Phase II Trial of Nivolumab, an Anti-PD-1 Monoclonal Antibody, as a Novel Neoadjuvant Pre-Surgical Therapy for Locally Advanced Oral Cavity Cancer
Phase: PHASE2
Conditions: Oral Cavity SCC
Sponsor: Medical University of South Carolina

Protocol version 6 dated December 6, 2019 
1 
NCT #:  NCT03021993 
MUSC CTO #: 102510 
BMS Protocol #:  CA209-831 
 
PHASE II TRIAL OF NIVOLUMAB, AN ANTI-PD-1 MONOCLONAL ANTIBODY, AS 
A NOVEL NEOADJUVANT PRE-SURGICAL THERAPY FOR LOCALLY ADVANCED 
ORAL CAVITY CANCER 
 
 
PRINCIPAL INVESTIGATOR  
David M. Neskey, MD, MSCR 
 
Medical University of South Carolina 
135 Rutledge Ave Rm 1106 
Charleston, SC 29425  
Phone: 843-876-0716  
E-mail: Neskey@musc.edu 
 
COORDINATING OFFICE: 
Sponsor-Investigator Support Unit 
Medical University of South Carolina 
86 Jonathan Lucas Street, Suite 373 
Charleston, SC 29425 
 
Devin Barnett, MS, CCRP 
Phone:  843-792-0275  
Email:  gibsond@musc.edu  
 
PROTOCOL VERSION HISTORY 
Version 6 dated December 6, 2019 
Version 5 dated August 8, 2019 
Version 4 dated May 29, 2018 
Version 3 dated September 1, 2017 
Version 2 dated August 1, 2017 
Version 1.2 dated January 25, 2017 
Version 1.1 dated December 2, 2016 
Version 1 dated October 28, 2016 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
2 
TABLE OF CONTENTS 
 
DEFINITIONS OF TERMS USED ............................................................................................. 4 
 
1 
SCHEMA ............................................................................................................................... 5 
 
2 
OBJECTIVES ....................................................................................................................... 6 
2.1 
Primary Objective .............................................................................................................................................. 6 
2.2 
Secondary Objectives ......................................................................................................................................... 6 
 
3 
BACKGROUND ................................................................................................................... 6 
3.1 
Clinical Burden of HNSCC ............................................................................................................................... 6 
3.2 
Benefits of Neoadjuvant Treatment .................................................................................................................. 6 
3.3 
Immunotherapy in HNSCC .............................................................................................................................. 7 
3.4 
Study Rationale .................................................................................................................................................. 7 
 
4 
SUBJECT SELECTION ...................................................................................................... 8 
4.1 
Inclusion Criteria ............................................................................................................................................... 8 
4.2 
Exclusion Criteria .............................................................................................................................................. 9 
4.3 
Inclusion of Women and Minorities ............................................................................................................... 10 
4.4 
Subject Registration ......................................................................................................................................... 10 
 
5 
STUDY INTERVENTION ................................................................................................. 10 
5.1 
Nivolumab Administration .............................................................................................................................. 10 
5.2 
Surgical Resection ............................................................................................................................................ 11 
5.3 
Pre and Post Medications ................................................................................................................................ 11 
 
6 
DOSE MODIFICATIONS ................................................................................................. 13 
6.1 
Management Algorithms ................................................................................................................................. 13 
6.2 
Discontinuation Criteria .................................................................................................................................. 13 
 
7 
CONCOMITANT THERAPY ........................................................................................... 14 
7.1 
Permitted Medications – Use with Caution ................................................................................................... 14 
 
8 
STUDY ASSESSMENTS ................................................................................................... 14 
8.1 
General Guidelines ........................................................................................................................................... 14 
8.2 
Pregnancy Test for WOCBP ........................................................................................................................... 15 
8.3 
Baseline Assessments: ...................................................................................................................................... 15 
8.4 
Radiographic Assessment: ............................................................................................................................... 15 
8.5 
Clinical Assessment: ........................................................................................................................................ 15 
8.6 
On Study Assessments ..................................................................................................................................... 16 
8.7 
Off Study and Follow Up ................................................................................................................................. 17 
8.8 
Study Calendar ................................................................................................................................................. 18 
 
9 
DRUG INFORMATION - NIVOLUMAB ....................................................................... 19 
9.1 
Drug Ordering and Accountability ................................................................................................................ 20 
9.2 
Product Description and Dosage Form .......................................................................................................... 20 
9.3 
Storage Conditions: .......................................................................................................................................... 20 
9.4 
Labeling: ........................................................................................................................................................... 20 
9.5 
Handling and Dispensing ................................................................................................................................. 20 
9.6 
Destruction ........................................................................................................................................................ 20 

Protocol version 6 dated December 6, 2019 
3 
10 
DEFINITION OF ENDPOINTS ................................................................................... 21 
10.1 
Primary Efficacy Endpoint ......................................................................................................................... 21 
10.2 
Secondary Efficacy Endpoints.................................................................................................................... 21 
10.3 
Definition of Secondary Outcomes/Endpoints: ......................................................................................... 22 
10.4 
Safety Endpoints .......................................................................................................................................... 22 
 
11 
STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE 
SIZE ........................................................................................................................................... 22 
11.1 
Definition of Evaluable Patients ................................................................................................................. 22 
11.2 
Data Analysis Plans ..................................................................................................................................... 23 
11.3 
Determination of Sample Size .................................................................................................................... 24 
11.4 
Safety Analysis ............................................................................................................................................. 24 
11.5 
Interim Analysis .......................................................................................................................................... 25 
 
12 
CORRELATIVE STUDIES ........................................................................................... 25 
12.1 
Evaluation of the Systemic and Intratumoral Immune Activation Following PD-1 Blockade: ........... 25 
12.2 
Determining Immune Reactivity to Autologous OCSCC: ....................................................................... 25 
 
13 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................. 26 
13.1 
Purpose ......................................................................................................................................................... 26 
13.2 
Definition of Serious Adverse Event .......................................................................................................... 26 
13.3 
SAE Reporting ............................................................................................................................................. 28 
13.4 
Definition of Adverse Event ........................................................................................................................ 29 
13.5 
Nonserious Adverse Event Collection and Reporting .............................................................................. 30 
13.6 
Definition of Severity................................................................................................................................... 30 
13.7 
Documentation of Adverse Events ............................................................................................................. 31 
 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................... 31 
14.1 
Informed Consent ........................................................................................................................................ 31 
14.2 
Institutional Review .................................................................................................................................... 32 
 
15 
MONITORING ............................................................................................................... 32 
15.1 
Protocol Deviations ..................................................................................................................................... 32 
15.2 
Data Safety Monitoring Board ................................................................................................................... 32 
 
REFERENCES ............................................................................................................................ 33 
APPENDIX A:  ACCEPTABLE FORMS OF CONTRACEPTION ..................................... 36 
APPENDIX B: MANAGEMENT ALGORITHMS ................................................................. 37 
 
 
 

Protocol version 6 dated December 6, 2019 
4 
DEFINITIONS OF TERMS USED 
AE 
 
adverse event 
AIDS  
acquired immunodeficiency syndrome 
ALT 
 
alanine transaminase 
AST 
 
aspartate transaminase 
BMS 
 
Bristol Myers Squibb 
BP 
 
blood pressure 
BUN 
 
blood urea nitrogen 
CBCD  
complete blood count with differential 
CR 
 
complete response 
CrCl  
 
creatinine clearance 
CT 
 
computed tomography 
DILI 
 
drug induced liver injury 
DSMC  
Data Safety Monitoring Committee 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
electronic case report form 
FDA 
 
Food and Drug Administration 
FSH 
 
follicle stimulating hormone 
GCP 
 
Good Clinical Practice 
HBV 
 
hepatitis B virus 
HCC 
 
Hollings Cancer Center 
HCG 
 
human chorionic gonadotropin 
HCV 
 
hepatitis C virus 
HIV 
 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HR 
 
heart rate 
IB 
 
Investigator’s Brochure  
ICH 
 
International Council of Harmonisation 
IIT 
 
Investigator Initiated Trial 
IRB 
 
Institutional Review Board 
IV 
 
intravenous 
LFT 
 
liver function test 
MRI 
 
magnetic resonance imaging 
MUSC  
Medical University of South Carolina 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse Events 
OCSCC 
oral cavity squamous cell carcinoma 
pCR 
 
pathologic complete response 
PET 
 
positron emission tomography 
PR 
 
partial response 
RECIST 
response evaluation criteria in solid tumors 
SAE 
 
serious adverse event 
SIS Unit 
Sponsor-Investigator Support Unit 
SOP 
 
standard operating procedure 
ULN 
 
upper limit of normal 
WBC  
white blood cell 
WOCBP 
woman of child bearing potential 
 
 

Protocol version 6 dated December 6, 2019 
5 
1 SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
6 
2 OBJECTIVES 
2.1 PRIMARY OBJECTIVE 
To determine the pathological overall response rate (PR+CR) of neoadjuvant pre- surgical 
PD-1 inhibition in patients with surgically amenable oral cavity cancer.   
2.2 SECONDARY OBJECTIVES 
• To evaluate the systemic and intratumoral immune activation following PD-1 blockade. 
• To determine immune reactivity to autologous OCSCC. 
2.3 EXPLORATORY OBJECTIVES 
• To compare genomic sequencing of patients before and after therapy with Nivolumab. 
 
3 BACKGROUND 
3.1 CLINICAL BURDEN OF HNSCC 
Over 300,000 patients develop squamous cell carcinoma of the oral cavity (OCSCC) 
worldwide and nearly half of these patients die from the disease each year [1].  The 
development of regional metastases in oral cavity cancer decreases the 5-yr survival by 50%, 
and therefore advanced OCSCC portends a poor prognosis with estimated survival rates at 5 
years ranging from 35-45% [2, 3].  Treatment of advanced oral cavity cancer often requires 
complex, multimodality therapy, employing surgical resection followed by post-operative 
radiation, with the addition of cisplatin-based chemotherapy for patients with high-risk of 
failure [4].  Despite these comprehensive treatment strategies, OCSCC recurs in 25-48% of 
patients [3, 5, 6].  Additionally, advances in reconstructive procedures have improved post-
operative function of oral cavity cancer patients but these surgeries continue to be associated 
with significant morbidity including disfigurement, speech and swallowing deficits, and 
tracheostomy or gastrostomy tube dependence. Given the poor prognosis, high recurrence 
rates, and associated post-operative morbidities observed in OCSCC, it is evident new 
strategies are needed to treat and aid in the management of OCSCC [7, 8]. 
3.2 BENEFITS OF NEOADJUVANT TREATMENT 
Neoadjuvant therapy is now being applied in multiple cancer types and has provided a new 
paradigm in the treatment of patients with breast and esophageal cancer in terms of overall 
and disease-free survival [9-12].  In the case of unresectable HNSCC, neoadjuvant 
chemotherapy has been applied prior to definitive radiotherapy or chemoradiotherapy with 
significant response rate in several phase II and III studies [13-15].  The results from these 
clinical trials support the concept that neoadjuvant treatment can be considered as a novel 
therapeutic strategy for the treatment of advanced HNSCC. Neoadjuvant chemotherapy prior 
to definitive surgery has been explored for the treatment of HNSCC with high rates of initial 
response ranging from 30-40% but a recent meta-analysis of 28 randomized trials revealed a 
modest survival benefit of only 6%[16-18].  Neoadjuvant treatment prior to definitive 

Protocol version 6 dated December 6, 2019 
7 
surgery has been shown to determine clinical efficacy and define molecular biomarkers 
predictive of response and has been tested in several studies including one at our own 
institution investigating the mTOR inhibitor, Rapamycin [16, 19-21].  In general, the 
potential benefits of effective neoadjuvant therapies include 1) the assessment of clinical 
response to novel, mechanism-based treatment options which can decrease tumor burden and 
thus reduce the extent of surgery [17]; 2) the exploration of molecular changes in cancer cells 
and surrogate tissues, such as blood, may provide valuable biomarkers to identify patients 
that may benefit the most from new targeted therapies [22].  A clinical response to 
neoadjuvant chemotherapy has prognostic value in multiple cancers, as pathologic complete 
response at the time of surgery is a recognized and validated surrogate marker for good 
clinical outcome [23, 24]. 
3.3 IMMUNOTHERAPY IN HNSCC 
Because of the combination for the need of new therapies and the benefits of a neoadjuvant 
treatment strategy, the possibility of immunotherapeutic approaches for HNSCC patients has 
gained interest.  Unfortunately, HNSCC patients have profound immune defects that are 
associated with a worse outcome and have been attributed to tumor production of inhibitory 
mediators and tumor-induced immune inhibitory cell populations [25-30].  Programmed 
Death receptor I (PD-1) and its ligand (PD-L1) appear to contribute to this immune 
dysfunction as 50-60% lymphocytes from HNSCC patients have upregulated PD-1 
expression and PD-1 blockade enabled lymphocyte proliferative reactivity to stimulation and 
indirectly overcame immune unresponsiveness by modulating immune inhibitory 
populations, including T regulatory cells [30-33].  Furthermore, tumor PD-L1 expression has 
been associated with improved objective response and clinical benefit in multiple tumor 
types [34]. Since 60-80% of OCSCC express PD-L1, it is anticipated PD-1 blockade will 
benefit 20-25% of patients with OCSCC [30, 33,  34]. Most recently the Checkmate 141 
Phase III trial revealed in patients with treatment-resistant and rapidly progressive head and 
neck carcinoma that nivolumab treatment was associated with an improved 12-month overall 
survival of 36%, compared with 17% in the Investigator Choice arm [40, 41]. 
3.4 STUDY RATIONALE 
Our past clinical trials with HNSCC patients have shown the feasibility of pre-surgical 
targeted or immunotherapy followed by multi-modality treatments combining surgery and 
adjuvant therapy leading to an improvement in recurrence free survival [35-37].  A similar 
multi-modality treatment is being proposed in this application to overcome immune lethargy 
by Nivolumab treatment to block PD 1 between the time of OCSCC diagnosis and surgical 
treatment.   This duration of time will allow for the administration of three doses of 
Nivolumab given on Days 1, 15 and 29.  The primary objective of the proposed study is to 
determine the efficacy of neoadjuvant PD-1 inhibition in patients with oral cavity cancer 
undergoing definitive surgical resection.  In addition to assessing the clinical efficacy of 
Nivolumab, secondary objectives will be to analyze the effectiveness of PD-1 antibodies at 

Protocol version 6 dated December 6, 2019 
8 
restoring the immune reactivity in the peripheral blood as well as stimulating intratumoral 
immune activity.  The rationale for this approach is based on the overexpression of lymphoid 
PD 1 in the HNSCC environment along with our prior demonstration of the feasibility of pre-
surgical immune modulatory treatment or targeted mTOR therapy having positive post-
surgical clinical effectiveness [30, 35, 36, 38].  Additionally, blocking PD 1 prior to surgical 
excision will allow restoration of immune competence to not only enable pre surgical 
immune responsiveness to HNSCC, but also post-surgical immunological surveillance for 
residual cancer.   
We hypothesize 25-30% overall response rate (PR+CR) in patients with OSCC, and these 
patients will reveal a systemic and intratumoral response following anti-PD-1 therapy along 
with immune reactivity to autologous OCSCC. 
 
4 SUBJECT SELECTION 
4.1 INCLUSION CRITERIA 
Patients eligible for study participation must meet all of the following criteria 
 
1. Newly diagnosed histologically proven locoregional OCSCC without evidence of 
distant metastases and a clinically determined T-stage of 2-4 (based on AJCC Staging 
Manual v.7 guidelines), 
 
OR 
 
Recurrent or persistent histologically proven locoregional OCSCC that was initially 
treated with surgery alone, and a clinically determined recurrent T-stage of 2-4 (based 
on AJCC Staging Manual v.7 guidelines).   
 
Note – OCSCC includes the subsites of oral tongue, floor of mouth, gingiva, retromolar 
trigone, and buccal mucosa.  
Note – To allow sufficient tumor tissue for the immunological analyses, patients with 
T-stage 1 OCSCC will be excluded 
 
2. Greater than or equal to 18 years of age 
3. ECOG performance status of 0 or 1 
4. Screening labs must meet the following criteria and must be obtained within 14 days 
prior to registration: 
• WBC  
> 2,000/µL 
• Absolute Neutrophil Count >1,500/µL 
• Platelets  
> 100 X 103/µL 
• Hemoglobin > 9.0 g/dL 

Protocol version 6 dated December 6, 2019 
9 
• Serum creatinine < 1.5 X ULN or CrCl > 40mL/min (if using the Cockcroft-
Gault formula below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                           72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
                            72 x serum creatinine in mg/dL 
• AST/ALT 
≤ 3 x ULN  
• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can 
have total bilirubin < 3.0 mg/dL)  
5. Reproductive Status: 
WOCBP must use appropriate method(s) of contraception. WOCBP should use an 
adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for 
nivolumab to undergo five half-lives) after the last dose of investigational drug. 
 
Men receiving nivolumab and who are sexually active with WOCBP will be instructed 
to adhere to contraception with a failure rate of less than 1% per year for a period of 31 
weeks after the last dose of investigational product. 
 
WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not 
postmenopausal. Menopause is defined clinically as 12 consecutive months of 
amenorrhea in a woman over 45.  
 
Women of childbearing potential must have a negative serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to registration 
Women who are not of childbearing potential (i.e., who are postmenopausal or surgically 
sterile) and azoospermic men, are not required to use contraception. 
See appendix A for acceptable methods of contraception.   
4.2 EXCLUSION CRITERIA 
Patients eligible for study participation CANNOT meet any of the following criteria 
 
1. Prior immunotherapy or treatment with another anti PD 1 agent 
2. Prior chemotherapy including Cetuximab or radiation therapy 
3. Previous severe hypersensitivity reaction to another monoclonal antibody 
4. Women who are pregnant, lactating or expecting to conceive  
5. Men who are expecting to father children within the research period 
6. Known history of HIV or AIDS 
7. Positive test for HBV sAg or HCV antibody indicating acute or chronic infection 

Protocol version 6 dated December 6, 2019 
10 
8. Concomitant malignancies except cutaneous squamous cell carcinoma or basal cell 
carcinoma 
9. Unresectable primary tumor or regional disease; presence of distant metastases.  
10. History of pneumonitis or interstitial lung disease 
11. Active, known or suspected autoimmune disease. Note:  Subjects are permitted to 
enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger 
12. Presence of condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone or equivalents) or other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease 
4.3 INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial.   
4.4 SUBJECT REGISTRATION 
The SIS Unit will provide subject registration services for the study.  After obtaining signed 
informed consent and completion of required baseline assessments, eligible subjects will be 
registered.  All study subjects will undergo an eligibility audit prior to registration.  A unique 
subject number will be assigned to each patient.  A registration confirmation will be emailed 
to the enrolling study team at the time of registration.  This confirmation will include the 
subject’s assigned cohort dose level and study ID number.  Registrations may occur between 
8AM and 5PM EST, Monday through Friday.  Registrations may take place outside of this 
timeframe if prior arrangements are made. 
 
5 STUDY INTERVENTION 
5.1 NIVOLUMAB ADMINISTRATION 
Nivolumab will be given every two weeks at a dose of 3mg/kg will be administered as a 60 
minute IV infusion (+/- 10 minutes). Study drug will be administered on an outpatient basis. 
Subjects may be dosed no less than 12 days from the previous dose of drug.  
  
REGIMEN DESCRIPTION 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Nivolumab 
3mg/kg 
IV 
Cycle 1 = Day 1 
Cycle 2 = Day 15 
Cycle 3 = Day 29 
 
Response assessment 
 

Protocol version 6 dated December 6, 2019 
11 
 
The dosing calculations should be based on the actual body weight at baseline. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the 
original dose, the dose must be recalculated. All doses should be rounded to the nearest 
milligram. There will be no dose reductions allowed. 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding polyethersulfone membrane in-line filter at the 
protocol-specified doses. It is not to be administered as an IV push or bolus injection. 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection (USP to protein concentrations as low as 1 
mg/mL). Care must be taken to assure sterility of the prepared solution as the product does 
not contain any antimicrobial preservative or bacteriostatic agent. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed according 
to Protocol Section 5.3. 
5.2 SURGICAL RESECTION 
Between days 28-35, subjects will be evaluated for disease progression through clinical and 
radiographic tumor assessment, and for toxicity by history, physical and clinical labs.  In 
the event of disease progression, subjects will proceed to definitive surgical resection 
between days 36-42 and no later than 50 days after randomization.  If disease is stable or 
response is observed, subjects will have the fourth administration of nivolumab on Day 43 
(+/- 1 day) followed by definitive surgical resection on day 50-56 and no later than 60 days 
randomization.   
5.3 PRE AND POST MEDICATIONS 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms of allergic-like 
reactions.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE v. 4.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
• For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; 
intervention not indicated) 
 
Cycle 4 = Day 43 if stable disease or response 
after day 29. 

Protocol version 6 dated December 6, 2019 
12 
Monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional nivolumab administrations. 
 
• For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor subject until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 
minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur then no further nivolumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the eCRF. The following prophylactic premedications are recommended 
for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen) should be administered at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 
mg of IV hydrocortisone or equivalent) may be used. 
 
• For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated).  
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will 
be permanently discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery 
from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized 
or generalized pruritus within 1 week after treatment), symptomatic treatment may be 
given (eg, oral antihistamine, or corticosteroids). 
 

Protocol version 6 dated December 6, 2019 
13 
6 DOSE MODIFICATIONS 
Dose reductions or dose escalations are not permitted.  Dose delays due to adverse events are 
not permitted.  If an AE occurs causing a missed dose, the subject will stop the nivolumab 
administration schedule and proceed to surgery.  Dose delays for other reasons are allowed 
with prior approval from the Sponsor-Investigator. 
6.1 MANAGEMENT ALGORITHMS 
Immuno-oncology agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with immuno-
oncology agents may mitigate severe toxicity.  
 
Management algorithms have been developed to assist investigators in assessing and 
managing the following groups of AEs:  Gastrointestinal, Renal, Pulmonary, Hepatic, 
Endocrinopathies, Skin, Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
algorithms. These algorithms can be referenced in the Nivolumab IB. The guidance provided 
in these algorithms should not replace the Investigator’s medical judgment but should 
complement it. 
 
6.2 DISCONTINUATION CRITERIA 
Subjects may discontinue study treatment at any time.  Subjects may be removed from study 
for any of the following reasons: 
 
• Radiographic disease progression that is not amendable to resection 
• Clinical disease progression that would not benefit from surgery 
• Inter-current illness that would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree or require discontinuation of study drugs 
• Completion of protocol treatment. 
• Death 
• Subject non-compliance 
• Treatment should be permanently discontinued for the following: 
o Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment  
o Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies: 
 Grade 3 drug-related 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 

Protocol version 6 dated December 6, 2019 
14 
 Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
o Any drug-related LFT abnormality that meets the following criteria 
require discontinuation:  
 AST or ALT > 8 x ULN 
 
 Total bilirubin > 5 x ULN 
 Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x 
ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o Grade 4 lymphopenia or leukopenia 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal insufficiency, 
ACTH deficiency, 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 Principal 
Investigator. 
  
7 CONCOMITANT THERAPY 
7.1 PERMITTED MEDICATIONS – USE WITH CAUTION 
As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab 
combinations, drugs with a predisposition to hepatoxicity should be used with caution in 
patients treated with nivolumab-containing regimen. 
 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief 
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-
autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted. 
 
8 STUDY ASSESSMENTS 
8.1 GENERAL GUIDELINES 
• Screening evaluations are to be done within 14 days of registration with the following 
exceptions: 

Protocol version 6 dated December 6, 2019 
15 
o informed consent, hepatitis B and C testing, and radiographic disease assessments 
to be done within 28 days of registration 
o serum pregnancy test must be done within 24 hours prior to registration 
• After registration, subjects should begin study drug within 72 hours.     
• On study assessments to be completed +/-3 days, radiographic assessments will be 
completed within +/- 7 days. 
8.2 PREGNANCY TEST FOR WOCBP 
A serum pregnancy test is required within 24 hours prior to registration.  If day 1 is more 
than 24 hours after the screening pregnancy test, the pregnancy test must be repeated prior to 
day 1 of drug administration.  A pregnancy test is also required at day 29 and prior to 
surgery. After discontinuation from nivolumab these should be repeated at approximately 30 
days and approximately 70 days. 
8.3 BASELINE ASSESSMENTS: 
• Medical history will be obtained to capture relevant underlying conditions. The baseline 
examinations should include weight, height, ECOG Performance Status, BP, HR, 
temperature, and oxygen saturation by pulse oximetry at rest (also monitor amount of 
supplemental oxygen if applicable) should be performed within 14 days prior to 
registration. Concomitant medications will be collected from within 14 days prior to the 
first dose through the study treatment period. 
• Laboratory assessments will be done within 14 days prior to registration and are to 
include: CBCD, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, calcium, Magnesium, Sodium, Potassium, Chloride, phosphate, 
LDH, glucose; TSH, free T3, and free T4.   
• The following baseline local laboratory assessments to be done within 28 days prior to 
registration: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA). 
• After patients are entered into this study, the clinical team will oversee collection of 
primary tumor biopsy if not previously performed.  
8.4 RADIOGRAPHIC ASSESSMENT: 
• Initial evaluation will include PET/CT or CT scan of the head and neck to assess local 
and regional disease extent.  PET/CT or CT of the chest, abdomen, and pelvis will also be 
utilized to assess for distant disease.  
• MRIs may be substituted in place of PET/CT or CT scan for clinical reasons such as 
subject intolerance of intravenous contrast material.  
• The same method of assessment (i.e. CT, MRI) and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
• RECIST 1.1 guidelines will be used. 
• Restaging scans of the head and neck will be performed following the 3rd cycle between 
Days 29-36 
• If tumor cannot be visualized on radiology exam, caliper measurement should be used. 

Protocol version 6 dated December 6, 2019 
16 
8.5 CLINICAL TUMOR ASSESSMENT: 
• Primary tumors will be assessed for progression using caliper measurement on prior to 
registration and following the third cycle of treatment Day 29-36.  Caliper measurements 
are only required if tumor cannot be visualized on radiology exam. 
• Tumors will be photographed at time of clinical assessment on day 1 and following the 
third cycle of treatment for a qualitative assessment of possible effects on reduction in 
tumor size, necrosis, erythema/inflammation, and vascularity. Standard flash or 
endoscopic digital photography may be used depending on the site and accessibility for 
photography. 
• Following completion of the trial, two blinded head and neck tumor surgeons 
(Photograph Examiner #1 and #2) will review the photographs separately. Each examiner 
will record estimated size, percent increase or decrease, and anatomic descriptive terms 
related to change in size, shape, texture, and color over time from the photographs. 
8.6 ON STUDY ASSESSMENTS 
• Toxicity assessments will be continuous during the treatment phase. Adverse events and 
laboratory values will be graded according to the NCI-CTCAE version 4.03.  
• On-study weight, ECOG performance status, and vital signs should be assessed at each 
on-study visit prior to dosing. Vital signs should also be taken as per institutional 
standard of care. Oxygen saturation by pulse oximetry at rest (also monitor amount of 
supplemental oxygen if applicable) should be assessed at each on-study visit prior to 
dosing. The start and stop time of the study therapy infusions should be documented.  
• Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, the changes should be 
reported as AEs. 
• Laboratory testing prior to each dose: Within 72 hours prior to re-dosing to include 
CBCD, LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, 
amylase, lipase.  
• Thyroid function testing should be done every 6 weeks (every 3 cycles) for subjects 
receiving nivolumab.  
• A minimum of five and a maximum of seven 5-mL tubes of peripheral blood will be 
collected for correlative studies.  See section 12 for more details.   
• Additional measures, including non-study required laboratory tests, should be performed 
as clinically indicated or to comply with local regulations. Laboratory toxicities (eg, 
suspected drug induced liver enzyme evaluations) will be monitored during the follow-up 
phase via on site/local labs until all study drug related toxicities resolve, return to 
baseline, or are deemed irreversible.  
• If a subject shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, 
fever) or symptoms (eg. dyspnea, cough, fever) consistent with possible pulmonary-
related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with 

Protocol version 6 dated December 6, 2019 
17 
possible pulmonary adverse events, the subject should be immediately evaluated to rule 
out pulmonary toxicity.  
• At the time of surgery, portions of the excised HNSCC tissues that are not required for 
clinical purposes (existing material) will be used for correlative research.  See section 12 
for more details.   
• Some of the assessments referred to in this section may not be captured as data in the 
eCRF. They are intended to be used as safety monitoring by the treating physician. 
Additional testing or assessments may be performed as clinically necessary or where 
required by institutional or local regulations.  
8.7 OFF STUDY AND FOLLOW UP 
8.8 SUBJECTS WILL BE FOLLOWED EVERY 3 MONTHS (+/- 15 DAYS) FROM 
THE DATE OF SURGERY UNTIL PROGRESSION OR UNTIL DEATH, 
WHICHEVER COMES FIRST, FOR A MAXIMUM OF 12 MONTHS AFTER 
THE LAST SUBJECT HAS BEEN REGISTERED TO THE TRIAL.  AES WILL 
BE RECORDED FOR 6 WEEKS AFTER SURGERY.  AES CAN BE REPORTED 
THROUGH REGULAR CLINIC VISITS OR OVER THE PHONE.

Protocol version 6 dated December 6, 2019 
18 
 
8.9 STUDY CALENDAR 
 
a. 
Performed as clinically indicated 
b. 
Follow up every three months (+/- 15 days) from the time of surgery until progression or death, for up to 12 months after the last subject has been registered to the trial. 
c. 
If disease is stable or response is observed at days 28-35, subjects will have the forth administration of nivolumab on Day 43, followed by definitive surgical resection on 
day 50-56.   
d. 
Serum pregnancy test to be done 30 days and 70 days after last drug administration.  
e. 
AEs will be recorded for 6 weeks after surgery. 
Activity 
Screening  
 
Patient Registration 
Nivolumab 
Administrationg 
If stable or 
response 
only: 
Surgeryc, h 
Follow Up 
Within 28 
days of 
Registration 
Within 14 
days of 
Registration 
Within 24 
hours of 
registration 
Day 
1i 
Day 
15 
Day 
29 
Day 43c 
Day 36-42 
or Day 50-
56 
30 
daysd 
42 
daysj 
70 
daysd 
Q 3 
monthsb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
History and Physical examination 
 
X 
 
Xa 
Xa 
Xa 
Xa 
 
 
 
 
 
ECOG PS  
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Vital signs, weight  
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
CBCD & CMP 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Mag, Phos 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
HVB and HVC screening 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH, free T3, free T4 
 
X 
 
X 
 
 
X 
 
 
 
 
 
LDH, amylase, lipase 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Serum Pregnancy test (WOCBP only) 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
Assessment of Concomitant medications 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Adverse events assessment 
 
 
 
X 
X 
X 
X 
 
 
X 
 
 
Tumor Photographsk 
 
 
 
X 
 
X 
 
 
 
 
 
 
Radiographic or Caliper Measurement 
Tumor Assessment k 
X 
 
 
 
 
X 
 
 
 
 
 
 
Survival Status and Disease Statusb 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab Administration 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
Any time after consent and prior to day 1 dose 
 
 
 
X 
 
 
 
 
Research blood collectionf 
Any time after consent and prior to day 1 dose 
 
 
 
X 
 
 
 
 

Protocol version 6 dated December 6, 2019 
19 
 
f. 
A minimum of five and a maximum of seven, 5-mL tubes of peripheral blood will be collected for correlative research in purple top tubes.  See section 12 for more 
details about tumor biopsy and research blood collection. 
g. 
Nivolumab may be administered +/- 1 day 
h. 
Surgery is to be performed any time between Days 36-42 for patients whose disease has progressed and no later than 50 days after randomization or between Days 50-56 
for patients who have stable disease or response, with surgery to be no later than 60 days after randomization. 
i. 
Screening labs done within 72 hours of day 1 do not need to be repeated. 
a. 
AEs will be assessed up to 6 weeks after surgery and may be assessed through clinic notes and/or reported via phone.   
b. 
See section 8.5 Clinical Tumor Assessment for more information.

Protocol version 6 dated December 6, 2019 
20 
 
9 DRUG INFORMATION - NIVOLUMAB 
9.1 DRUG ORDERING AND ACCOUNTABILITY 
BMS is supplying study drug.  Please see the pharmacy manual for instructions on how to order 
study drug from BMS. 
9.2 PRODUCT DESCRIPTION AND DOSAGE FORM 
Nivolumab (BMS-936558-01) Injection drug product is a sterile, non-pyrogenic, single-use, 
isotonic aqueous solution formulated at 10 mg/mL.  
 
• Other names:  MDX-1106, ONO-4538 and antiPD-1.   
• Potency:  100mg/Vial (10mg/mL) 
• Primary Packaging (volume)/Label type:  Carton of 5 or 10 vials 
• Secondary packaging (Qty)/Label type:  10-cc Type 1 flint glass vials stoppered with 
butyl stoppers and sealed with aluminum seals. 
• Appearance:  clear to opalescent, colorless to pale yellow liquid.  May contain particles 
9.3 STORAGE CONDITIONS: 
Investigational product must be stored at 2-8 degrees C (36-46 degrees F) and protected from 
light and freezing. 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab include laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator 
Brochure section for “Recommended Storage and Use Conditions” 
9.4 LABELING: 
Nivolumab may be labeled as BMS-936558-01 Solution for Injection. 
 
9.5 HANDLING AND DISPENSING 
The investigator should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as per product information and the Investigator 
Brochure and per local regulations. It is the responsibility of the investigator to ensure that 
investigational product is only dispensed to study subjects. The investigational product must be 
dispensed only from official study sites by authorized personnel according to local regulations. If 
concerns regarding the quality or appearance of the study drug arise, the study drug should not 
be dispensed and contact BMS immediately. 
 
Please refer to the current version of the Investigator Brochure and/or shipment reference sheets 
for additional information on storage, handling, dispensing, and infusion information for 
nivolumab. 
 
9.6 DESTRUCTION  
Sponsor/Investigator drug destruction is allowed provided the following minimal standards are 
met: 

Protocol version 6 dated December 6, 2019 
21 
 
 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the Sponsor SOPs and a copy provided to BMS upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, ie, incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for BMS to 
review throughout the clinical trial period as per the study agreement.  
 
If conditions for destruction cannot be met, please contact BMS.  
 
It is the Sponsor Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable 
federal, state, local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
10 DEFINITION OF ENDPOINTS 
10.1 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is objective response rate: pathologic complete response + 
pathologic partial response. Objective response rate: the sum of patients with either a pCR 
defined as no invasive and no in situ residuals present in the surgical specimen or partial 
pathologic response defined at least a 30% reduction in the size of the lesion in the surgical 
specimen. The reduction in size will be determined by comparing the pretreatment clinical 
measurements (the sum of the greatest axial measurement obtained radiographically, or using 
calipers if necessary, at the time of initial evaluation) with the final pathologic measurements.  
Partial response has been chosen as an efficacy endpoint because of the two stage design and 
small sample size of the proposed trial (i.e. a objective response must be observed in at least 1 
patient in first nine to proceed with the second stage).  The proposed study is based on the 
current available head and neck squamous cell carcinoma data and is not powered to assess an 
objective response rate defined as pathologic complete response + major pathologic response. 
10.2 
SECONDARY EFFICACY ENDPOINTS 
Immune capability will be measured as follows: 
 
1. Levels of Treg cells in pre and post treatment peripheral blood will be evaluated using 
immunostaining for CD4 and flow cytometric analysis of Foxp3.  Differences will be 
calculated (absolute change and percentage change) between pre and post treatment 
measures.  
2. Levels of activated T-cells in peripheral blood will be assessed using flow cytometry for 
expression of CD69, IFN γ, T-bet and ICOS in CD4+ cells. Differences will be calculated 
(absolute change and percentage change) between pre and post treatment measures. 

Protocol version 6 dated December 6, 2019 
22 
 
3. Intratumoral immune activity assessed by levels of immune stimulatory cytokines 
including IL-2, IFN γ, and IL-12 or inhibitory cytokine, IL10 and TGF-beta, in OCSCC 
tumor lysates will be measured flow cytometrically by cytokine bead array.  Differences 
will be calculated (absolute change and percentage change) between pre and post 
treatment measures. 
 
Immune reactivity against autologous OCSCC will be measured by T cell responsiveness of their 
pre and post treatment peripheral blood following a challenge with autologous OCSCC. 
 
1. Expression of IFN γ, IL-2 (Th1 responses) and IL 10  (Th2 responses) in CD4+ cells 
from peripheral blood of patients following PD-1 inhibition therapy will be compared 
between pre-treatment peripheral blood samples and post-treatment samples from the 
same patient.  
2. Expression of CD8+ cells expressing granzyme B (cytolytic response) from peripheral 
blood of patients following PD-1 inhibition therapy will be compared between pre-
treatment peripheral blood samples and post-treatment samples from the same patient. 
 
10.3 
DEFINITION OF SECONDARY OUTCOMES/ENDPOINTS: 
1. Increased immune capability will be defined as decrease in Treg population with 
subsequent increase in activated T cells population. 
2. Immune reactivity will be defined as increased Th1 response and CD8+ cytolytic 
response following challenge to autologous OCSCC in post treatment peripheral blood 
relative to pretreatment peripheral blood samples. 
10.4 
SAFETY ENDPOINTS 
Adverse events, assessed using the CTCAE v4, occurring between enrollment and 6 weeks 
following surgery will be collected.  
 
11 STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE SIZE 
11.1 
DEFINITION OF EVALUABLE PATIENTS 
11.1.1 EVALUABLE FOR SAFETY 
Any patient who receives one or more doses of nivolumab will be included in the safety 
population. 
11.1.2 EVALUABLE FOR EFFICACY 
Patients who receive at least two doses of nivolumab and undergo surgery will be included in 
the efficacy population. 
11.1.3 EVALUABLE FOR IMMUNE ACTIVATION AND REACTIVITY 
Patients who have received at least two doses of nivolumab and have both a pre-treatment 
and a post-treatment sample available for measuring immune markers will be included in the 
analyses for the secondary objectives of the study.  

Protocol version 6 dated December 6, 2019 
23 
 
11.2 
DATA ANALYSIS PLANS 
11.2.1 PRIMARY OBJECTIVE 
The clinical, radiographic and pathologic response rates will each be estimated with a 95% 
confidence interval, accounting for the two-stage design [41].  The null hypothesis is a 2% 
pathological response rate and the alternative is a 25% pathological response rate.  If no 
patients respond in the first nine evaluable patients enrolled, the study will be terminated and 
we will conclude that there is not sufficient activity to reject the null hypothesis. The trial 
may pause enrollment after the first nine patients (if needed) to follow the ninth patient for a 
pathologic response.  Note, however, that it is possible that an earlier patient may respond 
which would negate the need to stop enrollment (e.g. the 2nd patient may respond which 
would satisfy the criteria of at least one patient response in the first nine patients).  If at least 
one patient has a pathologic response among the first nine evaluable patients enrolled, an 
additional eight patients will be enrolled.  If two or more patients among 17 evaluable 
patients respond, we will reject the null hypothesis.  The reported p-value will be based on 
two-stage design and any deviations from the intended sample size will be accounted for 
using the approach by Koyama and Chen [41]. Deviations from the planned sample size 
would only include the need for replacement patients in the event of a patient withdrawal 
following a single dose of Nivolumab secondary to toxicity or patient preference.  If this 
were to occur these withdrawn patients would be excluded from the efficacy analysis. Only 
patients that receive at least 2 doses of Nivolumab will included in the efficacy analysis.  
Briefly, Koyama and Chen’s approach adjusts the final results of the Simon two-stage design 
(point estimate, 95% confidence interval, and p-value) by considering the evaluation of the 
data at the end of the 1st stage of the design.  Ignoring the two-stage nature of the design, the 
estimated response rate (i.e. number of responders divided by the total number of patients at 
the end of stage 2) tends to underestimate the true response rate. In addition, the p-value and 
95% confidence interval based simply on the maximum likelihood estimate using the total 
number of responses and total sample size will not be valid if the futility stopping evaluation 
is ignored.  The approach for implementing the adjustment can be found here: 
http://biostat.mc.vanderbilt.edu/wiki/Main/TwoStageInference 
 
11.2.2 SECONDARY OBJECTIVES 
Immune activation markers will be graphically displayed at baseline (pre-treatment) and at 
time of surgical resection, and summary statistics will be reported for baseline, follow-up and 
changes over time.  Based on our prior studies a 50% increase in immune stimulatory 
cytokines and 50% decrease in Treg levels is anticipated. 
 
Transformations will be taken as needed (e.g. log transform) to adhere to assumption of 
statistical methods.  Comparisons of baseline vs. follow-up measures will be made using 
paired t-tests.  Logistic regression will be used to evaluate the association between baseline 
immune markers and clinical response and to evaluate associations between changes in 
immune markers and response.  Both absolute change and percentage change in markers will 
be considered    
 

Protocol version 6 dated December 6, 2019 
24 
 
11.3 
DETERMINATION OF SAMPLE SIZE 
This study will enroll up to 19 patients.  The Simon two-stage design is based on a total of 17 
patients who are evaluable for efficacy. We may enroll up to 19 to allow for up to two patients to 
be inevaluable.  
 
Without treatment, the rate of response would be expected to be very low (<2%).  With 
treatment, we anticipate a meaningful pathological response rate of 25%.  Using a Simon optimal 
two-stage design with alpha of 4% and power of 91%, we can detect this difference with a 
sample size of no more than 17 patients. In stage 1, 9 patients will be enrolled. If none respond, 
the study will be stopped.  If one or more responds, we will continue to the 2nd stage and an 
additional 8 patients will be enrolled.  If a total of 2 or more patients respond out of 17 we will 
reject the null hypothesis and conclude that treatment with Nivolumab results in a meaningful 
pathological response for patients with HNSCC. 
11.4 
SAFETY ANALYSIS 
Adverse events occurring between enrollment and 6 weeks after surgery will be tabulated by 
type and grade.  Adverse events that are at least possibly related to nivolumab will be tabulated 
separately.  
 
Safety monitoring will occur continuously during the study.  We anticipate nivolumab to be 
well-tolerated in this patient population and would anticipate a low (≤5%) rate of grade 3 and 4 
adverse events that are at least possibly related to nivolumab.  If there were strong evidence 
during the course of the trial that the rate of grade 3 and 4 adverse events was 25% or higher, we 
would stop the study.  Using a likelihood-based approach, the study will stop if the likelihood 
ratio for a grade 3-4 AE rate of 25% vs. a grade 3-4 AE rate of 5% is 4 or higher.  This is based 
on the binomial distribution.    The stopping boundaries based on this approach are shown in the 
table below.  Note that the upper limit on the sample size 19 due to the potential need to enroll 
up to 19 patients in the case of up to two patients inevaluable for response. 
 
 
Stop the trial if: 
 
Observed rate 
Likelihood 
Ratio  
2 of 3-9 pts have grade 3-4 AEs 
22% - 67% 
≥ 4.78 
3 of 10-17 pts have grade 3-4 AEs 
18% - 30% 
≥ 4.57 
4 of 18-19 pts have grade 3-4 AEs 
21% - 22% 
≥ 4.36 
 
Additionally, if there is evidence that there is a delay in time to surgery due to adverse events, 
the study will be stopped.  It would be considered acceptable if 5% or fewer of patients 
experienced a delay (i.e. greater than 3 weeks from their last dose of nivolumab..  A rate of delay 
of 10% or greater would be considered unacceptable.  Given these assumptions and the use of a 
likelihood-based approaches as above (with a likelihood ratio of 4 or greater in favor of 20% 
causing study stoppage).  The stopping boundaries are listed below: 
 
 
Stop the trial if: 
 
Observed rate 
Likelihood 
Ratio  
3 of 3-15 pts have a surgery delay 
20% - 100% 
≥ 4.20 
4 of 9-19 pts have a surgery delay 
21% - 25% 
≥ 7.11 

Protocol version 6 dated December 6, 2019 
25 
 
11.5 
INTERIM ANALYSIS 
There are no interim analyses planned for this study.  However, given that the study design is a 
Simon two-stage design, the number of responses in the first nine patients will be evaluated and 
the study will be terminated after the ninth patient if none of these nine patients have achieved a 
clinical response.   
12 CORRELATIVE STUDIES 
After patients are entered into this study, the clinical team will oversee collection of primary tumor 
biopsy if not previously performed and peripheral blood at the onset of the study prior to initiating 
treatment.  Prior to surgical resection, peripheral blood will again be collected in an effort to measure 
pre- and post-treatment immune reactivities.  At each blood draw, each patient will have peripheral 
blood drawn into a minimum of five and a maximum of seven 5-ml purple top tubes. Portions of the 
excised HNSCC tissues that are not required for clinical purposes (existing material) will be used in 
addition to the peripheral blood for immunological assessments.  The peripheral blood and HNSCC 
tissues will be used to assess immunological responsiveness to the immunotherapy (see “Correlative 
Research” below) 
12.1 
EVALUATION OF THE SYSTEMIC AND INTRATUMORAL IMMUNE 
ACTIVATION FOLLOWING PD-1 BLOCKADE: 
Increased immune capability will be defined as follows: 
a. Reduced levels of Treg cells in pre and post treatment peripheral blood will be 
evaluated using immunostaining for CD4 and flow cytometric analysis of CD3 and 
Foxp3.  
b. Increased levels of activated T-cells in peripheral blood will be assessed using flow 
cytometry for expression of CD69, IFN-γ, T-bet and ICOS in CD4+ cells. 
c. Intratumoral immune activity assessed by increased levels of immune stimulatory 
cytokines including IL-2, IFN-γ, and IL-12 or inhibitory cytokine, IL10 and TGF-
beta, in OCSCC tumor lysates will be measured flow cytometrically by cytokine bead 
array. 
12.2 
DETERMINING IMMUNE REACTIVITY TO AUTOLOGOUS OCSCC: 
Immune reactivity against autologous OCSCC will be measured by T-cell responsiveness of their 
pre and post treatment peripheral blood following a challenge with autologous OCSCC. 
a. Following a challenge with autologous OCSCC, increased expression of IFN-γ, IL-2 
(Th1 responses) and decreased IL-10 (Th2 responses) in CD4+ cells from peripheral 
blood of patients following PD-1 inhibition therapy will be compared to pre-treatment 
peripheral blood samples from the same patient. 
b. Following a challenge with autologous OCSCC, Increased expression of CD8+ cells 
expressing granzyme B and perforin (cytolytic response) from peripheral blood of 
patients following PD-1 inhibition therapy will be compared pre-treatment peripheral 
blood samples from the same patient. 
 

Protocol version 6 dated December 6, 2019 
26 
 
12.3 
GENOMIC SEQUENCING 
Genomic sequencing will be done on samples collected prior to the start of therapy and after the 
completion of therapy (at the time of surgery).  The samples will be linked to the patients by a 
unique study ID.  Results of genomic sequencing will not be shared with subjects and the results 
of the sequencing will not alter clinical decisions.  The genomic sequencing correlative study is 
optional. 
13 ADVERSE EVENT REPORTING REQUIREMENTS 
13.1 
PURPOSE 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. AE are reported in a routine manner at scheduled times during a 
trial. Additionally, certain AEs must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe routine and expedited 
AEs reporting for this protocol.  
 
Throughout the study, the Investigator will be required to provide appropriate information 
concerning any findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safety of the drug under investigation.  
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
13.2 
DEFINITION OF SERIOUS ADVERSE EVENT 
An SAE is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  
• Potential DILI is also considered an important medical event.  
• Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  

Protocol version 6 dated December 6, 2019 
27 
 
• Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. 
 
The following hospitalizations are not considered SAEs for this protocol: 
• a visit to the emergency room or other hospital department lasting < 24 hours or that does 
not result in admission (unless considered an important medical or life-threatening event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
• Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEsPotential drug induced liver injury is 
defined as: 
 
1)  ALT or AST elevation > 3 times ULN  
AND 
2)  Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3)  No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety).  
The investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form [provided upon request from BMS]in accordance with SAE 
reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 

Protocol version 6 dated December 6, 2019 
28 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
13.3 
SAE REPORTING 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs that occur with 100 days of discontinuation of dosing 
must be collected.  
 
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy).  The 
investigator should report any SAE that occurs after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to the SIS 
Unit and BMS within 24 hours.  
 
SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy Surveillance 
Form: 
 
SAE Email Address:  WORLDWIDE.SAFETY@BMS.COM 
SAE Facsimile Number:  609-818-3804 
 
All SAEs reports (including follow up reports) must be reported to the SIS Unit via REDCap 
(redcap.musc.edu) 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS 
and any applicable health authority during the conduct of the study including periodic 
reconciliation.  
 
Any event that is both serious and unexpected must be reported to the FDA as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided 
with a simultaneous copy of all adverse events filed with the FDA.  

Protocol version 6 dated December 6, 2019 
29 
 
 
Reportable SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
The SIS Unit will be responsible for submitting the SAEs to the FDA and other regulatory 
agencies/oversight committees as required.  
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
13.4 
DEFINITION OF ADVERSE EVENT 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product. 
 
The causal relationship to study drug is determined by a physician and should be used to assess 
all AEs. The casual relationship can be one of the following: 
 
Definitely related: 
An adverse event occurring in a plausible time relationship to drug 
administration, and which cannot be explained by concurrent 
disease or other drugs or chemicals.  The response to withdrawal of 
the drug should be clinically plausible.  The event must be definite 
pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary and feasible. 
Possibly related: 
An adverse event with a reasonable time sequence to administration 
of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals.  Information on drug 
withdrawal may be lacking or unclear. 
Not related: 
An adverse event with a temporal relationship to drug 
administration which makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying diseases provide 
plausible explanations. 
 
 

Protocol version 6 dated December 6, 2019 
30 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
13.5 
NONSERIOUS ADVERSE EVENT COLLECTION AND REPORTING 
The collection of non-serious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.  
 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
Any significant worsening of a pre-existing condition noted during interim or final physical 
examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or 
not these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 
13.6 
DEFINITION OF SEVERITY 
Adverse events will be graded according to the revised NCI CTCAE v. 4.03.  If toxicities are not 
defined by the NCI CTCAE v. 4.03, the intensity of each adverse event should be graded as 
outlined below:   
 
GRADE 1 
MILD:  Sign or symptom noticeable, but does not interfere with normal daily 
activities. 
GRADE 2 
MODERATE:  Sign or symptom sufficient to interfere with normal daily 
activities. 
GRADE 3 
SEVERE:  Sign or symptom is incapacitating, with inability to perform daily 
activities. 

Protocol version 6 dated December 6, 2019 
31 
 
GRADE 4 
LIFE-THREATENING:  sign or symptom poses immediate risk of death to this 
patient. 
13.7 
DOCUMENTATION OF ADVERSE EVENTS 
The Investigator will monitor and/or ask about or evaluate AEs using non leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 
 
• AE name or term 
• When the AE first occurred (start date) 
• When the AE stopped (stop date), (or an indication of “ongoing”) 
• How long the AE persisted (optional) 
• Severity of the AE 
• Seriousness  
• Actions taken 
• Outcome 
• Investigator opinion regarding the relationship of AE to the study drug(s) 
 
14 ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with ICH CGP, the FDA, local IRB policies and in 
compliance with the protocol.  The protocol, any amendments and the subject informed consent will 
received IRB approval before initiation of the study or implementation of any protocol change. 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
14.1 
INFORMED CONSENT 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Informed consent will be obtained by personnel who are qualified by education, training and 
experience to perform the task.  The Sponsor-Investigator will not use the services of study 
personnel for whom sanctions have been invoked where there has been scientific misconduct or 
fraud.   
 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks and other critical issues regarding clinical studies in which they volunteer to participate.  
The approved consent form will adhere to the ethical principles that have their origin in the 
Declaration of Helsinki. 

Protocol version 6 dated December 6, 2019 
32 
 
14.2 
INSTITUTIONAL REVIEW 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46) 
 
15 MONITORING 
The SIS Unit will be responsible for the monitoring of study subject data and records; monitoring 
will be performed centrally. The SIS Unit will be responsible for forwarding any applicable reports 
to the HCC DSMC for review. 
The SIS Unit will conduct patient eligibility audit reviews for all patients prior to patient registration.  
During the course of the study, subjects will be selected for an audit at least once a year.  Progress 
reports will be submitted to the HCC DSMC at least once a year.   
15.1 
PROTOCOL DEVIATIONS  
For the purposes of this study, a protocol deviation is any variance from the protocol involving 
a subject or subjects that is not approved by the IRB prior to its initiation or implementation, and 
occurs when a member of the study team departs from the IRB-approved protocol in any way 
without the investigator first obtaining IRB approval. Protocol Deviations have special reporting 
requirements.  Any protocol deviation and any supporting documentation will be submitted to 
the SIS Unit within 10 days of notification as outlined in the Operations Manual for this study. 
15.2 
DATA SAFETY MONITORING BOARD 
The HCC DSMC will have oversight of the protocol. The HCC DSMC will meet at a minimum 
on a semi-annual basis to review the audits and progress reports for this IIT.  
In addition, all protocol deviations and SAEs as defined above will be reviewed by the HCC 
DSMC at monthly meetings. As new protocol deviations or serious adverse events are reported 
to the SIS Unit, the SIS Unit will review these reports for form completion and follow up if more 
information is warranted. The SIS Unit will forward the event report to the HCC DSMC so that 
the information can be reviewed at the next available DSMC meeting. During the DSMC review, 
the DSMC can make recommendations for any further study action. The SIS Unit will maintain a 
copy of the DSMC approval letters for each event reviewed for this study within the site’s central 
study file and will distribute to the participating site, if applicable. 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
33 
 
REFERENCES 
1.         Ferlay, J., et al., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC 
CancerBase No. 11 [Internet]. 2013. 
2. 
Bell, R.B., et al., Tongue cancer: Is there a difference in survival compared with other subsites in 
the oral cavity? J Oral Maxillofac Surg, 2007. 65(2): p. 229-36. 
3. 
Kademani, D., et al., Prognostic factors in intraoral squamous cell carcinoma: the influence of 
histologic grade. J Oral Maxillofac Surg, 2005. 63(11): p. 1599-605. 
4. 
Bernier, J., et al., Defining risk levels in locally advanced head and neck cancers: a comparative 
analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) 
and RTOG (# 9501). Head Neck, 2005. 27(10): p. 843-50. 
5. 
Koo, B.S., et al., Recurrence and salvage treatment of squamous cell carcinoma of the oral 
cavity. Oral Oncol, 2006. 42(8): p. 789-94. 
6. 
Schwartz, G.J., et al., Salvage treatment for recurrent squamous cell carcinoma of the oral 
cavity. Head Neck, 2000. 22(1): p. 34-41. 
7. 
Haddad, R.I. and D.M. Shin, Recent advances in head and neck cancer. N Engl J Med, 2008. 
359(11): p. 1143-54. 
8. 
Vermorken, J.B., et al., Platinum-based chemotherapy plus cetuximab in head and neck cancer. 
N Engl J Med, 2008. 359(11): p. 1116-27. 
9. 
Fisher, B., et al., Effect of preoperative chemotherapy on local-regional disease in women with 
operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-
18. J Clin Oncol, 1997. 15(7): p. 2483-93. 
10. 
Gebski, V., et al., Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in 
oesophageal carcinoma: a meta-analysis. Lancet Oncol, 2007. 8(3): p. 226-34. 
11. 
Bear, H.D., et al., Sequential preoperative or postoperative docetaxel added to preoperative 
doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant 
Breast and Bowel Project Protocol B-27. J Clin Oncol, 2006. 24(13): p. 2019-27. 
12. 
Mauri, D., N. Pavlidis, and J.P. Ioannidis, Neoadjuvant versus adjuvant systemic treatment in 
breast cancer: a meta-analysis. J Natl Cancer Inst, 2005. 97(3): p. 188-94. 
13. 
Vermorken, J.B., et al., Cisplatin, fluorouracil, and docetaxel in unresectable head and neck 
cancer. N Engl J Med, 2007. 357(17): p. 1695-704. 
14. 
Posner, M.R., et al., Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. 
N Engl J Med, 2007. 357(17): p. 1705-15. 
15. 
Kies, M.S., et al., Induction chemotherapy and cetuximab for locally advanced squamous cell 
carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol, 2010. 
28(1): p. 8-14. 
16. 
Kies, M.S., et al., Phase II trial of induction chemotherapy followed by surgery for squamous cell 
carcinoma of the oral tongue in young adults. Head Neck, 2012. 34(9): p. 1255-62. 
17. 
Licitra, L., et al., Primary chemotherapy in resectable oral cavity squamous cell cancer: a 
randomized controlled trial. J Clin Oncol, 2003. 21(2): p. 327-33. 
18. 
Ma, J., et al., Induction chemotherapy decreases the rate of distant metastasis in patients with 
head and neck squamous cell carcinoma but does not improve survival or locoregional control: a 
meta-analysis. Oral Oncol, 2012. 48(11): p. 1076-84. 
19. 
Thomas, F., et al., Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and 
neck squamous cell carcinoma. Clin Cancer Res, 2007. 13(23): p. 7086-92. 
20. 
Perrone, F., et al., TP53 mutations and pathologic complete response to neoadjuvant cisplatin 
and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. J Clin Oncol, 
2010. 28(5): p. 761-6. 

Protocol version 6 dated December 6, 2019 
34 
 
21. 
Osman, A.A., et al., Evolutionary Action Score of TP53 Coding Variants (EAp53) is Predictive of 
Platinum Response in Head and Neck Cancer Patients. Cancer Res, 2015. 
22. 
Hennessy, B.T., A.M. Gonzalez-Angulo, and G.N. Hortobagyi, Individualization of neoadjuvant 
therapy for breast cancer according to molecular tumor characteristics. Nat Clin Pract Oncol, 
2005. 2(12): p. 598-9. 
23. 
Ayers, M., et al., Gene expression profiles predict complete pathologic response to neoadjuvant 
paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. 
J Clin Oncol, 2004. 22(12): p. 2284-93. 
24. 
Gonzalez-Angulo, A.M., et al., Factors predictive of distant metastases in patients with breast 
cancer who have a pathologic complete response after neoadjuvant chemotherapy. J Clin Oncol, 
2005. 23(28): p. 7098-104. 
25. 
Drennan, S., et al., Increased frequency and suppressive activity of CD127low/- regulatory T cells 
in the peripheral circulation of patients with head and neck squamous cell carcinoma are 
associated with advanced stage and nodal involvement. Immunology, 2013. 140(3): p. 335-43. 
26. 
Schuler, P.J., et al., Dendritic cell generation and CD4+ CD25high FOXP3+ regulatory T cells in 
human head and neck carcinoma during radio-chemotherapy. Eur J Med Res, 2011. 16(2): p. 57-
62. 
27. 
Casos, K., et al., Tumor cells induce COX-2 and mPGES-1 expression in microvascular 
endothelial cells mainly by means of IL-1 receptor activation. Microvasc Res, 2011. 81(3): p. 
261-8. 
28. 
Wild, C.A., et al., Toll-like receptors in regulatory T cells of patients with head and neck cancer. 
Arch Otolaryngol Head Neck Surg, 2010. 136(12): p. 1253-9. 
29. 
Russell, S.M., et al., USC-HN2, a new model cell line for recurrent oral cavity squamous cell 
carcinoma with immunosuppressive characteristics. Oral Oncol, 2011. 47(9): p. 810-7. 
30. 
Malm, I.J., et al., Expression profile and in vitro blockade of PD-1 in HPV-negative head and 
neck squamous cell carcinoma. Head Neck, 2014. 
31. 
Chen, X., et al., PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol, 
2014. 
32. 
Pittet, C.L., et al., Human brain endothelial cells endeavor to immunoregulate CD8 T cells via 
PD-1 ligand expression in multiple sclerosis. J Neuroinflammation, 2011. 8: p. 155. 
33. 
Strome, S.E., et al., B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell 
carcinoma. Cancer Res, 2003. 63(19): p. 6501-5. 
34. 
Taube, J.M., et al., Association of PD-1, PD-1 ligands, and other features of the tumor immune 
microenvironment with response to anti-PD-1 therapy. Clin Cancer Res, 2014. 20(19): p. 5064-
74. 
35. 
Walker, D.D., et al., Immunological modulation by 1a,25-dihydroxyvitamin D3 in patients with 
squamous cell carcinoma of the head and neck. Cytokine, 2012. 58(3): p. 448-54. 
36. 
Walsh, J.E., et al., Use of 1a,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration 
into head and neck squamous cell carcinoma. Hum Immunol, 2010. 71: p. 659-665. 
37. 
Kulbersh, J.S., et al., 1a,25-Dihydroxyvitamin D3 to skew intratumoral levels of immune 
inhibitory CD34+ progenitor cells into dendritic cells. Otolaryngol Head Neck Surg, 2009. 
140(2): p. 235-240. 
38. 
Jie, H.B., et al., Intratumoral regulatory T cells upregulate immunosuppressive molecules in 
head and neck cancer patients. Br J Cancer, 2013. 109(10): p. 2629-35. 
39. 
Gillison, M.L., et al., Abstract CT099: Nivolumab (nivo) vs investigator's choice (IC) for 
recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 
CheckMate-141. Cancer Research, 2016. 76(14 Supplement): p. CT099-CT099. 

Protocol version 6 dated December 6, 2019 
35 
 
40. 
American Association of Cancer Research, Nivolumab Improved Survival For Patients With 
Head and Neck Squamous Cell Carcinoma. 2016. 
41. 
Koyama T, Chen H. Proper inference from Simon’s two-stage design.  Stat in Med, 2008.  
27(16): 3145-54. 
 

Protocol version 6 dated December 6, 2019 
36 
 
APPENDIX A:  ACCEPTABLE FORMS OF CONTRACEPTION 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or 
male subject’s WOCBP partner. Female partners of male subjects participating in the study 
may use hormone based contraceptives as one of the acceptable methods of contraception since 
they will not be receiving study drug 
• Nonhormonal IUDs, such as ParaGard 
• Tubal ligation  
• Vasectomy 
• Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge 
• Male Condom without spermicide  
• Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
• Female Condom 
• A male and female condom must not be used together 
 
 
 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
37 
 
APPENDIX B: MANAGEMENT ALGORITHMS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all immuno-
oncology agents and regimens. A general principle is that differential diagnoses should be diligently 
evaluated according to standard medical practice. Non-inflammatory etiologies should be considered 
and appropriately treated. Corticosteroids are a primary therapy for immuno-oncology drug-related 
adverse events. The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. Consultation with a  medical or 
surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is 
recommended. The frequency and severity of the related adverse events covered by these algorithms 
will depend on the immuno-oncology agent or regimen being used. 
 
 

Protocol version 6 dated December 6, 2019 
38 
 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
39 
 
 
 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 6 dated December 6, 2019 
41 
 
 

Protocol version 6 dated December 6, 2019 
42 
 
 

Protocol version 6 dated December 6, 2019 
43 
 
 

Protocol version 6 dated December 6, 2019 
44