Phase II Trial of Radiotherapy, Carboplatin/Paclitaxel and Nivolumab for High Risk HPV-Related Oropharynx Cancer
Phase: PHASE2
Conditions: Oropharynx Squamous Cell Carcinoma
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 2018.085    Radiotherapy, Carboplatin/Paclitaxel and Nivolumab for High Risk 
HPV-related Head and Neck Cancer 
  NCT03829722
 

1 
 
UMCC 2018.085 
 PHASE II TRIAL OF RADIOTHERAPY, CARBOPLATIN/PACLITAXEL AND NIVOLUMAB FOR HIGH RISK HPV-
RELATED OROPHARYNX CANCER  
 
Principal Investigators:  
Michelle Mierzwa MD 
Department of Radiation Oncology 
University of Michigan 
1500 E Medical Center Blvd 
Ann Arbor, MI 48109 
 
 
Radiation Oncology 
 
 
 
 
Translational lab science 
Aleksandar Dragovic MD- co-I 
 
 
 
Chad Brenner 
Caitlin Schonewolf MD- co-I 
 
 
 
Heather Walline 
Jennifer Shah MD- co-I 
 
Medical Oncology 
 
 
 
 
Otolaryngology  
 
 
 
 
Frank Worden MD- co-I  
 
 
 
Keith Casper MD- Co-I  
 
  
Paul Swiecicki MD-co-I  
 
Consultants: 
 
 
 
 
 
Biostatistics 
Yue Cao- Radiation Oncology 
 
 
 
Matt Schipper PhD 
Mark Prince- Otolaryngology 
 
 
 
Department of Radiation Oncology 
Chaz Stucken- Otolaryngology  
 
 
University of Michigan  
 
Steve Chinn Otolaryngology 
 
 
 
1500 E Medical Center Blvd 
 
Matt Spector- Otolaryngology  
 
 
Ann Arbor, MI 48109 
 
 
 
 
Scott McLean- Otolaryngology 
Andrew Shuman- Otolaryngology 
 
Study drug: nivolumab 
 
Initial Version:   10.22.2018 
Revised, v.2.0: 01.28.2019 
Revised v.2.1: 02.05.2019 
Revised v 2.2:  04.01.2019 
Revised v 3.0:  05.05.2020 
Revised v 4.0: 10.16.2020 
Revised v 4.1:  04.22.2021 
Revised v 5.0: 01.20.2022 
 
 
NOTE: To effectively manage restrictions put in place during public health or civil emergency or 
restrictions (i.e. COVID-19 pandemic) changes to protocol-required items are to be made to minimize or 
eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit 
exposure to infectious pathogens). These changes are listed in Appendix B of the protocol (Study 
Management During Public Health or Civil Emergency or Restrictions). 

2 
 
TABLE OF CONTENTS 
DEFINITIONS .......................................................................................................................... 5 
STUDY SCHEMA ..................................................................................................................... 6 
STUDY SYNOPSIS .................................................................................................................... 7 
1.0 
BACKGROUND AND RATIONALE .................................................................................. 10 
1.1 
Disease Background ...................................................................................................... 10 
1.2 
Study Agent(s) Background and Associated Known Toxicities ...................................... 12 
1.3 
Mid-treatment PET ........................................................................................................ 13 
1.4 
Correlative Studies ........................................................................................................ 17 
1.5 
Rationale…………………………………………………………………………………………………………………...18 
2.0 
STUDY OBJECTIVES ...................................................................................................... 18 
2.1 
Primary Objectives ........................................................................................................ 18 
2.2 
Secondary Objectives .................................................................................................... 18 
2.3 
Exploratory Objectives .................................................................................................. 18 
2.4 
Endpoints ....................................................................................................................... 19 
3.0 
PATIENT ELIGIBILITY .................................................................................................... 19 
3.1 
Inclusion Criteria ............................................................................................................ 19 
3.2 
Exclusion Criteria ........................................................................................................... 20 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ............................................... 21 
5.0 
TREATMENT PLAN ....................................................................................................... 21 
5.1 
Treatment Dosage and Administration ......................................................................... 21 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 25 
5.3 
Concomitant Medications/Treatments ......................................................................... 29 
5.4 
Other Modalities or Procedures .................................................................................... 30 

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5.5 
Duration of Therapy ...................................................................................................... 30 
5.6 
Off Treatment Criteria ................................................................................................... 31 
5.7 
Duration of Follow-Up ................................................................................................... 31 
5.8 
Off Study Criteria ........................................................................................................... 31 
6.0 
STUDY PROCEDURES ................................................................................................... 31 
6.1 
Screening/Baseline Procedures ..................................................................................... 31 
6.2 
Procedures During Treatment ....................................................................................... 32 
6.3 
Follow-Up Procedures ................................................................................................... 32 
6.4 
Schedule of Events Table ............................................................................................... 33 
7.0 
MEASUREMENT OF EFFECT .......................................................................................... 34 
7.1 
Antitumor Effect- Solid Tumors ..................................................................................... 34 
8.0 
ADVERSE EVENTS ........................................................................................................ 38 
8.1 
Experimental Therapy ................................................................................................... 38 
8.2 
Adverse Event Reporting Requirements ....................................................................... 38 
8.3 
Definitions ..................................................................................................................... 38 
8.4 
Adverse Event Characteristics ....................................................................................... 40 
8.5 
Serious Adverse Event Reporting Guidelines ................................................................ 40 
8.6 
Routine Reporting ......................................................................................................... 41 
8.7 
Reporting of Unanticipated Problems ........................................................................... 41 
8.8 
AE and SAE reporting………………………………… ……………………………………………………………. 42 
9.0 
DRUG INFORMATION .................................................................................................. 43 
10.0 CORRELATIVES/SPECIAL STUDIES ................................................................................. 44 
10.1 
ctDNA/tumor exosomes ................................................................................................ 44 
10.2 
Serum Immunophenotyping ......................................................................................... 45 

4 
 
10.3 
DCE-MRI ......................................................................................................................... 46 
10.4 
FDG-PET/CT Imaging………………………………………………………………………………………………….49 
11.0 
STATISTICAL CONSIDERATIONS.................................................................................. 50 
11.1 
Description and Justification of Design ......................................................................... 50 
11.2 
Data Analysis Plan.......................................................................................................... 50 
11.3 
Stopping Rules ………………………………………………………………………………………………………….51 
12.0 DATA AND SAFETY MONITORING ................................................................................ 52 
13.0 CLINICAL MONITORING PROCEDURES .......................................................................... 52 
14.0 
REFERENCES ............................................................................................................. 53 
15.0 
APPENDIX A .............................................................................................................. 55 
16.0 
APPENDIX B…………………………………………………………………………………………………………………….62 
 
 
 

5 
 
DEFINITIONS 
 
AIDS: Acquired Immune Deficiency Syndrome 
ASTRO: American Society for Therapeutic Radiation Oncology  
ANC: Absolute neutrophil count 
AUC: Area under the concentration curve (chemotherapy) or area under the curve (statistics)  
BED: Biologic equivalent dose 
CMR: Complete metabolic response 
CR: Complete response  
CTSU: Clinical Trials Support Unit 
CTV: Clinical target volume 
DSMC: Data and Safety Monitoring Committee 
ECG or EKG: Electrocardiogram 
ED: Effective dose 
FDG: 18F-Florodeoxyglucose, a PET/CT imaging agent  
GTV: Gross tumor volume 
Gy: Gray 
HIV: Human immunodeficiency virus  
HPV: human papilloma virus 
IGRT: Image-guided radiation therapy 
IMRT: Intensity modulated radiation therapy  
iPET: interval (midtreatment) PET/CT 
IV: Intravenous 
LRC: Local-regional control  
LRR: Local-regional recurrence 
LRPF: Freedom from local-regional progression  
MTV: Metabolic tumor volume  
NRG: NRG Oncology 
OARs: Organs at risk 
OPSCC: squamous cell carcinoma of the oropharynx 
OS: Overall survival  
pPET: pre-treatment PET/CT 
PD: Progressive disease 
PFS: Progression-free survival 
PMR: Partial metabolic response 
PR: Partial response 
PTV: Planning target volume 
RT: Radiation therapy or radiation treatment  
RTOG: Radiation Therapy Oncology Group  
SD: Stable disease 
SMD: Stable metabolic disease 
SUV: Standardized uptake value 
SUVmax: The SUV of the most intense voxel within a tumor 
SUVpeak: The average SUV within a 1.2-cm diameter sphere centered on the most metabolically active 
region of the tumor 
3D-CRT: Three dimensional-conformal radiation therapy

6 
 
 
SCHEMA 
 
 
 
 
 
 
 
Patients will start nivolumab 240 mg IV on day 1, then every 2 weeks (q2wks) for 4 total doses .   
Carboplatin/paclitaxel and RT will begin on day 8 and carboplatin/paclitaxel will be given weekly (7 doses) during RT.  
Adjuvantly, starting at week 9, patients will receive nivolumab 480 mg alone IV every 4 weeks (q4weeks) for a total of 
4 doses. 
 
 

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STUDY SYNOPSIS 
Title 
PHASE II TRIAL OF RADIOTHERAPY, CARBOPLATIN/PACLITAXEL AND 
NIVOLUMAB FOR HIGH RISK HPV-RELATED OROPHARYNX CANCER 
Phase 
II 
Methodology 
Single arm, open label 
Study Duration 
5 years (yrs) 
Study Center(s) 
Single-center  
Objectives 
Primary Objective  
To determine whether the addition of nivolumab can improve 2 
year (yr) PFS (progression free survival) as compared to historical 
standard of fractionated RT and carboplatin/paclitaxel in 
patients with high risk HPV-related squamous cell carcinoma of 
the oropharynx. 
 
2.2 Secondary Objectives 
1. 
To characterize patterns of failure (loco-regional relapse versus 
distant) PFS and overall survival; 
2. 
To characterize acute toxicity profiles (during radiation therapy 
and at 3 and 6 months) and late toxicity profiles at 1 and 2 years; 
3. 
To correlate metabolic image uptake data on mid-treatment 
FDG-PET scans performed between fractions 8-12 with standard 
12 week post-treatment PET-CT. 
 
Number of Subjects 
40 
Inclusion Criteria 
1. 
Histologically or cytologically proven squamous cell carcinoma of 
the oropharynx (tonsil, base of tongue, oropharyngeal wall, soft 
palate) that is p16 positive by immunohistochemistry or HPV 
positive by in situ hybridization  
2. 
Clinical stage:  stage III AJCC 8th edition staging (cT4 or cN3) OR 
“matted lymph nodes (LNs)” (defined as 3 LNs abutting one 
another with loss of intervening fat plane that is replaced with 
evidence of extracapsular spread) OR radiographic extracapsular 
extension (defined as overt loss of fat plane surrounding a LN) 
OR radiographically positive retropharyngeal LN >7mm in size 
3. 
Appropriate stage for protocol entry, including no distant 
metastases, based upon the following minimum diagnostic 
workup: 
• 
History/physical examination, including documentation of 
weight within 2 weeks prior to registration; 
• 
FDG-PET/CT scan for staging and RT plan within 4 weeks 
prior to registration; 
• 
Zubrod Performance Status 0-1 within 2 weeks prior to 
registration; 
• 
Age ≥ 18; 
4. 
CBC/differential obtained within 2 weeks prior to registration 

8 
 
on study, with adequate bone marrow function defined as 
follows: 
• 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3; 
• 
Platelets ≥ 75,000 cells/mm3; 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
AST/ALT < 3x ULN  
• 
Total Bilirubin <1.5 x ULN (except subjects with Gilbert 
Syndrome who must have a total bilirubin level ≤ 3 x ULN) 
5. 
Serum creatinine within normal institutional limits or a 
creatinine clearance ≥ 45 mL/min within 2 weeks prior to 
registration; 
6. 
Women of childbearing potential must agree to use a medically 
effective means of birth control throughout their participation in 
the treatment phase of the study and for five months after the 
last treatment. A woman of childbearing potential (WOCBP) is 
defined as any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) and is not postmenopausal. Menopause 
is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. 
In addition, females under the age of 55 years must have a 
serum follicle stimulating hormone (FSH) level > 40 mIU/mL to 
confirm menopause.  Men receiving nivolumab who are sexually 
active with WOCBP must agree to use effective contraception 
throughout their participation in the treatment phase of the 
study and for seven months after the last treatment. 
7. 
Due to the potential for serious adverse reactions in breastfed 
infants, women are advised not to breast-feed during treatment 
with the study drugs. 
8. 
The patient must provide study-specific informed consent prior 
to study entry. 
Exclusion Criteria 
1. Prior invasive malignancy (except non-melanomatous skin 
cancer) unless disease free for a minimum of 3 years (For 
example, carcinoma in situ of the breast, oral cavity, or cervix are 
all permissible); 
2. Any prior therapy for the study cancer; note that prior 
chemotherapy for a different cancer is allowable if > 3 years 
prior to study; 
3. Any history of active autoimmune disease that has required 
systemic treatment in the past 2 years (i.e., with use of disease 
modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic 
treatment. 
4. Prior radiotherapy to the region of the study cancer that would 
result in overlap of radiation therapy fields; 
5. Severe, active co-morbidity, including but not limited to the 

9 
 
following: 
• Unstable angina and/or congestive heart failure requiring 
hospitalization within the last 6 months; 
• Uncontrolled diarrhea; 
• Uncontrolled adrenal insufficiency; 
• Transmural myocardial infarction within the last 3 months; 
• Acute bacterial or fungal infection requiring intravenous 
antibiotics at the time of registration; 
• Chronic Obstructive Pulmonary Disease (COPD) exacerbation 
or other respiratory illness requiring hospitalization or 
precluding study therapy at the time of registration; 
• Acquired Immune Deficiency Syndrome (AIDS) based with 
CD4+ count < 350 cells per microL; note, however, that HIV 
testing is not required for entry into this protocol. The 
need to exclude patients with AIDS from this protocol is 
necessary because the treatments involved in this protocol 
may be significantly immunosuppressive. 
6. Pregnancy or women of childbearing potential and men who 
are sexually active and not willing/able to use contraception;  
7. Women who are breastfeeding and are not willing to discontinue 
breastfeeding during the trial and for 2 months following 
protocol therapy 
8. Poorly controlled diabetes (defined as fasting glucose level > 200 
mg/dL) despite 2 attempts to improve glucose control by fasting 
duration and adjustment of medications. Patients with diabetes 
will preferably be scheduled in the morning and instructions for 
fasting and use of medications will be provided in consultation 
with the patients’ primary physicians 
9. Diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 
7 days prior to the first dose of trial treatment. Short bursts of 
steroids of 5-7 days (for COPD exacerbation or other similar 
indication) are allowed. 
10. Known history of, or any evidence of active, non-infectious 
pneumonitis. 
11. Known history of active TB (Bacillus Tuberculosis). 
12. Known hypersensitivity to nivolumab, carboplatin, or paclitaxel,  
or any of their formulation excipients. Known hypersensitivity to 
polyoxyl 35 castor oil (Cremophor® EL) (a diluent of paclitaxel and 
other drugs). 
13. Known active Hepatitis B (e.g., HBsAg  reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
14. Received a live vaccine within 30 days of planned start of study 
therapy. 
15. Have any condition that, in the opinion of the investigator, would 
compromise the well-being of the subject or the study or prevent 
the subject from meeting or performing study requirements 

10 
 
 
Study Product(s), Dose, 
Route, Regimen 
Nivolumab IV 240mg q2wks x 4 doses before and during radiotherapy, 
then 480mg q4wks x 4 doses after completion of radiotherapy  
Duration of 
Administration 
Total duration of nivolumab is 21 wks 
Reference Therapy 
Concurrent standard of care therapies are RT/platinum chemotherapy 
Statistical Methodology 
The primary study endpoint is PFS 2 years after treatment which will be 
also be estimated using the Kaplan-Meier (KM) method.  A log-log 
transformation of the survival function will be used to calculate a lower 
90% confidence limit.  Estimated PFS at 2 years was 68% in 125 similar 
(stage III) historical control patients treated with standard therapy at 
the University of Michigan (UM) between the years of 2010-2015.  If 
the true PFS at 2 years for this treatment combination in this patient 
population is 85%, then a sample size of 40 enrolled patients provides 
at least 80% power to rule out 2 year PFS values of 70% or less.  This 
calculation assumes 10% of patients will be lost to follow-up by the 2 
year assessment point and that other patients will either be assessed 
for progression at 2 years or will have progressed or died prior to 2 
years.   
 
1.0  
BACKGROUND AND RATIONALE 
 
1.1 Disease Background Oropharyngeal Carcinoma 
Over the past three decades, there has been an increase in the incidence of HPV-related oropharyngeal 
squamous cell carcinoma (OPSCC) with good overall prognosis and high rates of loco-regional control (LRC) 
(d’souza 2007, Gillison, 2000, Fahkry, 2008, Ang 2010).  Current standard of care therapy includes definitive 
chemoradiation as well as resection followed by adjuvant radiation or chemoradiation.  Due to the good 
prognosis and relatively good health of most patients with HPV-related OPSCC, there has been widespread 
interest in treatment adaptive radiotherapy strategies including decreased doses of radiotherapy and 
chemotherapy.   Ideally, pre- or mid-treatment biomarkers of response would be used to adapt therapy. 
However, no proven clinical or radiographic biomarkers exist to monitor response during therapy.   
 
In the UM experience with treatment of 515 patients with HPV+ oropharyngeal cancer using concurrent RT with 
weekly carboplatin (AUC=1) and paclitaxel (30mg/m2), AJCC 8th edition, stage 1 and 2 patients had 90-95 % LRC 
at 2 years and 2 yr progression free survival (PFS) of 85%.  Figure 1 below shows that a subset analysis of 
patients with stage 3 (cT4 and cN3) disease had 2 yr LRC of 85% with 2 yr PFS of 67%, with a large proportion of 
those patients developing distant metastases (30%) (Hawkins, 2018).   
 

11 
 
  
We previously published our UM experience with “matted lymph node” patients defined as 3 lymph nodes (LNs) 
abutting one another with loss of intervening fat plane that is replaced with evidence of extracapsular spread 
(Spector, 2016).  This analysis also revealed that patients with “matted nodes” had relatively high rates of LRC, 
but are at higher risk for distant metastases (Figure 2) and thus have significantly lower DSS (disease specific 
survival) than HPV+ oropharynx patients without matted nodes.  
ECOG 1308 
attempted 
to utilize 
response to 
neoadjuvant chemotherapy as a biomarker for HPV+ oropharynx cancer patients who may be candidates for 
radiation de-escalation (Marur 2017). In this trial, they found an overall correlation between complete clinical 
response to neoadjuvant cisplatin/cetuximab/Taxol and loco-regional control after 54Gy de-escalated 

12 
 
radiotherapy. However, they found a high rate of loco-regional failure after RT de-escalation among cT4, cN2c 
and patients with significant smoking history where 2 yr LRC was 70%. 
 
Furthermore, our recent data (submitted for publication) in 282 p16+ OPSCC patients with both pretreatment CT 
and PET-CT shows that radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and T-
stage were significant on MVA for DMFS: C-index=0.86 (p<0.001).   
 
Figure 3.  Locoregional failure free survival, distant metastatic failure free survival and overall survival by (A) 
AJCC 8th edition group stage, (B) total MTV and (C) presence of radiographic extranodal extension (rENE), and/or 
positive retropharyngeal lymph nodes (RPN+). 
 
Thus, this study seeks to study the population of HPV-related oropharynx cancer patients that appear to be at   
highest risk for distant metastases and loco-regional failure include cT4, cN3  those with “matted nodes”, 
radiographic ECE (extracapsular extension) and radiographically positive retropharyngeal lymph nodes  
 
1.2  Study Agents and Associated Known Toxicities:  Nivolumab 
 
Nivolumab is a fully humanized IgG4 anti-PD1 monoclonal antibody.  In metastatic platinum-refractory squamous 
cell carcinoma of the head and neck, nivolumab has been shown to improve survival from 5.1 months to 7.5 
months in a randomized trial p=0.01 (Ferris, 2016).  In combination with concurrent RT and cisplatin in the 
upfront treatment of intermediate and high risk loco-regionally advanced Head and Neck Squamous Cell 
Carcinoma (HNSCC), nivolumab has been shown to be safe and feasible to administer (Gillison, 2018). Here, we 
propose to study combination carboplatin/paclitaxel, nivolumab and radiotherapy in HPV-related oropharynx 
cancer including cT4, cN3 and those with “matted nodes”. We hypothesize that this combination can improve 
progression-free survival (PFS). Our institutional experience in HPV-related oropharynx cancer treated with RT 
and concurrent carboplatin (AUC=1) and paclitaxel (30mg/m2) has been extremely favorable (Feng 2010).  
Furthermore, in comparison with concurrent cisplatin, the UM experience has shown that oncologic outcomes 
are similar with concurrent carboplatin/paclitaxel with decreased > grade 3 toxicity and need for late feeding tube 

13 
 
(Worden, 2008, Dobrosotskaya, 2013).   
 
This study will run concurrently at UM with a sister study in AJCC 8th ed stage I and II HPV+ oropharyngeal cancer 
patients where carboplatin/paclitaxel alone is given with FDG-PET adapted de-escalated radiotherapy (UMCC 
2017.113).  
 
At UM, we have found a LRC at 2 yrs of 95% for HPV+ AJCC 8th ed stage 1 and 2 patients and a slightly lower rate 
of 85% for stage 3 (cT4, cN3). Interestingly, our data further suggest that cT4 and cN3 tumors (AJCC 8th edition 
staging) have high rates of distant metastases (unpublished data).  
 
 
Experience with Nivolumab in Squamous cell carcinoma of the head and neck 
Nivolumab monotherapy has demonstrated clinical benefit in subjects with squamous cell carcinoma of the 
head and neck (SCCHN) who have progressed on or after a platinum-based therapy, and has been approved for 
use in the US.   
In locally advanced squamous cell carcinoma of the head and neck, nivolumab has been evaluated with 
concurrent cisplatin and radiotherapy on RTOG 3504, showing safety and feasibility of administration (Gillison 
2018).  Cisplatin  was discontinued early in 3   pts due to AEs unrelated to nivolumab. No DLT was observed. SAEs 
included anaphylaxis to cisplatin (cis) (n=1), cholecystitis (1), but none attributable to nivolumab. Grade >3 
toxicities attributable to nivo included fatigue (n=1),anorexia (1), WBC decrease (2), neutrophil count decrease 
(1), mucositis  (1), lipase elevation (n=2).  
 
 
 
 
 
1.3  
Mid-Treatment PET-CT 
 
Post-treatment PET-CT obtained 12 weeks after therapy has been shown to be a reliable predictor of treatment 
response and has been widely adopted. A recently published prospective, randomized control trial studying PET 
surveillance at 12 weeks post-treatment found PET-CT surveillance was not inferior to planned neck dissection 
for advanced (N2/N3) SCC of the head and neck (Mehenna, 2016).  While PET-CT surveillance at this interval was 
non-inferior in terms of survival benefit, this group resulted in fewer neck dissections overall, no difference in 
complication rate, and similar 2-year survival rate. Furthermore, PET-CT was more cost effective, saving about 
$2000 per patient over the trial duration in decreased number of operations (Mehenna, 2016).  
 
Prospective trials have demonstrated value of pre- treatment PET-CT (pPET) and mid-treatment interval PET-CT 
(iPET) as a potential radiographic biomarker to predict loco-regional control (LRC), disease-free survival (DFS) 
and distant metastasis free survival (DMFS).   For example, Pollom, et al. studied iPET at median radiation dose 
of 33.5Gy in OPSCC where 88% of patients were p16 positive and 40% were “smokers” (Pollom, 2016).   They 
found that pre-treatment MTV50% and iPET MTV2.0 were correlated with PFS (p=0.015), where MTVx was defined 
as the metabolic tumor volume above a threshold “x”.   Additionally, they found that nodal total lesion glycolysis 
(TLG) of > 5% per week correlated with PFS (p=0.03).  
  

14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3.  PFS according to MTV parameters. 
 
 
 
Figure 4.  PFS according to velocity of TLG decrease.  
 
 
 
Schwartz, et al. performed a retrospective analysis of pPET in 74 patients treated on RTOG 0522 patients 

15 
 
(Schwartz, 2016).  They found that the SUVmax and SUVmean were non-prognostic, but that a MTV40% of the 
primary tumor, as well as the total MTV (primary tumor + involved lymph nodes) higher than cohort mean, 
correlated with worse PFS (HR 2.34, 95% CI [1.02, 5.37], p=0.05) and LRC (HP 4.01, CI [1.28,12.52], p=0.02).  
Primary MTV remained prognostic in the 56 patients of this study who had p16+ OPSCC.   
 
 
Figure 5.  Schwartz, et al. Cumulative incidence estimates of local-regional relapse (Panel A) and distant 
metastasis (Panel B) and Kaplan-Meier estimates of progression-free survival (Panel C) and OS (Panel D) 
for patients with baseline primary MTV ≤ median or > median. Two-year local-regional relapse rates 
were 5.7% (95% CI: 0, 13.5) for patients with MTV ≤ median and 30.3% (95% CI: 14.3, 46.3) for patients 
with MTV > median. Two-year distant metastases rates were 2.9% (95% CI: 0, 8.5) for patients with MTV 
≤ median and 12.1% (95% CI: 0.8, 23.4) for patients with MTV > median. Two-year progression-free 
survival rates were 88.6% (95% CI: 78.0, 99.1) for patients with MTV ≤ median and 63.6% (95% CI: 47.2, 
80.0) for patients with MTV > median. Two-year overall survival rates were 94.3% (95% CI: 86.6, 100) for 
patients with MTV ≤ median and 84.9% (95% CI: 72.6, 97.1) for patients with MTV > median. 
 
An Australian study of pPET and iPET in 75 patients by Lin, et al. evaluated all head and neck mucosal sites of 
cancer (Lin, 2015).  They performed iPET at a mean of 18.5 days from the start of RT, and evaluated SUVmax, 
SUVmean, MTV and TLG in both primary tumor and lymph nodes.  They found that the pPET parameters were not 
predictive of treatment response.  However, multi-variate analysis demonstrated iPET reduction of total node 
MTV by 50% from baseline to correlate with loco-regional failure -free survival (FFS), DFS and OS (p=0.026, 
0.003, and 0.014, respectively).  iPET reduction of nodal TLG by > 50% from baseline was predictive of FFS, DFS 
and OS in multi-variate analysis (p=0.01, 0.01, 0.014).   

16 
 
 
 
  
Figure 6.  Kaplan-Meier survival rates in relation to the optimum total node TLG cut-off value of 50 % on 
iPET for locoregional failure-free survival (LRFFS), b regional failure-free survival (RFFS), c disease-free 
survival (DFS) and d overall survival (OS). 
 
In non-small cell lung cancer (NSCLC), the University of Michigan has conducted 2 consecutive prospective 
dose escalation trials to test a hypothesis that radiation dose can be escalated safely above 74 Gy when the 
radiation dose prescription is individualized at the beginning (UMCC 2003.073) and adapted to the reduced 
MTV on during-RT FDG-PET/CT (UMCC 2007.123) (Kong 2005, 2006, 2007, 2017).   The prescription dose of the 
first trial was individually set to correspond to a 15% risk of RT-induced lung toxicity (RILT) according to a NTCP 
model at the baseline. RT dose was further escalated in the second trial by adapting dose individually to the 
residual metabolic volume on FDG-PET/CT obtained during RT, so the residual metabolic volume would 
receive the maximal dose that would maintain a tolerable risk of RILT while the pre-RT CTV on CT was 
not compromised (would receive at least 60 Gy). On the first trial, patients treated to a higher dose had 
significantly better survival (p=0.02).  The median survival on the second trial has not yet been reached.   
 
This prospective study aims to collect pre- and mid-treatment PET-CT to investigate changes in FDG-PET after 
administration of nivolumab. Early timing of mid-treatment PET-CT between fractions 8-12 has been planned to 
minimize risk of mucositis induced false positivity.   

17 
 
 
1.4 
Correlative Studies 
 
Circulating tumor DNA (ctDNA) 
 
An additional exploratory aim of this study is to study circulating tumor DNA in the patients undergoing therapy 
on this study.  Based on review of our previous experience at UM, we estimate the 2 year LRC of our study 
population to be 85%.   Furthermore, 15-30% of HPV-related oropharynx cancer patients will go on to develop 
distant metastases.  We hypothesize that additional biomarkers will aid in personalized care with potential 
selective treatment de-intensification for our patients.   
 
 
One promising non-invasive biomarker is quantification of circulating tumor DNA (ctDNA).  It is known that 
tumor cell division and death causes release of cell free fragmented DNA into circulation.  ctDNA is composed of 
small fragments of nucleic acid that are not associated with cells.  ctDNA is currently being explored in many 
cancers in early stage and metastatic settings to evaluate response. Circulating tumor DNA has been detected in 
70-100% at diagnosis in a cohort of 640 patients with multiple types of advanced stage cancers (Bettegowda 
2014).  This study included 14 head and neck cancer patients of all stages and found 73% were positive for 
detectable ctDNA. 
 
The concept of ctDNA is not new to head and neck cancer.  In EBV (Ebstein Barr virus)-related endemic 
nasopharynx cancer, multiple publications have demonstrated detectable serum EBV DNA in > 80% patients 
with pre-treatment levels correlated to tumor stage (Le 2013, Chan 2012). Furthermore, clearance of EBV DNA 
after definitive chemoradiation is associated with improved PFS (Wang 2012, Lin 2004).   
 
Serum detection of ctDNA is now being explored in other head and neck cancers.  Gupta, et al. have  have 
explored serum detection of HPV DNA during de-escalated chemoradiation for oropharynx cancer showing that 
80% patients had detectable HPV16 data and that clearance by 4th week of RT is associated with improved 
prognosis (Gupta 2018). Emerging data in HPV+ recurrent or metastatic OPSCC shows that serum levels 
correlate with total disease burdeni and studies are ongoing to assess correlation with treatment response 
(Hanna 2018).  To date, no group has attempted to detect ctDNA in head and neck cancer through somatic 
mutations.  Dr. Brenner’s lab at the University of Michigan has the technical ability to detect HPV DNA as well as 
the capability to detect the most commonly mutated oropharynx cancer genes through a next generation 
sequencing approach to ctDNA cell fragments. In this trial, we plan to collect 6ml of EDTA blood at several time 
points correlated with clinical blood draw times in order to explore correlation with ctDNA and treatment 
response as well and potential early detection of recurrence.   
 
 
 
Flow cytometry for analysis of serum immune biomarkers 
 
 
 
Optimal serum biomarkers have not been developed for identifying the subset of patients who best respond to 
immune checkpoint blockade. The measurement of peripheral blood immune cell subsets as a biomarker for 
immune activation or inhibition may be an important, noninvasive method to predict treatment response. 
Patients with high risk HPV+ OPSCC are at risk for treatment failure, thus careful monitoring during treatment 
and in the post-treatment period is of extreme importance.  As an exploratory aim, we will plan to perform flow 
cytometry analysis pre-treatment, weekly during treatment and post-treatment.   
 
 

18 
 
DCE-MRI 
 
Several physiological and metabolic imaging modalities, most in isolation, have been investigated for prediction 
of treatment failure in head and neck cancer.  Fludeoxyglucose (FDG) positron emission tomography (PET), a 
marker for glucose metabolism, has shown high FDG uptake associated with poorer prognosis, whereas rapid 
metabolic response on PET/CT has been associated with high LRC.   Hypoxic PET, and perfusion CT/MRI and 
diffusion MRI have shown to be biomarkers for outcomes in HNSCC.   Persisting poorly perfused tumors during 
the early course of RT is associated with high risk for local and regional failure.  Diffusion imaging, a measure of 
water mobility in tissue and sensitive to cellularity, has shown that an increase in apparent diffusion coefficient 
(ADC) of the HNSCC during RT is associated with positive therapy response. Most clinical trials currently 
underway use a single imaging modality to guide radiation escalation or de-escalation and single imaging 
modalities are limited to image only one aspect of tumor biology.  The spatial relationship between imaging risk-
factor parameters in HNSCC are largely unknown. 
 
One exploratory aim of this study is to investigate whether FDG uptake, low blood volume, and low diffusion 
coefficient in HPV-related oropharynx cancer have any spatial correspondence and their early responses to RT to 
determine the implication of this overlap or lack thereof for adaptive boosting strategy.  
 
1.5 
Rationale 
 
Above, we have identified a group of HPV+ oropharynx cancer patients at highest risk for metastatic disease and 
loco-regional failure including the cT4,cN3 and “matted nodes” patients.  To date, only multi-agent induction 
chemotherapy have been shown to improve distant metastases in head and neck cancer, but these regimens 
have not improved loco-regional control or overall survival.  We hypothesize that the addition of nivolumab to 
definitive chemoradiation will improve loco-regional control and distant metastasis rate in these patients.   
 
 
 
 
2.0  
Study Objectives 
 
2.1 
Primary Objective  
2.1.1 
To determine whether the addition of nivolumab can improve 2 yr PFS (progression free survival) as compared 
to historical standard of fractionated RT and carboplatin/paclitaxel in patients with high risk HPV-related 
squamous cell carcinoma of the oropharynx.   
 
2.2 
Secondary Objectives 
2.2.1 
To characterize patterns of failure (loco-regional relapse versus distant) PFS and overall survival; 
2.2.2 
To characterize acute toxicity profiles (during radiation therapy and at 3 and 6 months) and late  
 
toxicity profiles at 1 and 2 years; 
2.2.3 
To correlate metabolic image uptake data on mid-treatment FDG-PET scans performed between fractions 8-12 
with standard 12 week post-treatment PET-CT. 
 
2.3 
Exploratory Correlative Science Objectives 
2.3.1 
To quantify circulating tumor HPV DNA in the blood pre-, mid- and post-treatment.  
2.3.2 
To perform integrative targeted sequencing of primary HPV+ tumor specimens to identify the distribution of 
lesions co-incident with commonly deregulated genes (as well as the transcriptional programs deregulated in 
these tumors and assess overall mutational burden). 

19 
 
2.3.3 
To describe the serum immune cell profile pre-treatment, weekly during RT and post-treatment by flow 
cytometry and correlate with clinical outcomes  
2.3.4 
To correlate pre-treatment tumor immune phenotype with clinical outcomes 
2.3.5 
To determine patient-reported quality of life at 3, 6 months and 1 year using FACTHN, U Washington QOL, 
CTCAE PRO as well as xerostomia questionnaire; 
2.3.6 
To determine swallowing outcomes using barium swallow pre-treatment as well as 3- and 12- months post 
treatment 
2.3.7 
To descriptively assess FDG-PET after nivolumab is administered. 
2.3.8 
To quantify the low blood volume and apparent diffusion coefficient in DCE-MRI of HPV-related oropharynx 
cancer in patients treated with anti-PD1 therapy 
 
2.4 
Endpoints 
The primary study endpoint is the PFS at 2 years which will be estimated using the Kaplan-Meier method. 
Secondary aims include estimation of toxicity, patterns of failure, freedom from local and distant progression 
and overall survival.  To characterize patterns of failure we will summarize at fixed timepoints, the proportion of 
patients who progressed in any location and whether the first progression was local, regional, distant or in 
multiple locations.  Overall survival will be estimated using the Kaplan-Meier methods with associated 90% 
confidence intervals.  Freedom from local/regional or distant progression will be estimated using cumulative 
incidence functions with death prior to progression as a competing risk. Toxicity outcomes will be estimated as 
proportions for patients with available toxicity data at 3, 6 12 and 24 months.  They will also be estimated as the 
proportion of all treated patients through cumulative incidence estimates with death or disease progression 
treated as competing risks and censoring for patients lost to FU.  Quality of Life (QOL) outcomes and swallowing 
study results will be summarized descriptively by timepoint.  If there is substantial missing data points in the 
QOL outcomes we will assess for informative missing data points by comparing earlier QOL scores and change in 
earlier QOL scores between patients missing QOL at later timepoints (e.g. 1 or 2 years).  Another secondary aim 
is to correlate metabolic image uptake data on mid-treatment FDG-PET scan with standard 12 week post-
treatment PET-CT. This will be done both at the patient level for summary measures and also spatially within a 
patient.   
 
3.0        PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
3.1.1 
Histologically or cytologically proven squamous cell carcinoma of the oropharynx (tonsil, base of tongue, 
oropharyngeal wall, soft palate) that is p16 positive by immunohistochemistry or HPV positive by in situ 
hybridization  
3.1.2 
Clinical stage:  stage III AJCC 8th edition staging (cT4 or cN3) OR “matted lymph nodes” (defined as 3 LNs 
abutting one another with loss of intervening fat plane that is replaced with evidence of extracapsular 
spread) OR radiographic extracapsular extension (defined as overt loss of fat plane surrounding a LN) OR 
radiographically positive retropharyngeal LN >7mm in size 
 
3.1.3 
Appropriate stage for protocol entry, including no distant metastases, based upon the following 
minimum diagnostic workup: 
History/physical examination, including documentation of weight within 2 weeks prior to 
registration; 
FDG-PET/CT scan for staging and RT plan within 4 weeks prior to registration; 
Zubrod Performance Status 0-1 within 2 weeks prior to registration; 
Age ≥ 18; 
 
3.1.4 
CBC/differential obtained within 2 weeks prior to registration on study, with adequate bone 
marrow function defined as follows: 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3; Platelets ≥ 75,000 cells/mm3; Hemoglobin ≥ 9.0 g/dL 

20 
 
 
AST/ALT <3 x ULN 
 
Total Bilirubin <1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level < 
3 x ULN) 
 
3.1.5 
Serum creatinine within normal institutional limits or a creatinine clearance ≥ 45 mL/min within 2 
weeks prior to registration; 
3.1.6 
Women of childbearing potential must agree to use a medically effective means of birth control 
throughout their participation in the treatment phase of the study and for five months after the last 
treatment. A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) 
and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under the age of 55 
years must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause.   
Men receiving nivolumab who are sexually active with WOCBP must agree to use effective 
contraception throughout their participation in the treatment phase of the study and for seven months 
after the last treatment. 
3.1.7 
Due to the potential for serious adverse reactions in breastfed infants from carboplatin/paclitaxel and 
nivolumab, women are advised not to breast-feed during treatment with carboplatin/paclitaxel or 
nivolumab  
3.1.8 
The patient must provide study-specific informed consent prior to study entry. 
 
3.2 
Exclusion Criteria 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum 
of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible); 
3.2.2 
Any prior therapy for the study cancer; note that prior chemotherapy for a different cancer is 
allowable if > 3 years prior to study; 
3.2.3 
Any history of active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
3.2.4 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy 
fields; 
3.2.5 
Severe, active co-morbidity, defined as follows: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; 
• 
Uncontrolled diarrhea; 
• 
Uncontrolled adrenal insufficiency; 
• 
Transmural myocardial infarction within the last 3 months; 
• 
Acute bacterial or fungal infection requiring systemic antibiotics at the time of registration; 
• 
Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of registration; 
• 
Acquired Immune Deficiency Syndrome (AIDS) with CD4+ count < 350 cells per microL; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in this protocol 
may be significantly immunosuppressive. 
3.2.6 
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able 
to use contraception; this exclusion is necessary because the treatment involved in this study may be 
significantly teratogenic. 
3.2.7 
Women who are breastfeeding and are not willing to discontinue breastfeeding during the trial  

21 
 
3.2.8 
Poorly controlled diabetes (defined as fasting glucose level > 200 mg/dL) despite 2 attempts to improve 
glucose control by fasting duration and adjustment of medications. Patients with diabetes will 
preferably be scheduled in the morning and instructions for fasting and use of medications will be 
provided in consultation with the patients’ primary physicians 
3.2.9 
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Short bursts of 
steroids of 5-7 days (for COPD exacerbation or other similar indication) are allowed. 
3.2.10 Known history of, or any evidence of active, non-infectious pneumonitis. 
3.2.11 Known history of active TB (Bacillus Tuberculosis). 
3.2.12 Hypersensitivity to nivolumab or any of its excipients or known hypersensitivity to 
carboplatin/paclitaxel. 
3.2.13 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
3.2.14 Received a live vaccine within 30 days of planned start of study therapy. 
3.2.15 Have any condition that, in the opinion of the investigator, would compromise the well-being of the 
subject or the study or prevent the subject from meeting or performing study requirements 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES  
Patient registration The University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed Consent 
document will be initially documented by the Screening and Enrollment Log. 
 
The UM CTSU Coordinator, who acts as the registrar, will review the submitted documents and process the 
registration. After informed consent is obtained and PRIOR to the initiation of protocol therapy all patients 
satisfying the inclusion/exclusion criteria must have eligibility confirmed by the Clinical Trials Support Unit. The 
patient will not be considered registered and enrolled in the study until all information is confirmed by the 
Clinical Trials Support Unit Data Manager. To enroll a patient, call 734-936-4300 Monday through Friday, 
9:00AM-5:00PM.  
 
Patients found to be ineligible for participation after being consented will be considered screen failures, and 
documented as such in the Screening and Enrollment Log. These patients will not have study identification 
number assigned to them, and will not receive study treatment. 
 
  
5.0 
TREATMENT PLAN 
 
5.1  
Treatment dosage and Administration 
Protocol treatment must start within 30 days of enrollment. Nivolumab (240mg) will be administered on 
Day 1 and then continued q2wk throughout RT.  On day 8, RT as well as carboplatin (AUC=1) and 
paclitaxel (30mg/m2) will be administered with paclitaxel infusion first, followed directly by carboplatin 
infusion.  RT (70Gy in 35 daily fractions on business days) will begin within 24 hours of chemotherapy 
infusion.  Carboplatin/paclitaxel will be administered weekly during RT.  Patients will receive a total of 7 
concurrent carboplatin/paclitaxel doses and 4 concurrent nivolumab doses.  Starting in week 9, after 
completion of RT, adjuvant nivolumab (480mg) will be given q4weeks for a total of 4 doses.  
Premedications and supportive care will be administered per institution guidelines.  On 
carboplatin/paclitaxel days, premedications will include antiemetics, histamine H1 and H2 antagonists, 
and dexamethasone according to the institution standards. 
 
 

22 
 
5.1.1 
Nivolumab 
 
Nivolumab (investigational product) will be supplied by Bristol Myers Squibb. 
 
Patients will start nivolumab 240 mg IV prior to chemotherapy and radiation.  Then, nivolumab will 
continue at 240 mg IV for 4 total doses q 2wks concurrent with RT.  Adjuvantly, patients will receive 
nivolumab 480 mg alone IV q 4weeks for a total of 4 doses.   
 
Drug Product Description, Preparation and Administration (nivolumab  
Investigator’s Brochure) 
 
Nivolumab is provided as a 10mg/mL solution in single-use vials. The drug product is sterile, non-
pyrogenic, single-use, isotonic aqueous solution for IV infusion. 
 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from light and 
freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and room light for up 
to 48 hours. 
Preparation  
Refer to the latest Investigator’s Brochure for drug preparation information.  
Nivolumab is a clear to opalescent, colorless to pale-yellow liquid, which may contain light (few) 
particulates.  
• 
When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection can be 
infused undiluted or diluted so as not to exceed a total infusion volume of 160 mL. 
• 
If diluted, dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to prepare an infusion with a protein concentration as low as 0.35mg/mL. The total 
volume of infusion must not exceed 160 mL.  
• 
For patients with body weights less than 40 kg, the total volume of infusion must not exceed 4 
mL/kg of body weight.  
• 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. Mix 
diluted solution by gentle inversion. Do not shake.  
• 
Discard partially used vials or empty vials of nivolumab.  
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with polyvinyl 
chloride (PVC) or polyolefin containers and infusion sets, and glass bottles. 
 
Storage of Infusion  
The product does not contain a preservative. 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If not used 
immediately, the infusion solution may be stored under refrigeration conditions (2°C to 8°C, 36°F to 
46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room temperature 
(up to 25°C, 77°F) and room light. The maximum of 8 hours under room temperature and room light 
conditions includes the product administration period. 

23 
 
 
Administration  
Administer the infusion over 30 minutes (study allows +/- 5 minutes window) through an intravenous 
line containing a sterile, non-pyrogenic, low protein binding (polyethyersulfone membrane) in-line filter 
(pore size of 0.2 micrometer to 1.2 micrometer). It is not to be administered as an IV push or bolus 
injection. 
Do not coadminister other drugs through the same intravenous line. Flush the intravenous line at end of 
infusion.  
 
 
5.1.2 
Carboplatin 
Chemistry: Carboplatin is a hydrophilic platinum-containing compound and is an analog of cisplatin, 
producing intrastrand DNA cross- links. 
 
Human Toxicology: Side effects of carboplatin include: myelosuppression, nausea, vomiting, abdominal 
pain, diarrhea, and constipation. Other toxicities include: allergic reactions (including hypersensitivity, 
i.e. rash, urticaria, erythema, pruritis, bronchospasm, and profound hypotension), peripheral 
neuropathy, paresthesias, loss of hair, hearing loss, visual disturbances, and change in taste. Serum 
creatinine elevations and blood urea elevations have occurred as well as abnormal liver function tests 
and decreased serum electrolyte values. Although rare, pain asthenia, cardiovascular, respiratory, 
genitourinary, and mucosal side effects have occurred in some patients. Cancer-associated hemolytic 
uremic syndrome has been reported. Rarely carboplatin may cause fetal harm; therefore, women of 
childbearing potential should be advised to avoid becoming pregnant. The renal effects of nephrotoxic 
compounds may be potentiated by carboplatin. Carboplatin is contraindicated in patients with a history 
of severe allergic reactions to cisplatin or to other platinum-containing compounds or mannitol. This 
drug should not be used in patients with severe bone marrow depression or significant bleeding. The 
occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator 
combination chemotherapy.  For a completed list of adverse effect see the current drug label. 
 
Pharmaceutical Data 
Pharmacokinetics: 
Distribution: Vd: 16 L (based on a dose of 300 to 500 mg/m2); into liver, kidney, skin, and tumor tissue 
Protein binding: Carboplatin: 0%; Platinum (from carboplatin): Irreversibly binds to plasma proteins 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds 
Half-life elimination: CrCl >60 mL/minute: Carboplatin: 2.6 to 5.9 hours (based on a dose of 300 to 500 
mg/m2); Platinum (from carboplatin): ≥5 days 
Excretion: Urine (~70% as carboplatin within 24 hours; 3% to 5% as platinum within 1 to 4 days) 
 
Formulation and Preparation:    
Carboplatin Injection is supplied as a sterile, pyrogen-free, aqueous solution available in 50 mg/5 mL, 
150 mg/15 mL, 450 mg/45 mL or 600 mg/60 mL multi-dose vials containing 10 mg/mL of carboplatin for 
administration by intravenous infusion. Each mL contains 10 mg carboplatin and Water for Injection. 
 
Carboplatin can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water or 
0.9% Sodium Chloride injection, USP. 

24 
 
 
Storage and Stability: Unopened vials of carboplatin for injection are stable for the life indicated on the 
package when stored at 25°C (77°F); excursion permitted to storage at controlled room temperature 
(15-30°C; 59-86°F), and protected from light. When reconstituted as directed, the solution of 
carboplatin exhibits no decomposition for eight hours at room temperature (25°C). Like cisplatin, this 
drug should not be given through aluminum needles or intravenous administration sets. Caution: The 
single-use lyophilized dosage form contains no antibacterial preservatives. Therefore, it is advised that 
the reconstituted product be discarded eight hours after dilution. 
 
Administration: Infuse intravenously at a rate per institution standard. 
 
Supplier: Carboplatin is commercially available and should be from commercial sources and 
billed to patients or their insurers.  
 
 
 
5.1.13 Paclitaxel  
 
Chemistry: Paclitaxel is a semi-synthetic antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization hence 
producing abnormal bundles of microtubules throughout the cell cycle. As a result, paclitaxel inhibits 
interphase and cellular function. 
 
Human Toxicology: Side effects of paclitaxel include: hypersensitivity reaction, 
myelosuppression, alopecia, peripheral neuropathy, nausea/vomiting, mucositis, alkaline 
phosphatase elevation, abnormal EKG, myalgia/arthlagia, asthenia, and hypotension. The 
development of severe hypersensitivity reactions is rare and documented in 1% of patients 
overall. For a completed list of adverse effects see the current drug label. 
 
 
Pharmaceutical Data 
Pharmacokinetics: 
Distribution (Vdss): 24-hour infusion: 227 to 688 L/m2; biphasic with initial rapid distribution to 
the peripheral compartment; later phase is a slow efflux of paclitaxel from the peripheral 
compartment; widely distributed into body fluids and tissues; affected by dose and duration of 
infusion 
Protein binding: 89% to 98% 
Metabolism: Hepatic via CYP2C8 and 3A4; forms metabolites (primarily 6α-hydroxypaclitaxel) 
Half-life elimination: 
Adults: 
3-hour infusion: Mean (terminal): ~13 to 20 hours 
24-hour infusion: Mean (terminal): ~16 to 53 hours 
Excretion: Feces (~71%; ~5% as unchanged drug); urine (~14%) 
Potential drug interactions: It has been demonstrated that paclitaxel is metabolized primarily 
by CYP450 2C8 and to a lesser extent 3A4.  As a result, the pharmacokinetics of paclitaxel 
may be altered in vivo as a result of interactions with compounds that are substrates, 
inducers, or inhibitors of CYP2C8 and/or CYP3A4 

25 
 
 
Formulation and Preparation:  
Paclitaxel is a clear, colorless slightly yellow viscous solution intended for dilution prior to 
intravenous infusion. Each mL of sterile non-pyrogenic solution contains 6 mg paclitaxel, 
Polyoxyl 35 Castor Oil (Cremophor® EL), dehydrated alcohol, and may contain possible citric 
acid.  Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), 150mg (25mL) and 300 mg 
(50 mL) vials. 
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium 
Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 
mg/mL. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. 
Upon preparation, solutions may show haziness, which is attributed to the formulation 
vehicle. No significant losses in potency have been noted following simulated delivery of the 
solution through intravenous tubing containing an in-line (0.22 micron) filter. Data collected 
for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) phthalate] show 
that levels increase with time and concentration when dilutions are prepared in PVC 
containers. Therefore, the use of plasticized PVC containers and administration sets is not 
recommended. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or 
polyolefin containers. 
 
Storage and Stability: Unopened vials of paclitaxel for injection are stable until the date 
indicated on the package when stored at controlled room temperature (20-25°C; 68° to 
77°F), and protected from light. Neither freezing nor refrigeration adversely affects the 
stability of the product. When diluted as directed, the solution of paclitaxel is physically and 
chemically stable for up to 27 hours at ambient temperature (approximately 25°C). 
 
Administration: Infuse paclitaxel intravenously at a rate per institution standards. Paclitaxel should 
be administered through an in-line filter with a microporous membrane not greater 
than 0.22 microns. Non-PVC containing administration sets, such as those which are 
polyethylene-lined, should be used. 
 
Supplier: Paclitaxel is commercially available and should be purchased from 
commercial sources and billed to patients or their insurers.  
 
 
5.2  
Toxicities and Dosing Delays/Dose Modifications 
 
 
5.2.1 Nivolumab 
Suggested supportive care measures for the management of adverse events with potential immunologic 
etiology are outlined below. Where appropriate and at the discretion of treating physicians, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as additional 
anti-inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The treatment 

26 
 
guidelines are intended to be applied when the investigator determines the events to be related to 
nivolumab.  
 
Treatment delay is up to 6 weeks for nivolumab are allowable. It is permissible in cases of a dose held 
due to AE to skip the dose in the cycle in order to bring the patient back on track with the next Cycle 
visit. 
 
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed. 
Nivolumab should be delayed for the following: 
Grade 2 non-skin, drug-related AE, with the exception of fatigue 
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
 
Grade 3 skin, drug-related AE 
 
Grade 3 drug-related laboratory abnormality, with the following exceptions:   
 
Grade >3 lymphopenia or asymptomatic amylase or lipase does not require dose 
delay 
Grade >3 AST, ALT, Total Bilirubin will require dose discontinuation 
All grade 1 or higher ocular AEs should be evaluated within 48 hours of occurrence 
by Radiation Oncology (Radonc) MD. 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if clinically 
indicated and resume nivolumab dosing when re-treatment criteria are met. 
 
For nivolumab: A dose given more than 3 days after the intended dose date will be considered a dose 
delay 
 
There will be no dose reductions for nivolumab. 
 
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. 
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is complete. 
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 BMS Medical 
Monitor. 
Participants with drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the UM principal investigator (PI) (or 

27 
 
designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement. 
Treatment Discontinuation Criteria 
 
For all subjects, global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time will be captured on the health outcomes 
questionnaires. Tumor assessments for subjects who discontinue study treatment without 
radiographic progression, should continue as per protocol until radiographic progression is 
determined. 
 
Nivolumab Dose Discontinuation 
 
Treatment with nivolumab should be permanently discontinued for any of the following: 
 
Any Grade 2 drug-related uveitis, 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 non-skin, drug-related AE lasting > 7 days, or recurs with the following exceptions for 
laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, infusion reactions, and endocrinopathies.  This excludes 
grade 3 mucositis as grade 3 mucositis including the need for placement of feeding tube is anticipated 
in 25% of patients with standard of care chemoradiation.  For any patient where nivolumab is held 
during RT for grade 3 mucositis or feeding tube placement, patient should be re-evaluated within 4 
weeks of the completion of RT.  If feeding tube has been removed and/or mucositis has improved to < 
Grade 2, adjuvant nivolumab should be restarted.  
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic hormone 
replacement do not require discontinuation. Adrenal insufficiency requires discontinuation regardless 
of control with hormone replacement. 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires discontinuation 
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation: 
o Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation* 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN 
* In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently discontinued. If 
the investigator determines a possible favorable benefit/risk ratio that warrants continuation of study 
treatment, a discussion with the UM-PI must occur. 
 
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not require 
discontinuation: 
• 
Grade 4 neutropenia < 7 days 
• 
Grade 4 lymphopenia or leukopenia or amylase or lipase < 7 days 
• 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 

28 
 
sequelae and are corrected with supplementation/appropriate management within 72 hours of 
their onset 
• 
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the BMS Medical 
Monitor. 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
• 
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events are 
allowed. 
• 
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the UM PI (or 
designee) must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue every 6 
weeks or more frequently if clinically indicated during such dosing delays. 
 
Algorithms for management of nivolumab toxicity can be found in Appendix A.  These algorithms are to be 
used in conjunction with treating physician discretion possibly in addition to other medications.   
 
 
 
 
5.2.2 Carboplatin/paclitaxel 
 
 
 
Toxicity 
Action Taken 
 
• 
AST and/or ALT is > 2.5 x ULN 
• 
Alkaline phosphatase ≥ 2.5 x ULN 
and AST and ALT is > 1.5 x ULN 
 
Step 1: Interrupt paclitaxel treatment until the toxicity 
has resolved, up to 2 weeks (14 days).   
Paclitaxel should be reduced by 15 mg/m2  when 
restarted. 
Monitor as clinically indicated. 
If CrCl < 30, hold carboplatin.  When CrCl returns to ≥ 30, initiate/resume carboplatin at previous dose. 
 
Hematologic Toxicity 
 
• 
Neutrophil count is < 1000 cells/ 
mm3 
 
• 
Platelet count is < 75,000 
cells/mm3 
 
Step 1: Interrupt treatment (carboplatin and paclitaxel) 
until the toxicity has resolved to < Grade 1 or pre-therapy 
baseline, up to 2 weeks (14 days). 
Step 2: Restart treatment monitor as clinically indicated. 

29 
 
 
• 
Grade 4 neutropenia (< 500 
cells/mm3) lasting 7 days or more 
 
• 
Grade 3 or 4 neutropenia with an 
oral temperature of at least 38.5°C 
 
Step 1: Interrupt treatment with carboplatin/paclitaxel 
until resolved to ≤ Grade 1, up to 2 weeks (14 days). 
Step 2: Restart treatment with carboplatin by tat AUC 1 
Monitor as clinically indicated. 
Other Toxicities 
• Any Grade 4 or at the discretion of 
treating Medical Oncologist 
 
Discontinuation of treatment with chemotherapy and 
follow-up per protocol. 
 
 
 
 
5.3 
Concomitant Medications/Treatments 
5.3.1 
Steroids or other immunosuppressive medications are prohibited for treatment of toxicities 
during protocol therapy, and used only if these medications are deemed medically necessary 
after thoughtful review.   Premedications for chemotherapy are allowed. 
 
5.3.2 
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 
In the absence of formal clinical drug interaction studies, caution should be exercised when 
administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome 
P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is 
concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, 
lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. 
Caution should also be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, 
rifampin) of CYP2C8.  
Due to potential drug interactions, the complete patient medication list, including paclitaxel, 
should be screened prior to initiation of and during treatment with paclitaxel and patients on 
potential interacting drugs monitored. 
Since these lists of potentially interacting drugs are not complete, it is important to regularly 
consult frequently-updated drug information resources.  
 
5.4 
Other Modalities 
 
 
5.4.1 
Radiation Therapy  
 
Simulation and Treatment Planning 
Patients should undergo simulation to include 5-point aquaplast masking and CT scan with IV contrast 
unless contraindicated in the Department of Radiation Oncology at the University of Michigan.  The 
treatment planning CT scan should be obtained in the immobilization device and in the treatment 
position with a slice thickness of 3 mm or less. 

30 
 
 
Dose Specifications 
 
 
-GTVp is gross primary tumor volume. GTVn is gross nodal tumor volume. 
 
-CTV1 is gross clinical volume with tight (typically 0.5 cm) margins around the GTV. 
-CTV2 includes areas containing sub-clinical at-risk around the gross disease and at areas at risk of lymph 
node metastases. 
 
-PTV1 and PTV2 consist of uniform 3 mm expansions of the CTV1 and 2 respectively. 
 
Patients will initially receive a single prescription of 70 Gy to PTV1 in 35 fractions with RT given once 
daily, 5 days a week along with weekly carboplatin/paclitaxel (standard therapy). All fields must be 
treated daily. On days when chemotherapy is given, it will be administered prior to RT.  Prescription to 
high risk PTV will be 70Gy in 35 fractions and to PTV2 will be 56Gy in 35 fractions.   
 
 
 
Optimization goals: 
 
The primary PTV dose will be 99% +/- 7% of the prescribed dose and to sub- clinical PTVs within +/- 5% 
of the prescribed dose. The maximal “hot spot” within a PTV will be <115% of the prescribed dose to 
that target delivered to a volume of at least 0.5 cc. The maximal dose outside the targets will be <105% 
of the prescribed dose delivered to at least 0.5 cc. volume. The maximal dose to the spinal cord, 
expanded by 0.5 cm, will be < 50 Gy, to the non-expanded cord < 45 Gy, and where applicable, to the 
optic pathways < 50 Gy and to the brainstem <54 Gy.  Other normal tissue optimization are per 
institutional standards. 
 
5.5 
Duration of Therapy 
Therapy will continue for 21 weeks total.  This includes 4 doses of of nivolumab (240mg/m2) before 
and concurrent with RT/carboplatin/paclitaxel and 4 adjuvant nivolumab doses (480mg/m2) after the 
end of RT unless one of the following apply: 
• 
Disease progression as defined in Section 7.0 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event 
• 
Patient voluntarily withdraws from treatment 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment    
 
 
 
5.6 
Off Treatment Criteria 
Patients will be removed from protocol therapy when any of the criteria listed in Section 5.5 apply.  The 
reason for ending protocol therapy and the date will be documented in the source.  All patients who 
discontinue therapy should comply with protocol specific follow-up procedures as outlined in Section 
5.7.  The only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely.   
 
5.7 
Duration of Follow-up 

31 
 
Patients will be followed for 2 years after completion of or removal from treatment or death, whichever 
comes first. Patient removed from treatment for unacceptable adverse events will be followed until 
resolution or stabilization of adverse event and not followed further.  Clinical examinations will be 
performed as comparable to clinical practice: at 1 month after the completion of therapy and then 
approximately every 3 months for 2 years (+/- 2 months).  This follow up schedule will adhere to 
standard of care clinical follow up.  Therefore, missed visits and visits that diverge from this regimen will 
not be considered protocol deviations.   
 
 
5.8 
Off Study Criteria 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment; 
5.8.3 
Patient is unable to comply with protocol requirements; 
5.8.4 
Treating physician judges continuation on the study would not be in the patient’s best interest; 
5.8.5 
Patient becomes pregnant or female partner of male patients (pregnancy to be reported along same 
timelines as a serious adverse event); 
5.8.6 
Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of 
the skin) that requires treatment, which would interfere with this study; 
5.8.7 
If a research subject cannot be located to document survival after a period of 2 years, the subject 
may be considered “lost to follow-up.” All attempts to contact the subject during the two years must 
be documented; 
5.8.8 
Termination of the study by The University of Michigan or other regulatory bodies; 
5.8.9 
Patient completes protocol treatment and follow-up criteria 
 
 
6.0 
STUDY PROCEDURES  
6.1 
Screening/Baseline Procedures NOTE: This section lists required baseline evaluations needed before the 
initiation of protocol treatment. 
 
6.1.2 
Screening procedures include: Comprehensive metabolic panel, CBC with diff, Magnesium, TSH and 
cortisol within 2 weeks prior to enrollment, Radonc evaluation including nutritional assessment 
within 4 wks of enrollment, pretreatment imaging to assess staging including CT neck and chest 
(may be done as part of head and neck protocol PET-CT) within 4 wks of enrollment 
6.1.3 
Quantification of patients smoking history including number of pack years (# packs per day x # years) 
and whether they have smoked more than 100 cigarettes within last 365 days 
6.1.4 
Pre-treatment blood draw for ctDNA/exosomes/immune flow cytometry (optional per the subject) 
6.1.5 
Pre-treatment patient reported quality of life questionnaire  
6.1.6 
Pre-treatment barium swallow videofluoroscopy examination  
6.1.7 
Pre-treatment MRI in Radiation Oncology is planned.  Will not be completed if patient has a 
contraindication to MRI.  Please note that patients with a contraindication to MRI or who refuse MRI 
will continue with trial as otherwise planned 
6.1.8 
Tumor biopsy specimen is required for sequencing analysis.  Archival tissue is acceptable if available.  
If archival tissue is not available, subjects will be asked to undergo a fresh tissue biopsy.    
 
6.2 
Procedures During Treatment 
6.2.2 
Day 1.  Nivolumab Administration 
6.2.3 
Day 8.  Carboplatin/paclitaxel as well as start of radiotherapy (all to occur within a 24 hour period).   

32 
 
6.2.4 
Weekly CBC, CMP (incluing Mg), LFTs, TSH, cortisol  
6.2.5 
Weekly Radonc MD evaluation with toxicity evaluation 
6.2.6 
Weekly PRO (CTCAE PRO) 
6.2.7 
Between RT fractions 8-12, mid-treatment MRI and FDG-PET-CT  
6.2.8 
Weekly blood for ctDNA and exosomes (optional per the subject) 
6.2.9 
Weekly carboplatin/paclitaxel administration , with nivolumab administration every 2 weeks. 
 
6.3 
Follow-up Procedures- patients will be followed at 3,6,12, and 24 months post RT 
6.3.2 
FDG-PET-CT at 3mo (+/- 2 wks) after completion of RT 
6.3.3 
Q3mo (+/- 1 month) clinical followup with multi-disciplinary head and neck cancer team (Oto, 
Radonc, MedOnc) 
6.3.4 
Barium swallow evaluation 3mo and 12 mo post RT 
6.3.5 
Q3 mo QOL evaluation (FACT HN, U Washington and Xerostomia questionnaires).  Financial toxicity 
survey collected a 3 mo post RT only 
6.3.6 
Q3mo toxicity and nutritional evaluation 
6.3.7 
Blood for correlatives at 3,6,12,24 months post RT (optional per the subject) 
6.3.8 
In the event of recurrence- FDG-PET-CT and biopsy confirmation are required 
 
 

33 
 
 6.4 Schedule of Events 
Scree
ning 
Pre- 
Thera
py 
Day 1 Pre-RT 
Between 
fractions 
8-12 
Weekly 
during 
CRT 
+ 1 
Month6 
+ 3 
month6 
+ 6 
month6 
+ 12 
month6 
+ 24 
month6 
Recurrence 
Rad Onc eval6 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
CBC with diff, CMP, 
Mg, LFTs, TSH, cortisol7
X 
X 
 
 
 
X10 
X10 
X10 
X 
X 
 
 
Pregnancy test 
X12 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
X11 
 
 
X11 
 
 
 
 
 
 
 
PET/CT3 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Toxicity & nutritional 
Evaluation4 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
QOL 
Questionnaire5 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Videofluoroscopy1 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Dental 
Evaluation2 
 
 
 
X 
 
 
 
 
 
 
 
 
Carboplatin/paclitaxel 
 
 
 
 
 
X 
 
 
 
 
 
 
Nivolumab 
 
 
X 
 
 
X8 
X9 
 
 
 
 
 
Blood for correlatives13
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Primary tumor 
specimen for 
correlatives required 
 
X14 
 
 
 
 
 
 
 
 
 
X13 
1 videofluoroscopy to be completed at baseline, 3 mo post RT and 12 mo post-RT per standard of care.  Baseline can 
occur prior to the initiation of Nivolumab, during the first week of therapy (between the first dose of Nivolumab and 
radiation) or during the first week of radiation.   
2  Pre-RT dental evaluation is encouraged but not required for all patients due to insurance issues 
3  PET-CT to be completed at baseline within 4 wks of registration, mid-treatment (fx 8-12) and 3 mo post-RT (+/- 3 
weeks) 
4  toxicity evaluation per CTCAE v 5.0 
5  QOL Suggested but not required.  Financial toxicity will only be given at one time point 3 months post RT.  All other 
questionnaires given at baseline and all follow-ups through 1 year.  The CTCAE PRO will be given weekly during RT (this 
will be the only questionnaire administered during RT.  As patients can be seen in a variety of clinics, and occasionally 
do not follow a standard clinic schedule, missed QOLs will not be reported as a protocol deviation.  Nutritional 
assessment to be completed within 6 wks of start of therapy 
6 Radonc exam will include med hx and physical as well as pregnancy test if applicable. Follow Up: Examinations will be 
performed as comparable to clinical practice: at 1 month (+/- 2 weeks) after the completion of therapy and then 
approximately every 3 months (+/- 1 month) for 2 years (+/- 2 months).  This follow up schedule will adhere to 
standard of care clinical follow up.  Therefore, missed visits and visits that diverge from this regimen will not be 
considered protocol deviations.  RadOnc evaluation must be completed at baseline, but follow-up visits may be 
completed by RadOnc, Oto, or MedOnc.  Baseline Radonc eval will include smoking history as per “pretreatment 
evaluation” section.  Minimum follow-up is 3 mo after completion of protocol therapy. 
7 Baseline within 2 weeks of registration 
8 Nivolumab will be started on day 1 and given as follows: 240 mg IV q2 wks for 4 doses concurrent with RT.    
9 Adjuvantly, patients will receive nivolumab 480 mg alone IV q 4weeks for a total of 4 doses. 
10 Labs during RT, and in follow up 1-mo through 3-mo will occur with each chemotherapy dose 

34 
 
11 MRI is encouraged but not required- patients with a contraindication to MRI or who are unable to tolerate MRI will 
continue on the study as otherwise planned 
12 Pregnancy test should also be performed as part of pre-RT workup in women of child bearing potential 
13 Collection and banking of blood samples for correlative studies (genetic testing) is optional per the subject.  
   14   Tumor biopsy specimen is required for sequencing analysis. Archival tissue is acceptable if available. If 
           archival tissue is not available subjects will be asked to undergo a fresh tissue biopsy. 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect 
 Efficacy on imaging will be determined by imaging and clinical exam.  .  Initial staging imaging will be 
obtained at registration; then routine PET-CT imaging will be obtained at 3 months (+/- 1 month) from 
completion of definitive therapy as per standard of care. After 3 mo post-RT PET scan, patients will be 
followed by head and neck clinical exam.  Further imaging will be ordered based on clinical symptoms or 
findings as per standard of care.  
Response and progression will be evaluated in this study and will be scored as no evidence of disease, 
local progression, regional progression, and distant progression.  This will assessed based upon imaging 
and clinical exam.   
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with study drug. 
 
Evaluable for objective response. All patients who complete the entire course of radiation 
therapy and who complete standard of care 3 mo post-therapy PET-CT scan will be evaluable for 
response.   
 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter in the plane of measurement is to be recorded) with 
a minimum size of: 
 
• 
10mm by CT scan (irrespective of scanner type) for studies with a slice thickness of 
<5mm or twice the slice thickness or MRI 
• 
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  All tumor 
measurements must be recorded in millimeters (or decimal fractions of  centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
 

35 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable, and the conditions under which such lesions should be considered may 
be defined in the protocol when appropriate. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using CT scan), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
>10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 

36 
 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
 
Cytology, Histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two 
separate observations conducted not less than 4 weeks apart. There can be no 
appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD. There can be no appearance of 
new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started, or the 
appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 

37 
 
 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response 
for this 
Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/SD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented 
at least once 
>4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation 
of treatment. 
 
Note: If subjects respond to treatment and are able to have their disease resected, the patient’s 
response will be assessed prior to the surgery. 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 

38 
 
8.0 
ADVERSE EVENTS 
8.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure. 
 
8.2 
Adverse Event Reporting Requirements 
Data on adverse events will be collected from the time of the initial study drug administration 
through 100 days after the last dose of nivolumab. Any serious adverse event that occurs more 
than 100 days after the last study nivolumab dose and is considered related to the study must 
also be reported. Serious Adverse Events (SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event return to 
baseline; 
• 
There is satisfactory explanation other than the study agent nivolumab for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of AEs 
and SAEs are given below. It is the responsibility of the principal investigator to ensure that all 
staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
nivolumab dose is considered to be pre-existing in nature. Any known pre-existing conditions 
that are ongoing at time of study entry should be considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, occurring 
from the initial nivolumab dose through 100 days following the last dose of nivolumab must be 
recorded as an adverse event in the patient’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to the study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-
existing condition that occurs after the patient begins study [treatment or intervention] is also 
considered an adverse event. 
8.3 
Definitions 
8.3.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.  
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures will not be 
reported as adverse events. However, the medical condition for which the procedure was 
performed must be reported if it meets the definition of an adverse event unless it is a pre-
existing (prior to protocol treatment) condition. 
 

39 
 
• 
Symptoms of the original or targeted disease are not to be considered adverse events for this 
study. The following symptoms are indicative of underlying oropharynx cancer and will not 
be reported as adverse events (unless the event is considered serious): 
o Pain, dysphagia, otalgia, odynophagia in the setting of clinical evidence of disease 
progression 
 
• 
Abnormal laboratory values or test results constitute adverse events if they induce clinical 
signs or symptoms or require therapy. They are to be captured under the signs, symptoms or 
diagnoses associated with them. 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator [sponsor 
(UNIVERSITY OF MICHIGAN)”], it results in any of the following outcomes: 
  
o Death 
If death results from (progression of) the disease, the disease should be reported as event 
(SAE) itself. 
 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the investigator [or 
sponsor], its occurrence places the patient or subject at immediate risk of death. It does not 
include an adverse event that, had it occurred in a more severe form, might have caused 
death.  
 
o Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours. 
 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
o A congenital anomaly/birth defect 
 
o Important medical event 
Any event that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition of “Serious Adverse Event”. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of the 
study. Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs. However, if the preexisting condition worsened 

40 
 
during the course of the study, it should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those adverse events are described in the 
approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are described in the FDA 
Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is also summarized 
in the protocol and in the consent document.  See section 9.1 for the list of expected 
adverse events related to the drug under study. 
8.3.4 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the Package Insert, 
Investigator’s Brochure, in published medical literature, in the protocol, or in the informed 
consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
 AE description and grade: The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be down loaded from the CTEP web site. 
(http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
 
The investigator or co-investigator is responsible for assignment of attribution. 
 
Definite – The AE is clearly related to the study [treatment/intervention]. 
 
Probable – The AE is likely related to the study [treatment/intervention]. 
 
Possible – The AE may be related to the study [treatment/intervention]. 
 
Unlikely – The AE is doubtfully related to the study [treatment/intervention]. 
 
Unrelated – The AE is clearly NOT related to the study [treatment/intervention]. 
8.5 
Serious Adverse Event Reporting Guidelines 
8.5.1 
The Principal Investigator must be notified within 2 business day of study team’s knowledge of 
any event meeting the criteria and definition of a serious adverse event, regardless of 

41 
 
attribution, occurring during the study or within 100 days of the last administration of the study 
related [treatment/intervention]. 
8.5.2 
The investigator must report all events meeting the criteria and definition of a serious adverse 
event to the local IRB per current institutional guidelines.  When applicable, the  CTSU Serious 
Adverse Event form will be used. 
• 
Contact information for study PI: Michelle Mierzwa, 734-936-4300 phone, 
mmierzwa@med.umich.edu. 
• 
For IND/IDE trials: The study sponsor will be responsible for notifying the Food and Drug 
Administration (FDA) of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible, but in no case later than 7 calendar days after the sponsor's initial 
receipt of the information. Unexpected suspected serious adverse reactions that are not 
fatal or life threatening need to be reported to the FDA as soon as possible, but in no case 
later than 15 calendar days after the sponsor's initial receipt of the information.  In addition, 
the sponsor must notify FDA and all participating investigators in an Investigational New 
Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines 
that the information qualifies for reporting. 
8.6 
Routine Reporting 
 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.7 
Reporting of Unanticipated Problems 
 
There are types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent unanticipated problems but are not considered adverse events. 
For example, some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) 
that may represent an unanticipated problem, the investigator should assess whether the 
incident, experience, or outcome represents an unanticipated problem. The incident, experience 
or outcomes is considered unanticipated if it meets all of the following criteria: 
 
1. 
Unexpected (in terms of nature, severity, or frequency); 
2. 
Related or possibly related to participation in the research; 
3. 
Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB -per current institutional 
guidelines.  
 
 
 

42 
 
8.8 
AE and SAE reporting to Bristol-Myers Squibb (in addition to institutional requirements) 
• 
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. 
Medwatch SAE form should be used to report SAEs to BMS as well as UM.as to the UM IRB and the 
FDA.  
• 
The MedWatch form is available at: MedWatch 3500 Form.  
• 
Worldwide.Safety@bms.com 
• 
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 sponsor 
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.  
• 
In addition to the Sponsor Investigator’s responsibility to report events to their local IRB, suspected 
serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the 
relevant competent health authorities in all 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 \ 1 Business Day of becoming aware of the event. SAEs must be recorded on 
MedWatch. 
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or,  
3. Approved site SAE form  
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.)  

43 
 
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 \ 1 Business Day to BMS using 
the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
9.0  
Drug Information: Nivolumab 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of 
differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed 
by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-
L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell responses to both foreign antigens as well as 
self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using standard 
mammalian cell cultivation and chromatographic purification technologies. The clinical study product is a sterile 
solution for parenteral administration.  
Pharmacokinetics (adapted from Nivolumab IB Version 17.0, 6/27/2018) 
The PK of nivolumab was studied in subjects with cancer over a dose range of 0.1 to 20 mg/kg administered as a 
single dose or as multiple doses of nivolumab every 2 or 3 weeks. Nivolumab clearance (CL) decreases over time, 
with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of approximately 24.5% 
(47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in 
CLss is not considered clinically relevant. The geometric mean volume of distribution at steady state (Vss) was 
6.8 L (27.3%), and geometric mean elimination half-life (t1/2) was 25 days (77.5%). Steady-state concentrations 
of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, and systemic accumulation was 
approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 
10 mg/kg administered every 2 weeks. Additionally, nivolumab has a low potential for drug-drug interactions. 
The clearance of nivolumab increased with increasing body weight. The PPK analysis suggested that the 
following factors had no clinically important effect on the CL of nivolumab: age (29 to 87 years), gender, race, 
baseline LDH, PD-L1 status, solid tumor type, baseline tumor size, and hepatic impairment.   
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, and body weight had an effect on 
nivolumab CL, the effect was not clinically meaningful. PPK analysis suggest that nivolumab CL in subjects with 
cHL was approximately 32% lower relative to subjects with NSCLC; however, the lower CL in cHL subjects was 
not considered to be clinically relevant as nivolumab exposure was not a significant predictor for safety risks for 
these patients.  
PPK and exposure response analyses have been performed to support use of nivolumab 240 mg Q2W, 360 mg 
Q3W, and 480 mg Q4W dosing regimens in subjects with cancer in addition to the 3 mg/kg Q2W regimen. A flat 
dose of nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for subjects weighing 80 
kg, the observed median body weight in nivolumab- treated cancer patients, while the nivolumab 360 mg Q3W 
and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in combination with other 
agents using alternative dosing schedules to Q2W. Using a PPK model, the overall distributions of nivolumab 
exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with either nivolumab 3 mg/kg 
or 240 mg Q2W. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cavgss are expected to be similar to those 

44 
 
following nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are predicted to be 6% and ~16% lower, 
respectively, and are not considered to be clinically relevant. Following nivolumab 360 mg Q3W and 480 mg 
Q4W, Cmaxss are predicted to be approximately ~23% and ~43% greater, respectively, relative to that following 
nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab exposures (median and 90% prediction 
intervals) following administration of 240 mg flat Q2W, 360 mg Q3W, and 480 mg Q4W regimens across the 35 
to 160 kg weight range are predicted to be maintained well below the corresponding exposures observed with 
the well tolerated 10 mg/kg nivolumab Q2W dosing regimen.  
The PK of single-dose nivolumab monotherapy in subjects with sepsis is under evaluation; however, no data are 
currently available.  
Drug Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of the investigational drug nivolumab. The drug accountability records will capture 
drug receipt, drug dispensing, drug return and final disposition.   
 
Return/Retention of Drug 
All drug destruction will be performed on site per UM institutional guidelines.  
 
10.0 Correlative Studies 
Collection and banking of blood samples for correlative studies (genetic testing) is optional per the 
subject. 
 
10.1  
Circulating tumor DNA (ctDNA) and tumor exosomes 
Hypothesis 1: Recurrent cancer in HPV positive OPSCC can be detected in serum biospecimens 
collected at routine interval time points and will identify tumor recurrence earlier than clinical exam. 
 
 
Correlative Justification 
 
Patients with high risk HPV+ OPSCC are at risk for treatment failure, thus careful monitoring during 
treatment and in the post-treatment period is of extreme importance. The measurement of 
serum circulating free (cf)DNA and antitumor antibodies as a biomarker for recurrence may be an 
important, noninvasive method to detect treatment failures. We have previously examined serum 
antitumor antibodies (E6 and E7) in a longitudinal sample of patients who were treated under UMCC 
2002-0221. Our preliminary data indicate that patients who have decreased clearance of E6/E7 antibody 
from their baseline measurement are at risk for disease recurrence. Finally, we have funding to perform 
targeted next generation sequencing on the primary tumor specimens from all patients enrolling in this 
trial, which can be used to prioritize evaluable somatic mutations in cfDNA from both the blood of 
each patient for targeted sequencing studies (Hypothesis 1). Therefore, our goal is to collect 
longitudinal samples of serum as a part of our trial to determine if serum biomarkers can predict 
recurrence in HPV+ OPSCC. Our hypothesis is that serum biospecimens collected at routine interval time 
points will identify tumor recurrence earlier than clinical exam. 
 

45 
 
ctDNA/Exosome/ImmuneSample Collection 
We plan to collect and bank serial serum samples until 24 months from diagnosis. These samples are 
obtained at baseline, weekly during chemoradiation and at 3, 6, 12, 24 months post-therapy (see 
Schedule of events). Samples will be banked for planned analysis in the Brenner/Walline/Zhou labs. 
Blood Samples 
Patient’s blood will be drawn at baseline, weekly during treatment, and at 4 wks, 3 mo, 6mo, and 12 
months post-therapy as part of their routine follow up appointments.   At baseline, two heparinized 
green top 6 mL tubes and two Paxgene blood collection tubes will be drawn.  At each subsequent time 
points, only two Paxgene tubes will be drawn. Sample tubes will be provided by Brenner Lab.  We will 
extract measure cfDNA from serum samples using the QIAamp Circulating Nucleic Acid Kit according to 
manufacturer instructions, cfDNA will be sequenced according to standard protocol in the Brenner lab.  
We will perform functional immunophenotyping by flow cytometry to assess the consequence of 
therapy on the circulating hematopoietic compartment 
 
 
Sample Transportation 
Whenever as specimen has been obtained (i.e. after a blood draw), the designee will transport the 
sample directly to the Brenner laboratory. 
 
 
Tumor exosome analysis 
 
Tumor extracellular vesicles (TEV) will be isolated from pre-treatment serum samples using an 
optimized spin column method and verified using TEM. For each sample isolation, DNA, RNA, and 
microRNA (miRNA) will be extracted from tumor EV fractions and fluorometrically quantitated. DNA 
will be assessed for presence and type of high-risk HPV using a highly sensitive multiplex PCR-
MassArray strategy. MiRNA will be reverse-transcribed and expression of cancer relevant miRNAs will 
be measured using a validated qRT-PCR miRNA array customized for HNSCC. The miRNA panel includes 
biomarkers reported to have changes in expression associated with prognosis, radiation response, and 
survival. We will serially assess tumor-associated DNA and miRNA from tumor EVs in post-treatment 
patient liquid biopsies for the duration of patient follow-up to identify changes associated with 
response to treatment, cancer progression, or tumor free survival.  
 
10.2  
Serum Immunophenotyping 
Hypothesis 2: Functional immunophenotyping during therapy will identify prognostic and predictive 
biomarkers in HPV positive OPSCC for response to immune checkpoint blockade in conjunction with 
chemoradiation.   
 
Correlative Justification 

46 
 
Optimal serum biomarkers have not been developed for identifying the subset of patients who best 
respond to immune checkpoint blockade. The measurement of peripheral blood immune cell subsets as 
a biomarker for immune activation or inhibition may be an important, noninvasive prognostic 
biomarkers for patients who respond well to nivolumab. Patients with high risk HPV+ OPSCC are at risk 
for treatment failure, thus careful monitoring during treatment and in the post-treatment period is of 
extreme importance.  Other groups have identified the ratio of T-cell invigoration to tumor burden has 
been associated with response to anti-PD-1 response in metastatic melanoma patients, highlighting the 
potential use of peripheral blood flow cytometry as a predictive biomarker for immune checkpoint 
blockade in other disease sites.  
 
Functional Immunophenotyping  
 
Peripheral Blood Mononuclear Cells (PBMCs) will be isolated from pre-treatment and mid-treatment 
whole blood samples using centrifugation to analyze the changes of different immune cell sub 
populations.  Samples will be labeled with a panel of fluorescently labeled antibodies and stimulated 
with a leukocyte activation cocktail. Multiparametric flow cytometry analysis will include enumeration 
and functional evaluation of antigen presenting cell subsets, innate lymphoid cell subsets, myeloid 
derived suppressor cells, and T cell subsets (including NKT cells, CD8+ effector cells, and CD4+ helper 
cells). Cytokine secretion, proliferation, immunoinhibitory ligand expression, and transcription factor 
profile will be quantified by flow cytometry in T cell subsets. 
 
10.3  
DCE-MRI 
Hypothesis: Changes in BV and apparent ADC seen on DCE-MRI between pre-treatment and mid-
therapy will be significantly inversely correlated with changes in the metabolic tumor volume (MTV).   
 
Methods: 
The MRI scan will be performed in the exact patient position used for the simulation CT, including the 
same head rest and mask used for simulation. The MRI scanner installed recently at the UM 
Department of Radiation Oncology will be used for imaging. It has a large bore which facilitates imaging 
using these devices. Images will include FLAIR T2-weighted imaging, pre contrast T1-weighted imaging, 
diffusion weighted imaging, T1-weighted dynamic contrast enhancement imaging with single-bolus 
intravenous injection of Gd-DTPA, and post Gd-DTPA T1-weighted imaging. All images will be obtained 
with multiple-slices or 3D to cover the whole tumor volume. The scan time will be estimated to be one 
hour. 
 
 
 
 
Identification of Subvolumes of the Tumor 
Global-initiated regularized local fuzzy clustering (GIRLFC) is a method that is designed to first 
globally initiate training to identify fuzzy clusters of the physiological imaging parameters in the 
feature space, and then classify each tumor volume with local regularization to subvolumes 
according to the global feature clusters. This method is designed not only to identify the subvolumes 
of individual tumors based upon the heterogeneous distributions of physiological imaging 
parameters but also to be able to compare the classified subvolumes of the tumors across patients 
and over multiple time points. The fuzzy clustering method, specifically fuzzy C- means clustering 
(FCM), chosen in the GIRLFC method aims to deal with (1) intrinsic variations of the physiological 
parameters in the tumors, (2) partial volume effects due to the limited resolution of imaging sources, 
and (3) uncertainty due to noise. 
 

47 
 
Fuzzy C-Means clustering is a method of unsupervised learning to assign a set of observations to 
belong to subsets (clusters) with probability memberships. To partition a set of observations [xk], 
e.g., image voxels, into c clusters, an objective function with local spatial regularization is to be 
minimized. 
 
In Eq [1], the first term is a standard FCM cost function and the second term provides a spatial 
constraint to overcome the effect of image noise and to improve spatial connectivity. Here uik is a 
probabilistic (fuzzy) membership of observation xk belonging to class i vi is a prototype vector of class i, 
xk is a mean or median value of neighbors of voxel k, m defines fuzziness of the membership, and α 
is a weighting factor of spatial constraints. A 2D or 3D kennel, depending upon image resolution, 
can be used to define neighbors of each voxel for spatial constraint. Solutions that minimize the 
objective function of Eq [1] are given by: 
 
 
which are solved iteratively until reaching a stopping criterion. The values for m and α are 
usually determined empirically. The analysis can be applied to either single- or multiple- component 
parameters. 
 
In order to evaluate longitudinal changes in physiological imaging parameters of interest in the tumor, 
first a set of data is used as training data to determine definitions of clusters (prototype vectors and 
relationships between fuzzy memberships and observations), and then the remaining sets of data 
are partitioned according to the class definitions of training data. To avoid a bias from large 
tumors in training data, each of the tumor volumes is up-sampled or down-sampled to have an 
equal number of voxels contributing to the training data while maintaining the initial distribution of the 
physiological imaging parameters from the original into the re-sampled tumor. To do so, a histogram 
of the physiological imaging parameters of each tumor is generated, and re-sampled to create a new 
tumor volume with the same size. The re- created tumor volume, while preserving the original 
distribution (histogram) of the imaging parameters, cannot maintain the original spatial relationship 
between voxels, which is not critical for training data to determine prototype vectors of global clusters. 
To partition individual tumors in the second data set, fuzzy membership of each voxel of each tumor is 
classified using the prototype vectors found in analysis of the training data by Eq [2], where spatial 
constraint is used to improve spatial continuity. Finally, the highest probability of fuzzy membership of 
each voxel is used to assign the voxel to a discreet class. As a result, the tumor is partitioned into 
spatial subvolumes based upon the similarity of the physiological parameters of interest. The 

48 
 
temporal changes in partitioned subvolumes of the tumor are evaluated for their association with 
outcomes. 
 
To evaluate this method to identify significant subvolumes of the tumor related to outcomes, we 
will apply the method to BV and BF images derived from DCE MRI of patients with advanced head and 
neck cancer. 
 
 
 
 
Diffusion-weighted MRI 
A diffusion weighted, single shot, spin-echo, echo planar imaging (EPI) series with diffusion 
sensitization will be constructed along three orthogonal directions, with the diffusion-weighted 
images (DWI) contributing approximately two minutes of scan time to the MRI. The product of the 
three orthogonal DW images exhibits strong sensitivity to diffusion but without sensitivity to the 
structural directionality of the tissues. This isotropic feature is crucial to follow serial changes in 
water diffusion without confounding effects due to tissue orientation. ADC maps will be calculated 
from the DW images as follows: 
where S is the DW image at b-values of b0=0 and b1=800 s/mm2. 
 
 
Subsequent to image registration, contours will be manually drawn over tumors as delineated on 
T2-weighted, T1-weighted or contrast-enhanced images. From the volume-of-interest (VOI) tumor 
volume and mean ADC will be assessed pre- and 2 weeks post-treatment initiation. Subsequent 
to contouring the tumors, a geometric warping interpolant, i.e. thin plate spline, algorithm will be 
used to map (warp) the tumor volumes from interval exams onto the tumor volumes from pre-
therapy b0 DW images (reference dataset). The Parametric Response Map of ADC (PRMADC) will be 
determined by first calculating the difference between the ADC values (∆ADC = mid-treatment ADC 
– pre-treatment ADC) for each voxel within the tumor pre- treatment and at week 2 post-treatment 
initiation. Voxels yielding ∆ADC greater than a predetermined threshold set to 25 ADC units [= x 10-5 
mm2/s] will be designated as significantly increased. Voxels whose ADC values significantly 
decreased by more than 25 x 10-5 mm2/s (i.e. ∆ADC < -25 x 10-5 mm2/s) will be designated as 
significantly increased, and the rest of the voxels as non-changed. The volume fractions within the 
tumor as determined by PRMADC will be denoted by PRMADC+ (increased ADC), PRMADC- 
(decreased ADC), and PRMADC0 (unchanged ADC). PRM thresholds of significant change will be 
empirically assessed over a range of ∆ADCs (0 to 70). PRMADC+ with a threshold of ±25 ADC units 
provided the best correlation with tumor control in our previous study (Galban et al) and will be 
tested in the current study. 
 
 
 
 
Risks in MRI 
 
Our MRI protocol has risks and discomforts similar to clinical MRI with intravenous injection of a 

49 
 
contrast agent. Subjects run the risk of claustrophobia when they are lying inside the MRI scanner.  
They may also feel uncomfortable because of the loud noises made by the machines and the physical 
sensations they may feel during the process. Subjects are also exposed to some risk because of the 
injected contrast agent, gadolinium-DTPA, which may cause headache, nausea, and local burning. 
Because of the use of the contract agent, all female subjects of child- bearing potential will be required 
to use adequate birth control. Patients who have implanted or internalized metallic objects cannot 
participate in this research. Recent FDA guideline indicates there is an association between exposure to 
gadolinium and the development of Nephrogenic Fibrosing Dermopathy (NFD) (also known as 
Nephrogenic Systemic Fibrosis (NSF)) in 3-5% of the patients with advanced renal failure. We will follow 
the Institutional Standard Practice guidelines, which is based upon the FDA guideline, to screen the 
patients with renal disease, dysfunction, and dialysis for this study. 
 
10.4 
FDG-PET/CT Imaging 
All PET exams should contain 3 trans-axial whole body series, attenuated and non-attenuated, 
corrected PET and CT images; 
The emission PET scan will begin 60 +/- 10 minutes after injection; 
The patient will empty his/her bladder immediately before the acquisition of images; 
The patient will be positioned on the flat table imaging couch in treatment planning position. 
The transmission scan should be a low-dose CT scan without IV contrast (oral contrast is 
permitted per institutional procedure) for the PET/CT, done before the emission imaging. The 
transmission scan type, length, etc., should exactly match that used in the calibration and qualification 
procedure. 
An emission scan from the skull base to thighs will be performed. The number of bed positions will be 
determined by the patient’s height.  The acquisition time per bed position will be 2 minutes. Typical 
parameters are 6-8 bed positions, leading to an emission scan time of 12-16 minutes.  
 
 
 
 
Expected Adverse Events Related to FDG-PET Imaging 
 
Adverse events (AEs) from FDG-PET/CT are exceedingly rare. If an AE from functional imaging is to 
occur, it would most likely be related to the intravenous catheter infusion site, consisting of 
erythema and discomfort from the IV. An allergic reaction to the FDG is possible as well. The most 
expected AEs from a PET scan include discomfort and claustrophobia. 
 
Expected Adverse Events from the FDG Injection: 
• 
Bruising; 
• 
Bleeding; 
• 
Phlebitis; 
• 
Infection at the site of injection; 
• 
Allergic-type or other adverse reaction to FDG. 
 
Expected Adverse Events from the PET Scan: 
• 
Discomfort; 
• 
Claustrophobia. 
 
Expected Adverse Events from the CT Scan: 
• 
Discomfort; 

50 
 
• 
Claustrophobia; 
• 
Malfunction of implanted electronic medical devices, e.g., pacemakers, neurostimulators, insulin 
pumps. 
 
Estimation of Radiation Doses Due to FDG-PET/CT 
Reports of radiation doses from PET/CT scanning have varied in the literature. These differences can be 
attributed to different methods of attenuation correction, the timing of the scan, the area of the body 
being evaluated, and the radiopharmaceutical being investigated. This research study involves radiation 
exposure from 1 research FDG-PET/CT scan for patients. The radiation exposure from each FDG-PET/CT 
scan is equal to a uniform whole-body exposure of approximately 14 mSv, with approximately 11 mSv 
from the injected radioactive FDG and 3 mSv from the CT component.  
 
 
 
11.0  
Statistical Considerations and Justification of Sample Size 
 
11.1  
Description and Justification of Design 
The sample size of 40 patients is justified with respect to the primary aim of detecting improved 
PFS.  We will estimate PFS over time using the Kaplan-Meier (KM) method.  The primary study endpoint 
is PFS 2 years after treatment which will be also be estimated using the KM method.  A log-log 
transformation of the survival function will be used to calculate a lower 90% confidence limit.  Estimated 
PFS at 2 years was 68% in 125 similar (stage III) historical control patients treated with standard therapy 
at UM between the years of 2010-2015.  If the true PFS at 2 years for this treatment combination in this 
patient population is 85%, then a sample size of 40 enrolled patients provides at least 80% power to rule 
out 2 year PFS values of 70% or less.  This calculation assumes 10% of patients will be lost to follow-up 
by the 2 year assessment point and that other patients will either be assessed for progression at 2 years 
or will have progressed or died prior to 2 years.  We note that the power from a log-rank test comparing 
the PFS curve for these patients to that of the historical control actual patient level data is only slightly 
higher (~85% depending on assumptions regarding survival distribution and follow-up).    UM 
retrospective data also demonstrates 10% risk of death within 1 year of RT completion and 0% deaths 
due to toxicity.   
 
Based on previous experience, 30 eligible patients per year will be seen in Radiation Oncology 
at UM. Assuming successful enrollment of 1/2 of these patients we expect to enroll 40 patients in 
approximately 2.5-3 years.  The primary analysis will be based on an Intent to treat population and all 
enrolled subjects who begin protocol treatment will be included in the primary analysis including those 
who may have discontinued treatment due to toxicity or early disease progression. 
  
 
11.2 
Analysis Plan 
The primary study endpoint is the PFS at 2 years which will be estimated using the KM method.   To 
test the null hypothesis that the true rate is less than or equal to 70% we will compare the lower bound 
of a 1-sided 90% confidence limit to 70%.  The confidence limits for the KM estimates will be calculated 
using a log-log transformation.  Patients with no observed progression or death will be censored at the 
last date they were assessed for loco-regional or distant progression. We note that we also have access 
to patient level data for historical control patients treated without Nivolumab.  These data will allow us 

51 
 
to perform secondary analyses directly comparing a range of outcomes between protocol patients and 
historical control patients with for example, propensity score matching.   
 
Secondary aims include estimation of toxicity, patterns of failure, freedom from local and distant 
progression and overall survival.  To characterize patterns of failure we will summarize at fixed 
timepoints, the proportion of patients who progressed in any location and whether the first 
progression was local, regional, distant or in multiple locations.  Overall survival will be estimated using 
the Kaplan-Meier methods with associated 90% confidence intervals.  Freedom from local/regional or 
distant progression will be estimated using cumulative incidence functions with death prior to 
progression as a competing risk. Toxicity outcomes will be estimated as proportions for patients with 
available toxicity data at 3, 6 12 and 24 months.  They will also be estimated as the proportion of all 
treated patients through cumulative incidence estimates with death or disease progression treated as 
competing risks and censoring for patients lost to FU.  Quality of Life (QOL) outcomes and swallowing 
study results will be summarized descriptively by timepoint.  If there is substantial missingness in the 
QOL outcomes we will assess for informative missingness by comparing earlier QOL scores and change 
in earlier QOL scores between patients missing QOL at later timepoints (e.g. 1 or 2 years).  Another 
secondary aim is to correlate metabolic image uptake data on mid-treatment FDG-PET scan with 
standard 12 week post-treatment PET-CT. This will be done both at the patient level for summary 
measures and also spatially within a patient.   
 
Exploratory endpoints include cell free DNA (cfDNA) characterization, tumor exosome characterization 
and serum immune phenotype characterization by flow cytometry pre-treatment, weekly during 
treatment, post-treatment and at recurrence.  Exploratory analyses primarily involve summarizing 
these endpoints which will be done using frequency tables for categorical endpoints and summary 
statistics such as mean, standard deviation and various percentiles for continuously distributed 
endpoints.  A few of the exploratory aims involve assessing the relationship between the exploratory 
endpoints and clinical outcomes.  These will be done both descriptively using the appropriate 
correlation metric, graphically and also in the context of a regression model for the clinical outcome 
(e.g. Cox model for survival type outcomes) with the exploratory endpoint included as a covariate.   
 
11.3 
Stopping Rules 
 
With standard treatment, fewer than 10% of patients are expected to experience delays or dose 
reductions for RT or chemo.  An interim analysis will be performed after 20 patients have been enrolled. 
We will monitor the number of patients for whom this occurs to assess for the possibility that the 
addition of nivolumab significantly increases this proportion, the table below provides the specific 
stopping boundaries.  For example, if 2 or more of the first 5 patients experience either delays or dose 
reductions in chemo or RT, enrollment will be halted to allow thorough review of the data.   
 
Enrollment will be halted to allow thorough review as per the following: 
 
Number with dose delay / 
reduction 
Number treated 
2 
3 
2 
4 
2 
5 

52 
 
3 
6 
3 
7 
4 
8 
4 
9 
4 
10 
4 
11 
5 
12 
5 
13 
6 
14 
 
Enrollment will be halted to allow thorough review of safety data if at any time prior to the planned 
interim safety analysis >5 patients experience dose delays or reductions in chemotherapy or RT due to 
toxicity. 
 
 
12.0 
Data and Safety Monitoring 
 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer 
Center Data and Safety Monitoring Plan. 
 
The study team will provide continuous review of the data and patient safety and meet monthly or more 
frequently depending on the activity of the protocol. The discussion will include matters related to the 
safety of study participants (SAE/UaP reporting), validity and integrity of the data, enrollment rate 
relative to expectations, characteristics of participants, retention of participants, adherence to the 
protocol (potential or real protocol deviations) and data completeness. At these regular meetings, the 
protocol specific Data and Safety Monitoring Report form will be completed and signed by the Principal 
Investigator or by one of the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Rogel Cancer Center 
Data and Safety Monitoring Committee (DSMC) on a monthly basis for independent review. 
 
13.0 
Clinical Monitoring Procedure 
 
Clinical Monitoring Plan 
This trial will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer Center 
Data and Safety Monitoring Plan by the Oncology Clinical Trial Support Unit (O-CTSU). 
 
Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep records, 
including the identity of all participating subjects (sufficient information to link records, e.g., CRFs and 
hospital records), all original signed informed consent forms, copies of all CRFs, serious adverse event 
forms, source documents, and detailed records of treatment disposition. The records should be retained 
by the investigator according to Standard Practice Guidelines. 
 
 

53 
 
14.0 
References 
 
Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal 
Cancer. NEJM. [epub 2010 June 7]. 
 
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage 
human malignancies. Science translational medicine. 2014;6(224):224ra24. doi: 
10.1126/scitranslmed.3007094. PubMed PMID: 24553385;. 
Chan AT, Ngan RKC, Hui EP, et al. A multicenter randomized controlled trial (RCT) of adjuvant 
chemotherapy (CT) in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA following 
primary radiotherpay (RT) or chemoradiotherapy (CRT). J Clin Oncol. 30:5511, 2012. 
Dobrosotskaya, I, Bellile, E, Spector, M, et al. Weekly chemotherapy with radiation versus high-dose 
cisplatin with radiation as organ preservation for patients with HPV-positive and HPV-negative locally 
advanced squamous cell carcinoma of the oropharynx.  Head Neck 36(5): 617-23, 2014.  
 
D'Souza G, Kreimer AR, et al. Case-control study of human papillomavirus and oropharyngeal cancer." 
NEJM. 356(19): 1944-1956, 2007. 
 
Fahkry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive 
head and neck squamous cell carcinoma in a prospective clinical trial. JNCI. 100(4); 261-9 [Epub 2008 
Feb 12]. 
 
Feng, F, Kim, H, Lyden, T, et al.  Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in 
patients with oropharyngeal cancer:  clinical and functional outcomes.  J Clin Onc 28(16): 2732-8.  2010. 
 
Ferris, RL, Blumenschein, J, Fayette, J, et al. Nivolumab for Recurrent Squamous Cell Carcinoma of the 
Head and Neck. NEJM. 375:1856-67, 2016. 
 
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 92:709-20, 2000. 
Gillison, M, Ferris, R, Zhang, Q, et al.  Safety Evaluation of Nivolumab Concomitant With  Platinum-
Based Chemoradiation therapy for Intermediate and High-Risk Local-Regionally Advanced Head and 
Neck Squamous Cell Carcinoma: RTOG  Foundation 3504 .  Oral abstract at ASTRO/ASCO Head and Neck 
Symposium, Feb 2018, Phoenix, AZ.   
Gupta, G, Kumar, S, Marron, D, et al. Circulating Tumor HPV16 DNA as a Biomarker of Tumor  Genomics 
and Disease Control in HPV-associated Oropharyngeal Squamous Cell Carcinoma. Oral abstract at 
ASTRO/ASCO Multi-disciplinary Head and Neck Cancer Symposium Feb 2018. Phoenix, AZ. 
 
Hanna, G, Supplee, J, Kuang, Y, et al. Plasma HPV cell-free DNA monitoring in advanced HPV-associated 
oropharyngeal cancer. Ann Oncol Jul 13 2018. doi: 10.1093/annonc/mdy251. [Epub ahead of print] 
PMID: 30010779.  
 
Hawkins, P, Mierzwa, M, Belille, E, et al. Impact of AJCC 8th edition clinical stage and smoking history on 
oncologic outcomes in human-papilloma virus -associated oropharyngeal squamous cell carcinoma.  
2018. Head and Neck. Epub ahead of print. 
 

54 
 
Lin JC, Wang WY, Chen KY, et al. Quantification of plasma Epstein-Barr virus DNA in patients with 
advanced nasopharyngeal carcinoma. NEJM. 350:2461-70, 2004b. PMID:15190138 
 
Kong FM, Frey KA, et al. A pilot study of [18F]fluorodeoxyglucose positron emission tomography scans 
during and after radiation-based therapy in patients with non small-cell lung cancer. J Clin Oncol. 
25(21): 3116-23, 2007. 
 
Kong FM, Hayman JA, et al. Final toxicity results of a radiation-dose escalation study in patients with 
non- small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. IJROBP. 65(4): 
1075-86, 2006. 
 
Kong FM, Ten Haken RK, et al. High-dose radiation improved local tumor control and overall survival 
in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation 
dose escalation study. IJROBP. 63(2): 324-33, 2005. 
 
Kong, F, Ten Haken, R, Schipper, M, et al. Effect of Midtreatment PET/CT-Adapted Radiation 
Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung 
Cancer: A Phase 2 Clinical Trial. JAMA Oncol, Oct 1;3(10):1358-1365, 2017. 
 
Le QT. An international collaboration to harmonize the quantitative plasma Epstein-Barr Virus (EBV) 
DNA assay for future biomarker-guided trials in nasopharyngeal carcinoma. Clin Canc Res. 2013 Apr 
15;19(8):2208-15. 
 
Marur, S, Li, S, Cmelak, A. et al.  E1308: Phase II Trial of Induction Chemotherapy Followed by 
Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous 
Cell Carcinoma of the Oropharynx—ECOG-ACRIN Cancer Research Group.  JCO. 35(5): 490-498. 2017. 
 
Mehanna H, Wong WL, McConkey CCet al. PET-CT Surveillance versus Neck Dissection in Advanced 
Head and Neck Cancer. The New England journal of medicine 2016; 374:1444-1454. 
 
Pollom EL, Song J, Durkee BYet al. Prognostic value of midtreatment FDG-PET in oropharyngeal cancer. 
Head & neck 2016; 38:1472-1478. 
 
Schwartz, D, Harris, J, Yao, M.  Metabolic tumor volume as a prognostic imaging based biomarker for 
head and neck cancer.  Pilot results for RTOG 0522. Int J Radiat Oncol Biol Phys.  91(4): 721-9.  
 
Spector, M, Chinn, S, Bellile, E, et al.  Matted nodes as a predictor of distant metastasis in advanced 
stage III/IV oropharyngeal squamous cell carcinoma.  Head and Neck. 38(2): 184-90, 2016.  
 
Wang WY, Twu CW, Chen HH, et al. Long-term survival analysis of nasopharyngeal carcinoma by plasma 
Epstein-Barr virus DNA levels. Cancer. Oct 12. 2012 PMID: 23065693.  
 
Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced 
oropharynx cancer: response and survival associated with HPV copy number. J Clin Oncol. 26: 3138-
46, 2008. 
 
 

55 
 
15.0 
Appendix A 
 

56 
 

57 
 

58 
 

59 
 
 
 
 
 
 
 
 
 
 

60 
 
 
 
 
 
 
 
 
 
 

61 
 
 
 
 
 
 
 
 
 
 
 
 
 

62 
 
 
16.0  Appendix B 
Study Management During Public Health or Civil Emergency or Restrictions 
 
Changes to protocol-required items were made to minimize or eliminate immediate hazards 
or to protect the life and well-being of research participants (e.g., to limit exposure to 
infectious pathogens).  
 
These changes may be implemented and/or adapted without causing a deviation or 
considered minor deviations during a national emergency. HOWEVER, the usual protocol 
parameters must be reinstated when the emergency is over or whenever local authorities 
and policies permit. 
 
 
1) When possible, visits may be conducted remotely using phone or video. 
2) Physical exam and vital sign measurements may be missed if visits are conducted remotely. 
3) Study-specific imaging can be as previously required, combining to make as few visits and encounters 
for the patient as possible. PET scans can be completed.  It is possible that tests such as the 
videofluoroscopy may be deferred; see point #9 below. 
4) Questionnaires can be mailed, faxed, or sent through the patient portal to the patient.  These 
documents may be returned via mail, faxing, or bringing to the clinic on a subsequent appointment.   
5) Saliva will not be collected per protocol clarification letter Adv00042400 (finalized in amendment to 
version 3.0). 
6) Blood correlative collections will continue at baseline and during each weekly treatment visit. 
Samples in follow-up visits will be on a case-by-case basis and may be collected if there is another 
clinical lab appointment already required for that visit. 
7) Clinical labs can be collected at local labs for follow-up visits. 
8) Consent/re-consent can be performed over the phone/remotely or via SignNow, an FDA 21 Part 11 & 
HIPPA compliant tool offered through University of Michigan Health Information Technology Services 
(HITS). 
9) When staff is not available to complete the videofluoroscopy tests, due to staffing changes and 
interruptions, these may be skipped and listed as deviations, or deferred.   
10) It is permissible that baseline labs, dental evaluation, standard of care primary tumor specimen 
collection, and standard clinical imaging, to be done at local facilities, if needed.