risk of fatal pneumonitis related to pembrolizumab therapy. 
 
 
 


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6.2 
Pre-Study Assessments 
Clinical evaluation:  complete history, CCMI (see section 11.3, Appendix C), 
physical examination to include height (baseline only) and weight, dental exam; 
ECOG performance status. 
Laboratory studies:   
 Pregnancy Test: A urine or serum pregnancy test (β-HCG) is 
required for all women of childbearing potential at screening within 
72 hours prior to the first dose of treatment under this protocol.   If 
the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.   
 CBC with differential  
 Serum Chemistries: These include the following parameters: 
sodium, potassium, phosphorus, chloride, bicarbonate, BUN, serum 
creatinine (calculate creatinine clearance via Cockcroft-Gault, see 
section 11.1 Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT) 
 Uric acid 
 Urinalysis: includes blood, glucose, protein, specific gravity, and 
microscopic exam if abnormal results are noted 
 Coagulation Studies: PT/INR and PTT 
 Thyroid Panel: TSH, T3, free T4; if consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful. 
Check respiratory history (signs/symptoms): 
Archival tissue: request access to archival tissue to support correlative studies 
(see section 6.6); consent for the use of any residual material from biopsy will be 
required for enrollment.  Patients without adequate tissue for bio correlates will 
not be excluded or required to have a repeat biopsy. 
Concomitant Medications: Review (see section 4.4) 
Toxicity Assessment: per NCI CTCAEv4 
Tumor imaging: Baseline imaging will require neck CT or MRI (either with 
contrast) as well as chest imaging (either chest CT (recommended) or chest x-
ray).  If PET-CT (or PET-MRI) is clinically indicated additional chest and neck 
CT will not be necessary 
6.3 
Treatment Assessments 
6.3.1 D1 Cycle 1 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
including weight and ECOG performance status. 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  


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 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT)  
Check Respiratory signs/ Symptoms: 
Concomitant Medications: Review 
Toxicity: Per both NCI CTCAEv4 and PRO-CTCAE (see section 6.5) 
QOL: FACT-HN (see section 11.2, Appendix B) 
Blood Draws for Correlatives: see section 6.6.2; 3x 8mLs whole blood in ACD 
tubes and a serum separator tube (gel barrier) required at each scheduled draw 
(Required) 
6.3.2 D1 Cycle 2, 5 and 6 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
including weight and ECOG performance status. 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT)  
Check Respiratory signs/ Symptoms: 
Concomitant Medications: Review 
Toxicity: Per NCI CTCAEv4  
6.3.3 D1 Cycle 3 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
including weight and ECOG performance status. 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT)  
 Urinalysis: includes blood, glucose, protein, specific gravity, and 
microscopic exam if abnormal results are noted 
 Coagulation Studies: PT/INR and PTT 
 Thyroid Panel: TSH, T3, free T4; if consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful. 
Check Respiratory signs/ Symptoms: 
Concomitant Medications: Review 
Toxicity: Per NCI CTCAEv4  
 


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6.3.4 D1 Cycle 4 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
including weight and ECOG performance status. 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT)  
Check Respiratory signs/ Symptoms: 
Concomitant Medications: Review 
Toxicity: Per both NCI CTCAEv4 and PRO-CTCAE (see section 6.5) 
QOL: FACT-HN (see section 6.5) 
 
6.4 
Follow-Up 
6.4.1 D1 Week 20 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
including weight and ECOG performance status. 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT)  
 Urinalysis: includes blood, glucose, protein, specific gravity, and 
microscopic exam if abnormal results are noted 
 Coagulation Studies: PT/INR and PTT 
 Thyroid Panel: TSH, T3, free T4; if consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful. 
Check Respiratory signs/ Symptoms: 
Concomitant Medications: Review 
Toxicity: Per both NCI CTCAEv4 and PRO-CTCAE (see section 6.5) 
QOL: FACT-HN (see section 11.2, Appendix B)  
Blood Draws for Correlatives: see section 6.6.2; 3x 8mLs whole blood in ACD 
tubes and serum separator (gel barrier) required at each scheduled draw 
(Required) 
Tumor Imaging: At this visit, a PET scan is required. If PET was done at baseline, 
remain consistent with the type of PET scan (either PET-CT or PET-MRI).  If a 
PET scan is refused by insurance, a neck CT or MRI (consistent with the test 
ordered at baseline whether associated with PET or not) will be acceptable. 


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6.4.2 Long-Term Follow-Up 
Long-term follow-up visits will start at week 28, and then take place every 3 
months (+/- 30 days) thereafter for one year, then every 6 months (+/- 45 days) 
for a year. After two years, follow-up is per institutional care and documentation 
for study purposes will be limited to first subsequent anti-cancer treatment, PFS 
and OS only for a maximum of five years. 
 
Clinical evaluation:  Per institutional standard of care. 
Toxicity evaluation: Serious adverse events (SAEs) or any grade of Events of 
Clinical Interest (see section 7.3 and the ECI Guidance Document that is provided 
as a document separate from this protocol) that occur within 90 days of the end of 
pembrolizumab (or prior to start of new anti-cancer therapy) must be recorded.  If 
all cycles occur on schedule, this should correspond to approximately week 28.  
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: These include sodium, potassium, phosphorus, 
chloride, bicarbonate, BUN, serum creatinine, glucose, calcium, 
magnesium, albumin  
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT)  
 Thyroid Panel: TSH, T3, free T4; if consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful. 
Tumor imaging: For the first 2 years of follow-up, imaging will consist of a neck 
CT or MRI (consistent with the test ordered at baseline) during each of these 
visits (PET is not required).  Indeterminate pulmonary nodules should be followed 
per institutional standard of care.  Screening chest CT is recommended 
at least annually for patients with a smoking history.    
Blood Draws for Correlatives: see section 6.6.2; 3x 8mLs whole blood in ACD 
tubes and a serum separator tube (gel barrier) (Required) at the second long-term 
follow-up visit (~week 40 from start of treatment) 
6.5 
Patient Reported Outcomes version of the CTCAE  
A subset of items pertinent to H&N cancer will be drawn from the PRO-CTCAE 
system. These items will be used to evaluate the presence and/or severity of range 
of symptoms, as well as the degree to which symptom/toxicity interferes with 
usual function.  These measures are: 
• Atttention/Memory: Concentration, memory 
• Cutaneous: Rash, hair loss 
• Pain: General pain, headache 
• GI: Taste changes, decreased appetite, nausea, vomiting, diarrhea 
• Sleep/wake: Insomnia, fatigue 
• Respiratory: Shortness of breath, cough, wheezing 
• Neurologic: numbness and tingling, dizziness 
• Mood: anxious, discouraged, sad 


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• Misc: Nosebleed 
• Visual/perceptual: Ringing ear 
• Oral: dry mouth, difficulty swallowing, mouth/throat sores, cehliosis, 
voice quality changes, hoarseness 
6.6 
Correlative Studies Procedures 
These are described in more detail in the laboratory manual.  
6.6.1 Archival Tissue 
Archival tumor tissue (paraffin-embedded blocks/slides) from the patient’s 
original diagnostic biopsy will be requested and collected from all enrolled 
patients.  See accompanying laboratory manual for additional details.  
6.6.2 Blood samples 
Patients will have a three ACD tubes (whole blood, 3 x 8mL) and a serum 
separator tube (gel barrier) collected at the times as noted in the Time and Event 
table. Sample collection, storage, and shipment instructions for serum samples 
will be provided in the Laboratory Manual. 
6.7 
Assessment of Safety 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events table (section 6.0).  Toxicity will be assessed 
according to the NCI CTCAE v4. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment. Patient reported outcomes will be assessed via the PRO-CTCAE, 
see section 6.5. 
 
For subjects receiving treatment with pembrolizumab all AEs of unknown 
etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an ECI of a potentially immunologic etiology (termed 
immune-related adverse events, or irAEs); see the separate ECI guidance 
document (provided as a document separate from this protocol) regarding the 
identification, evaluation and management of potential irAEs.   
 
Please refer to section 7.0 for detailed information regarding the assessment and 
recording of AEs.   
6.8 
Assessment of Efficacy 
Patients who have received at least 1 dose of pembrolizumab will be evaluable for 
assessment of response and progression.   Patients whose cancer growth is 
documented by physical examination without imaging confirmation will count as 
progression.  Patients who drop out of the study for any reason (ex. toxicity of 
treatment, decide to withdraw) will still be followed for PFS and OS.    


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6.8.1 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
• >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 20 mm by chest x-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.   
 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions, will be considered non-measurable.  Lesions considered truly 
non-measurable include:leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
6.8.2 Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline.   
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as “present” 
or “absent”, or in rare cases “unequivocal progression”.   
6.8.3 Evaluation of Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all target lesions.  Any pathological 
lymph node (LN) (whether target or non-target) must have decreased in short axis 
to <10mm. 
 
Partial response (PR)−At least a 30% decrease in the sum of the LD of the target 
lesions taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline if that is the smallest on study.  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
6.8.4 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and 
normalization of tumor marker levels.  All LN must be non-pathological in size 
(<10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and maintenance of tumor marker level above the 
normal limits. 
 
Progressive disease (PD)−Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
7.0 
ADVERSE EVENTS 


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7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
 
All adverse events that occur after the consent form is signed but before treatment 
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. 
 
From the time of treatment through 30 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.1.4. The investigator will make every attempt to follow all subjects with 
non-serious adverse events for outcome. 
 
Adverse events will not be collected for subjects during the pre-screening period 
(for determination of archival tissue status) as long as that subject has not 
undergone any protocol-specified procedure or intervention.  If the subject 
requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.  
 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 


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Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group. 
 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
 
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 


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in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
• Note: In addition to the above criteria, adverse events meeting either of 
the below criteria, although not serious per ICH definition, are 
reportable to the Merck in the same timeframe as SAEs to meet certain 
local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
 
For the time period beginning when the consent form is signed until treatment, 
any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study that occurs to 
any subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to 
a serious adverse event, including death due to any cause other than progression 
of the cancer under study whether or not related to the Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside of 
the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded 
to the Merck Global Safety facsimile number:  +1-215-993-1220 
 


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7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
drug.    Documentation should occur at least monthly.  
7.3 
SAEs or Serious SARs and Events of Clinical Interest 
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout.  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 90 day follow-up period after treatment is discontinued (or 
to the initiation of new anti-cancer treatment, whichever is earliest).  
7.3.2 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the 
NCCN Project Manager must also be notified via email of all SAEs within 24 
hours of learning of its occurrence. 
7.3.3 Reporting  
IRB Reporting Requirements: 
UNC: 
• UNC will submit an aggregated list of all SAEs to the UNC IRB annually 
at the time of study renewal according to the UNC IRB policies and 
procedures. 
• The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
 
Affiliate sites:   
• For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 


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For affiliate sites relying on the UNC-IRB, an aggregated list of all SAEs 
will be submitted to the UNC IRB annually at the time of study renewal 
according to the UNC IRB policies and procedures. In addition, any SAEs 
that qualify as an Unanticipated Problem will be entered into Oncore and 
reported to the UNC IRB by the UNCCN Project Manager using the IRB’s 
web-based reporting system (see section 9.5.3) within 7 days of the 
Investigator becoming aware of the problem.   
Pregnancy 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them. Pregnancies and lactations 
that occur after the consent form is signed but before treatment 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.   
 
It is the responsibility of investigators or their designees to report any pregnancy 
or lactation in a subject (spontaneously reported to them), including the pregnancy 
of a male subject's female partner that occurs during the trial or within 120 days 
of completing the trial completing the trial, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, as a 
serious adverse event.  The patient is to be discontinued immediately from any 
protocol directed therapy. All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious adverse 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 UNCCN Project Manager who will report the 
event within 2 days to the manufacturer (Merck; see below). 
 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to the UNCCN Project Manager within 24 hours via facsimile to 919-966-4300.  
The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
 
FDA Expedited Reporting requirements: 
If an investigator deems that an event is both a serious SAR AND unexpected, it 
must also (in addition to Oncore) be recorded on the MedWatch Form 3500A as 
per 21 CFR 312.32.  The MedWatch form should be faxed to the UNCCN Project 
Manager at 919-966-4300 (or emailed, with address provided at the Start up 
Meeting (SIM)) along with supporting documentation defining the event and 
causality.  The UNCCN Project Manager will send report to Merck. The 
MedWatch 3500a form can be accessed at:  
 


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http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.ht
m  
 
(Please be sure and access form 3500a, and not form 3500).   UNC, as the 
Sponsor of the study, will make the final determination regarding FDA 
submission.   
 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA. 
 
The UNCCN Project Manager will also be responsible for informing each 
Affiliate site of all serious and unexpected SARs reported to the FDA via fax as 
soon as possible.   
 
Merck Reporting Requirements: 
Any SAE, or follow up to a SAE, including death due to any cause other than 
progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related 
to Merck product, must be reported within 24 hours to the UNCCN Project 
Manager who will report the event within 2 working days to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the UNCCN Project Manager 
who will report the event  to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to 
the UNCCN Project Manager via facsimile at 919-966-4300, or scanned and 
emailed to UNCCN Project Manager (address to be provided at the SIM) who 
will then fax to the Merck Global Safety facsimile number:  +1-215-993-1220. 
 
All 15-Day Reports and Annual Progress Reports must be submitted as required 
to FDA. Investigators will cross-reference these reports to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
 
Events of Clinical Interest 


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Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be recorded as such on the Adverse Event case 
report forms/worksheets and reported within 24 hours to the UNCCN Project 
Manager who will report the event within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
For the time period beginning when the consent form is signed until treatment, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety 
if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to Merck product, must be reported within 24 hours to the Sponsor 
and within 24 hours to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 5.1.11 Pembrolizumab 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.   
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than 
or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.   
 
 
 
Pregnancy and Lactation 
See above in this section for additional information. Such events must be reported 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220). 
 
Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck unless 
there is evidence suggesting a causal relationship between the drug and the event. 
Any such event will be submitted to the Sponsor within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media. 


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Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study. 
 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and 
safety data to ensure the safety of the subjects in the trial. Any suspected endpoint 
which upon review is not progression of the cancer under study will be forwarded 
to Merck Global Safety as a SAE within 2 working days of determination that the 
event is not progression of the cancer under study 
 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be 
considered a SAE. 
 
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
 
 


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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design 
This one arm, open label, phase II trial will enroll 29 patients in order to evaluate 
the efficacy of pembrolizumab, concomitant with and following standard of care 
definitive radiation, for locally advanced SCCHN patients who are not good 
candidates for cisplatin.  Objectives include estimating PFS and OS, response 
rates, safety & toxicity, and quality of life in these patients.  Correlative studies, 
based on serial blood collections and tumor samples, may be done under a 
separate protocol based on availability of archival diagnostic tissue (see section 
1.9). 
8.2 
Sample Size and Accrual 
In the Bonner study, median PFS (mPFS) was improved from 12.4 months to 17.1 
months with the addition of cetuximab to radiotherapy.  Consistent with modern 
practice and inclusion criteria requiring cisplatin ineligibility, we expect to accrue 
a somewhat sicker and more advanced population than Bonner and therefore have 
decreased our null hypothesis from Bonner’s 12.4 months to 10 months.  
However, we hope to provide a larger gain in PFS as we hope that 
pembrolizumab will be more active than cetuximab; in particular, where 
cetuximab had no impact on distant control, we believe that the existing data on 
pembrolizumab in the metastatic setting gives reason to believe that 
pembrolizumab should improve distant control.  We therefore hypothesize that 
the addition of pembrolizumab to radiotherapy will improve mPFS from 10 
months to 16 months.  Assuming uniform accrual, no loss to follow-up, 
exponentially distributed times, and a one-side alpha of 0.1, 29 patients are 
needed to provide 80% power to detect this level of improvement.  We anticipate 
accrual to take 24 months, with follow-up time of at least 12 months.  This 
calculation was made using the SWOG Statistical Center online tool for one arm 
survival (https://stattools.crab.org/#). 
8.3 
Data Analysis Plans 
The primary endpoint is the estimation of PFS following standard head and neck 
cancer radiation concurrent with and following pembrolizumab and will be done 
using the Kaplan-Meier (KM) method.    The KM method will also be used to 
estimate all other “time to event” outcomes (ex. OS, time to locoregional 
recurrence, time to distant metastases); median times along with rates at 20 
weeks, 1 and 2 years will be reported, along with 95% confidence intervals.  All 
patients who receive at least one dose of pembrolizumab will be included in these 
estimates, with censoring used as needed (ex. if a patient drops out of the study, or 
analysis is done before all patients have had the event of interest).  The KM 
method, along with Log-rank tests, will be used for exploratory objectives which 
include comparisons between groups (ex. HPV status, biological markers). 
 


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Descriptive statistics (percentages and means/standard deviations) will be used to 
summarize the overall response rate (ORR), complete response rate (CRR) and 
quality of life scores.  Depending on the availability of data, longitudinal models 
may be used to describe changes in quality of life scores over time.  Fisher’s exact 
tests and Wilcoxon rank sum tests will be used to explore the association of 
exploratory endpoints (ex. HPV status and tumor biomarkers) with response as 
appropriate.   
 
Safety will be evaluated by estimating the proportion of patients who receive 
<95% of the intended dose of radiation (i.e., <67 Gy) and by reporting any 
clinically relevant toxicity (both patient and physician reported).  Additionally, 
continuous monitoring for toxicity will be employed.  Sequential boundaries will 
be used to monitor for unacceptable toxicity.  For this study this will be defined as 
failing to receive at least 95% of the intended dose of XRT.   
 
The accrual will be halted if excessive numbers of patients fail to receive at least 
95% of the intended dose of XRT --that is, if the number of patients is equal to or 
exceeds bn out of n patients (see table below). This is a Pocock-type stopping 
boundary that yields the probability of crossing the boundary at most 0.05 when 
the rate of failing to receive at least 95% of the intended dose of XRT is equal to 
the acceptable rate of 10%.  
[http://cancer.unc.edu/biostatistics/program/ivanova/ContinuosMonitoringForTox
icity.aspx] 
 
Number of 
Patients, n 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 
2 3 3 3 3 4 4 4 4 5 5 5 5 5 6 6 6 6 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
Patients, n 
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35  
 
 
 
 
Boundary, bn 
6 7 7 7 7 7 7 8 8 8 8 8 8 9 9 
 
 
 
 
 
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 


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Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  
Otherwise, the Investigator’s signature documenting understanding of 
the protocol and providing commitment that this trial will be 
conducted according to all stipulations of the protocol is sufficient to 
ensure compliance) 
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the LCCC CPO UNCCN at the University of 
North Carolina before enrollment to study.  To register a patient call the UNCCN 
at 919-966-7359 M-F 8:30am- 5pm EST. Fax (919-966-4300) or email (address 
to be provided at SIM) registration form, signed informed consents and all source 
documents to confirm eligibility. 
9.4 
Data Management and Monitoring/Auditing 
The CPO UNCCN of the UNC LCCC will serve as the coordinating center for 
this trial. Data will be collected through a web based clinical research platform, 
OnCore®.  Other study institutions will be given a password to directly enter their 
own data onto the web site via electronic case report forms (eCRFs).  UNCCN 


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personnel will coordinate and manage data for quality control assurance and 
integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions.  The 
investigators at each site will allow monitors to review all source documents 
supporting data entered into OnCore®.   The UNCCN Data Coordinator can be 
reached at 919-843-2742 or 1-877-668-0683. 
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six or twelve months, depending on the 
participation of affiliate sites. 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.   
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
• To UNC Principal Investigator for agreement  
• The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the 
UNCCN Regulatory Associate). 
9.5.2 Single Patient/Subject Exceptions 
For Institutions Relying on UNC’s IRB:  
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB.  
 
For Institutions Relying on Their Own IRB: 


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Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the 
participating institution’s IRB, per its policy.  Please forward the IRB response to 
the UNCCN Regulatory Associate by facsimile or via email within 10 business days 
after the original submission.   
9.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 


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Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNCCN Project Manager within 
5 days. UNC-CH will determine if the violation affects the safety of the patient 
and integrity of the data.  Once your institution’s IRB response is received, please 
forward to the UNCCN Regulatory Associate. 
 
Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNCCN Project Manager.   The 
UNCCN Project Manager will report the event to the UNC IRB using the IRB’s 
web-based reporting system.  Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 
 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNCCN Regulatory Associate 
prior to submission to their IRB.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 


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Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
 


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60 
10.0 REFERENCES 
 
1. 
Pignon, J.P., et al., Meta-analysis of chemotherapy in head and neck cancer 
(MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother 
Oncol, 2009. 92(1): p. 4-14. 
2. 
Forastiere, A.A., et al., Concurrent chemotherapy and radiotherapy for organ 
preservation in advanced laryngeal cancer. N Engl J Med, 2003. 349(22): p. 
2091-8. 
3. 
Huguenin, P., et al., Concomitant cisplatin significantly improves locoregional 
control in advanced head and neck cancers treated with hyperfractionated 
radiotherapy. J Clin Oncol, 2004. 22(23): p. 4665-73. 
4. 
Sharma, A., et al., Concomitant chemoradiation versus radical radiotherapy in 
advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly 
cisplatin: a phase II randomized trial. Ann Oncol, 2010. 21(11): p. 2272-7. 
5. 
Newlin, H.E., et al., Concomitant weekly cisplatin and altered fractionation 
radiotherapy in locally advanced head and neck cancer. Cancer, 2010. 116(19): 
p. 4533-40. 
6. 
Traynor, A.M., et al., Comprehensive IMRT plus weekly cisplatin for advanced 
head and neck cancer: the University of Wisconsin experience. Head Neck, 2010. 
32(5): p. 599-606. 
7. 
Bonner, J.A., et al., Radiotherapy plus cetuximab for squamous-cell carcinoma of 
the head and neck. N Engl J Med, 2006. 354(6): p. 567-78. 
8. 
Bonner, J.A., et al., Radiotherapy plus cetuximab for locoregionally advanced 
head and neck cancer: 5-year survival data from a phase 3 randomised trial, and 
relation between cetuximab-induced rash and survival. Lancet Oncol, 2010. 
11(1): p. 21-8. 
9. 
Lassen, P., J. Overgaard, and J.G. Eriksen, Expression of EGFR and HPV-
associated p16 in oropharyngeal carcinoma: correlation and influence on 
prognosis after radiotherapy in the randomized DAHANCA 5 and 7 trials. 
Radiother Oncol, 2013. 108(3): p. 489-94. 
10. 
Rosenthal DI, H.P., Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner 
JA, Impact of p16 status on the results of the phase III cetuximab 
(cet)/radiotherapy (RT). ASCO Meeting Abstracts, 2014. 
11. 
Merck Sharp & Dohme, I., Pembrolizumab Investigator's Brochure. 2014. 
12. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
13. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic cells 
enhances T cell activation and cytokine production. J Immunol, 2003. 170(3): p. 
1257-66. 
14. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
15. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
16. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 
2002. 2(2): p. 116-26. 


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17. 
Thompson, R.H., et al., PD-1 is expressed by tumor-infiltrating immune cells and 
is associated with poor outcome for patients with renal cell carcinoma. Clin 
Cancer Res, 2007. 13(6): p. 1757-61. 
18. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of 
tumors: Jekyll or Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-400. 
19. 
Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin 
Cancer Res, 1998. 17(1): p. 77-81. 
20. 
Deschoolmeester, V., et al., Tumor infiltrating lymphocytes: an intriguing player 
in the survival of colorectal cancer patients. BMC Immunol, 2010. 11: p. 19. 
21. 
Diez, M., et al., Histopathologic prognostic score in colorectal adenocarcinomas. 
Anticancer Res, 1998. 18(1B): p. 689-94. 
22. 
Galon, J., et al., Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
23. 
Hodi, F.S. and G. Dranoff, The biologic importance of tumor-infiltrating 
lymphocytes. J Cutan Pathol, 2010. 37 Suppl 1: p. 48-53. 
24. 
Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol, 2009. 10(9): p. 840-1. 
25. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother, 
2008. 57(1): p. 97-106. 
26. 
Lee, H.E., et al., Prognostic implications of type and density of tumour-infiltrating 
lymphocytes in gastric cancer. Br J Cancer, 2008. 99(10): p. 1704-11. 
27. 
Leffers, N., et al., Prognostic significance of tumor-infiltrating T-lymphocytes in 
primary and metastatic lesions of advanced stage ovarian cancer. Cancer 
Immunol Immunother, 2009. 58(3): p. 449-59. 
28. 
Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and 
modification of positive selection in the thymus of PD-1-deficient mice. J Exp 
Med, 2000. 191(5): p. 891-8. 
29. 
Hiraoka, N., Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol, 2010. 15(6): p. 544-51. 
30. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in 
tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell 
carcinoma. BJU Int, 2011. 107(9): p. 1500-6. 
31. 
Seiwert, T.Y., et al., A phase Ib study of MK-3475 in patients with human 
papillomavirus (HPV)-associated and non-HPV-associated head and neck (H/N) 
cancer. ASCO Meeting Abstracts, 2014. 32(15_suppl): p. 6011. 
32. 
Garon E, L.N., Rizvi NA, Blumenschein GR, Balmanoukian AS, Eder JP, 
Goldman JW, Hui R, Soria JC, Gangadhar TC, Sun JM, Patnaik A, Gubens MA, 
Lubiniecki GM, Zhang J, Niewood M, Emancipator K, Dolled-Filhart M, Hanson 
ME, Gandhi L, Safety and clinical activity of MK-3475 in previously treated 
patients (pts) with non-small cell lung cancer (NSCLC). ASCO Meeting 
Abstracts, 2014. 
33. 
Ribas A, H.F., Kefford R, Hamid O, Daud A, Wolchok JD, Hwu WJ, Gangadhar 
TC, Patnaik A, Joshua AM, Hersey P, Weber JS, Dronca RS, Zarour HM, 
Gergich K, Li X, Iannone R, Kang SP, Ebbinghaus S, Robert C, Geffen D, 


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62 
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 
patients (pts) with melanoma (MEL). ASCO Meeting Abstracts, 2014. 
34. 
Deng, L., et al., Irradiation and anti-PD-L1 treatment synergistically promote 
antitumor immunity in mice. J Clin Invest, 2014. 124(2): p. 687-95. 
35. 
Dovedi, S.J., et al., Acquired resistance to fractionated radiotherapy can be 
overcome by concurrent PD-L1 blockade. Cancer Res, 2014. 74(19): p. 5458-68. 
36. 
Pfister, D.e.a. NCCN Practice Guidelines in Oncology, Head and Neck Cancers, 
Version 2.2011. 
37. 
Hitt, R., et al., A randomized phase III trial comparing induction chemotherapy 
followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of 
unresectable head and neck cancer. Annals of Oncology, 2014. 25(1): p. 216-225. 
38. 
Cohen, E.E.W., et al., Phase III Randomized Trial of Induction Chemotherapy in 
Patients With N2 or N3 Locally Advanced Head and Neck Cancer. Journal of 
Clinical Oncology, 2014. 32(25): p. 2735-+. 
39. 
Haddad, R., et al., Induction chemotherapy followed by concurrent 
chemoradiotherapy (sequential chemoradiotherapy) versus concurrent 
chemoradiotherapy alone in locally advanced head and neck cancer 
(PARADIGM): a randomised phase 3 trial. Lancet Oncology, 2013. 14(3): p. 
257-264. 
40. 
Gregoire, V., et al., Proposal for the delineation of the nodal CTV in the node-
positive and the post-operative neck. Radiother Oncol, 2006. 79(1): p. 15-20. 
41. 
Gregoire, V., et al., CT-based delineation of lymph node levels and related CTVs 
in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG 
consensus guidelines. Radiother Oncol, 2003. 69(3): p. 227-36. 
42. 
O'Sullivan, B., et al., The benefits and pitfalls of ipsilateral radiotherapy in 
carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys, 2001. 51(2): p. 
332-43. 
43. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med., 2012. 366(26): p. 2443-54. doi: 
10.1056/NEJMoa1200690. Epub 2012 Jun 2. 
 


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11.0  APPENDICES 
11.1 
Appendix A Cockcroft-Gault Formula 
 
Estimated creatinine clearance (mL/min) = (140-age in years) X (weight in kg) 
 
 
 
 
 
      72 X (serum creatinine in mg/dL) 
 
For females, use 85% of calculated creatinine clearance value. 
 
 
 


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11.2 
Appendix B FACT-Head and Neck Version 4 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 .............................................................................................. 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 .............................................................................................. 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting 
the needs of my 
family
 .............................................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have 
pain
 .............................................................................................. 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 .............................................................................................. 
0 
1 
2 
3 
4 
GP6 
I feel 
ill
 .............................................................................................. 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
bed
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 


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Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel 
sad
 .............................................................................................. 
0 
1 
2 
3 
4 
GS1 
I feel close to my 
friends
 .............................................................................................. 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 .............................................................................................. 
0 
1 
2 
3 
4 
GS3 
I get support from my 
friends
 .............................................................................................. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my 
illness
 .............................................................................................. 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 .............................................................................................. 
   0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 .............................................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box               and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life
0 
1 
2 
3 
4 


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GE2 
I am satisfied with how I am coping with my 
illness
 .............................................................................................. 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 .............................................................................................. 
0 
1 
2 
3 
4 
GE4 
I feel 
nervous
 .............................................................................................. 
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 .............................................................................................. 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 .............................................................................................. 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 .............................................................................................. 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 .............................................................................................. 
0 
1 
2 
3 
4 
GF4 
I have accepted my 
illness
 .............................................................................................. 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 .............................................................................................. 
0 
1 
2 
3 
4 


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GF6 
I am enjoying the things I usually do for 
fun
 .............................................................................................. 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
0 
1 
2 
3 
4 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
 
 
 
 
 
 
 
 
 
H&N1 I am able to eat the foods that I 
like
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N2 My mouth is 
dry
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N3 I have trouble 
breathing
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N4 My voice has its usual quality and 
strength
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N5 I am able to eat as much food as I 
want
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N6 I am unhappy with how my face and neck 
look
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N7 I can swallow naturally and 
easily
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N8 I smoke cigarettes or other tobacco 
products
 ............................................................................................ 
0 
1 
2 
3 
4 


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H&N9 I drink alcohol (e.g. beer, wine, 
etc.)
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with 
others
 ............................................................................................ 
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid 
foods
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or 
neck
0 
1 
2 
3 
4 
 


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11.3 
Appendix C Charlson Comorbidity Index Scoring System