Phase II Study of IMRT Re-Irradiation With Concurrent/Adjuvant Nivolumab in Patients With Locoregionally Recurrent or Second Primary Squamous Cell Cancer of the Head and Neck
Phase: PHASE2
Conditions: Recurrent Head and Neck Squamous Cell Carcinoma
Sponsor: Emory University

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TITLE: 
Phase 
II 
Study 
of 
IMRT 
Re-Irradiation 
with 
concurrent/adjuvant Nivolumab in patients with locoregionally 
recurrent or second primary squamous cell cancer of the head and 
neck (BMS Protocol CA209-9KY) 
 
COORDINATING SITE: 
Winship Cancer Institute, Emory University 
Atlanta, Georgia 30322 
 
PARTICIPATING SITES: 
Cleveland Clinic, Cleveland, Ohio 
Medical College of Wisconsin, Milwaukee, Wisconsin 
 
PRINICIPAL INVESTIGATOR / Protocol Chair (Coordinating Center): 
Nabil F Saba 
Professor and Director of Head and Neck Oncology 
Winship Cancer Institute of Emory University 
1365 Clifton Road, C2110 
Atlanta, GA, 30322 
404 778 3995 
nfsaba@emory.edu 
 
CO-PRINICIPAL INVESTIGATOR: 
Shlomo Koyfman 
Assistant Professor 
Department of Radiation Oncology 
Cleveland Clinic 
9500 Euclid Avenue CA-50 
Cleveland, OH 44195 
216-444-7552 
KOYFMAS@ccf.org 
 
CO-INVESTIGATOR 
Stuart Wong 
Associate Professor of Medicine and Otolaryngology 
Division of Hematology and Oncology, Department of Medicine 
Medical College of Wisconsin 
9200 West Wisconsin Avenue 
Milwaukee WI, 53226 
866 680-0505 
swong@mcw.edu 
 
BIOSTATISTICIAN 
Yuan Liu 
Assistant Professor 
Biostatistics & Bioinformatics Shared Resource at Winship Cancer Institute 
Department of Biostatistics & Bioinformatics, Rollins School of Public Health 
Emory University 

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Room 352, 1518 Clifton Rd. Atlanta GA 30322 
Tel: 404-778-1989 
Yliu31@emory.edu 
 
 
Multi-site Coordinator 
Quin Boynes 
Emory University, Winship Cancer Institute 
Phone 404-778-1319 
Fax: 404-778-0417 
E-mail: quin.l.boynes@emory.edu 
 
 
 
BMS supplied agent: Nivolumab 

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PROTOCOL SYNOPSIS 
 
Title of study 
Phase II Study of IMRT Re-Irradiation with concurrent/adjuvant 
Nivolumab in patients with locoregionally recurrent or second 
primary squamous cell cancer of the head and neck 
Investigational drugs 
Nivolumab 
Protocol Date and 
Version 
Version 11.0 July 27, 2023 
Protocol number 
Winship 4221-17; BMS CA209-9KY 
Principal 
Investigators 
1. Nabil Saba, M.D. (Emory) 
2. Shlomo Koyfman (Cleveland Clinic) 
Co-Investigators 
1. Stuart Wong 
2. Jonathan Beitler 
3. Molly Eaton 
4. Conor Steuer 
5. Dong M. Shin 
6. Mark Mc Donald 
7. Kristin Higgins 
8. David Adelstein 
9. Jessica Geiger 
10. William Stokes 
11. Neil Woody 
Research 
Investigators 
1. Rafi Ahmed 
2. Mohamed Abazeed 
3. Georgia Chen 
4. Andreas Wieland 
Funding Organization BMS 
Study Sites 
1. Emory University 
2. Cleveland Clinic 
3. Medical College of Wisconsin 
Clinical Phase 
Phase II 
Objectives 
Primary Objectives: 
1- To assess the 1-year PFS for patients with RPA class I and 
II disease treated with  nivolumab and IMRT re-irradiation 
Secondary Objectives: 
1- Evaluate the OS of patients treated with re-irradiation and 
nivolumab 
2- Evaluate patient QOL 
3- Evaluate patterns of failure including rates of locoregional 
failure and distant failure 
4- Identify and estimate the incidence rate of acute and late 
toxicities associated with combined re-irradiation and 
nivolumab followed by nivolumab 
Exploratory Objectives: 
• To identify potential biomarkers related to clinical benefit to 
concurrent nivolumab and re-irradiation in patients with 
recurrent HNSCC. 

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SAEStudy Design 
This will be a phase II single arm study of IMRT re-irradiation in 
combination with nivolumab in the concurrent and maintenance 
setting. Patients with RPA class I and II based on the recursive 
partitioning analysis (RPA) classes reported by Ward et al (ASTRO 
2016) will be enrolled. The allowable treatment approaches include 
IMRT. Based on this analysis, only patients with RPA classes I and 
II will be included; Class III patients will be excluded. 
RT will be given as 60-66Gy in once daily fractions (2 Gy per 
fraction). 
Nivolumab will be administered 2 weeks prior to the beginning of 
radiation therapy (1 dose at Week -2) and continue every 2 weeks 
during radiation (4 doses at Weeks 0, 2, 4, 6) for a total of 5 doses. 
Nivolumab will then be given every 4 weeks for 10 additional doses 
for a total of 15 doses of Nivolumab. 
Number of Patients 
From the MIRI study, the 1-year PFS rate for class I and II 
combined was 43.8% (95% CI: 38.6 - 49.7%).  Assuming a one 
sided alpha of 0.05 and an 85% power to detect an improvement in 
1-yr PFS from 40% to 55% we estimate 46 patients will need to be 
accrued in 2.5 years and followed for an additional 2 years 
(estimated maximum total of 51 patients). Accounting for a 20% 
drop out rate, 62 patients will need to be consented.  
Inclusion Criteria 
Patient selection: 
1- Patients with recurrent squamous cell carcinoma or a 
second primary arising in a previously irradiated field 
2- Patients must be ≥ 18 years of age. 
3- Life expectancy of greater than 6 months. 
4- Patients cannot have distant metastases and have to be 
candidates for curative re-irradiation 
5- Patients with salivary gland tumors are excluded (patients 
with nasopharynx CA or sinonasal cancers can participate) 
6- Patients with unresectable disease are eligible. 
7- Patients who undergo surgical resection will be allowed 
regardless of HPV status provided they: have one of the 
following criteria: 1- Positive margins on pathology; 2- 
evidence of extracapsular spread on nodal pathology; 3- 
gross residual disease on postoperative or simulation 
imaging; 4 – N2/3 disease; 5 – T3/4 disease; 6 – multifocal 
perineural invasion and/or lymphovascular space invasion. 
8- The majority of the anticipated target volume (>50%) must 
have been previously treated to ≥40Gy. Prior RT must have 
been completed >6 months prior to initiation of IMRT 
reirradiation. If previous RT records are unavailable, 
investigators can estimate the dose to previously treated 
tissues based on completion notes or other treatment 
history 
9- An ECOG performance score 0-2 
10- Granulocytes >1500/mm3, platelets >100,000/mm3, bilirubin 
<1.5 mg/dl, creatinine <1.5 mg/dl 
11- No other concurrent invasive malignancies treated for the 
past year (localized prostate cancer or early stage skin 
cancer are not exclusion criteria) 

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12- Patients with carotid artery involvement or encasement will 
be allowed provided they have no symptoms related to 
carotid involvement 
13- No prior exposure to immunotherapy agents 
14- Ability to understand and the willingness to sign a written 
informed consent document 
Exclusion Criteria 
1- Any known factors that would pose a contraindication to 
receiving nivolumab 
2- RPA class III patients defined as those expected to begin 
reirradiation within 2 years of first course of radiation 
therapy AND are PEG dependent or have a tracheostomy 
(patients who have undergone total laryngectomy are not 
excluded) 
3- Patients with metastases 
4- Prior treatment with a PD-1/PD-L1 inhibitor. 
5- Female patients of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to 
enrollment. 
6- Patients with primary salivary gland cancers, or non 
squamous histology are excluded. 
7- Patients who have had chemotherapy or biological therapy 
within 4 weeks of the study. 
8- Uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, autoimmune disease requiring 
systemic steroids, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with 
study requirements. 
9- Patients who are pregnant or breast-feeding 
10- Patients with known active HIV, Hep B, or Hep C infection 
11- Subjects with a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily  prednisone  
equivalents) or other immunosuppressive  medications  
within 14 days of study drug administration. Inhaled or 
topical steroids and adrenal replacement doses > 10 mg 
daily prednisone equivalents are permitted in the absence of 
active autoimmune disease. 
Discontinuation 
Criteria 
1- Patients with grade 3 or 4 infusion reaction must not receive 
further treatment with nivolumab. 
2- If treatment is interrupted for >3 consecutive weeks, 
patient’s protocol treatment will be discontinued. 
3- Extraordinary Medical Circumstances: If at any time the 
constraints of this protocol are detrimental to the patient's 
health, the protocol treatment should be discontinued. 
4- Patients who develop progressive disease will be 
discontinued from the protocol therapy. 
5- Patients who develop unacceptable toxicity will be 
discontinued from the protocol therapy. 
6- Patients may withdraw consent and withdraw from the study 
at any time for any reason. 

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SCHEMA 
 
 
 

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TREATMENT STUDY CALENDER 
 
 
Test 
Pre-therapy 
(Day -30 
to -1 before 
Nivolumab) 
Every 2 
weeks during 
each Nivo 
cycle before 
and during 
radiation 
Every 4 weeks 
during each 
Nivo cycle for 
maintenance 
phasek 
Wk 18 and 30 
disease 
assessmenta 
Wk 52 (1yr after 
start of radiation) 
or at the time of 
disease 
progression 
Wk 104 (yr 2 after 
start of radiation) or 
at the time of 
disease progression 
History and physicalb 
X 
Xk 
Xk 
Xk 
X 
X 
Weight and ECOG PS 
X 
Xk 
X 
X 
X 
X 
Tumor 
applicable) 
measurement 
(if X 
X 
X 
X 
CBC and diff c 
X 
X 
X 
X 
X 
Chemistries (Na, CL, CO2, K, 
BUN, Creatinine, Ca, Phos) 
X 
Xk 
Xk 
X 
X 
Liver function paneld 
X 
X 
X 
X 
X 
PT, PTT, INR 
X 
X 
X 
TSH 
X 
X 
X 
X 
Tissue for research purposes - 
fresh biopsy (paraffin embedded if 
fresh tissue not available)e, f 
X 
X 
Blood for research purposes 
X 
X 
X 
X 
X 
Toxicity assessmentg 
X 
X 
X 
X 
X 
QOL assessment 
X 
Wk 
6 
completion 
radiation 
at 
of 
X 
X 
X 
Radiology: 
1. PET/CT 
or 
2. CT- or MRI-neck AND CT- 
chest, CT-abdomen 
for 
tumor measurementsh 
X i 
X 
X 
X 

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Serum B-HCGj 
X 
a. Disease assessments may be done +/- 2 weeks of specified time in protocol to allow for scheduling and/or transportation needs of the patient 
b. If Nivolumab or radiation has to be permanently discontinued due to side effects, H&P must be done 4 and 8 weeks after treatment 
discontinuation. 
c. CBC and diff include WBC, ANC, HCT, HGB, PLT, % lymphocytes, % monocytes, % neutrophils. 
d. Liver function panel includes Alk Phos, total bilirubin, SGOT (AST), SGPT (ALT), total protein. 
e. Fresh biopsy will be obtained before the first treatment when feasible.  If tissue is not obtained, it is not considered a protocol deviation. 
f. Participating sites could have restricted number of research specimens (up to 6 draws per patient) depending on financial constraints; 
g.. Toxicity assessment: Common Toxicity Criteria (CTC) version 4.03 will be used. All toxicity grades (including grade 1) should be captured on 
the case report forms. All toxicities that occurred during treatment and until 100 days following completion of therapy should be followed until 
resolution. 
h Tumor measurement: The scans may be performed within +/- 2 weeks of intended f/u times (wks 18, 30, 52, and 104). Additional scans should 
be obtained as clinically indicated if progression is suspected or symptoms warrant further investigation. No tumor measurements are required 
in the postoperative high risk setting where no gross disease is apparent. 
i. For patients enrolled post salvage surgery, a CT of the Neck and Chest or a PET scan will be required as a baseline study prior to enrollment. 
The sites can use a simulation CT of the Neck and Chest for this purpose. 
j. Pregnancy test should be done in woman of childbearing age who are sexually active and may potentially be pregnant. Prior to study enrollment, 
women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential 
risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing 
potential and should practice an effective method of birth control. All WOCBP MUST have a negative pregnancy test within 7 days prior to first 
receiving Nivolumab. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. 
In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. The Investigator must immediately notify BMS in the event of a confirmed pregnancy in 
a patient participating in the study. 
k. May allow a window of 7 days of delay for labs (CBC diff and Chemistries) and 7 days of delay for nivolumab infusion if nivolumab given every 
4 weeks; may also allow a window of 3 days between History, PE and ECOG PS status and nivolumab infusion (regardless of the nivolumab 
schedule) 
 
  

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................................... 3 
SCHEMA .............................................................................................................................. 6 
TREATMENT STUDY CALENDER ...................................................................................... 7 
TABLE OF CONTENTS ....................................................................................................... 9 
1. 
INTRODUCTION .................................................................................................. 11 
1.1. MEDICAL BACKGROUND ................................................................................... 11 
1.1.1. Treatment of Recurrent Locoregionally Advanced Head and Neck Squamous 
Cell Carcinoma  ...........................................................................................  11 
1.1.2. The Role of Reirradiation in HNSCC ............................................................ 12 
1.1.3. Immunotherapy in HNSCC ........................................................................... 12 
1.1.4. PD-1 and Nivolumab in HNSCC in the context of radiation therapy .............. 13 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT .................... 17 
2.1. RATIONALE FOR PERFORMING THE TRIAL ..................................................... 17 
2.2. TRIAL OBJECTIVES ............................................................................................ 17 
2.2.1. Primary Objective ......................................................................................... 17 
2.2.3.   Secondary Objectives .................................................................................. 17 
3. 
STUDY POPULATION ......................................................................................... 17 
3.1. SELECTION OF STUDY POPULATION .............................................................. 17 
3.1.1. Inclusion Criteria ............................................................................................ 18 
3.1.2. Exclusion criteria:........................................................................................... 18 
3.1.3. Discontinuation Criteria ................................................................................ 19 
3.1.4. Premature Discontinuation of the Study as a Whole..................................... 19 
4. 
STUDY DESIGN AND TREATMENT ................................................................... 19 
4.1 
OVERALL TRIAL DESIGN AND PLAN ................................................................. 19 
4.2 
RADIATION THERAPY ........................................................................................ 19 
4.2.1. IMRT reirradiation .......................................................................................... 19 
4.2.2. Immobilization and Simulation...................................................................... 19 
4.2.3. Target Delineation ........................................................................................ 20 
4.2.4. Critical Normal Structures ............................................................................ 20 
4.2.5. Treatment Planning and Delivery ................................................................. 20 
4.2.6. Image Guidance for IGRT ............................................................................ 20 
4.2.7. Definition of Normal Tissues/Organs at Risk (OARs) .................................... 21 
4.2.8. Dose Prescription ......................................................................................... 22 
4.2.9. Radiation Therapy Treatment Interruptions .................................................. 23 
4.3. NIVOLUMAB ADMINISTRATION: ........................................................................ 23 
4.3.1. Administration of Nivolumab .......................................................................... 23 
4.3.2. Dose delay criteria apply for all drug-related AEs ........................................... 24 
4.3.3. Nivolumab Dose Discontinuation Due to Drug-Related AE(s) ........................ 24 
4.3.4. Criteria to Resume Nivolumab Dosing ........................................................... 25 
4.3.5. Nivolumab Infusion Reactions........................................................................ 25 
4.3.6. Duration of Nivolumab ................................................................................... 26 
4.3.7. Patient Reported Outcomes (PROs) .............................................................. 27 
4.3.8. Nivolumab Dose Levels ............................................................................... 27 
4.3.9. Nivolumab Packaging, Labelling, and Storage ............................................. 27 
4.4. MANAGEMENT 
OF SIDE EFFECTS FOLLOWING TREATMENT WITH 
NIVOLUMAB  
 
 
 
 
 
 ....  27 
4.4.1. Management of immunological toxicities following treatment with nivolumab27 
4.4.2. Management of non-immunological toxicities following treatment with 
nivolumab  
 
 
 
 
 
 .  28 
4.4.4.   Treatment Compliance ................................................................................. 28 
4.5.   ENDPOINTS OF SAFETY .................................................................................... 28 
5. 
ADVERSE EVENTS DEFINITIONS AND REPORTING ....................................... 28 
5.1. ADVERSE EVENT DEFINITION .......................................................................... 28 

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5.2. SERIOUS ADVERSE EVENT DEFINITION .......................................................... 28 
5.3. INTENSITY OF ADVERSE EVENT ...................................................................... 29 
5.4. CAUSAL RELATIONSHIP OF ADVERSE EVENT ................................................ 29 
5.5. ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING .................. 29 
5.6. OTHER REPORTING ........................................................................................... 31 
6. 
BIOMARKER(S) AND CORRELATIVE STUDIES ............................................... 33 
6.1. CORRELATIVE TISSUE RESEARCH .................................................................. 33 
6.2. CORRELATIVES WITH BLOOD .......................................................................... 33 
6.3. PROPOSED BIOMARKER EVALUATIONS ......................................................... 35 
7. 
INVESTIGATIONAL PLAN .................................................................................. 36 
7.1. VISIT SCHEDULE ................................................................................................ 36 
7.2 
SCREENING PERIOD ......................................................................................... 36 
7.3 
END OF STUDY TREATMENT AND FOLLOW-UP PERIOD ............................... 36 
7.4 
DURATION OF THERAPY ................................................................................... 36 
7.5 
DURATION OF FOLLOW-UP ............................................................................... 36 
8. 
STATISTICAL METHODS ................................................................................... 36 
9. 
ADMINISTRATION, HANDLING OF DATA AND SAFETY MONITORING .......... 37 
9.1. PROTOCOL AMENDMENTS ............................................................................... 37 
9.2. INFORMED CONSENT ........................................................................................ 37 
9.3. ETHICS AND GOOD CLINICAL PRACTICE ........................................................ 37 
9.4. REGULATORY AUTHORITIES ............................................................................ 38 
9.5. DATA QUALITY ASSURANCE ............................................................................. 38 
9.5.1 Data Management ....................................................................................... 38 
9.5.2. Meetings and Conference Calls ................................................................... 38 
9.5.3. Monitoring and Auditing ............................................................................... 38 
10. 
COORDINATING CENTER & SITE RESPONSIBILITIES .................................... 40 
10.1. PROTOCOL CHAIR ............................................................................................. 40 
10.2. COORDINATING CENTER .................................................................................. 40 
10.3. PARTICIPATING SITES ....................................................................................... 41 
10.3.1 Staffing ........................................................................................................ 41 
10.3.2. Documentation ............................................................................................. 41 
10.3.3. Confidentiality .............................................................................................. 41 
10.3.4. Record Retention ......................................................................................... 41 
10.3.5. Publication ................................................................................................... 41 
10.3.6. Additional Information .................................................................................. 41 
10.4. RECORDS ........................................................................................................... 42 
10.4.1. Source Documents ...................................................................................... 42 
10.4.2. Direct Access to Source Data and Documents ............................................. 42 
10.5. STATEMENT OF CONFIDENTIALITY ................................................................. 42 
10.6. COMPLETION OF STUDY ................................................................................... 42 
11. 
REFERENCES ..................................................................................................... 43 
12. 
APPENDICES ...................................................................................................... 46 
APPENDIX 1 - PERFORMANCE SCALES ................................................................... 46 
APPENDIX 2 - FACT-G AND FACT-HN QUESTIONNAIRES ....................................... 47 
APPENDIX 3 - PROTOCOL FOR PROCESSING PBMC FROM CPT SODIUM CITRATE 
52 
APPENDIX 4 - PROTOCOL FOR PROCESSING FROZEN TISSUE/BIOPSIES ........... 53 

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1. 
INTRODUCTION 
 
1.1. 
MEDICAL BACKGROUND 
 
1.1.1. Treatment of Recurrent Locoregionally Advanced Head and Neck Squamous 
Cell Carcinoma 
Head and neck squamous cell carcinoma (HNSCC) remains one of the most devastating 
cancers in the United States. The sites affected by HNSCC (oral cavity, oropharynx, 
hypopharynx and larynx) are critical to the complex and vital functions of speech and 
swallowing. Therefore, HNSCC is clinically challenging because the treatment frequently 
alters or destroys a patient’s ability to have oral intake and to communicate verbally. Optimal 
treatment of HNSCC is based on the site and size of the tumor as well as clinical assessments 
of the presence or absence of cervical lymph node metastasis. Large tumors or tumors with 
regional metastases are typically treated with combined modality therapy, including surgery, 
radiation, and/or chemotherapy. Smaller tumors without cervical metastases can often be 
effectively controlled with either surgery or radiation therapy alone. 
Approximately 30-40% of patients irradiated for HNSCC will recur with isolated locoregional 
disease and a substantial number will develop a second primary cancer (1, 2). Treatment of 
these non-metastatic patients with recurrent or second primary (RSP) cancers originating 
within a previously radiated field presents a challenging clinical scenario. Historically, systemic 
therapy alone produced median survival of only 8 months. Re-irradiation of RSP carcinoma 
was associated with significant acute and late morbidity with improved but still modest control 
rates. Attempts to improve outcomes with concurrent chemotherapy and hyper-fractionation 
provided only modest improvements. Overall, the risk benefit ratio of re-irradiation was 
questionable in many of these “curable” patients. 
Therapeutic advances, such as the use of multi-modality therapies, have significantly 
improved survival of advanced-stage HNSCC patients over the past 10-15 years (3-5). 
However, still 30-40% of patients have recurrences (1, 2). There has been little improvement 
in survival for patients who have locoregional or metastatic recurrence. Chemotherapeutic 
agents employed in the management of locally recurrent and/or metastatic HNSCC have 
response rates in the range of 10-40% (6-11). Unfortunately, the duration of response is 
limited (2-4 months) and survival advantage has not been shown beyond the median survival 
of 6-10 months (12, 13). 
Immunotherapy has recently become an attractive option in HNSCC. PD-1 is one of the 
clinically significant checkpoint molecules that have been shown to suppress T-cell function 
upon binding to its ligands, PD-L1 and PD-L2, which have been shown to be expressed in 
tumor cells from both preclinical models and clinical settings of cancer patients undergoing 
immunotherapy (14, 15). Tumor expression of PD-L1 was tightly correlated with clinical 
responsiveness to nivolumab in the early clinical trials, supporting the adaptive immune 
resistance hypothesis (16). Both human papilloma virus (HPV)-positive and HPV-negative 
HNSCC have been shown to express PD-L1 (17, 18). Nivolumab is a potent and highly 
selective humanized monoclonal antibody that binds PD-1 and blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. A phase III clinical trial comparing nivolumab vs. 
investigator’s choice (IC) chemotherapy (methotrexate, docetaxel, or cetuximab) in patients 
with recurrent and/or metastatic HNSCC showed an overall survival (OS) benefit with 
nivolumab (7.5 months median OS) vs IC chemotherapy (5.1 months) (HR 0.7, P=0.01) and 
minimal toxicities (19). Objective response rate was 13% with nivolumab versus 5.8% with IC. 
In a subset analysis, patients with PD-L1 expression had higher response rates compared to 
patients without PD-L1 expression, and HPV-positive patients showed longer OS compared 
to HPV-negative patients. Although these are encouraging results, the clinical benefit was 
seen in only a limited number of patients. Thus, identification of combination regimens is 
urgent in the management of HNSCC. With long term follow up (a median follow up of   11.4 

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months), nivolumab continued to significantly outperform chemotherapy with a significantly 
superior overall survival (p=0.0048) (ASCO 2017 (20)). 
 
1.1.2. The Role of Reirradiation in HNSCC 
With the advent of advanced radiation planning techniques (e.g. IMRT, VMAT), the feasibility 
and safety of re-irradiation has greatly improved, as has the therapeutic ratio. A recent multi- 
institutional collaborative study (named MIRI) of over 400 patients treated with IMRT based 
re-irradiation at 8 institutions, found that the overall acute grade 4-5 toxicity was only 5.6%, 
and grades ≥3 late toxicity was only 13% at two years. Overall, the 2-yr (40%) and 5-yr (22%) 
survival rates compared favorably to historical data (21). Most importantly, a recursive 
portioning analysis identified three distinct subgroups of patients with 2-yr OS of 62%, 40% 
and 17%, respectively, for classes I, II and III (21). This finding underscores the suboptimal 
outcomes in class III patients (e.g. <2 years between the first and planned second RT courses 
and in patients with pre-re-irradiation gastrostomy or tracheostomy tubes) for whom prolonged 
conventionally fractionated IMRT based re-irradiation may not be of benefit. On the other 
hand, IMRT based re-irradiation produces better results in patients with class I (e.g. >2 yrs 
between the first and planned second RT courses, and for patients managed with initial 
resection followed by post-op re-irradiation) and class II disease (e.g. all others), the 
associated 2 yr overall survival of 50% underscores the need for further improvements to this 
treatment paradigm in these patients. In a subset analysis of the MIRI collaborative study, the 
addition of systemic therapy (platinum or cetuximab based) did not appear to positively impact 
outcomes. 
 
1.1.3. Immunotherapy in HNSCC 
This study seeks to investigate the potential benefit of the addition of adjuvant immunotherapy 
to IMRT based re-irradiation in RPA Class I and II patients with RSP head and neck squamous 
cancer (21). Targeted immunotherapy has resulted in improved survival and durable objective 
responses in different solid tumors and offers a rationale for use in HNSCC (22). PD-L1 
expression is observed in close to 68% of HNSCC patients regardless of HPV status (23, 24). 
Furthermore immune checkpoint inhibitors (CPIs) such as the PD-1 inhibitor nivolumab were 
recently noted to have a significant clinical activity in heavily pre-treated patients with HNSCC 
regardless of the HPV status (25). The results from Checkmate-141 a phase III trial 
randomizing patients with recurrent or metastatic platinum-refractory HNSCC to nivolumab 
versus investigator’s choice (IC) of chemotherapy, have shown a doubling of the 1-year overall 
survival (OS) (36.0% versus 16.6%, p= 0.0101)(25, 26). The median OS was 7.5 vs. 5.1 
months for nivolumab vs. IC (HR 0.70, p = 0.01). OS by PD-L1 status was 8.7 vs. 4.6 months 
for PD-L1+ > 1% versus PD-L1 < 1%. Longer-term follow-up data (presented at ASCO 2017 
(20)) show that nivolumab continued to show a significant survival benefit and better tolerability 
vs IC in patients with platinum-refractory R/M HNSCC. At 11.4-months minimum follow-up, 
median OS (95% CI) was 7.7 months (5.7, 8.8) for nivolumab vs 5.1 months (4.0, 6.2) for IC; 
HR (95% CI) = 0.71 (0.55, 0.90); P = 0.0048. For nivolumab vs IC, the 18-mo OS rate was 
21.5% vs 8.3% and ORR was 13.3% vs 5.8%. Nivolumab doubled the median duration of 
response vs IC (9.7 vs 4.0 months). Grade 3–4 treatment-related adverse event rates for 
nivolumab vs IC were 15.3% vs 36.0%. 
 
Data reported at the ESMO 2016 meeting indicated that patients receiving nivolumab had a 
preservation of their quality of life measures compared to patients receiving chemotherapy. 
This supports the use of nivolumab in a heavily pre-treated patient population who are at high 
risk of recurrence and disease related mortality such as patients with re-irradiation. 
 
Data from another a single arm study in recurrent/metastatic HNSCC treated with 
pembrolizumab (N=132) showed an ORR 18%; with 71% of responses lasting > 12 months 
and including both PD-L1 + and PD-L1- disease. The median progression free survival was 2 
months (17% at 12 months) and median OS was 8 months (27). This led the FDA in  August 

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of 2016 to approve pembrolizumab for treating recurrent or metastatic HNSCC that has 
progressed following platinum based therapy and further underscores the rationale for moving 
forward with this approach. Further data from a phase II expansion study using a fixed dose 
of pembrolizumab in patients who failed platinum and cetuximab revealed an overall response 
rate of close to 18% in this heavily pre-treated patient population (28). 
 
Given these initial exciting results in patients with advanced HNSCC, there is strong rationale 
for the addition of PD-1 inhibition to an IMRT re-irradiation backbone. This study explores this 
combination therapy against the standard IMRT re-irradiation alone. 
 
1.1.4. PD-1 and Nivolumab in HNSCC in the context of radiation therapy 
Immunotherapy has now emerged as an alternative approach based on recent success in 
melanoma, lung and renal cell cancer. Checkpoint inhibitors and CTLA-4 inhibitors are being 
investigated in HNSCC in both the recurrent/metastatic setting with recently reported 
promising results (26, 28) and in the definitive setting with CTLA-4 inhibitors (ipilimumab). 
Pembrolizumab, a PD-1 blocker, was recently shown in a Phase I trial to have promising 
response outcomes in HPV+ recurrent HNSCC. 
The effects of standard of care therapy on immune response (CD4(+), CD8(+) T cells, 
regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC)) in HNSCC suggest 
an immunosuppressive effect. Standard chemoradiotherapy and radiotherapy to both sites of 
gross and elective risk nodal regions in HNSCC have been found to reduce circulating T cell 
responses and upregulate MDSCs. PD-1 expression on CD4(+) T cells is upregulated by 2- 
fold after CRT. PD-1 blockade resulted in downregulation of MDSC, as well as TAM, 
CD47/SIRP pathway, and upregulated effector T cells and dendritic cells. Lower doses of 
radiotherapy without chemotherapy after surgery for HPV+ OPC may create an optimal 
microscopic tumor microenvironment that promotes neo-antigen expression and an abscopal 
effect without promoting a negative immunosuppressive environment. Combining this 
approach with PD-1 inhibition may lead to non-redundant immune response through several 
pathways that is additive and sustained. 
PD-L1 and PD 1 expression may be virally mediated in HNSCC, and represent a potential 
biomarker to blockage with checkpoint inhibitors (29). PD-L1 expression however is variable 
and not clearly understood. HPV-SCC have also been shown in RNA sequencing TCGA data 
to express PD-L1. It remains unclear, as to the optimal method of PD-L1 measurement for 
patient stratification for future trials or whether PD-L1 expression predicts for response to 
checkpoint inhibitors. This has led to a search for other tumor biomarkers in addition to 
immune cell profiling to refine patient selection. Somatic gene alterations in HNSCC 
responsible for immune evasion, inflammation, and antigen presentation may play a role in 
response to checkpoint inhibition (30). Other investigations reported in metastatic solid tumors 
include possible association between checkpoint response and genomic instability due to 
mismatch repair deficiency leading to immune stimulation against epitopes (31), mutational 
burden and improved outcomes in melanoma and NSCLC with checkpoint inhibitors (32) and 
the possible correlation between neoantigen burden and response to immunotherapy. 
Neoantigen specific T-cell therapy that exposes epitopes derived from genetic aberrations has 
demonstrated promising results when combined with checkpoint inhibition (33-36). 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds to PD-1. Blockade of the 
PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 
blockade resulted in a reproducible enhancement of both proliferation and IFN-γ release in 
the MLR.30. The effect of nivolumab on antigen-specific recall responses was investigated 
using a CMV-restimulation assay of human peripheral blood mononuclear cells (PBMCs) 
followed by ELISA-based detection of IFN-γ production. These data indicated that nivolumab, 
versus an isotype-matched control antibody, augmented IFN-γ secretion from CMV-specific 
memory T cells in a dose-dependent manner. 

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Summary of Nivolumab Clinical Activity in the Metastatic Setting: 
The PK, clinical activity, and safety of nivolumab have been assessed in approximately 32 
clinical studies sponsored by BMS. Approximately 7,600 subjects have received nivolumab in 
single- or multiple-dose Phase 1/2/3 studies or studies with nivolumab in combination with 
other therapeutics (ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies). 
 
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor types, 
including melanoma, RCC, and NSCLC. Clinical activity was noted across a range of doses 
(0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg). In CA209003, a total of 306 subjects 
with melanoma, RCC, and NSCLC have been evaluated for clinical activity. A response of 
either CR or PR, as determined by investigator assessed tumor evaluations based on RECIST 
1.1 criteria108, has been reported at all dose levels. 
 
In NSCLC, the most active doses were 3 and 10 mg/kg. The overall ORR of 17% was reported 
with a 48-week progression-free survival rate (PFSR) of 22% (95% CI: 15-30%), and a 24- 
month overall survival rate of 24% (95% CI: 16-32%). Only a single response (1/33) was 
reported at 1 mg/kg. Durable responses were observed in both squamous and non-squamous 
subtypes. 
 
Historically, ORR of 5% to 10% and median PFS (mPFS) of 2 to 3 months has been reported 
with docetaxel treatment in previously-treated NSCLC subjects. A complete response (CR) or 
partial response (PR) was reported in 31% (95% CI: 22% - 41%) of the 107 response- 
evaluable subjects with melanoma treated with nivolumab monotherapy Q2W at doses 
ranging from 0.1 to 10 mg/kg in CA209-003. Responses were durable with a PFSR at 24 
weeks of 38% (95% CI: 28-47%) and OS at 24 months of 48% (95% CI: 38-57%). 
 
In CA209017, a phase 3 trial in 272 patients with metastatic squamous NSCLC with 
progression on or after platinum-based chemotherapy, subjects were randomized to 
nivolumab 3 mg/kg IV q2 week (n=135) or docetaxel (n=137) at 75 mg/m2 every 3 weeks. 
Median OS was 9.2 months in the nivolumab group (95% CI: 7.3-13.3) vs 6.0 months in the 
docetaxel group (95% CI: 5.1-7.3) (HR of 0.59, P=0.00025). 
 
Summary of Nivolumab Safety in the Metastatic Setting 
In clinical trials, nivolumab has demonstrated an acceptable benefit-risk across multiple tumor 
types, including advanced melanoma, RCC, NSCLC, and some lymphomas. The two clinical 
trials that have contributed the most to the clinical experiences of nivolumab monotherapy are 
studies CA209003 and CA209037. Overall, the safety profile is quite similar between these 
two studies and is discussed further in the sections below. CA209003 is a completed Phase 
1 open label, multiple dose escalation study in 306 subjects with select previously treated 
advanced solid tumors, including melanoma, RCC, NSCLC, colorectal cancer, and hormone- 
refractory prostate cancer. Subjects received nivolumab at doses of 0.1, 0.3, 1, 3, or 10 mg/kg 
intravenously every 2 weeks, up to a maximum of 2 years of total therapy. A total of 306 
subjects were treated with nivolumab in the dose range of 0.1 - 10 mg/kg. No maximal 
tolerated dose was identified in CA209003. 
 
The incidence, severity and relationship of AEs were generally similar across dose levels and 
tumor types. Nivolumab related AEs of any grade occurred in 75.2% of subjects. Of the 306 
treated subjects, 303 (99.0%) subjects have at least 1 reported AE regardless of causality. 
The most frequently reported AEs were fatigue (54.9%), decreased appetite (35.0%), diarrhea 
(34.3%), nausea (30.1%), and cough (29.4%). Treatment-related AEs were reported in 230 
(75.2%) of the 306 subjects. The most frequently reported treatment-related AEs were fatigue 
(28.1%), rash (14.7%), diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs 
were low grade. Treatment-related high grade (Grade 3-4) AEs were reported in 52 (17.0%) 
of subjects. The most common treatment-related high grade AEs were fatigue (2.3%) and 

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diarrhea (1%). Drug-related SAEs occurred in 11.5% of subjects. Grade 3-4 drug-related 
SAEs reported in  at  least  2  subjects  included:  diarrhea (3 subjects, 1.0%),  pneumonitis 
(3 subjects, 1.0%), pneumonia (2 subjects, 0.7%) and lipase increased (2 subjects, 0.7%). 
Select AE categories (events with a potential inflammatory mechanism requiring more 
frequent monitoring and/or unique intervention such as immune-suppressants and/or 
endocrine replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin 
AEs, and endocrinopathies. In addition, select AEs include  a  category  for  infusion reactions 
Table 1). Each category is composed of a discrete set of preferred terms, including those of 
greatest clinical relevance. These select AEs are considered events of interest based on the 
mechanism of action and were previously referred to as immune-related AEs or immune-
mediated AEs. Most high grade events resolved following the treatment guidelines for the 
treatment of pulmonary events, GI events, hepatic events, renal events, and endocrine events, 
respectively. Overall, the safety profile at 3 mg/kg (n = 54) was similar to safety profile across 
the dose ranges from 0.1 mg/kg to 10 mg/kg (n = 306). 
 
Table 1: 
Treatment-related Select Adverse Events by Treatment - All CTC 
Grades Reported in at Least 10 Treated Subjects in CA209003 
Preferred Term 
3mg/kg n=54 
Total (0.1 to 10 mg/kg) N=306 
Any Grade 
Grade 3-4 
Any Grade 
Grade 3-4 
Any Select AE 
23 (43) 
2 (4) 
140 (46) 
19 (6) 
Any Endocrinopathies 
4 (7) 
0 
29 (10) 
3 (1) 
Endocrinopathies Thyroid 
4 (7) 
0 
26 (9) 
2 (1) 
Blood TSH increased 
2 (4) 
0 
11 (4) 
1 (0.3) 
Hypothyroidism 
1 (2) 
0 
11 (4) 
1 (0.3) 
Any Skin AEs 
12 (22) 
0 
75 (25) 
1 (0.3) 
Rash 
5 (9) 
0 
45 (15) 
0 
Pruritus 
3 (6) 
0 
32 (11) 
1 (0.3) 
Any GI AE 
7 (13) 
0 
43 (14) 
3 (1) 
Diarrhea 
6 (11) 
0 
41 (13) 
3 (1) 
Any hepatic AE 
3 (6) 
2 (4) 
18 (6) 
4 (1) 
ALT increased 
1 (2) 
0 
11 (4) 
1 (0.3) 
Any Pulmonary AE 
2 (4) 
0 
17 (6) 
6 (2) 
Pneumonitis 
1 (2) 
0 
12 (4) 
4 (1) 
Other Select AE 
3 (6) 
0 
15 (5) 
2 (1) 
Infusion-related reaction 
3 (6) 
0 
12 (4) 
0 
Abbreviations: ALT: alanine aminotransferase, TSH: thyroid stimulating hormone 
Source: MDX1106-03. Clinical data cut-off date: 18-Mar-2013 
Total includes subjects who also received 0.1 mg/kg (n = 17), 0.3 mg/kg (n = 18), 1 mg/kg (n 
= 86), and 10 mg/kg (n = 131) in addition to those illustrated at 3 mg/kg (n = 54). 
 
Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the 306 
nivolumab treated subjects on CA209003. The most frequent of these were pneumonitis (8 
subjects; 2.6%) and colitis (3 subjects; 1.0%). There were 3 (1%) drug related deaths; each 
occurred after development of pneumonitis. CA209037 is an ongoing Phase 3, open-label 

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study of nivolumab (3 mg/kg administered by intravenous [IV] infusion every 2 weeks [Q2W]) 
vs investigator’s choice therapy in subjects with previously-treated advanced melanoma. As 
of 30-Apr-2014, 268 subjects have been treated with 3 mg/kg IV nivolumab in CA209037 with 
safety results as outlined below (source document interim CSR, DCN930081508) 111 that are 
consistent with the Phase 1 experience of CA209003. 
 
In CA209037, nivolumab related AEs of any grade occurred in 67.5% of subjects. Of the 268 
subjects treated with nivolumab, 255 (95.1%) subjects had at least 1 reported AE regardless 
of causality. The most frequently reported treatment-related AEs were fatigue (25.0%), 
pruritus (16.0%), diarrhea (11.2%), and nausea (9.3%). Most treatment-related AEs were low 
grade. 
 
Treatment-related high grade (Grade 3-4) AEs were reported in 24 (9.0%) of subjects. The 
most common treatment-related high grade AEs were fatigue (0.7 %), anemia (0.7%), diarrhea 
(0.4%), and vomiting (0.4%). Drug-related SAEs occurred in 4.5% of subjects. Grade 3-4 drug- 
related SAEs reported in at least 2 subjects included diarrhea (2 subjects, 0.7%). In addition, 
drug-related SAE of hyperglycemia occurred in 0.7%. 
 
Select AE categories (events with a potential inflammatory mechanism requiring more 
frequent monitoring and/or unique intervention such as immunosuppressants and/or 
endocrine replacement therapy) were: 
• 
Skin (29.1%) including pruritus (16.0%) and rash (9.3%) 
• 
GI (11.6%) including diarrhea (11.2%) and colitis (1.1%) 
• 
Endocrine (7.8%) including hypothyroidism (7.8%) and hyperthyroidism (1.9%) 
• 
Hepatic (4.5%) including AST increased (4.1%) and ALT increased (2.6%) 
• 
Pulmonary (2.2%) including pneumonitis (1.9%) 
• 
Hypersensitivity/infusion reaction (1.9%) 
• 
Renal (1.5%) including increased creatinine (0.7%), increased urea (0.4%), and 
tubulointerstitial nephritis (0.4%) 
 
In general, these select AEs were considered by the investigator to be related to study drug, 
except for AEs in the hepatic and renal select AE categories. There were few high-grade select 
adverse events (n = 20), and the majority of high-grade events (13 of 20) subsequently 
resolved, including those for which immunosuppressive therapy was not initiated. Treatment- 
related AEs leading to discontinuation were reported in 6 (2.2%) of the 268 nivolumab treated 
subjects in CA209037 including single events of colitis, pancreatitis, increased ALT, increased 
lipase, autoimmune neuropathy, and demyelination. In CA209037, one subject experienced 
drug-related grade 5 hypoxias, possibly pneumonitis, in the setting of lymphangitic spread 
and possible pneumonia. 
 
Taken together, these data from studies from CA209003 and CA209037 highlight the 
acceptable safety profile with similar trends in AEs in the 574 subjects treated with nivolumab 
in these 2 studies. Additional details on the safety profile of nivolumab, including results from 
other clinical studies, are also available in the BMS-936558 (nivolumab) IB. 
 
In addition, Nivolumab has been studied in the phase I portion of the RTOG 3504 trial in which 
it was seen to be safe to combine with head and neck radiotherapy and cisplatin based 
chemotherapy. Similarly, other PD-1 inhibitors are being actively investigated in a phase III 
setting with concurrent radiotherapy with or without other systemic therapies. As such, an 
adequate experience of a favorable safety profile supports the anticipated safety of this 
combination without other cytotoxic chemotherapy and no specific safety run-in is required. 

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2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT 
 
2.1. 
RATIONALE FOR PERFORMING THE TRIAL 
This study seeks to investigate the potential benefit of the addition of adjuvant immunotherapy 
to IMRT based re-irradiation in RPA Class I and II patients with locoregional recurrent or 
second primary (RSP) head and neck squamous cancer. Our hypothesis is that nivolumab 
will lead to an improved disease control in this population at high risk of relapse which will 
translate into an improved 1 year progression-free survival (PFS) compared to the standard 
re-irradiation with IMRT. We also believe based on the recent PRO data presented at ESMO 
2016, that nivolumab will preserve the quality of life in this heavily pre-treated patient 
population. Given these initial exciting results in patients with advanced head and neck 
squamous cancer, there is strong rationale for the addition of PD-1 inhibition to an IMRT re- 
irradiation backbone. This study explores this combination therapy against the standard IMRT 
re-irradiation with or without other systemic therapies used in the MIRI cohort. 
 
2.2. 
TRIAL OBJECTIVES 
 
2.2.1. Primary Objective 
To assess the 1-year PFS for patients with recurrent or second primary head and neck 
squamous cancer treated with IMRT re-irradiation with concurrent and adjuvant nivolumab 
 
2.2.3.   Secondary Objectives 
1- Evaluate the 1-yr OS of patients treated with re-irradiation and nivolumab 
2-   Evaluate patient QOL 
3- Evaluate patterns of failure including local, regional and distant failure rates at 1yr 
4- Identify and estimate the incidence rate of acute and late toxicities associated with 
combined re-irradiation and concurrent and adjuvant nivolumab 
 
Exploratory Objectives: 
To identify potential biomarkers related to clinical benefit to concurrent and adjuvant nivolumab 
and re-irradiation in patients with RSP HNSCC. 
 
3. 
STUDY POPULATION 
Number of Centers 
Three sites will be involved. 
 
Number of Participants 
A total of 46 patients will need to be accrued in 2.5 years and followed for an additional 2 years 
(estimated maximum total of 51 patients). Accounting for a 20% drop out rate, 62 patients will 
need to be consented.  
3.1. 
SELECTION OF STUDY POPULATION 
Main Diagnosis for Study Entry 
All patients included in this trial must be candidates for re-irradiation with IMRT 
 
3.1.1. Inclusion Criteria 
1- Patients with recurrent squamous cell carcinoma or a second primary arising in a 
previously irradiated field 

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2- Patients must be ≥ 18 years of age. 
3- Life expectancy of greater than 6 months. 
4- Patients cannot have distant metastases and have to be candidates for curative re- 
irradiation 
5- Patients with salivary gland tumors are excluded (patients with nasopharynx CA or 
sinonasal cancers can participate) 
6- Patients with unresectable disease are eligible. 
7- Patients who undergo surgical resection will be allowed regardless of HPV status 
provided they: have one of the following criteria: 1- Positive margins on pathology; 2- 
evidence of extracapsular spread on nodal pathology; 3- gross residual disease on 
postoperative or simulation imaging; 4 – N2/3 disease; 5 – T3/4 disease; 6 – multifocal 
perineural invasion and/or lymphovascular space invasion. 
8- The majority of the anticipated target volume (> 50%) must have been previously treated 
to ≥40Gy; Prior RT must have been completed >6 months prior to initiation of IMRT 
reirradiation. If previous RT records are unavailable, investigators can estimate the dose 
to previously treated tissues based on completion notes or other treatment history. 
9- An ECOG performance score 0-2 (see Appendix 1) 
10- Granulocytes >1500/mm3, platelets >100,000/mm3, bilirubin <1.5 mg/dl, creatinine <1.5 
mg/dl 
11- No other concurrent invasive malignancies treated for the past year (localized prostate 
cancer or early stage skin cancer are not exclusion criteria); 
12- Patients with carotid artery involvement or encasement will be allowed provided they have 
no symptoms related to carotid involvement; 
13- No prior exposure to immunotherapy agents 
14- Ability to understand and the willingness to sign a written informed consent document 
 
3.1.2. Exclusion criteria: 
1- Any known factors that would pose a contraindication to receiving nivolumab 
2- RPA class III patients defined as those expected to begin reirradiation within 2 years of 
first course of radiation therapy AND are PEG dependent or have a tracheostomy 
(patients who have undergone total laryngectomy are not excluded) 
3- Patients with metastases 
4- Prior treatment with a PD-1/PD-L1 inhibitor. 
5- Female patients of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to enrollment. 
6- Patients with primary salivary gland cancers are excluded. 
7- Patients who have had chemotherapy or biological therapy within 4 weeks of registration. 
8- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
autoimmune disease requiring systemic steroids, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
9- Patients who are pregnant or breast-feeding 
10- Patients with known active HIV, Hep B, or Hep C infection 
11- Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days 
of study drug administration. Inhaled or topical steroids and adrenal replacement doses 
> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
 
3.1.3. Discontinuation Criteria 
Patients will be removed from study when any of the following criteria applies: 
- 
Patients with grade 3 or 4 infusion reaction must not receive further treatment with 
nivolumab 

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- 
If radiotherapy is interrupted for > 3 consecutive weeks, patient’s protocol treatment will 
be discontinued. 
- 
Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, the protocol treatment should be discontinued. 
- 
Patients who develop progressive disease will be discontinued from the protocol therapy. 
- 
Patients who develop unacceptable toxicity will be discontinued from the protocol 
therapy. 
- 
Patients may withdraw consent and withdraw from the study at any time for any reason. 
 
3.1.4. Premature Discontinuation of Patients from the Study 
Those who discontinue protocol therapy early will be followed for response until progression 
and for survival for 2 years from the date of initiation of radiation. Patients removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
 
4. 
STUDY DESIGN AND TREATMENT 
 
4.1       OVERALL TRIAL DESIGN AND PLAN 
This will be a phase II single arm study of IMRT re-irradiation in combination with nivolumab 
in the concurrent and maintenance setting. IMRT based reirradiation must be used. VMAT 
and Cyberknife technologies will be allowed. 
 
Treatment plan: 
 
RT will be given as 60-66Gy in 30-33 once daily fractions. Nivolumab will be given 2 
weeks prior to the initiation of IMRT (week -2), and every 2 weeks for 4 more doses 
during radiation (weeks 0, 2, 4, 6) (240 mg over 30-60 minutes IV each dose, for a total 
of 5 doses). After the completion of IMRT, nivolumab will be given on a q4wk schedule 
for  an  additional  10  treatments  (480  mg  over  30-60  minutes  IV  each  dose4.2 
RADIATION THERAPY 
 
4.2.1. IMRT reirradiation 
IMRT reirradiation will be delivered in 60-66Gy in 30-33 once daily fractions over 6-6.5 weeks. 
Missed treatments due to holidays or logistic reasons can be compensated for by delivering 
an additional BID treatment during the week, OR treating on the Saturday or Sunday of that 
week, OR adding to the end of treatment. 
 
4.2.2. Immobilization and Simulation 
Patients must have an immobilization device (e.g. Aquaplast mask) made prior to treatment 
planning CT scan. Use of an immobilizing mouthpiece is optional as clinically indicated but 
preferred for any target of the oropharynx, or the hard palate/paranasal region. It is preferable 
to perform treatment planning CT scan with IV contrast if there are no medical 
contraindications to the use of contrast. The treatment planning CT scan must be performed 
with the immobilization device and in the treatment position. Slice thickness should be 0.3 cm 
or thinner. 
 
4.2.3. Target Delineation 
In setting of gross disease: In the setting of gross disease, the gross tumor volume (GTV) is 
defined as any tumor visible on imaging and/or physical exam. The Clinical Target Volume 
(CTV_66) is defined as the GTV plus an additional 3-5mm expansion that includes adjacent 
tissue at risk but respects normal tissue boundaries to tumor spread (e.g. bone, uninvolved 
muscle, etc).   Generally an elective nodal volume will not be targeted.  However, there   are 

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several instances where an optional CTV_56.1 can be used to target initially uninvolved 
adjacent tissue for select patients with high risk of microscopic disease extent. Examples may 
include gross multifocal nodal disease, in which a CTV_56.1 can target an adjacent uninvolved 
nodal echelon to provide margin on the involved nodes, or disease that is grossly involving a 
cranial nerve for which a CTV_56.1 can be used to target the pathway of the nerve to the skull 
base. The Planning Target Volume (PTV_66) should be a 3mm isotropic expansion around 
CTV_66. If a CTV_56.1 is used, then a 3mm isotropic expansion around it will be generated 
to create the PTV_56.1.  This volume should be given in 33 fractions. 
 
In high risk postoperative setting 
There is no gross tumor volume in the postoperative patient. However, the tumor/involved 
nodal bed should be included in the CTV_60Gy. Areas that are surgically dissected but 
uninvolved with tumor (e.g. elective neck dissection that is negative for disease) should 
generally not be targeted. However, there are several instances where an optional CTV_54 
can be used to target adjacent tissue for select patients with high risk of microscopic disease 
extent. Examples may include pathologically proven multifocal nodal disease, in which a 
CTV_54 can target an adjacent uninvolved nodal echelon to provide margin on the involved 
nodes, or disease that is grossly involving a cranial nerve for which a CTV_54 can be used to 
target the pathway of the nerve to the skull base. The Planning Target Volume (PTV_60) 
should be a 3mm isotropic expansion around CTV_60. If a CTV_54 is used, then a 3mm 
isotropic expansion around it will be generated to create the PTV_54. This volume should be 
given in 30 fractions. 
 
 
4.2.4. Critical Normal Structures 
The normal tissue volume to be contoured will depend on the site of origin of the cancer. For 
all patients, they will include the brainstem, spinal cord, cochlea, mandible, constrictors, 
esophagus, trachea, oral cavity, glottis/supraglottic larynx, supraglottis, lips and parotid and 
submandibular salivary glands. Any of these structures surgically removed or absent can be 
ignored. The carotid artery should also be contoured. For tumors near the low neck, the 
brachial plexus must be contoured. For tumors near the skull base, the following should also 
be included: eyes, lenses, optic nerves, optic chiasm, and pituitary. 
 
4.2.5. Treatment Planning and Delivery 
Megavoltage energy photon beam irradiation is required. Inverse planning using intensity 
modulated RT or Cyberknife is mandatory. Static beam intensity modulation or volumetric arc 
based planning are acceptable for planning.  Proton therapy is not allowed. 
 
4.2.6. Image Guidance for IGRT 
IGRT with daily conebeam CT is required. If a cone beam CT is not available, portal images 
or other on board imaging should be used daily. Region-of-Interest (ROI) or “clip box” for fusion 
should be set to encompass the PTV and adjacent spinal cord. When the skull base is 
targeted, the globes and optic nerves should routinely be included, if possible, for alignment 
purposes. Following the registration, the translational and (if the appropriate technology is 
available) rotational corrections should be applied to the treatment couch. If all the variances 
are less than 10 mm (this typically corresponds to one half of the usual PRV margin), the 
treatment can proceed with appropriate corrections; however, re-imaging is not mandatory. If 
one or more of the corrections are larger than 10 mm, the imaging must be repeated in addition 
to performing table/positioning adjustments. However, the use of numerous repeat IGRT 
studies should be avoided (see next section). 

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4.2.7. Definition of Normal Tissues/Organs at Risk (OARs) 
NOTE: Only the parts of the normal tissues/organs at risk outside the PTVs will be considered 
for dose optimization purposes, except for the spinal cord and brainstem. Only those OAR that 
are in proximity to the treatment volume must be contoured. Contouring OAR that are far from 
the treated area and will receive negligible doses is unnecessary. 
 
Spinal Cord: The cord begins at the cranial-cervical junction (ie, the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior 
border of the spinal cord volume will be defined at approximately T3-4 (ie, just below the lowest 
slice level that has PTV on it). The spinal cord shall be defined based on the treatment planning 
CT scan. In addition, however, a Planning Risk Volume (PRV) spinal cord shall be defined as: 
SpinalCord_05 = cord + 5 mm in all directions. 
 
Brain Stem: The inferior most portion of the brainstem is at the cranial-cervical junction where 
it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall 
be defined based on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) brainstem shall be defined as: BrainStem_03 = brainstem + 3 mm in all 
directions. 
 
Globe of the eye: Self-explanatory 
Optic Nerve: Self-explanatory 
Optic Chiasm: Self-explanatory 
Cochlea: Self-explanatory 
Carotid Artery: This will include the carotid artery at the same level of the PTV plus an 
additional 2cm cranial and caudal to the level of the PTV. When the PTV is located above the 
carotid bifurcation, only the internal carotid artery (not the external branch) should be 
contoured. 
 
Lips: The definition of lips is self-explanatory. 
 
Oral Cavity: The oral cavity will be defined as a composite structure posterior to lips consisting 
of the anterior 1/2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and superiorly the 
palate, and inferiorly to the plane containing the tip of the mandible. 
 
Parotid Glands: Parotid glands will be defined in their entirety (superficial and deep lobes) 
based on the treatment planning CT scan. 
 
Submandibular Glands: Submandibular glands will be defined in their entirety based on 
treatment planning CT scans. 
 
Pharynx: This will be defined as the pharyngeal wall plus adjacent constrictor muscles deemed 
not to require treatment (external to PTVs). This extends from the superior constrictor region 
(level of the inferior pterygoid plates) to the cricopharyngeal inlet (level of the posterior cricoid 
cartilage). 
 
Esophagus: This will be defined as the cervical or superior (S) esophagus, a tubular structure 
that starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic inlet. 

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Glottic/Supraglottic Larynx: This will be defined as the glottic and supraglottic larynx, including 
the tip of the epiglottis, the aryepiglottic folds, arytenoids, false cords, and true cords, bounded 
by the thyroid cartilage laterally, anteriorly including the anterior edge of the pre-epiglottic fat, 
and posteriorly bounded by the anterior edge of the pharyngeal wall or the posterior edge of 
the arytenoid and/or cricoid cartilage. 
 
Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with PTVs. 
 
Brachial Plexus: The defined ipsilateral brachial plexus originates from the spinal nerves 
exiting the neuroforamine on the involved side from around C5 to T2. However, for the 
purposes of this protocol, only the major trunks of the brachial plexus will be contoured using 
the subclavian and axillary vessels as a surrogate for identifying the location of the brachial 
plexus. This neurovascular complex will be contoured starting proximally at the bifurcation of 
the brachiocephalic trunk into the jugular/subclavian veins (or carotid/subclavian arteries) and 
following along the route of the subclavian vein to the axillary vein ending after the 
neurovascular structures cross the second rib. 
 
Unspecified Tissue Outside the Targets (E-PTV): This will be defined as tissue located 
between the skull base and thoracic inlet external to all PTVs and defined normal structures 
within the external contour of the patient. 
 
Skin: This will be defined as an inner ring of tissue comprising the external skin and the tissue 
3mm underneath it. 
4.2.8. Dose Prescription 
Doses to PTVs 
All plans must be normalized such that 95% of the volume of the prescription PTV (PTV_66 
for gross disease; PTV_60 for postoperative cases) is covered with the prescription dose 
(66Gy or 60Gy respectively). At 1 cc PTV_66 volume or PTV_60 volume on the DVH curve, 
the dose should not be > 110% of the prescribed dose. Ideally, less than 10% of PTV_66 or 
PTV_60 should receive 105% of the prescription dose (69.3Gy or 63.5Gy respectively). 
However, up to 20% of PTV_66 or PTV_60 can receive 105% of the prescription dose (69.3Gy 
or 63.5Gy) to allow for meeting dose constraints. For any volume of tissue outside the PTV(s) 
that has a size of 1 cc or more, the dose should not be > 66 Gy for definitive cases and >60Gy 
for postoperative cases. 
 
Doses to Normal Structures 
Spinal Cord: The cumulatibe dose to the spinal cord should not exceed 52Gy. In the event 
that the old plan is not available for review, the dose to the spinal cord should not exceed 
10Gy and preferably be less than 8Gy to any volume in excess of 0.03 cc (approximately 3 
mm x 3 mm x 3 mm). 
In treatment planning, the spinal cord should be given the highest priority. 
Spinal Cord PRV: The cumulative dose to the spinal cord PRV should not exceed 55Gy. In 
the event that the old plan is not available for review, the dose to the spinal cord should not 
exceed. The Spinal Cord PRV should not exceed 16Gy and ideally less than 14Gy. 
Brainstem: The cumulative dose to the brainstem should ideally be limited to 0.03cc to 60Gy.  
However, if disease is in close proximity to brainstem and requires higher doses, especially if 
the original RT course exceeded this dose, this is acceptable.  Ideally the max dose per 
fraction to the brainstem should be <1Gy per fraction.  If the disease mandates exceeding this 
constraint, the patient should be informed of the risks of severe or life threatening toxicity.    In 
the event that the old plan is not available for review the brainstem should not exceed 12Gy to 
any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm) and preferably should 
be less than 10Gy and the PRVbrainstem (brainstem +3mm) should be limited to 16Gy.  
However, if disease is in extremely close proximity to the brainstem, this may need to be 
exceeded.  In this case, Ideally the max dose per fraction to the brainstem should be <1Gy 

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per fraction.     
Coverage can be compromised to meet spinal cord and brainstem constraints as clinically 
indicated at the discretion of the treating radiation oncologist. 
Optic Nerves and Chiasm: The cumulative dose to the optic structures should not exceed 
55 Gy. In the event the that old plan is not available for review, the dose to the optic structures 
should not exceed a max dose of 10Gy to any volume greater than 0/03cc. In the rare event 
that a single optic nerve is involved with tumor, these constraints can be violated to achieve 
coverage of thetuor. However this would not apply to the optic chiasm or bilateral optic nerves. 
Orbits: Should be limited to a cumulative max dose of 50Gy including previous radiation. 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy when 
possible. 
Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy when 
possible. 
Parotid Glands (not targeted): In most cases, it will be easier to spare one parotid than the 
other. The treatment planning goal will be for this individual parotid gland to receive a mean 
dose of <26 Gy. 
Submandibular gland (not targeted): If level Ib is not a target, aim to reduce mean 
contralateral submandibular gland to < 39 Gy. 
OARpharynx/constrictors: Reduce the dose as much as possible. Some recommended (but 
not mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 
50Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy. 
Cervical Esophagus: Reduce the dose as much as possible. Some recommended (but 
treatment goals include: Mean dose < 30 Gy. 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. The glottic 
larynx mean dose is recommended to be <25 Gy. 
Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 66 Gy, except in 
areas overlapping PTV. 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside 
the targets can receive 66 Gy or more 
Brachial Plexus: The dose to the plexus should be limited as much as possible. The plexus 
can never exceed 66Gy unless it is clinically involved with tumor. If it is uninvolved, it should 
be limited to <30Gy whenever possible. 
 
4.2.9. Radiation Therapy Treatment Interruptions 
Treatment interruptions are strongly discouraged. Treatment breaks must be clearly indicated 
in the treatment record when they occur. Patients who have treatment interruptions in radiation 
for >3 weeks will be taken off study. The interruption of radiation therapy for grade 4 mucositis 
/ dermatitis / dysphagia is at the discretion of the treating radiation oncologist. Treatment 
breaks, if necessary, ideally should not exceed five treatment days at a time and ten treatment 
days total. Treatment breaks should be allowed only for resolution of severe acute toxicity 
and/or for intercurrent illness and not for social or logistical reasons. 
 
 
4.3. 
NIVOLUMAB ADMINISTRATION: 
 
4.3.1. Administration of Nivolumab 
 
4.3.1. Administration of Nivolumab 
Nivolumab will be administered at a fixed dose of 240 mg over 30-60 minutes IV two weeks 
prior to the beginning of RT and every 2 weeks during radiotherapy for a total of 5 doses. 
Then Nivolumab will be given at 480 mg over 30-60 minutes IV every 4 weeks for 10 additional 
doses after radiotherapy. . The first dose will be given two weeks prior to the first fraction of 
radiation (+/- 5 days), and continued every 2 weeks (+/- 3 days). Nivolumab will thus be given 
in at -2 weeks, then week 0, 2, 4 and 6. Adjuvant nivolumab will then be given for a total of 10 
additional doses after the completion of radiotherapy every 4 weeks (+/- 7 days). 
 
There are no premedications for nivolumab recommended. 

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Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. 
 
 
4.3.2. Dose delay criteria apply for all drug-related AEs 
Treatment delay up to 6 weeks for nivolumab from the last dose are allowable (any dose 
delays greater than these will require approval from the local principal investigator). 
 
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed. 
Nivolumab should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities 
• 
Any Grade ≥ 3 skin drug-related AE 
• 
Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
total bilirubin or asymptomatic amylase or lipase: 
o Grade 3 lymphopenia does not require a dose delay 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose 
delay. The local principal investigator should be consulted for such Grade ≥ 3 
amylase or lipase abnormalities. 
• 
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
• 
NOTE: Grade 3 dysphagia, dehydration, mucositis and pain are routinely encountered 
during reirradiation and will not require a delay in Nivolumab administration. 
 
4.3.3. Nivolumab Dose Discontinuation Due to Drug-Related AE(s) 
Treatment with nivolumab should be permanently discontinued for any of the following: 
 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
• 
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion 
reaction, regardless of duration 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.  
• 
Any Grade 3 neurologic toxicity including encephalitis required discontinuation of 
Nivolumab.  
• 
Any Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 

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• 
Any Grade 3 drug-related laboratory abnormalities do not require 
treatment 
discontinuation except: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation. 
o Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation 
 
AST or ALT > 5 -10x ULN for > 2 weeks 
 
AST or ALT > 10x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events, which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset. The local principal investigator should be consulted for 
Grade 4 amylase or lipase abnormalities 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing. 
 
4.3.4. Criteria to Resume Nivolumab Dosing 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤ 1 or baseline, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
• 
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by the local principal investigator. 
o Subjects who received systemic corticosteroids for management of any drug- 
related toxicity must be off corticosteroids or have tapered down to an 
equivalent dose of prednisone ≤ 10 mg/day. 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. 
• 
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted above. 
 
4.3.5. Nivolumab Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions 
should be reported within 24 hours as an SAE if criteria are met. Infusion reactions should be 
graded according to National Institute of cancer (NCI) common terminology criteria for adverse 
event (CTCAE, Version 4.03) guidelines. 

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Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated) 
• 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations. 
 
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours) 
• 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms 
recur, then no further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). 
• 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325-1000 mg should 
be administered >30 minutes before nivolumab infusion. If necessary, corticosteroids 
(up to 25 mg of SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support 
indicated). 
• 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. 
Nivolumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms. 
 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine or corticosteroids). 
 
4.3.6. Duration of Nivolumab 
Nivolumab will be given for a total of 15 doses (1 before RT, 4 during radiation therapy and 10 
following completion of radiation), or until progressive disease, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first. For all subjects, global 

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deterioration of health status requiring discontinuation of treatment without objective evidence 
of disease progression at that time is allowed, if necessary. 
4.3.7. Patient Reported Outcomes (PROs) 
The FACT-HN and FACT-G (Appendix 2) Quality of Life (QOL) assessments will be 
performed at baseline, end of IMRT, and weeks 18, 30, 52, and 104. Patients who do not 
have QOL collected or refuse QOL completion will not be considered a protocol deviation. 
Paper or electronic questionnaires may be completed by the patient. A copy of the 
responses needs to be kept in the study subject’s research binder. 
 
4.3.8. Nivolumab Dose Levels 
There will be no dose reductions allowed for nivolumab; delays will be allowed as detailed in 
the section describing nivolumab administration. 
 
4.3.9. Nivolumab Packaging, Labelling, and Storage 
Please refer to the Investigators Brochure for detailed information. Medication numbers will 
be unique to each bottle and will be used for tracking purposes only. 
 
Supply 
Nivolumab is supplied in a 100 mg/ 100 ml solution in a single use vial. 
 
Storage Conditions 
Nivolumab must be stored in accordance with the instructions on the label (Refer to 
investigator brochure. Supplies must be kept refrigerated (2 – 8 deg C). Do not freeze and 
protect from light). 
 
Drug Accountability 
Investigational supply of Nivolumab is obtained from Bristol Myers Squibb. Drug supplies, will 
be kept in a secure, limited access storage area under the storage conditions. Where 
necessary, a temperature log must be maintained to make certain that the drug supplies are 
stored at the correct temperature. 
 
The responsible person must maintain records of the product’s delivery to the study site, the 
inventory at the site and the use by each patient. The Principal Investigator (and participating 
site investigators) are responsible for all destructions/disposals of partially used and unused 
supplies. Supplies are not to be shipped back to BMS. BMS only needs to be notified of 
dtestructions/disposals of partially used samples. A copy of the drug destruction certificate 
must be maintained for provision to BMS at the end of the study. 
 
These records will include dates, quantities, batch/serial numbers, expiry (“use by”) dates, and 
the unique code numbers assigned to the investigational product(s) and study patients. The 
responsible person will maintain records that document adequately that the patients were 
provided the doses specified by the CSP and reconcile all investigational product(s) received 
from BMS. The responsible person must verify that all unused or partially used drug supplies 
have been returned by the clinical study patient. 

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4.4. MANAGEMENT OF SIDE EFFECTS FOLLOWING TREATMENT WITH NIVOLUMAB 
 
4.4.1. Management of immunological toxicities following treatment with nivolumab 
A proactive and early approach to management of immunological toxicities is crucial. The 
toxicities can be managed by a variety of treatment options to relieve symptoms and to reduce 
the risk of worsening symptoms. 
 
4.4.2. Management of non-immunological toxicities following treatment 
with 
nivolumab 
A proactive and early approach to management of immunological toxicities is crucial. The 
toxicities can be managed by a variety of treatment options to relieve symptoms and to reduce 
the risk of worsening symptoms. 
 
4.4.4.   Treatment Compliance 
Records of study medication used, dosages administered and intervals between visits will be 
recorded by study personnel. 
 
 
4.5.      ENDPOINTS OF SAFETY 
Safety of nivolumab will be evaluated as indicated by intensity and incidence of adverse 
events, graded according to US NCI CTCAE Version 4.03. Safety endpoints include: 
 
• 
Events leading to dose holding 
• 
Events leading to permanent treatment discontinuation 
• 
The overall incidence and CTC criteria grade of adverse events, as well as relatedness of 
adverse events to treatment 
• 
Causes of death 
 
 
5. 
ADVERSE EVENTS DEFINITIONS AND REPORTING 
 
5.1. 
ADVERSE EVENT DEFINITION 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation participant administered study drug 
and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational product, whether or 
not considered related to the investigational product. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
 
 
5.2. 
SERIOUS ADVERSE EVENT DEFINITION 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
results in death 
• 
is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 

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• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
• 
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
• 
elective surgery, planned prior to signing consent 
• 
admissions as per protocol for a planned medical/surgical procedure 
• 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
• 
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
• 
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
 
5.3. 
INTENSITY OF ADVERSE EVENT 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the CRF. 
 
 
5.4. 
CAUSAL RELATIONSHIP OF ADVERSE EVENT 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 

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5.5. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of discontinuation of dosing must be reported to 
BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin 
biopsy). 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, are collected, including those thought to be associated with 
protocol-specified procedures. The investigator should report any SAE occurring after 
these aforementioned time periods, which is believed to be related to study drug or 
protocol-specified procedure. 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness; 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of 
a study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
• 
If the BMS safety address is not included in the protocol document (eg, multicenter studies 
where events are reported centrally), the procedure for safety reporting must be 
reviewed/approved by the BMS Protocol Manager. Procedures for such reporting must be 
reviewed and approved by BMS prior to study activation. 
• 
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form) should be 
used to report SAEs to BMS . The BMS protocol ID number must be included on whatever 
form is submitted by the Sponsor/Investigator. 
o The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i 
o The MedWatch form is available at: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UC 
M048334.pdf 
• 
• 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not 
previously described in the IB). An event meeting these criteria is termed a Suspected, 
Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these 
events will be in the form of a SUSAR Report and provided in the FastTrack portal 
system. 
o Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected 
SAE, an SAE considered associated with study procedures that could modify the 
conduct of the study, lack of efficacy that poses significant hazard to study 
subjects, clinically significant safety finding from a nonclinical (eg, animal) study, 
important safety recommendations from a study data monitoring committee, or 
Principal Investigator decision to end or temporarily halt a clinical study for safety 
reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the 
ESR with the IB. Where required by local regulations or when there is a central 
IRB/IEC for the study, the investigator will submit the ESR to the appropriate 
IRB/IEC. The investigator and IRB/IEC will determine if the informed consent 
requires revision. The investigator should also comply with the IRB/IEC 
procedures for reporting any other safety information. 
o In addition to the Principal Investigator’s responsibility to report events to their 
local HA, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all 

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concerned countries according to local regulations (either as expedited and/or in 
aggregate reports). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on either CIOMS or MedWatch form & pregnancies 
must be reported on a Pregnancy Surveillance Form or can be submitted on the 
aforementioned SAE form to BMS. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number:  +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to 
BMS Global Pharamacovigilance (WoldwideWorldwide.Safety@bms). Frequency of 
reconciliation should be every 3 months and prior to the database lock or final data 
summary. BMS GPV&E will email, upon request from the Investigator, the GPV&E 
reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation 
report will be used for case identification purposes. If the Investigator determines a case was 
not transmitted to BMS GPV&E, the case should be sent immediately to BMS. 
 
5.6. 
OTHER REPORTING 
Non-serious Adverse Event 
• 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [eg, IND 
US trial] as part of an annual reporting requirement. 
• 
Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the 
subjects. 
 
A non-serious adverse event is an AE not classified as serious. 
 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All non-
serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last 
dose of study treatment. 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as 
appropriate. 

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Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
to BMS as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value). 
 
Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as: 
 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant). 
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form. A BMS Pregnancy Surveillance 
Form may be provided upon request. 

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Any pregnancy that occurs in a female partner of a male study participant should be reported 
to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
In order for Principal Investigator or designee to collect any pregnancy surveillance information 
from the female partner, the female partner must sign an informed consent form for disclosure 
of this information. 
 
For this reason, female participants in t he study will need to use appropriate methods of birth 
control on study through 5 months post discontinuation of nivolumab. For male participants 
that have female partners of child bearing potential, they will need to use appropriate methods 
of birth control on study thorugh 7 months post discontinuation of nivolumab. 
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
 
Other Safety Considerations 
 
Any significant worsening noted during interim or final physical 
examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
AE, as appropriate, and reported accordingly. 
 
 
6. 
BIOMARKER(S) AND CORRELATIVE STUDIES 
Baseline PDL1 status will be required for analysis; collection of the diagnostic biopsy specimen 
upon recurrence or disease persistence will be required for enrollment; a new biopsy will not 
be mandated upon study entry; collection of diagnostic tissue biopsy at presentation will be 
required for additional correlative studies; P16 status will be required and performed at local 
institutions; 
 
6.1. 
CORRELATIVE TISSUE RESEARCH 
Tissue/Specimen Submission 
Tumor tissue samples will be collected at pre-treatment and at the time of disease progression 
if clinically feasible. Tumor tissue collected at the time of pre-treatment may represent frozen 
samples if collected using a previously established repository or, most likely, formalin-fixed 
paraffin-embedded (FFPE) blocks. If the former, a section of the tissue will be submitted to 
the respective lab(s). For the latter, an FFPE tumor block will be submitted to the respective 
lab(s) (see below for more details). A biopsy at the time of progression is strongly encouraged 
but if not obtained, does not constitute a protocol violation. If a biopsy is obtained, extra cores 
may be obtained to allow for biomolecular evaluation. For cases treated at Emory University, 
tumor tissue samples will be submitted to Rafi Ahmed’s laboratory and will be banked in the 
department of pathology at Emory University. For cases treated at the Cleveland Clinic, tumor 
tissue samples will be submitted to Mohamed Abazeed’s laboratory and will be banked in his 
laboratory. The respective labs may exchange samples at will. Genomic profiling of tissue 
samples will be mainly conducted at the Cleveland Clinic. Note that all tissue obtained for 
correlative reseach is supernumerary to the needs of establishing a clinical diagnosis of 
recurrence. 
 
FFPE tumor samples (Mandatory) 
A FFPE tumor block should be submitted with the submission form. A Pathology Report and 
one H&E stained slide documenting that the submitted block or slides contain tumor should 
also be submitted with the tissue. The report and H&E stained slide must include the protocol 

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number and patient’s case number. The patient’s name and/or other identifying information 
should be removed from the report. The surgical pathology numbers and information must 
NOT be removed from the report. 
 
The pre- and post-progression tumor biopsies can be obtained from the primary tumor or 
lymph node metastasis as a punch biopsy or a core needle biopsy: a punch or core in formalin 
and secondary 1-2 punches or cores in liquid nitrogen (or dry ice/ethanol slurry). The biopsy 
samples should be prepared as: 1) formalin-fixed paraffin-embedded tumor blocks and 
shipped to the designated laboratories in ambient temperature, and 2) flash frozen samples in 
liquid nitrogen (or dry ice/ethanol slurry) and shipped on dry ice. The frozen specimens can be 
stored at -80 degree C (-70 degree C to -90 degree C) until ready to ship. If a -80 degree C 
freezer is not available, samples can be stored short term in a -20 degree C freezer (non- 
frost-free refrigerator preferred) for up to 7 calendar days (please ship out Monday- 
Wednesday only). 
 
6.2. 
CORRELATIVES WITH BLOOD 
Blood samples must be submitted with the submission form documenting the date of collection 
of the sample. Blood samples will be obtained at baseline and prior to each nivolumab infusion 
during radiation therapy; subsequently blood will be obtained at weeks 18, 30 52, and 104 as 
outlined in study calendar above. Peripheral blood mononuclear cells (PBMCs) and plasma 
will be isolated from collected CPTs and cryopreserved as outlined in the blood processing 
Appendix 3. 
 
Specimen collection summary for correlative studies (Samples can be batched and sent 
in one shipment) 
 
Specimens for Correlative Studies 
Specimens taken from 
patient: 
Collected when: 
Submitted as: 
Shipped: 
A paraffin-embedded 
tissue of the primary 
tumor taken before 
initiation of treatment 
Pre-treatment 
Paraffin-embedded tissue 
block 
Block shipped 
ambient 
Fresh frozen tissue of 
the primary or 
metastatic tumor taken 
before initiation of 
treatment (for research 
purposes only: 
OPTIONAL) 
Pre-treatment 
Frozen tumor in a 2 mL 
cryovial 
Tumor sent frozen on 
dry ice via overnight 
carrier 
A paraffin-embedded 
tissue of the primary or 
metastatic tumor (for 
research purposes only: 
OPTIONAL) 
At the time of 
disease progression 
Paraffin-embedded tissue 
block 
Block shipped 
ambient 
Fresh frozen tissue of 
the primary or 
metastatic tumor (for 
research purposes only: 
OPTIONAL) 
At the time of 
disease progression 
Frozen tumor in a 2 mL 
cryovial 
Tumor sent frozen on 
dry ice via overnight 
carrier 
PBMCs and PLASMA: 4 
CPTs (8 mL each) of 
whole blood for 
Pre-treatment and 
prior to each 
Nivolumab infusion 
during radiation 
Frozen plasma samples 
containing 2 mL per 
aliquot in 2 mL cryovials: 
Plasma sent frozen 
on dry ice or liquid 
nitrogen via 
overnight carrier 

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collection of plasma and 
therapy ; 
Cryopreserved PBMCs 
PBMCs 
subsequently at wk 
containing 107 PBMCs 
18, 30, 52 and 104. 
per aliquot in 2 mL 
cryovials 
 
Submit materials for translational research as following: 
 
U. S. Postal Service Mailing Address: 
Ahmed Lab 
Department of Microbiology & Immunology 
Emory University 
1462 Clifton Road NE, Room 412 
Atlanta, GA 30322 
 
Or 
Abazeed Laboratory 
Cleveland Clinic Foundation 
Department of Translational Hematology Oncology Research 
2111 E 96th Street 
Lerner Res Stockroom 
NE6-258 Abazeed Lab 
Cleveland, OH 44106 
 
For Non-urgent, Non-frozen Specimens Only 
Courier Address (FedEx, UPS): 
Ahmed Lab 
Department of Microbiology & Immunology 
Emory University 
1462 Clifton Road NE, Room 412 
Atlanta, GA 30322 
 
Or 
Abazeed Laboratory 
Cleveland Clinic Foundation 
Department of Translational Hematology Oncology Research 
2111 E 96th Street 
Lerner Res Stockroom 
NE6-258 Abazeed Lab 
Cleveland, OH 44106 
 
For Frozen Specimens and Urgent FFPE Samples 
Ahmed Lab 
Department of Microbiology & Immunology 
Emory University 
1462 Clifton Road NE, Room 412 
Atlanta, GA 30322 
 
Or 
Abazeed Laboratory 
Cleveland Clinic Foundation 
Department of Translational Hematology Oncology Research 
2111 E 96th Street 
Lerner Res Stockroom 
NE6-258 Abazeed Lab 
Cleveland, OH 44106 

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6.3. 
PROPOSED BIOMARKER EVALUATIONS 
A. Despite the unprecedented success of PD-1 targeted therapies a significant number of 
patients still fail to respond due to mainly unknown reasons. A deeper understanding of the 
mechanisms underlying responsiveness to blockade of the PD-1 pathway and the 
identification of predictive biomarkers are thus essential to optimize current treatments and to 
develop novel treatment approaches in order to improve response rates. Two recent studies 
analyzing the CD8 T cell response in the peripheral blood of non-small lung cancer and 
melanoma patients undergoing PD-1 targeted therapies observed an increase in activated 
and proliferating PD-1+ CD8 T cells in a subset of patients which in combination with tumor 
burden correlated with clinical outcome (37, 38). We will therefore monitor T cell activation 
and proliferation in the peripheral blood by multi-parameter flow cytometry of isolated PBMCs 
including but not limited to the following markers: CD3, CD4, CD8, CD45RA, CCR7, CD27, 
CD28, CD38, HLA-DR, Ki-67, PD-1. Activated CD38+ HLA-DR+ CD8 T cells at the peak of 
activation/proliferation will be isolated by flow cytometric sorting followed by DNA and RNA 
isolation. RNA will be used to transcriptionally profile CD8 T cells responding to therapy using 
RNAseq. Furthermore, we will use DNA isolated from activated CD8 T cells in the peripheral 
blood and from frozen tumor tissue to analyze and compare the T cell receptor repertoire of 
activated/proliferating CD8 T cells in the blood and tumor-infiltrating lymphocytes in the 
obtained biopsy. It has recently been shown that a particular subset of PD-1+ CD8 T cells 
expressing the transcription factor TCF-1 possesses stem cell-like feature and is responsible 
for the proliferative burst of antigen-specific CD8 T cells following PD-1 pathway in a mouse 
model of persistent viral infection (39). Two recent studies also demonstrated that 
costimulatory signaling through CD28 is required for CD8 T cell proliferation following PD-1 
pathway blockade (40, 41). We hypothesize that increased numbers of CD28+ and/or TCF- 
1+ among PD-1+ CD8 T cells will be predictive of response to PD-1 pathway blockade. To 
test this hypothesis, we will characterize tumor-infiltrating lymphocytes by immunofluorescent 
staining of FFPE sections using antibodies directed against CD4, CD8, PD-1, CD28, TCF-1 
as well as additional markers, and correlate with the observed CD8 T cell responses in the 
blood as well as with clinical outcome. 
 
B. We expect that recurrent cancers will have a substantially higher alteration frequency and 
a distinct composition of genetic lesions compared to matched treatment naïve tumors. The 
extent of genetic alterations has been previously associated with response to checkpoint 
blockade. Therefore, we posit that the extent of non-synonymous mutational load will be 
predictive of the presence of neo-antigens and therefore predictive of response to nivolumab 
in patients with recurrent head and neck cancer. We will assess mutational and neoantigen 
load using whole exome sequencing. We will assess transcriptomic states using RNAseq. We 
will correlate clinical outcomes with the extent and composition of mutations and identify 
transcriptomic states (or gene signatures) that could predict improved clinical outcomes (see 
Appendix 4 for instructions on processing frozen tumor samples for DNA/RNA extraction). 
 
C. Submit materials for translational research as following: 
 
For FFPE tissue samples 
Cancer Genetics (CGI) 
CGI will provide shipping supplies to each site 
 
 
7. 
INVESTIGATIONAL PLAN 
 
7.1. 
VISIT SCHEDULE 
Details of study procedures are in Study Calendar. 

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7.2 
SCREENING PERIOD 
Therapeutic Parameters 
 
Pre-study scans used to assess all measurable or non-measurable sites of disease must be 
done within 30 days prior to registration. 
 
Pre-study CBC (with differential and platelet count) should be done ≤ 30 days before 
registration. All required pre-study chemistries, should be done ≤ 30 days before registration. 
 
7.3 
END OF STUDY TREATMENT AND FOLLOW-UP PERIOD 
Patients will be followed for 2 years from the initiation of treatment. The imaging studies will 
be performed at baseline and at week 18, 30, 52, and 104. Patients will continue to be followed 
thereafter by their treating physicians as per standard of care. 
 
7.4 
DURATION OF THERAPY 
Patients will receive radiation in concurrence with nivolumab and post radiation maintenance 
nivolumab for 10 cycles unless: 
 
• 
Radiation is interrupted for > 3 consecutive weeks, in which case they will be removed 
from the protocol. 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
• 
Patient develops progressive disease; then the patient will discontinue protocol therapy. 
• 
Patient develops unacceptable toxicity; then the patient will discontinue protocol therapy. 
• 
Patients may withdraw consent and withdraw from the study at any time for any reason. 
 
7.5 
DURATION OF FOLLOW-UP 
For this protocol, all patients, including those who discontinue protocol therapy early, will be 
followed for response until progression and for survival for 2 years from the start of radiation. 
All patients must also be followed through completion of all protocol therapy. Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. 
 
 
8. 
STATISTICAL METHODS 
Power Caclulation: From the MIRI study, the 1-year PFS rate for class I and II combined was 
43.8% (95% CI: 38.6 - 49.7%) Assuming a one sided alpha of 0.05 and an 85% power to 
detect an improvement in 1-yr PFS from 40% to 55% we estimate 46 patients will need to be 
accrued in 2.5 years and followed for an additional 2 years (estimated maximum total of 51 
patients). Accounting for a 20% drop out rate, 62 patients will need to be consented. The sample 
size calculation was based on assumptions of exponentially distributed death times and use of 
the exponential MLE test (42). Definition of clinical outcomes: PFS is defined as months from 
treatment started to evidenced progression or death and censored at last follow up without 
progression, and OS is defined as months from treatement started to death or censored at last 
follow up if alive. 
Analysis plan: For primary objective, the 1-yr PFS and its 95% confidence interval will be 
estimated by Kaplan-Meier method for all patients, as well as in each stratum defined by p16 
and RPA status, but this study is not powered at the level of subgroups. For the secondary 
objectives, Kaplan-Meier method will be used to assess 1-yr OS, PFS, or pattern of failure, 
and the incidence rate of acuate and late toxicities will be described as frequency and 
percentage. QOL will be summerized by mean and standard deviation. For exploratory 
objectives, the predictability of related biomarkers (baseline PDL1 status, T-cell activation 
biomarkers, CD28 and TCF1 positivity on T lymphocytes and other biomarkers) to clinical 

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outcomes (OS and PFS) will be explored using both univariate and multivariable Cox 
proportional hazards model controlling for potential confounders. 
 
9. 
ADMINISTRATION, HANDLING OF DATA AND SAFETY MONITORING 
 
9.1. 
PROTOCOL AMENDMENTS 
Any changes to the protocol will be made in the form of an amendment and must be approved 
by the coordinating site IRB before implementation. Any modifications made to the protocol or 
informed consent document according to local requirements or any other reason may also 
require approval from sponsoring agencies. 
 
9.2. 
INFORMED CONSENT 
An investigator will explain to each subject the nature of the study, its purpose, procedures 
involved, expected duration, potential risks and benefits. Each subject will be informed that 
participation in the study is voluntary and that she may withdraw from the study at any time, 
and that withdrawal of consent will not affect her subsequent medical treatment. This informed 
consent will be given by means of a standard written statement and will be submitted for IRB 
approval prior to use. No patient will enter the study before her informed consent has been 
obtained. In accordance with the Health Information Portability and Accountability Act 
(HIPAA), the written informed consent document (or a separate document to be given in 
conjunction with the consent document) will include a subject authorization to release medical 
information to the Principal Investigator and supporting agencies and/or allow these bodies, a 
regulatory authority, or Institutional Review Board access to subjects’ medical information that 
includes all hospital records relevant to the study, including subjects’ medical history. 
 
9.3. 
ETHICS AND GOOD CLINICAL PRACTICE 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration 
of 
Helsinki, 
concerning 
medical 
research 
in 
humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, 
Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
9.4. 
REGULATORY AUTHORITIES 
Institutional Review Board 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
 
9.5. 
DATA QUALITY ASSURANCE 
 
9.5.1    Data Management 
All information will be collected on study-specific case report forms by the study staff at each 
institution. The necessary forms will be provided to each site by the Coordinating Center. 

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The completed forms will be forwarded to the Coordinating Center for central review and 
inclusion in the study dataset with relevant source documentation as outlined in the case report 
forms.  The data submission schedule is as follows: 
 
At the time of registration: 
 
- 
Registration Form 
- 
Informed Consent Form (signed by the subject) 
- 
Eligibility Checklist 
- 
Source documents related to eligibility. 
 
Within 2 weeks after registration: 
 
- 
Baseline study case report forms 
- 
Pertinent source documents 
 
Within 2 weeks after 30 day follow-up: 
 
- 
On study case report forms 
- 
Pertinent source documents 
 
All study data will be reviewed for completeness and accuracy by the Protocol Chair. The 
Principal Investigator (or his/her designee) at each respective institution is responsible for 
review, and ensuring the completeness and accuracy, of the data generated by his/her 
institution. The study data will also be periodically reviewed by the Emory Winship Cancer 
Institute Clinical Research Office. 
 
9.5.2. Meetings and Conference Calls 
Scheduled meetings and conference calls will take place as needed with the PI and co- 
investigators and study personnel involved at coordinating center and participating site. In 
addition, separate meetings will be scheduled and include the protocol principal investigator, 
study coordinator(s), data manager(s). During these meetings matters related to the following 
will be discussed: safety of protocol participants, validity and integrity of the data, enrollment 
rate relative to expectation, characteristics of participants, retention of participants, adherence 
to protocol (potential or real protocol violations), data completeness, and progress of data for 
objectives. 
 
9.5.3. Monitoring and Auditing 
The Emory Winship Cancer Institute (Winship) clinical trials office will serve as the 
coordinating center for the Emory patients. The coordinating center will review responses and 
toxicity and report these to the regularly scheduled meetings of the DSMC of the Emory 
Winship Cancer Institute. Each participating site is expected to have its own data monitoring 
and safety plan (DMSP) with regard to forwarding information to their IRBs. If the data reveals 
a change in the risk/benefit ratio, the investigator will notify the IRB and the PI. 
 
The PI and co-investigators will review the data and forward any changes or protocol 
amendments to the IRBs. All serious adverse events will be reported immediately to the IRB. 
All study participant information will be kept in a confidential manner by the assigning of a 
random number to each study participant. All data will be kept confidential as per institutional 
guidelines and policies. Any breach of confidentiality is a serious matter and conflicts with 
institutional policies and will be reported to the IRB. A cumulative summary of all adverse 
events occurring on this study and a report of the data safety and monitoring plan will be 
submitted to the IRBs with the annual renewal reports. 

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The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study. The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being 
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research. Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually. For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed. For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed. 
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP). 
 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory 
documents. Following the monitoring review, monitors will provide a preliminary report of 
monitoring findings to the PI and other pertinent individuals involved in the conduct of the 
study. The PI is required to address and respond to all the deficiencies noted in the preliminary 
report. Prior to the completion of the final summary report, monitors will discuss the preliminary 
report responses with the PI and other team members (when appropriate). A final monitoring 
summary report will then be prepared by the monitor. Final DSMC review will include the 
final monitoring summary report with corresponding PI response, submitted CAPA (when 
applicable), PI Summary statement, and available aggregate toxicity and safety data. 
 
The DSMC will render a recommendation and rating based on the overall trial conduct. The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB. Continuing Review submissions will include the DSMC recommendation letter. 
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes. The Committee 
reserves the right to conduct additional audits if necessary. 
 
The trial be monitored at each other site by having sites participate in the Emory working group 
meetings occurring every Thursday morning at 745 AM (EST); the sites will be providing 
information and updates on their enrolled patients to the Emory HNCA working group; this will 
be a weekly meeting; 
 
The following applies for monitoring of Sub-sites: 
 
At the time of study initiation at a non-Emory site, the Emory Principal Investigator, Winship 
regulatory specialist, and Winship research coordinators will perform a site initiation 
teleconference. During this teleconference, the Emory team will review the study, enrollment, 
reporting, and regulatory compliance. The participating site will have internal monitoring 
meetings. These meetings which will include the participating site investigator, the clinical 
research coordinator and the regulatory affairs coordinator, will meet at least on a monthly 
basis to review and discuss study data to ensure subject safety. The research coordinators 
will maintain a spread sheet which will be de-identified and will summarize all the patient data 
for subjects actively being treated on the trial as well as a roadmap detailing pending 
tests/treatments for each individual subject. The spread sheet will be shared with the Emory 
PI via e-mail monthly. Teleconferences will be conducted weekly between the PI at Emory and 
the research team at the participating site(s). The purpose of the meetings is to discuss the 
enrollment, regulatory updates, monitor toxicities, and evaluate the progress of the trial. A 
record of the teleconferences will be kept in the regulatory binder. Scheduled teleconferences 
may stop after all patients have completed assigned protocol therapy and the PI at Emory will 

Protocol Version 10.0 
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communicate with participating sites via email as needed. This communication will also 
be maintained in the regulatory binder. Chart reviews will be performed on selected cases by 
the participating site staff to confirm that the data collection is accurate. 
 
Winship’s MSC will perform an on-site or remote monitoring visit within the first three months 
of enrollment of the first subject. Quarterly monitoring visits will occur (annually once onsite 
and three times remotely) until subject follow-up is terminated. Monthly reviews of data in 
OnCore will be conducted to ensure compliance or identify discrepancies. 
 
 
10. 
COORDINATING CENTER & SITE RESPONSIBILITIES 
 
10.1. 
PROTOCOL CHAIR 
The Protocol Chair is responsible for performing the following tasks: 
 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version of the protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE). 
• 
Reviewing data from all sites. 
 
10.2. 
COORDINATING CENTER 
The Coordinating Center is responsible for performing the following tasks: 
 
• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from each 
site. 
• 
Managing central patient registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
• 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
10.3. 
PARTICIPATING SITES 
Participating sites are responsible for performing the following tasks: 
 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• 
Submitting data to the Coordinating Center. 
• 
Registering all patients with the Coordinating Center by submitting patient registration 
form, and signed informed consent promptly. 
• 
Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
• 
Collecting and submitting data according to the schedule specified by the protocol. 
Additional information for participating sites: 

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10.3.1 Staffing 
The participating sites will provide experienced staff, and adequate equipment and facilities to 
support this clinical trial. The participating sites will also be responsible for research staff 
training, human subjects research, and HIPAA compliance, as well as the continuing 
education in these areas as required by local institutional standards. 
 
10.3.2. Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not 
limited to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient 
brochures and recruitment material, etc.), IRB membership rosters, summary of unanticipated 
problems or protocol deviations, and documentation of expertise of the investigators. The 
Coordinating Center will provide each participating site with a comprehensive list of the 
necessary documents. It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below. 
 
10.3.3. Confidentiality 
All unpublished information that the Coordinating Center gives to the investigator shall be kept 
confidential and shall not be published or disclosed to a third party without the prior written 
consent of the Protocol Chair (or her designee). 
 
10.3.4. Record Retention 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at 
each site at such time that the records may be destroyed. This will also follow each institution 
guidelines. 
 
10.3.5. Publication 
It is understood that any manuscript or releases resulting from the collaborative research will 
be circulated to all participating sites prior to submission for publication or presentation. The 
Protocol Chair will be the final arbiter of the manuscript content. 
 
10.3.6. Additional Information 
Each participating site is responsible for submitting additional information as requested by the 
Protocol Chair (or her designee). 
 
 
10.4. RECORDS 
Case Report Forms (CRFs) for individual patients will be provided by the Principal Investigator. 
 
 
10.4.1. Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
 
Data entered in the CRFs that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study; also current 
medical records must be available. 

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For CRFs all data must be derived from source documents. 
 
10.4.2. Direct Access to Source Data and Documents 
The investigator/institution will permit study-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the clinical study monitor, auditor and 
inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site 
monitor and auditor may review all CRFs, and written informed consents. 
 
10.5. STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
 
Patient confidentiality will be ensured by using patient identification code numbers. 
 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the study 
need to be available for inspection on request by the participating physicians or the Grantor’s 
representatives, by the IRB and the regulatory authorities. 
 
10.6. COMPLETION OF STUDY 
The IRB/competent authority needs to be notified about the end of the trial (last patient/patient 
out, unless specified differently in the CSP) or early termination of the trial. 

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11. 
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Vokes EE, Even C, Worden FP, Saba NS, Docampo LCI, Haddad RI, Rordorf T, Kiyota N, Tahara M, Lynch MJ, 
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12. 
APPENDICES 
 
 
APPENDIX 1 - PERFORMANCE SCALES 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, 
able to carry on all pre- 
disease performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on 
normal activity or to do active 
work 
2 
In bed < 50% of the time. 
Ambulatory and capable of 
all 
self-care, but unable to carry 
out any work activities. Up 
and about more than 50% of 
waking hours. 
60 
Requires occasional 
assistance, but 
is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care 
3 
In bed > 50% of the time. 
Capable of only limited self- 
care, confined 
to bed or chair more than 
50% of waking hours 
40 
Disabled, requires special 
care and assistance. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent 
4 
100% bedridden. 
Completely disabled. 
Cannot carry on any 
self-care. Totally confined to 
bed or chair 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 

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APPENDIX 2: FACT-G AND FACT-HN QUESTIONNAIRES 
 
 

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APPENDIX 3 - PROTOCOL FOR PROCESSING PBMC FROM CPT SODIUM CITRATE 
 
1. CPT tubes should be at stored at Room Temperature. Following blood collection, CPT 
tubes should be inverted approximately 10 times. 
2. CPT tubes must be kept at Room Temperature following blood collection. CPT tubes 
should be processed within 2-3 hours of blood draw. Leave rocking until processing. 
3. Spin CPT tubes at 2820rpm (1600g), 25minutes, 22°C (acceleration: 9, brake:3). Be 
careful on the position of the tubes (tubes are tall and need to be centered). 
4. Carefully remove top layer (plasma) without disturbing the PBMC layer. Save 2 ml of 
plasma and freeze in a 2 mL cryovial. Store at -20ºC. 
5. Collect PBMCs without touching the separation gel and transfer cells to collection tube 
(15mL falcon tube if 1 or 2 CPTs, 50 mL falcon tube if more CPTs are processed). 
6. Rinse each CPT tube with 3 mL PBS+2% FBS (P2) once. Carefully pipette up and down 
to re-suspend cells sitting directly on the separation gel. Transfer to collection tube. 
7. Add P-2 to cells in collection tube to bring volume up to maximum. 
8. Centrifuge at 1200 rpm for 10 minutes. 
9. Decant and re-suspend pellet; add 5mL of sterile ACK Lysing Buffer, let stand for 3-5 
minutes 
10. Add P-2 to bring volume up to maximum to stop lysis. 
11. Centrifuge at 1500 rpm for 8 minutes. 
12. Decant and re-suspend pellet in full tube volume of P2 
13. Centrifuge at 1500 rpm for 8 minutes 
14. Decant and re-suspend pellet in P2 (as a rough guideline: 1ml P2 per processed CPT 
tube) 
aliquot 10 uL cell mixture into 90 uL of trypan blue for counting 
15. Fill tube volume with P2, spin at 1500 rpm for 8 min. 
16. Decant and re-suspend pellet in FBS at a concentration of 2x107/mL, pipette up and 
down. 
17. Add equal volume of FBS+20%DMSO drop by drop while swirling tube containing 
PBMCs. 
(Final concentration is 10x106 cells/ml, 5-10 M cells/vial, when possible freeze more than 
1 vial) 
18. Divide into sterile cryovials (labeled with special sticker and also labeled in the top). 
19. Transfer vials into room temperature temp cryovial freezing chamber (Mr. Frosty) and 
place in -80°C. Remember to mark how many times the freezing chamber was used! If 
used 5 times, you need to exchange the Isopropanol. 
20. Transfer frozen aliquots to liquid nitrogen the following day 

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APPENDIX 4 - PROTOCOL FOR PROCESSING FROZEN TISSUE/BIOPSIES FOR 
DNA/RNA EXTRACTION 
 
1. The frozen sample is thawed on ice. The tissue is placed in a suitably sized vessel and 
the appropriate volume of Buffer RLT is added. 
2. A hand-held homogenizer is used to disrupt the tissue sample. Core and FNA biopsy 
sample are vigorously triturated with an appropriately sized pipette tip. 
3. Pipet the lysate directly into a QIAshredder spin column placed in a 2 ml collection tube, 
and centrifuge for 2 min at full speed. 
4. Centrifuge the lysate for 3 min at full speed. Carefully remove the supernatant by 
pipetting, and transfer it to an AllPrep DNA spin column placed in a 2 ml collection tube. 
Close the lid gently, and centrifuge for 30 s at >8000 x g. 
5. Place the AllPrep DNA spin column in a new 2 ml collection tube and store at room 
temperature or at 4o C for later DNA purification per the AllPrep DNA purification 
instructions. 
6. Use the flow-through for RNA purification per the AllPrep RNA purification instructions. 

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APPENDIX 5- RECURSIVE PARTITIONING ANALYSIS FOR OVERALL SURVIVAL IN PATIENTS 
TREATED WITH REIRRADIATION IN A MULTIINSTITUTIONAL ANALYSIS (WARD, ET AL. IJROBP 
2017) 
 
 
 
 
 
NOTE: RPA class III patients are defined as those expected to begin reirradiation within 2 
years of first course of radiation therapy AND are PEG dependent or have a tracheostomy 
(patients who have undergone total laryngectomy and have a stoma are not included in this 
category of organ dysfunction)