Window Study of Nivolumab With or Without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: Dana-Farber Cancer Institute

Protocol Version Date:  Septemebr 9, 2019
IND #: Study Exempt from IND Requirements per 21 CFR 312.2(b).
Local Protocol #: 16-284 
Title: Window Study of Nivolumab with or without Ipilimumab in Squamous Cell Carcinoma 
of the Oral Cavity
Principal Investigator (Overall): Jonathan D. Schoenfeld, MD, MPH
Principal Investigator (Beth Israel): Anu Desai, MD
Coordinating Center: Dana-Farber Cancer Institute
External Center: Beth Israel Deaconess Medical Center
 
Statistician:   Bhupendra Rawal, MS
Agents:  Nivolumab and Ipilimumab (Supplied by Bristol-Myers Squibb)
 

Window Study of Nivolumab with or without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity              
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SCHEMA

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TABLE OF CONTENTS
1.
OBJECTIVES......................................................................................................................................................5
1.1
Study Design.....................................................................................................................................................5
1.2
Primary Objectives...........................................................................................................................................5
1.3
Secondary Objectives .......................................................................................................................................5
2.
BACKGROUND..................................................................................................................................................6
2.1
Study Agents .....................................................................................................................................................6
2.2
Study Disease..................................................................................................................................................16
2.3
Rationale.........................................................................................................................................................16
2.4
Correlative Studies Background.....................................................................................................................17
3.
PARTICIPANT SELECTION.........................................................................................................................18
3.1
Eligibility Criteria ..........................................................................................................................................18
3.2
Exclusion Criteria........................................................................................................................................19
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations..................................................20
4.
REGISTRATION/ENROLLMENT PROCEDURES ...................................................................................20
4.1
General Guidelines for DF/HCC and DF/PCC Institutions ..........................................................................20
4.2
Registration Process for DF/HCC Institutions ..............................................................................................21
4.3
General Guidelines for Other Investigative Sites...........................................................................................21
4.4
Registration Process for Other Investigative Sites.........................................................................................21
5.
TREATMENT PLAN .......................................................................................................................................22
5.1
Treatment regimen ........................................................................................................................................22
Treatment will be administered on an outpatient basis. Expected toxicities and potential risk as well as 
management of these toxicities are described in Appendix D and E. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the participant’s 
malignancy during the course of treatment..............................................................................................................22
5.2
Pre-treatment Criteria..................................................................................................................................23
5.3
Agent Administration ....................................................................................................................................26
5.4
Definition of Dose-Limiting Toxicity...........................................................................................................31
5.5
General Concomitant Medication and Supportive Care Guidelines .............................................................33
5.6
Duration of Therapy........................................................................................................................................34
5.7
Criteria for Taking a Participant Off Protocol Therapy................................................................................35
5.8
Duration of Follow Up ...................................................................................................................................35
5.9
Criteria for Taking a Participant Off Study ...................................................................................................35
6.
DOSING DELAYS/DOSE MODIFICATIONS .............................................................................................36
6.1
Anticipated Toxicities .....................................................................................................................................36

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6.2
Toxicity Management .....................................................................................................................................36
6.3
Dose Modifications/Delays ............................................................................................................................38
7.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................................38
8.
PHARMACEUTICAL INFORMATION....................................................................................................43
9.
STUDY CALENDAR........................................................................................................................................44
10.
MEASUREMENT OF EFFECT......................................................................................................................48
10.1
Antitumor Effect– Solid Tumors ................................................................................................................48
10.2
Other Response Parameters ......................................................................................................................52
11.
ADVERSE EVENT REPORTING REQUIREMENTS................................................................................52
11.1
Definitions..................................................................................................................................................52
11.2
Procedures for AE and SAE Recording and Reporting.............................................................................54
11.3
Reporting Requirements for Participating Investigators ..........................................................................54
11.4
Reporting Requirements for DFCI IRB.....................................................................................................54
11.5
Expedited Reporting to Hospital Risk Management..................................................................................55
11.6
Reporting Requirements for FDA..............................................................................................................55
11.7
Reporting Requirements for BMS..............................................................................................................55
11.8
Monitoring of Adverse Events and Period of Observation........................................................................56
12.
DATA AND SAFETY MONITORING...........................................................................................................56
12.1
Data Reporting ..........................................................................................................................................56
12.2
Safety Meetings..........................................................................................................................................57
12.3
Monitoring.................................................................................................................................................57
12.4
Multi-Center Guidelines............................................................................................................................57
13.
REGULATORY CONSIDERATIONS...........................................................................................................58
13.1
Protocol Review and Amendments ............................................................................................................58
13.2
Informed Consent.......................................................................................................................................58
13.3
Ethics and Good Clinical Practice (GCP) ................................................................................................58
13.4
Study Documentation.................................................................................................................................59
13.5
Records Retention......................................................................................................................................59
14.
STATISTICAL CONSIDERATIONS.............................................................................................................60
15.
PUBLICATION PLAN.....................................................................................................................................61
16.
REFERENCES..................................................................................................................................................62
APPENDICES.............................................................................................................................................................65
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..........................................................................77

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DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. DF/HCC 
includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.......................................77
2.
GENERAL ROLES AND RESPONSIBILITIES ..........................................................................................78
2.1
DF/HCC Sponsor ...........................................................................................................................................78
2.2
Coordinating Center.......................................................................................................................................79
2.3
Participating Institution .................................................................................................................................79
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS........................................................80
3.1
Protocol Distribution......................................................................................................................................80
3.2
Protocol Revisions and Closures....................................................................................................................80
3.3
Informed Consent Requirements ....................................................................................................................80
3.4
IRB Documentation ........................................................................................................................................81
3.5
IRB Re-Approval ............................................................................................................................................81
3.6
Participant Confidentiality and Authorization Statement ..............................................................................81
3.7
DF/HCC Multi-Center Protocol Registration Policy.....................................................................................82
3.8
DF/HCC Protocol Case Number....................................................................................................................83
3.10
Safety Assessments and Toxicity Monitoring.............................................................................................84
3.11
Data Management .....................................................................................................................................84
4.
REQUISITIONING INVESTIGATIONAL DRUG ......................................................................................85
5.
MONITORING: QUALITY CONTROL .......................................................................................................85
5.1
Ongoing Monitoring of Protocol Compliance ...............................................................................................85
5.1.1
Remote Monitoring....................................................................................................................................85
DFCI CTO will virtually monitor sites throughout the study. On-site monitoring visits will be supplemented with 
virtual monitoring visits. The DF/HCC Lead Institution will request source documentation from Participating 
Institutions as needed to complete virtual monitoring activities. Participating Institutions will be asked to 
forward de-identified copies of participants’ medical record and source documents to the DF/HCC Lead 
Institution to aid in the source documentation verification process........................................................................85
5.1.2
On-Site Monitoring....................................................................................................................................86
5.2
Monitoring Reports ........................................................................................................................................86
5.3
Accrual Monitoring ........................................................................................................................................86
6.
AUDITING: QUALITY ASSURANCE..........................................................................................................86
6.1
Audit Plan: DF/HCC Sponsored Trials .........................................................................................................86
6.2
Audit Notification ...........................................................................................................................................86
6.3
Audit Reports..................................................................................................................................................87
6.4
Participating Institution Performance ...........................................................................................................87

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1. OBJECTIVES
1.1
Study Design
This is an open label, randomized, window-of-opportunity trial testing either nivolumab alone, or 
nivolumab in combination with ipilimumab in patients with locally advanced squamous cell 
carcinoma of the oral cavity prior to surgical resection. Nivolumab as a single agent was chosen 
because of preliminary evidence of efficacy of this drug in the metastatic setting in patients with 
squamous cell carcinoma of the head and neck (SCCHN). The combination of nivolumab and 
ipilimumab was chosen because of mechanistic rationale, preclinical data and clinical evidence 
suggesting synergy between these two agents.  Indeed, the combination of nivolumab and 
ipilimumab is now FDA approved as treatment for patients with metastatic melanoma and 
combinations of CTLA-4 and PD-1 pathway inhibitors have demonstrated promising efficacy 
across multiple disease types, including melanoma and non-small cell lung cancer.  The current 
study will evaluate response to nivolumab or nivolumab combined with ipilimumab prior to 
standard of care surgery for patients with locally advanced oral cavity cancers. 
1.2
Primary Objectives
To determine the 1) safety, tolerability; and 2) response rate to window treatment with single 
agent nivolumab or nivolumab combined with ipilimumab using bidirectional measurements 
(product of longest 2 diameters of lesions) of primary and nodal lesions to be removed at the time 
of surgery
1.3
Secondary Objectives
To determine the radiologic response rate following the window treatment as determined by 
RECIST v1.1, and burden of disease measurements for each cohort 
To determine pathologic response rates following window treatment and rates of pathologic 
downstaging as compared to pre-surgical staging
o
To correlate pathologic response with radiologic response 
To estimate the 1-year disease free and overall survival rates
To explore immunologic changes in the tumor microenvironment (infiltrating immune 
populations including T-cells, myeloid derived suppressor cells, NK cells, and expression of 
immune checkpoints such as PD-1, PD-L1, PD-L2, and others) and correlate those markers with 
radiologic and pathologic response, as well as changes in circulating immune markers such as T-
cell subsets, B-cells, and myeloid cells. We will also explore the ability of radiologic parameters 
to predict response rates as well as immunologic changes in the tumor microenvironment. 

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2.
BACKGROUND
2.1
Study Agents
2.1.1
Nivolumab
2.1.1.1
Mechanism of action and pharmacology
Cancer immunotherapy is based on the premise that the body’s immune system can recognize a 
tumor as foreign and mount an effective antitumor response capable of eliminating that tumor. This 
likely requires immune recognition of specific tumor antigens, but also effective functioning of 
activated T-cells capable of eliminating tumor cells as they arise and causing tumor shrinkage where 
existing tumor deposits are present. Conversely, tumor progression is likely intimately intertwined 
with mechanisms by which tumors evade immune recognition and attack. 
One mechanism by which tumors may evade immune attack is by coopting inherent immune 
checkpoints that function under normal circumstances to maintain immune homeostasis and prevent 
harmful autoimmunity. Thus, one strategy that exists for cancer immunotherapy is to modulate these 
regulatory immune checkpoints that largely exist on the surface of T-cells.  This can ideally 
overcome tumor mediated immune suppression, and potentiate nascent antitumor immune responses 
that might otherwise have been unable to lead to meaningful tumor regression. 
Programmed death receptor-1 (PD-1, CD279), is a 55 kD type I transmembrane protein is a member 
of the CD28 family of T-cell constimulatory molecules that also includes CD28, CTLA-4, ICOS, 
and BTLA [1]. PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273) [2]. PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems [2, 3]. PD-1 delivers a negative signal by the 
recruitment of SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region 
[4, 5]. PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells [5].
Further evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. 
PD-1-deficient mice develop various autoimmune phenotypes, including dilated cardiomyopathy, a 
lupus-like syndrome with arthritis and nephritis, and accelerated diabetes mellitus [6-8]. The 
emergence of these autoimmune phenotypes is dependent upon the genetic background of the mouse 
strain and many of these phenotypes emerge at different times and show variable penetrance. In 
addition to the phenotypes of null mutations, PD-1 inhibition by antibody-mediated blockade in 
several murine models has been found to play a role in the development of autoimmune diseases 
such as encephalomyelitis, graft-versus-host disease, and type I diabetes[9, 10]. Taken together, these 
results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these 
responses are variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or 
inhibition is not accompanied by a universal loss of tolerance to self-antigens.
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor 
activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors that are negative 

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for the expression of PD-L1[11-16]. This suggests that host mechanisms (ie, expression of PD-L1 in 
antigen-presenting cells) limit the antitumor response. Consequently, both PD-L1 positive and 
negative tumors may be targeted using this approach. In humans, constitutive PD-L1 expression is 
normally limited to macrophage-lineage cells, although expression of PD-L1 can be induced on other 
hematologic cells as well, including activated T cells. However, aberrant expression of PD-L1 by 
tumor cells has been reported in a number of human malignancies [17-22]. PD-L1 expressed by 
tumor cells has been shown to enhance apoptosis of activated tumor-specific T cells in vitro [5]. 
Moreover, the expression of PD-L1 may protect the tumor cells from the induction of apoptosis by 
effector T cells[23]. Retrospective analyses of several human tumor types suggest that tumor over-
expression (as measured by IHC) of PD-L1 may permit immune evasion by tumors. In renal cell 
carcinoma, high surface expression levels of PD-L1 on tumor cells are related to tumor 
aggressiveness [20, 21].  Subjects with high tumor and/or lymphocyte PD-L1 levels are 4.5 times 
more likely to die from their cancer than subjects exhibiting low levels of PD-L1 expression. In 
addition, in multivariate analysis, high expression of PD-L1 is correlated to have a worse overall 
survival rate compared to low expression levels of PD-L1[24].
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab is expressed in Chinese 
hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and 
chromatographic purification technologies. The clinical study product is a sterile solution for 
parenteral administration. 
OPDIVO™ (nivolumab) is approved for use in multiple countries including the United States (US, 
Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 
and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro 
[25]. Nivolumab binds with high affinity to activated human T-cells expressing cell surface PD-1 
and to cynomolgus monkey PD-1. In a mixed lymphocyte reaction (MLR), nivolumab promoted a 
reproducible concentration-dependent enhancement of IFN-α release [26]. 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well 
tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, 
administered twice weekly for 27 doses. While nivolumab alone was well tolerated in cynomolgus 
monkeys, combination studies have highlighted the potential for enhanced toxicity when combined 
with other immunostimulatory agents.
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus 
monkeys with nivolumab was conducted. Administration of nivolumab at up to 50 mg/kg 2QW was 
well tolerated by pregnant monkeys; however, nivolumab was determined to be a selective 
developmental toxicant when administered from the period of organogenesis to parturition at <=10 
mg/kg (area under the concentration-time curve [AUC] from time zero to 168 hours [AUC (0-168 
h)] 117,000 g  h/mL). Specifically, increased developmental mortality (including late gestational 
fetal losses and extreme prematurity with associated neonatal mortality) was noted in the absence of 
overt maternal toxicity. There were no nivolumab-related changes in surviving infants tested 

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throughout the 6-month postnatal period. Although the cause of these pregnancy failures was 
undetermined, nivolumab-related effects on pregnancy maintenance are consistent with the 
established role of PD-L1 in maintaining fetomaternal tolerance in mice [27]. 
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with non-small cell 
lung cancer (NSCLC), melanoma, and clear-cell renal cell carcinoma (RCC) in addition to other 
tumor types. Please refer to the 2015 IB for specific details. Nivolumab is being investigated both as 
monotherapy and in combination with chemotherapy, targeted therapies, and other 
immunotherapies. 
Nivolumab is approved in multiple countries including the US for treatment of previously treated, 
unresectable or metastatic melanoma, advanced renal cell carcinoma and previously treated, 
metastatic squamous NSCLC, the EU for treatment of previously treated, unresectable or metastatic 
melanoma, and Japan for treatment of unresectable melanoma. Please see the IB for more details. 
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 10 
mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The 
geometric mean (% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume of 
distribution at steady state (Vss) was 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) 
was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg Q2W, and systemic accumulation was approximately 3-fold. The exposure 
to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered 
every 2 weeks. The clearance of nivolumab increased with increasing body weight. The PPK analysis 
suggested that the following factors had no clinically important effect on the CL of nivolumab: age 
(29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK analysis suggested no difference in CL 
of nivolumab based on age, gender, race, tumor type, baseline tumor size, and hepatic impairment. 
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild 
hepatic impairment had an effect on nivolumab CL, the effect was not clinically meaningful. When 
nivolumab is administered in combination with ipilimumab, the CL of nivolumab was increased by 
24%, whereas there was no effect on the clearance of ipilimumab. Additionally, PPK and exposure 
response analyses have been performed to support use of 240 mg Q2W dosing in addition to the 3 
mg/kg Q2W regimen. Using the PPK model, exposure of nivolumab at 240 mg flat dose was 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, which was the approximate median body 
weight in nivolumab clinical trials (please see 2015 IB for more details). 
2.1.1.2
Clinical safety
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 8,600 subjects treated to date. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the 
safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. Clinically relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 

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In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues 
to 
evolve. 
The 
most 
advanced 
combination 
under 
development 
is 
nivolumab+ipilimumab, as is proposed in this study. Results to date suggest that the safety profile 
of nivolumab+ipilimumab combination therapy, described in more detail below, is consistent with 
the mechanisms of action of nivolumab and ipilimumab. The nature of the AEs is similar to that 
observed with either agent used as monotherapy; however, both frequency and severity of most 
AEs are increased with the combination.
Safety data for nivolumab administered in the context of NSCLC and melanoma are detailed 
below; additional information for other diseases can be found in the IB. 
Safety data for subjects with previously treated advanced or metastatic NSCLC treated with 
nivolumab monotherapy in CA209017 (131 subjects), CA209057 (287 subjects), and CA209063 
(117 subjects) were pooled and safety analyses were performed for these pooled subjects who 
receiving nivolumab monotherapy (a total of 535 subjects). 
Based on the pooled analyses, nivolumab monotherapy at a dose of 3 mg/kg administered IV Q2W 
has an acceptable safety profile, as demonstrated by the frequency, severity, and types of AEs, 
drug-related deaths, SAEs, and AEs leading to discontinuation. The following were the key safety 
findings for these pooled subjects: 
The most frequently reported drug-related AEs (reported in ≥ 10% of subjects) were fatigue 
(19.6%), decreased appetite (12.3%), nausea (12.0%), and asthenia (10.5%). The majority of drug-
related AEs were of Grade 1-2 in severity. Drug-related Grade 3-4 AEs were observed in 11.0 % 
of subjects and included fatigue (1.7%), pneumonitis (1.3%), and diarrhea (0.9%). 
Drug-related SAEs and drug-related AEs leading to discontinuation were reported in 7.9% and 
6.0% of subjects, respectively. The most frequently reported event (>=1% of subjects) was 
pneumonitis (1.9%). The majority of subjects experiencing drug-related SAEs and drug-related 
AEs leading to discontinuation had an event with worst grade of Grade 3-4 in severity. 
The most frequently reported drug-related select AE categories were skin (15.1%), GI (8.4%), 
and endocrine disorders (7.3%). 
o The majority of select AEs in each category (described in more detail in the IB) were considered 
by the investigator to be related to the study drug, except for AEs belonging to the hepatic, and 
renal select AE categories. 
o Across select AE categories, the majority of events were manageable, with resolution occurring 
whether or not immunosuppressive medication was needed. Among these medications, 
corticosteroids were the most common immunosuppressive concomitant medication administered. 
Most deaths (293/339) were due to disease progression. Two deaths (0.4%) were attributed to 
study drug toxicity: drug-related hypoxic pneumonia reported within 30 days of last nivolumab 
dose (ie, on-study) and drug-related ischemic stroke within 100 days of last nivolumab dose. One 
additional death, although reported prior to database lock for CA209057 CSR, had its causality 
changed after database lock to drug-related paraneoplastic limbic encephalitis. 
Hematology laboratory results, liver function, renal function, and thyroid function remained 
stable in the majority of subjects. Abnormalities were primarily Grade 1-2 in severity. 

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The immunogenicity of nivolumab was low and not clinically meaningful. 
Safety data for subjects with previously treated and untreated unresectable or metastatic melanoma 
treated with nivolumab monotherapy in CA209037 (268 subjects), CA209066 (206 subjects), and 
CA209067 (313 subjects) were pooled and safety analyses were performed for these pooled 
subjects receiving nivolumab monotherapy (a total of 787 subjects). 
Based on the pooled analyses, nivolumab monotherapy at a dose of 3 mg/kg administered IV Q2W 
has an acceptable safety profile, as demonstrated by the frequency, severity, and types of AEs, 
drug-related deaths, SAEs, and AEs leading to discontinuation (summarized in Table 5.5.2.1-1). 
The following were the key safety findings for these pooled subjects: 
The most frequently reported drug-related AEs (>=10% of subjects) were fatigue (29.2%), 
pruritus (18.4%), diarrhea (17.2%), rash (16.9%), and nausea (13.7%). No drug-related Grade 3-4 
AEs with the exception of lipase increased (2.0%), diarrhea (1.3%), and ALT increased (1.1%) 
were reported in ≥ 1% of subjects. 
No drug-related SAEs of any grade were reported in ≥ 1% of subjects. The most frequently 
reported drug-related SAEs of any grade were hyperglycemia (0.6%), colitis, diarrhea, and 
pneumonitis (0.5% each). 
No drug-related AEs leading to discontinuation of study drug were reported in ≥ 1% of subjects. 
The most frequently reported drug-related AEs leading to discontinuation of study drug were ALT 
increased (0.9%), diarrhea (0.8%), AST increased (0.5%), and colitis (0.5%). 
The most frequently reported drug-related select AE categories with nivolumab monotherapy 
were skin (38.4%), GI (17.7%), endocrine (10.8%), and hepatic (6.9%). The majority of select 
AEs were considered by the investigators to be related to study treatment. 
o Drug-related select AEs were mostly Grade 1-2. 
o Across categories, the majority of high-grade events subsequently resolved, including those for 
which immunosuppressive medication was not initiated. 
o The majority of deaths (229/251) were due to disease progression. Only 1 death was attributed 
to study drug toxicity; this death was due to drug-related neutropenia reported between 31 and 100 
days of last nivolumab dose.
o Abnormalities in select hematology assessments and liver/kidney function tests were primarily 
Grade 1-2 in severity. 
o The immunogenicity of nivolumab was low and not clinically meaningful.
2.1.1.3
Clinical Efficacy   
Nivolumab has demonstrated efficacy across multiple tumor types including NSCLC and 
melanoma (described below), and other malignancies including renal cell carcinoma, esophageal 
cancer, and others (described in more detail in the IB). Nivolumab is also currently undergoing 
testing in patients with metastatic squamous cell carcinoma of the head and neck in a randomized 
phase 3 trial for which preliminary reports where nivolumab improved survival as compared with 
chemotherapy following progression on a platinum agent were recently presented at the 2016 
AACR Annual Meeting. Other inhibitors of the PD-1 pathway have also demonstrated promising 
response rates in metastatic head and neck cancer patients [28]. 
In subjects with previously treated, unresectable or metastatic NSQ NSCLC (CA209057), 

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nivolumab monotherapy demonstrated superior OS compared with docetaxel, with a clinically 
meaningful and statistically significant improvement observed (HR=0.73 [95.92% CI: 0.59, 0.89]; 
stratified log-rank test p-value = 0.0015). In subjects with previously treated, unresectable or 
metastatic SQ NSCLC (CA209017), nivolumab monotherapy demonstrated superior OS compared 
with docetaxel, with a clinically meaningful and statistically significant improvement observed 
(HR=0.59 [96.85% CI: 0.43, 0.81]); stratified log-rank test p-value = 0.0002). 
Results of secondary endpoints of ORR, DOR, and TTR further support the antitumor activity of 
nivolumab in both SQ and NSQ NSCLC subjects. In CA209057, PFS was not statistically different 
between treatment groups; however, while the median PFS favored docetaxel, the overall HR and 
1-year PFS rate favored nivolumab, indicating the potential for long-term PFS benefit from 
nivolumab in a subset of subjects. In CA209017, nivolumab treatment resulted in a clinically 
meaningful and statistically significant improvement in PFS with a 38% reduction in the risk of 
progression as compared with docetaxel. 
Nivolumab demonstrated superior OS compared with dacarbazine in previously untreated subjects 
with BRAF wild-type advanced (unresectable or metastatic) melanoma, with a clinically 
meaningful and statistically significant improvement observed (HR=0.42 [99.79% CI: 0.25,0.73]; 
p<0.0001). Results of secondary and exploratory endpoints of PFS, ORR, DOR, and TTR further 
support the robust and durable antitumor activity of nivolumab in this population. 
2.1.2
Nivolumab combined with ipilimumab 
2.1.2.1
Preclinical activity and data
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity by activating a more robust anti-tumor immune response compared to 
either agent alone. In vitro combinations of nivolumab plus ipilimumab increase IFN-gamma 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. 
In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased 
the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral T 
regulatory cells, as compared to either agent alone [29]. 
Preclinically, a 4-week toxicity study of nivolumab in combination with ipilimumab conducted in 
cynomolgus monkeys demonstrated that the combination of nivolumab and ipilimumab resulted 
in dose-dependent gastrointestinal (GI) toxicity. Histologic findings included inflammatory 
changes in the large intestine, which increased in incidence and severity in a dose-dependent 
manner. GI toxicity/colitis was not observed in cynomolgus monkeys administered nivolumab 
alone, but was observed in monkeys receiving ipilimumab. Nivolumab in combination with 
ipilimumab was also associated with lymphoid hypocellularity of the cortex and/or medulla of the 
thymus and with acinar cell degranulation in the pancreas. Additional findings included interstitial 
mononuclear cell infiltrates in the kidneys, portal mononuclear cell infiltrates in the liver and 
myeloid hypercellularity in the bone marrow. Nivolumab in combination with ipilimumab at the 
high-dose level (ie, 50 mg/kg and 10 mg/kg, respectively) was associated with the death of 1 

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animal, attributed to acute gastric dilatation without histopathological evidence of colitis upon 
pathology evaluation of the GI tract.
2.1.2.2
Clinical safety of single agent of ipilimumab and pharmacology
Ipilimumab has specificity and a high affinity for human CTLA-4. The calculated dissociation 
constant value from an average of several studies was 5.25 nM. Binding of ipilimumab to purified, 
recombinant human CTLA-4 antigen was also demonstrated by enzyme-linked immunosorbent 
assay with half-maximal binding at15 ng/mL, whereas saturation was observed at approximately 
0.1 µg/mL. No cross-reactivity was observed against human CD28. Ipilimumab completely 
blocked binding of B7.1 and B7.2 to human CTLA-4 at concentrations higher than 6 µg/mL and 
1 µg/mL, respectively. 
Ipilimumab has a terminal half-life of approximately 15.4 days. The expected in vivo degradation 
of monoclonal antibodies is to small peptides and amino acids via biochemical pathways that are 
independent of cytochrome P450 enzymes. The population PK of ipilimumab was studied with 
785 subjects and demonstrated that PK of ipilimumab is linear and exposures are dose proportional 
across the tested dose range of 0.3 to 10 mg/kg, and the model parameters are time invariant. Upon 
repeated dosing of ipilimumab, administered every three weeks, minimal systemic accumulation 
was observed by an accumulation index of 1.5-fold or less and ipilimumab steady-state 
concentrations were achieved by the third dose. The ipilimumab clearance of 16.8 mL/h from 
population PK analysis is consistent with that determined by PK analysis. The terminal half-life 
(T-HALF) and Vss of ipilimumab calculated from the model were 15.4 days, and 7.47 L, which 
are consistent with that determined by non-compartmental analysis (NCA). Volume of central (Vc) 
and peripheral compartment were found to be 4.35 L and 3.28 L, respectively, suggesting that 
ipilimumab first distributes into plasma volume and subsequently into extracellular fluid space. 
Clearance of ipilimumab and Vc were found to increase with increase in body weight. 
Nevertheless, there was no significant increase in exposure with increase in body weight when 
dosed on a mg/kg basis, supporting dosing of ipilimumab based on a weight normalized regimen. 
Additional details are provided in Appendix E and the Investigator Brochure.
Bristol-Myers Squibb (BMS) and Medarex, Inc. (MDX, acquired by BMS in Sep-2009) have co-
sponsored an extensive clinical development program for ipilimumab, encompassing more than 
19,500 subjects (total number of subjects enrolled in ipilimumab studies) in several cancer types 
in completed and ongoing studies, as well as a compassionate use program. The focus of the 
clinical program is in melanoma, prostate cancer, and lung cancer, with advanced melanoma being 
the most comprehensively studied indication. Ipilimumab is being investigated both as 
monotherapy and in combination with other modalities such as chemotherapy, radiation therapy, 
and other immunotherapies. 
Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 
completed Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically 
meaningful and statistically significant survival benefit in pretreated advanced melanoma and 
previously untreated advanced melanoma, respectively. Refer to the IB for additional details. 
While the types of safety events observed in subjects receiving ipilimumab do not appear to 
change, even in combination with other anti-cancer agents, the proportion of subjects experiencing 

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one type or another irAE may be impacted by the choice of combination partner. For example, 
skin and GI irAEs predominate in monotherapy studies. In MDX010-20, the ipilimumab 
monotherapy arm was administered 3 mg/kg ipilimumab every 3 weeks for four doses. In this arm, 
there were 79% drug related adverse events, with 21% being Grade 3/4 and 3/131 (2%) Grade 5. 
The most frequent adverse events of interest were rash (30%), pruritis (33%), diarrhea (33%), 
colitis (8%), endocrine disorders (9%), AST/ALT increased (2%), and hepatitis (1%). Any grade 
immune related adverse events were 60% and the Grade 3/4 immune related adverse events for the 
same cohort was 13% with the most frequent adverse events being diarrhea (5%), colitis (5%), 
rash (2%), and endocrine disorders (3%). Additional details on the safety profile of ipilimumab, 
including results from other clinical studies, are also available in the ipilimumab IB.
Yervoy TM (ipilimumab) has been approved for use in over 47 countries including the United 
States (US, Mar-2011), the European Union (EU, Jul-2011), and Australia (Jul-2011). Of note, 
ipilimumab will be given at a lower dose (1mg/kg) in this trial as compared to many previously 
conducted trials in order to reduce the rates of ipilimumab induced toxicity. 
2.1.2.3
Clinical safety of nivolumab combined with ipilimumab
The safety profile of nivolumab + ipilimumab combination therapy was consistent with the 
mechanisms of action of nivolumab and ipilimumab. A dose of 3 mg/kg nivolumab/3 mg/kg 
ipilimumab exceeded the MTD, and both 1 mg/kg nivolumab/3 mg/kg ipilimumab and 3 mg/kg 
nivolumab/1 mg/kg ipilimumab were identified as the MTD. Of note, this study uses the 3 mg/kg 
nivolumab/1 mg/kg ipilimumab combination, but only a single dose of ipilimumab, as compared 
to at least 4 doses which has generally been used in other studies. 
In a Phase 1 study, CA209004, ascending doses of nivolumab were studied concomitantly with 
ascending doses of ipilimumab in subjects with unresectable or metastatic melanoma. In each arm 
in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses with 
nivolumab administered once every 3 weeks for 8 doses. Starting at week 24, ipilimumab and 
nivolumab were administered once every 12 weeks for 8 doses. The three initial dose-escalation 
cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n = 14), Cohort 2 
(nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 3 mg/kg plus 
ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a which evaluated 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16). The following DLTs were observed in 
Cohort 1 - Grade 3 elevated AST/ALT (1 subject); in Cohort 2 - Grade 3 uveitis (1 subject) and 
Grade 3 elevated AST/ALT (1 subject) and in Cohort 3 - Grade 4 elevated lipase (2 subjects) and 
Grade 3 elevated lipase (1 subject). Based on these data, Cohort 2 was identified as the maximum 
tolerated dose (MTD) and Cohort 3 exceeded the MTD.
Among the 53 patients in the concurrent-regimen group, adverse events of any grade, regardless 
of whether they were attributed to the therapy, were observed in 98% of patients. Treatment-related 
adverse events were observed in 93% of patients, with the most common events being rash (in 
55% of patients), pruritus (in 47%), fatigue (in 38%), and diarrhea (in 34%). Grade 3 or 4 adverse 
events, regardless of attribution, were observed in 72% of patients, and grade 3 or 4 treatment-
related events were noted in 53%, with the most common events being elevated levels of lipase (in 
13% of patients), aspartate aminotransferase (in 13%), and alanine aminotransferase (in 11%). A 
total of 6 of 28 patients (21%) had grade 3 or 4 treatment related events that were dose-limiting. 

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Serious adverse events related to the treatment were reported in 49% of patients in the concurrent 
regimen group. Common grade 3 or 4 selected adverse events that were related to the therapy 
included hepatic events (in 15% of patients), gastrointestinal events (in 9%), and renal events (in 
6%). Isolated cases of pneumonitis and uveitis were observed, a finding that is consistent with 
previous experience with monotherapy. A total of 11 patients (21%) discontinued therapy owing 
to treatment-related adverse events, No drug-related deaths were reported [30].
More recently, the results of a phase 3 trial comparing the combination of nivolumab and 
ipilimumab to either agent alone in metastatic melanoma were reported [31]. Nivolumab was given 
at a dose of 1 mg / kg and ipilimumab was given at a dose of 3mg/kg every three weeks for a total 
a four cycles. After this, nivolumab was continued alone every two weeks. There were 314 patients 
enrolled on the treatment arm combining nivolumab and ipilimumab.  Adverse events of any grade 
occurred in 95.5% of those in this group. The most common adverse events group were diarrhea 
(in 44.1% of patients), fatigue (in 35.1%), and pruritus (in 33.2%). The incidence of treatment-
related adverse events of grade 3 or 4 was also higher in the nivolumab plus-ipilimumab group 
(55.0%) than in the nivolumab group (16.3%) or the ipilimumab group (27.3%). Treatment-related 
adverse events of any grade that led to discontinuation of the study drug occurred in 7.7% of the 
patients in the nivolumab group, 36.4% of those in the nivolumab-plus ipilimumab group, and 
14.8% of those in the ipilimumab group, with the most common events being diarrhea (in 1.9%, 
8.3%, and 4.5%, respectively) and colitis (in 0.6%, 8.3%, and 7.7%, respectively). One death due 
to toxic effects of the study drug was reported in the nivolumab group (neutropenia) and one in 
the ipilimumab group (cardiac arrest), but none were reported in the nivolumab-plus-ipilimumab 
group.
Preliminary experience in lung cancer as part of the Checkmate-012 study has evaluated the 
combination of nivolumab and ipilimumab in patients with advanced non-small cell lung cancer.  
Preliminary data was presented at the 2015 World Conference on Lung Cancer. Four 
administration/dosing schedules for the combination of nivolumab and ipilimumab were explored. 
In arm A, both agents were administered at a dose of 1 mg/kg every 3 weeks (Q3W, N = 31). In 
arm B, nivolumab was administered at 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg 
every 6 weeks (Q6W; N = 40). Arm C and D dosed nivolumab at 3 mg/kg Q2W and ipilimumab 
1 mg/kg every 12 weeks (Q12W; N=38) or Q6W (N = 39). Treatment-emergent grade 3/4 adverse 
AEs occurred in 28% to 35% of patients in each group but led to discontinuation in just 3% to 10% 
of cases. All grade treatment-related AEs occurred in 77%, 73%, 74%, and 69% of patients in 
groups A, B, C, and D, respectively. The safety profile was consistent with previous studies of the 
combination, and the discontinuation rate associated with AEs was similar to rates observed with 
nivolumab alone. The only grade 3/4 adverse events that occurred in as many as 10% of patients 
were hepatic in arm B (10%) and skin-related in arm C and D (13%). Grade 3/4 pulmonary AEs 
occurred in no more than 3% of patients in any of the groups. There were no treatment-related 
deaths in the trial. 
This data suggests that delivering fewer doses of ipilimumab at a lower dose of 1mg/kg will reduce 
the toxicity of this agent combined with nivolumab. This study will use only a single 
administration of ipilimumab at the lower dose of 1mg/kg, in a cohort that will open only after 
nivolumab single agent treatment has been deemed tolerable in this population. 
2.1.2.4
Clinical efficacy of nivolumab combined with ipilimumab

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The combination of nivolumab and ipilimumab has been studied most extensively in melanoma, 
where combination therapy is now FDA approved. 
In the Phase 1 study CA209004, ascending doses of nivolumab were studied concomitantly with 
ascending doses of ipilimumab in subjects with unresectable or metastatic melanoma. In each arm 
of this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses with 
nivolumab administered once every 3 weeks for 8 doses. Starting at week 24, ipilimumab and 
nivolumab were administered once every 12 weeks for 8 doses. The three initial dose-escalation 
cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n=14), Cohort 2 
(nivolumab 1.0 mg/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 3.0 mg/kg plus 
ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a that evaluated 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16). In the concurrent-regimen cohorts, across 
all dose levels, confirmed objective responses according to modified WHO criteria were observed 
in 21 of 52 patients (40%; 95% confidence interval [CI], 27 to 55) who had a response that could 
be evaluated. In addition, 4 patients had an objective response according to immune-related 
response criteria and 2 had an unconfirmed partial response. These patients were not included in 
the calculation of objective response rates.
After noting that several patients had major responses (approaching complete response), a post 
hoc analysis of the number of patients with tumor reduction of 80% or more was conducted. This 
depth of response was uncommon in published studies of checkpoint blockade [32]. A total of 16 
patients had tumor reduction of 80% or more at 12 weeks, including 5 with a complete response. 
In the concurrent-regimen group, overall evidence of clinical activity (conventional, unconfirmed, 
or immune-related response or stable disease for >24 weeks) was observed in 65% of patients 
(95% CI, 51 to 78). Responses were ongoing in 19 of 21 patients who had a response, with the 
duration ranging from 6.1 to 72.1 weeks at the time of data analysis [30].
More recently, the results of a phase 3 trial comparing the combination of nivolumab and 
ipilimumab to either agent alone in metastatic melanoma were reported [31]. Nivolumab was given 
at a dose of 1 mg / kg and ipilimumab was given at a dose of 3mg/kg every three weeks for a total 
a four cycles. After this, nivolumab was continued alone every two weeks. The median 
progression-free survival was 6.9 months (95% confidence interval [CI], 4.3 to 9.5) in the 
nivolumab group, 11.5 months (95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab group, and 
2.9 months (95% CI, 2.8 to 3.4) in the ipilimumab group. Significantly longer progression-free 
survival was observed in the nivolumab plus-ipilimumab group than in the ipilimumab group 
(hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001) and in the 
nivolumab group than in the ipilimumab group (hazard ratio, 0.57; 99.5% CI, 0.43 to 0.76; 
P<0.001). 
The tumor-burden change was assessed as the change from baseline in the sum of the longest 
diameters of the target tumor lesions. The median change was −34.5% (interquartile range, −75.4 
to 15.4) in the nivolumab group, −51.9% (interquartile range, −75.8 to −10.2) in the nivolumab 
plus-ipilimumab group, and 5.9% (interquartile range, −28.0 to 33.3) in the ipilimumab group. 
Preliminary experience in lung cancer as part of the Checkmate-012 study has evaluated the 
combination of nivolumab and ipilimumab in patients with advanced non-small cell lung cancer.  
Preliminary data was presented at the 2015 World Conference on Lung Cancer. Four 

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administration/dosing schedules for the combination of nivolumab and ipilimumab were explored. 
In arm A, both agents were administered at a dose of 1 mg/kg every 3 weeks (Q3W, N = 31). In 
arm B, nivolumab was administered at 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg 
every 6 weeks (Q6W; N = 40). Arm C and D dosed nivolumab at 3 mg/kg Q2W and ipilimumab 
1 mg/kg every 12 weeks (Q12W; N=38) or Q6W (N = 39). All four regimens demonstrated 
activity, with the arms containing nivolumab at 3 mg/kg showing the best objective response rate 
(ORR). In arm C, the ORR was 39% and in arm D the ORR was 31%. The ORRs were 25% and 
13%, in arm B and arm A, respectively. 
2.2
Study Disease
SCCHN is the 6th most common type of cancer with an incidence of approximately 550,000 new 
cases worldwide each year. Approximately two thirds of these patients have non-metastatic 
advanced disease (stage III/IV), and are candidates for curative treatment using either upfront 
chemoradiation or surgery followed by radiation-based therapy. Patients with locally advanced 
SCCHN who are treated non-surgically, receive chemotherapy and radiation therapy. Surgical 
resection is also a common treatment for participants with resectable SCCHN. Postoperative 
radiotherapy (PORT) is the standard of care for most resected stage III/IV with the addition of 
chemotherapy for participants at high risk of recurrence [33]. Yet local-regional recurrence is 
common among such participants.
Locally advanced squamous cell carcinoma of the oral cavity has a particularly poor prognosis, 
with a 5-year survival of approximately 30-50% [34]. Initial management with surgical resection 
is standard, but is associated with significant morbidity and impacts on quality of life[35]. These 
impacts are somewhat dependent on the size of the tumor, with larger tumors requiring removal of 
more tissue and the subsequent use of grafts to maintain functional integrity.  
Preoperative treatment has previously been investigated as treatment for tumors of the oral cavity.  
Licitra et al. evaluated 3 cycles of cisplatin and fluorouracil as compared with proceeding to 
surgery directly in a randomized multicenter trial of 198 patients [36]. Although survival was not 
improved, preoperative therapy may have reduced the number of patients who needed 
manibulectomy or adjuvant radiation therapy. More recently, Zhong et al. randomized 256 patients 
with oral cavity cancer to preoperative chemotherapy with TPF compared with proceeding directly 
to surgery [37]. Induction chemotherapy did not increase the perioperative morbidity and was 
associated with a clinical response rate of 80%; however, there was no benefit in terms of disease-
free or overall survival with extended follow up.  
2.3
Rationale
The rationale of the current study is based on the premise that patients with squamous cell 
carcinoma of the oral cavity fare poorly overall with standard treatments, and thus, new approaches 
are needed to improve outcomes in this disease. 
As described above, immunotherapy represents a promising potential treatment strategy for 
patients with metastatic squamous cell carcinoma of the head and neck, with likely efficacy in the 

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metastatic setting based on several promising preliminary studies [28].  As has been the case in 
other malignancies, head and neck patients who respond to immune checkpoint blockade could 
potentially demonstrate durable responses, even after immune checkpoint blockade treatment is 
stopped [38]. 
Evidence obtained from patients treated with immune checkpoint therapy for non-small cell lung 
cancer suggests that patients who have received fewer previous lines of therapy may derive a 
greater benefit from immune checkpoint blockade then heavily pretreated patients[39]. Thus, it is 
rational to explore the use of immune checkpoint blockade in the upfront setting in treatment naïve 
patients with relatively lower overall burden of disease to potentially obtain a more favorable 
response.  Squamous cell carcinomas of the oral cavity, in particular, are often related to tobacco 
use, and therefore harbor a significant number of mutations that may render them intrinsically 
more sensitive to immune checkpoint blockade. Additionally, a significant number of oral cavity 
tumors may express PD-L1 on the surface of tumor cells [40], which has been suggested as a 
potential predictive biomarker of response to PD-1 inhibiting therapy in SCCHN as well as other 
malignancies. 
As described above, the addition of CTLA-4 blockade to PD-1 blockade with nivolumab has 
demonstrated synergy in preclinical models and is now FDA approved for the treatment of 
metastatic melanoma.  The benefit of combined PD-1 / CTLA-4 inhibition may be particularly 
apparent in patients whose tumors don’t express significant levels of PD-L1 and/or have relatively 
few tumor infiltrating lymphocytes, which would include a significant number of oral cavity 
tumors [40].  The combination of CTLA-4 and PD-1/PD-L1 blockade is actively being pursued in 
a number of malignancies including head and neck cancer, and there is reason to think that the 
combination may improve response rates across a variety of disease types including SCCHN.   
Because of the preliminary activity seen with PD-1 inhibition in SCCHN in the metastatic setting 
and potential for synergistic benefit with combined CTLA-4/PD-1 blockade, a window of 
opportunity study is well-suited to begin to explore these strategies in the upfront setting.  Patients 
typically undergo a relatively brief period of at least several weeks before definitive surgery for 
oral cavity cancer due to a variety of medical and logistic issues; during this period of time they 
are typically not receiving active treatment that could potentially be of benefit, both 
symptomatically as well as in regards to disease-specific and overall survival. Surgery with or 
without adjuvant treatment for oral cavity cancers can be significantly morbid. Therefore, 
treatments that can potentially reduce the burden of disease may be able to decrease the side effects 
associated with these procedures. Finally, a window of opportunity study would allow for 
pathologic confirmation of response seen to nivolumab monotherapy or the combination of 
nivolumab and ipilimumab, helping to guide further evaluation of these agents in this setting.  The 
tissue obtained before and after treatment will also be of great value exploring predictors of 
response and effects of checkpoint blockade on the tumor microenvironment. 
2.4
Correlative Studies Background
There is great interest in identifying tumor markers that may predict response to PD-1 blockade or 
combined blockade of both PD-1 and CTLA-4 receptors.  Based on prior studies conducted in 
patients across several disease types, expression of PD-L1 on tumor cells and tumor infiltrating 

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immune cells could potentially serve as a predictor of response, at least in patients treated with 
PD-1 therapy alone [41, 42].  Tumor infiltrating lymphocytes at baseline and / or mutational burden 
may also serve as a predictive marker in patients treated with either PD-1 or CTLA-4 blockade, 
although this has not yet been demonstrated in head and neck cancer [43-45]. Additionally, it is 
currently unknown whether therapy with either PD-1 or CTLA-4 will impact expression of PD-L1 
or the immunologic composition of the tumor microenvironment. Given the amount of tissue that 
will be available in this window study as per standard of care resection, we will be able to 
investigate these changes and potentially identify mechanisms of resistance to immune checkpoint 
blockade in SCCHN patients, including upregulation of other targetable checkpoint receptors such 
as PD-L2.  Evaluating these changes in patients who don’t respond to PD-1 or combined PD-
1/CTLA-4 therapy will facilitate the design of future combination therapy that seeks to further 
increase the number of responding patients. Additionally, we will attempt to correlate changes in 
the tumor microenvironment with radiologic changes as well as circulating immune biomarkers to 
facilitate non-invasive monitoring of immune responses in future studies. 
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study:
1. Pathologically confirmed squamous cell carcinoma of the oral cavity. Clinical stage >=T2 
(primary tumor greater than 2 cm in size) and/or evidence of regional nodal involvement by 
clinical exam or imaging
2. Only patients 18 years and older are eligible. There is no upper age limit but the patients must 
be able to medically tolerate the regimen. Adverse event data are currently unavailable on 
the use immune checkpoint blockade for participants < 18 years of age, and thus children are 
excluded from this study
3. ECOG performance status <=1 (see Appendix A)
4. Patients much be a surgical candidate (e.g. their disease must be considered resectable before 
any treatment and must have no serious medical contraindications that definitively preclude 
undergoing general anesthesia)
Ability to understand and the willingness to sign a written informed consent document
5. Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of 
contraception (see Appendix B). 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. WOCBP is defined as any woman or 
adolescent who has begun menstruation and is not post- menopausal. A post-menopausal 
woman is defined as a woman who is over the age of 45 and has not had a menstrual period 
for at least 12 months

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6. Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) to be scheduled within 24 hours 
prior to the start of nivolumab
7. Men who are sexually active with WOCBP must agree to use any contraceptive method (see 
Appendix B) with a failure rate of less than 1% per year. Men receiving nivolumab and who 
are sexually active with WOCBP will be instructed to adhere to contraception for a period of 
31 weeks after the last dose of investigational product Women who are not of childbearing 
potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do 
not require contraception)
8. Participants must have normal organ and marrow function as defined below:
Laboratory parameters: WBC ≥ 2000/uL, Absolute neutrophil count (ANC) ≥ 1500/mm3; 
Platelets ≥ 100,000/mm3; Hemoglobin (Hgb) ≥ 9 g/dL; Aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Bilirubin ≤ 2.5 × ULN (≤ 4 
× ULN for subjects with Gilbert’s disease); Alkaline phosphatase ≤ 2.5 × ULN; Creatinine ≤ 1.5 
× ULN
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study.
1. Pathologically proven, radiologic or clinical evidence of distant metastatic disease (this 
includes all disease below the clavicles, as well as disease metastatic to the bone, brain, or in 
the spinal canal) 
2. Any prior immunologic cancer therapy with systemic inhibitors of the PD-1 or CTLA-4 
pathway
3. Uncontrolled intercurrent illness including but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements
4. Individuals with a history of a different malignancy are ineligible except for the following 
circumstances: if they have been disease-free for at least 2 years and are deemed by the 
investigator to be at low risk for recurrence of that malignancy; or if diagnosed and treated 
within the past 2 years for cervical cancer in situ or basal cell or squamous cell carcinoma of 
the skin
5. Prior radiation to the head and neck region 
6. Prior chemotherapy within the last 2 years
7. History of pneumonitis or interstitial lung disease

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8. Has evidence of active, noninfectious pneumonitis that required treatment with steroids.
9.  Active, suspected or prior documented autoimmune disease that has required systemic 
treatment in the last 2 years with immune modifying agents (e.g. replacement therapy such as 
thyroxine, insulin or physiologic corticosteroids is not an exclusion criteria). This does not 
include patients with vitiligo or type 1 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
10. The subject is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, 
or HCV RNA.These tests do not have to be resulted prior to registration if patient is low risk.   
11. Lack of availability for follow up assessments
12. Concurrent administration of other cancer specific therapy during the course of this study is 
not allowed
13. Patients who require systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease
14. History of allergy to study drug components
15. History of severe hypersensitivity reaction to any monoclonal antibody
16. The investigator’s belief that the subject is medically unfit to receive nivolumab, and/or 
ipilimumab or unsuitable for any other reason
17. Has received a live vaccine within 28 days of planned start of study therapy
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations
Women, minorities and other underrepresented populations are all at risk to develop squamous 
cell carcinoma of the oral cavity, with smoking and alcohol use as the critical risk factors for the 
disease. Socioeconomically-deprived populations tend to have higher rates of smoking and 
potentially higher risks of alcohol use, and therefore it is possible this study will be more likely to 
enroll these individuals. However, there is no reason to think that immune checkpoint blockade 
will have a differential effect on these populations. The eligibility criteria should not substantially 
differentially affect their enrollment in the trial, although some minority populations are more 
likely to have certain comorbid conditions such as heart failure, which may preclude them from 
the trial. 
4.
REGISTRATION/ENROLLMENT PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions

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Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration/enrollment, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s registration 
on the study must be canceled. Registration cancellations must be made in OnCore as soon as 
possible. 
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at DF/HCC by the study coordinator. All 
sites should reach the study coordinator to verify the dose level availabilities. The required forms 
can be found in Appendix D. Following registration, participants should begin protocol therapy 
within 7 days. Issues that would cause treatment delays should be discussed with the overall PI. 
If the subject does not receive protocol therapy following registration, the subject must be taken 
off-study in the CTMS (OnCore) with an appropriate date and reason entered.
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating site 
and faxed (617-582-8911) or e-mailed to the study coordinator:

Copy of screening test results, including imaging and pathology results

Signed participant consent form

HIPAA authorization form

Eligibility checklist

Clinic note, covering screening requirements and baseline AEs
The participating site will then call 617-582-8939 or e-mail the study coordinator to verify 
eligibility. The study coordinator will follow DF/HCC policy (SOP #: REGIST-101) and register 
the participant on the protocol. The study coordinator will fax or e-mail the study participant 
number, and the Cohort assignment, to the participating site. 

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5.
TREATMENT PLAN 
5.1
Treatment regimen
Treatment will be administered on an outpatient basis. Expected toxicities and potential risk as 
well as management of these toxicities are described in Appendix D and E. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the participant’s malignancy during the course of treatment.  
The treatment schema is shown below:
The initial window treatment regimen prior to surgery is described below:
Cohort 1: Nivolumab to be delivered at a dose of 3mg/kg two weeks (weeks 1 and 3) 
Cohort 2: Nivolumab to be delivered at a dose of 3mg/kg two weeks (weeks 1 and 3); ipilimumab 
to be delivered at a dose of 1mg/kg once (week 1, same day as nivolumab). 

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5.2
Pre-treatment Criteria
5.2.1
Screening for trial eligibility
Day -21 to Day 1: Screening Visit
Eligibility and exclusion criteria are provided in Section 3.  These criteria will be assessed within 
21 days of the first dose of study treatment (nivolumab +/- ipilimumab) to establish eligibility and 
baseline values.  
Informed consent will be obtained after the study has been fully explained to the subject and before 
the conduct of any screening procedures or assessments.  If screening assessments occur within 3 
days before start of study treatment, then they may serve as the baseline cycle 1 day 1 visit and 
cycle 1 day 1 labs do not need to be performed.
Demographic information and baseline characteristics will be collected at the Screening Visit.  
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance 
with prevailing regulations).  Baseline characteristics will include ECOG PS (Appendix A), 
disease status, medical histories, and prior and concomitant medications. P16 / HPV status will 
also be collected when available. 
Additionally, given the potential difficulty with radiologic measurements in the oral cavity, photo 
documentation of the tumor size along with bidirectional clinical measurements is strongly 
encouraged in all patients. 
Additional testing required, as per Section 3, is:  hematology panel (see Table 1), chemistry panel 
(see Table 1), coagulation panel, urine or serum HCG (in women of childbearing potential; see 
Section 3 for when serum HCG testing is required), TSH (with reflexive Free T4 and Free T3), 
Mg, LDH, amylase, lipase.
Archival tumor sample should be collected (block or if not possible, 20 unstained slides). If 
unavailable, a baseline tumor biopsy is also recommended. 
Table 1: Clinical Laboratory tests.
Category
Tests
Hematology panel

Hematocrit, hemoglobin, platelet count, WBC with 
differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), ANC
Chemistry Panel

Chloride, potassium, sodium, BUN, serum creatinine, 
phosphorus, 
calcium, 
albumin, 
total 
protein, 
alkaline 
phosphatase, ALT, AST, total bilirubin, glucose
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; β-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; WBC = white blood 

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5.2.2
On treatment visits
Reasonable effort should be made to conduct study visits on the day scheduled (+/- 3 days).
Any changes from screening clinical evaluation findings that meet the definition of an AE will be 
recorded on the AE page of the eCRF.
Cycle 1, Day 1 
If screening assessments occur within 3 days before start of study treatment, then they may serve 
as the baseline cycle 1 day 1 visit and screening tests do not need to be repeated.  Pharmacy is 
allowed to follow the DFCI dosing weight practice which is to use the weight from baseline or the 
previous dose if it has not changed more than >/= 5%.≥ 5%.
Draw blood sample for:
-Hematology panel (Table)
-Chemistry panel (Table)
-Mg, LDH, amylase, lipase, LFTs 
Record:
-ECOG PS
-Weight
-Vital signs
-Physical exam
-Concomitant medication use
Review all laboratory results before administering study treatment.
Criteria to treat: 
-WBC ≥ 2000/ul
-ANC ≥ 1500ul 
-Hgb > 9g/dL
-Platelets ≥100,000/ul
-ALT/AST ≤ 3x ULN 
-Total bilirubin ≤ 1.5 ULN (or 3 in a patient with well documented Gilbert’s syndrome 
-Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the 
Cockcroft-Gault formula below):
o Female CrCl = (140 - age in years) x weight in kg x 0.85
                           72 x serum creatinine in mg/dL
o Male CrCl = (140 - age in years) x weight in kg x 1.00 
                         72 x serum creatinine in mg/dL
Every-2-week assessments, day 1 of cycle 2 (within 3 days of treatment): 
Draw blood/collect urine sample for:
cells
 

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-Hematology panel
-Chemistry panel
-Mg, LDH, amylase, lipase, TSH (with reflexive Free T4 and Free T3), LFTs 
Record:
-ECOG PS
-Weight
-Vital signs
-Physical exam
-
Given the potential difficulty with radiologic measurements in the oral cavity, photo 
documentation of the tumor size along with bidirectional clinical measurements is strongly 
encouraged in all patients around the time of cycle 2 treatment 
-Concomitant medication use
-AEs or SAEs
Review all laboratory results before administering study treatment.
Criteria to treat: 
-WBC ≥ 2000/ul
-ANC ≥ 1500ul 
-Hgb > 9g/dL
-Platelets ≥100,000/ul
-ALT/AST ≤ 3x ULN 
-Total bilirubin ≤ 1.5 ULN (or 3 in a patient with well documented Gilbert’s syndrome 
-Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the 
Cockcroft-Gault formula below):
o Female CrCl = (140 - age in years) x weight in kg x 0.85
                           72 x serum creatinine in mg/dL
o Male CrCl = (140 - age in years) x weight in kg x 1.00 
                         72 x serum creatinine in mg/dL
5.2.3
Additional On-Treatment Assessments
Tumor Assessments
Tumor assessments will be performed using volumetric criteria, and RECIST 1.1 (see Section 11).  
Response evaluations will be performed at baseline and then following window treatment. 
Research Blood Sample Collection
Three research blood sample collections should be collected at the following time points:
1. At baseline, within 21 days prior to cycle 1 day 1 of protocol therapy (ideally as close to 
administration of cycle 1 day 1 therapy as possible) 
2. At week 2-4 prior to surgery, and then again following surgery before adjuvant therapy (if 
indicated). 
Specific instructions for research blood draw handling are described in Section 7 and appendices. 

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Tumor biopsy.  
Tumor biopsy should be performed when feasible at baseline, although archival tissue is 
acceptable. 
Further details about collection and handling of tumor biopsy specimens and archival tissue can 
be found in Section 7 and appendices.
5.3
Agent Administration 
5.3.1
Nivolumab 
5.3.1.1
Storage and dispensing
Please refer to the current version of the Investigator Brochure for complete storage, handling, 
dispensing, and infusion information. It is acceptable to prepare and administer nivolumab per 
institutional practice.
5.3.1.2
Dosing
Pharmacy is allowed to follow the DFCI dosing weight practice which is to use the weight from 
baseline or the previous dose if it has not changed more than ≥ 5%. Other investigative sites should 
also follow this practice. All doses should be rounded to the nearest milligram. There are no 
premedications recommended for nivolumab for the first cycle. If an acute reaction is noted, it 
should be managed according to 5.3.1.5. Subjects may be dosed no less than 12 days from the 
previous dose. 
Antiemetic premedications 
Antiemetic premedications should not be routinely administered prior to dosing of nivolumab. See 
5.3.1.9 for premedication recommendations following an infusion related reaction. 
5.3.1.3
Criteria to resume treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade <=1 
or baseline value, with the following exceptions:
-Subjects may resume treatment in the presence of Grade 2 fatigue.
-Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in the 
presence of Grade 2 skin toxicity.
-Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of 
Grade 2 AST/ALT OR total bilirubin. Subjects with combined Grade 2 AST/ALT AND total 
bilirubin values meeting discontinuation parameters (5.3.1.5) should have treatment permanently 
discontinued
-Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed.
-Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement 

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may resume treatment.
If the criteria to resume treatment are met, the subject may receive treatment, as long as they have 
not yet reached week 4 of the protocol calendar.  If week 4 has been reached, the patient should 
proceed with surgery when feasible and medically appropriate.  Any remaining doses of nivolumab 
will not be given.  
5.3.1.4
Discontinuation criteria 
Tumor assessments should continue as per protocol even if study drug is discontinued. 
Treatment should be permanently discontinued for the following: 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment. 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions 
for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, hypersensitivity reactions, and infusion reactions: 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation. 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation: 
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:
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.
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.

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Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
5.3.1.5
Treatment of infusion reactions 
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, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE (version 4.0) guidelines. 
Treatment recommendations are provided below and may be modified based on exact clinical 
circumstances as appropriate. 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated). Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or 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. 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; presser or ventilator support 
indicated).

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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. The patient should be 
treated for therapy induced 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).
5.3.2
Ipilimumab 
5.3.2.1
Storage and dispensing
Please refer to the current version of the Investigator Brochure for complete storage, handling, 
dispensing, and infusion information. It is acceptable to prepare and administer ipilimumab per 
institutional practice.
5.3.2.2
Dosing
Pharmacy is allowed to follow the DFCI dosing weight practice which is to use the weight from 
baseline or the previous dose if it has not changed more than ≥ 5%. Other investigative sites should 
also follow this practice. All doses should be rounded to the nearest milligram. There are no 
premedications recommended for ipilimumab. If an acute reaction is noted, it should be managed 
according to 5.3.2.6. 
5.3.2.3
Antiemetic premedications 
Antiemetic premedications should not be routinely administered prior to dosing of ipilimumab. 
See 5.3.2.9 for premedication recommendations following an infusion related reaction. 
5.3.2.4
Criteria to resume treatment 
N/A as only a single dose of ipilimumab is administered in this trial. 
5.3.2.5
Treatment of infusion reactions 
Since ipilimumab 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, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE (version 4.0) guidelines. 

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Treatment recommendations are provided below and may be modified based on exact clinical 
circumstances as appropriate. 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated). Remain at bedside and monitor subject until recovery from symptoms. 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 ipilimumab 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 ipilimumab 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. 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 ipilimumab 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; presser or ventilator support 
indicated).
Immediately discontinue infusion of ipilimumab. 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. Ipilimumab 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). 
5.3.3
Standard of care treatment following window treatment with nivolumab with or 
without ipilimumab
5.3.3.1
Surgery
Surgery will be scheduled following restaging imaging either during week 3 or week 4 of treatment 
(no sooner than 72 hrs and no longer than 7 days following administration of the 2nd cycle of  

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nivolumab when tolerated).  The exact surgical procedure and perioperative care is at the discretion 
of the treating surgeon as per standard of care, but should in general include resection of the 
primary lesion and an ipsilateral or bilateral neck dissection with or without a reconstruction or 
graft.  
As evidenced by patients with melanoma treated with checkpoint blockade, patients who derive 
clinical benefit from these agents may, in some cases, experience a transient tumor “flare” prior to 
a prolonged systemic response.  It is unknown whether this will occur in patients treated on this 
trial. Since this transient flare could potentially be indicative of an anti-tumor immune response, 
investigators are encouraged to proceed with treatment as per protocol; however, if there is 
symptomatic progression with significantly increased pain, airway compromise, or any other 
symptoms or exam findings deemed concerning by the treating physician then the patient may 
proceed to surgery early. As long as the patient has received experimental treatment he/she will be 
monitored and considered similar to other patients enrolled in this protocol. 
5.3.3.2
Adjuvant treatment
The need for adjuvant treatment will be determined by the treating physicians based on the initial 
clinical staging in conjunction with pathology at the time of surgery and the patient’s performance 
status and medical comorbidities. If indicated, adjuvant treatment (radiotherapy with or without 
concurrent chemotherapy) will begin approximately 5-8 weeks following surgery as per standard 
of care.  
5.4
Definition of Dose-Limiting Toxicity
Nivolumab, ipilimumab, and the combination of these two agents have been evaluated in prior 
phase I protocols and are being evaluated specifically in patients with SCCHN.  However, although 
this is not a phase I protocol, the use of these drugs and the combination in the preoperative setting 
is relatively novel, and therefore we plan to include a safety-run-in to ensure that treatment is well 
tolerated in this setting.  A separate safety run in will be performed for each cohort. As described 
in detail Section 14, the safety run-in will first be performed in the nivolumab single agent cohort, 
using the definitions and window period defined in this section. Once the safety run in has 
completed successfully with single agent nivolumab, patients will be enrolled to the 
nivolumab/ipilimumab cohort safety run-in.   
The DLT window for this study will be the period between the first treatment and the time of 
surgery.  We will also closely monitor toxicities in the post operative period and during adjuvant 
treatment; however, given the significant variability in surgical procedure and adjuvant treatment 
and significant toxicities associated with this when administered as SOC, these will not be 
considered DLTs. Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE Version 4.0). A DLT will be defined 
as follows:
A patient in either cohort that is medically unable to undergo planned surgery because of toxicities 
deemed to be the result of experimental treatment or where surgery is delayed by >1 month beyond 
the originally scheduled date. 

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Other DLTs will be graded according to the National Cancer Institute’s CTCAE version 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf ). A 
DLT is any event that: a) occurs during the DLT evaluation period; and b) is possibly, probably, 
or definitely related to the administration of nivolumab and/or ipilimumab; and c) fulfills any of 
the following criteria:
1. Any Grade ≥ 3 pneumonitis, neurological event or uveitis.
2. Any Grade 2 pneumonitis, neurological event or uveitis, with the following exception:
Grade 2 pneumonitis, neurological event or uveitis that downgrade to Grade ≤ 1 within 3 days 
after onset, whereby maximal supportive care, including systemic corticosteroids, is permitted.
3. Any other Grade ≥ 3 toxicity, with the following exceptions:
Grade 3 irAEs that downgrade to Grade ≤ 2 within 3 days, or to Grade ≤ 1 or baseline within 
14 days after onset, whereby maximal supportive care, including systemic corticosteroids, is 
permitted. 
Grade 3 colitis that downgrades to Grade ≤ 2 within 7 days after onset, whereby maximal 
supportive care, including systemic corticosteroids, is permitted. 
Grade 3 asymptomatic endocrinopathy, managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy.
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.).
Grade 3 fatigue for ≤ 7days.
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) 
that resolves within 6 hours with appropriate clinical management.
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times ULN) 
within 7 days after onset, whereby maximal supportive care, including systemic corticosteroids, is 
permitted.
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 days 
after onset, whereby maximal supportive care, including systemic corticosteroids, is permitted.
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) does not 
require medical intervention, and (3) improves to Grade 2 within 7 days.
Grade 3 and 4 lymphopenia.
Grade 3 thrombocytopenia that (1) is not associated with clinically significant bleeding, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days.

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Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days.
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but where the increment 
of deterioration is considered not clinically significant by both investigator and sponsor.
Immune-related AEs (irAEs) are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a DLT.
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as a DLT after consultation with the sponsor and Investigators, based 
on the emerging safety profiles of nivolumab and ipilimumab.  Likewise, subjects who become 
not evaluable for DLT because they discontinued or interrupted treatment due to toxicities other 
than DLTs may be counted as DLT subjects. 
5.5
General Concomitant Medication and Supportive Care Guidelines
The treating physicians may deliver supportive care as indicated or as specified above in section 
5.2, 5.3 and the IB. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician. 
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 28 days before the first dose of study treatment 
should be recorded.  Relevant concomitant medications administered after the last dose of trial 
treatment should be recorded for SAEs as specified in Section 11.1.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial:
Antineoplastic systemic chemotherapy or biological therapy 
Immunotherapy not specified in this protocol

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Investigational agents other than nivolumab with or without ipilimumab 
Any systemically active oral, injected, or implanted hormonal method of contraception except 
for progesterone coated intrauterine devices (IUDs) that had been previously implanted. 
Live vaccines within 28 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Systemic glucocorticoids for any purpose other than to modulate symptoms from radiation or 
an event of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
The following treatments are permitted throughout the duration of the study treatment phase and 
during follow-up:
Standard therapies for pre-existing medical conditions unless listed as prohibited therapy 
below. Any medication intended solely for supportive care (e.g., analgesics, anti-diarrheal, anti-
depressants) may be used at the investigator’s discretion.  Antiemetics and anti-diarrheal 
medications should not be administered prophylactically before initial treatment with study drugs.  
At the discretion of the investigator, prophylactic antiemetic and anti-diarrheal medication(s) may 
be used as per standard clinical practice before subsequent doses of study drugs or before, during 
or after radiation treatment.
Anticoagulants - Anticoagulation with heparin, heparin derivatives, and/or warfarin may be 
given at the discretion of the treating physician. Coagulation parameters should be checked at least 
once monthly, or more frequently at discretion of treating physician. 
Pain medications administered per standard clinical practice are acceptable while the patient is 
enrolled in the study.
Patients who experience toxicities should be treated symptomatically as clinically indicated.  
Medications that are considered necessary for the subject’s welfare and that are not expected to 
interfere with the evaluation of study treatment or be restricted may be given at the discretion of 
the investigator.  Ancillary treatments will be given as medically indicated.
5.6
Duration of Therapy
In the absence of DLTs study treatment is expected to continue until the second dose of 
nivolumab is administered.  At that time, all subsequent cancer treatment will be administered 
as per standard of care. 

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5.7
Criteria for Taking a Participant Off Protocol Therapy
Participants should also be removed from protocol therapy if any of the following occurs:

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply 

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Intercurrent illness that prevents further administration of treatment and/or would affect 
the assessment of the subject’s clinical status to a significant degree

Pregnancy
Participants will be removed from the protocol therapy when any of these criteria apply. The reason 
for removal from protocol therapy, and the date the participant was removed, must be documented 
in the case report form (CRF). Alternative care options will be discussed with the participant.
Information will be entered in OnCore when a participant is removed from protocol therapy. 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Jonathan Schoenfeld, MD, MPH at 617-632-
3591 or at Partners pager 18874.
5.8
Duration of Follow Up 
5.8.1
The patient will be followed at least every other week during the window phase of 
this trial (weeks 1-4)
5.8.2
First restaging will be performed after window treatment and prior to surgery (week 
3 or week 4) 
5.8.3
Following surgery on week 3 or 4, patients will be followed as per standard of care. 
This may include radiation with or without concomitant chemotherapy at the discretion of the 
treating physicians.  As per standard of care, patients will have restaging exam and scans between 
10 and 16 weeks following the completion of all cancer directed therapy or earlier if clinically 
indicated. The scans at the 3 month follow up time point are optional, but highly encouraged.
 
5.9
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).

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The research team will update the relevant Off Treatment/Off Study information in OnCore. 
6.
DOSING DELAYS/DOSE MODIFICATIONS
Toxicity assessments will be done using the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE version 4.0) which is identified and located on 
the 
CTEP 
website 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit 1 year after enrollment. 
Participants continuing to experience toxicity at the last scheduled study visit may be kept on the 
study until the toxicity has resolved or is deemed irreversible.
6.1
Anticipated Toxicities
 
Adverse events (both non-serious and serious) associated with nivolumab with or without 
ipilimumab exposure may represent an immunologic etiology.  These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment.  Most related AEs are 
thought to be due to the effects of inflammatory cells on specific tissues. Please refer to Appendix 
D and E and the current versions of Investigator’s Brochures for expected toxicities related to 
nivolumab and ipilimumab.
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.
6.2
Toxicity Management
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of adverse 
events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological. 
(Please see Appendix C).
Early recognition and intervention are recommended according to the management algorithms; 
and in addition include ophthalmologic evaluations for any visual symptoms in order to evaluate 
for nivolumab or ipilimumab related uveitis.

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The recommendations are to follow the algorithms in the nivolumab investigator brochure for 
immune related events; while the ipilimumab investigator brochure contains similar algorithms, 
the algorithms in the nivolumab brochure have been aligned to accommodate combinations as well 
as nivolumab monotherapy.  
For subjects expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following recommendations 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections.
Early consultation with an infectious disease specialist should be considered. Depending on the 
presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for 
endoscopy may also be appropriate.
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis.
Additional details on the safety of nivolumab and ipilimumab, including results from clinical 
studies, are available in the Appendix D and E and the IB.
6.2.1.1
Management algorithms for nivolumab (Please see Appendix C) 
Immuno-Oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 
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 
adverse events: Gastrointestinal, renal, pulmonary, hepatic, endocrinopathies, skin, neurological. 
The algorithms recommended for utilization in this protocol are found in the Investigator 
Brochure. 
For subjects expected to require more than 4 weeks of corticosteroids or other
immunosuppressants to manage an adverse event, consider recommendations provided in the IB.
Because of the potential for clinically meaningful nivolumab related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
pulmonary toxicity, GI, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity and 
nephrotoxicity.
6.2.1.2
Management algorithms for ipilimumab (Please see Appendix C)
Immuno-Oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Ipilimumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 

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38
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 
adverse events: Gastrointestinal, renal, pulmonary, hepatic, endocrinopathies, skin, neurological. 
The algorithms recommended for utilization in this protocol are found in the Investigator 
Brochure. 
For subjects expected to require more than 4 weeks of corticosteroids or other
immunosuppressants to manage an adverse event, consider recommendations provided in  the IB.
Because of the potential for clinically meaningful ipilimumab related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
pulmonary toxicity, GI, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity and 
nephrotoxicity.
6.3
Dose Modifications/Delays
Dose modifications to nivolumab and ipilimumab are not permitted in this study.  
6.3.1
Delays in nivolumab administration 
Study drug administration should be delayed for the following:
-Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: Grade 2 drug-
related fatigue or laboratory abnormalities do not require a treatment delay. 
-Any Grade 3 skin, drug-related adverse event.
-Any Grade 3 drug-related laboratory abnormality, with the following exceptions: Grade 3 
amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations 
of pancreatitis do not require a dose delay. 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing 
for drug-related Grade ≥  2 toxicity
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay 
dosing for drug-related Grade ≥ 3 toxicity
-Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Note: If any treatment delay would extend the second cycle beyond the planned surgical date, it is 
suggested that the second cycle be held and the patient proceed to surgery as scheduled or as soon 
as medically indicated.   
7.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 

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Biopsy confirmed squamous cell carcinoma is a requirement to be enrolled on this study.  Tissue will 
be obtained prior to any treatment for research purposes whenever possible.  If diagnostic biopsy was 
performed prior to enrollment on study (archival sample) and extra specimen is available from this 
biopsy, then this tissue may be obtained for use.  A separate research biopsy is also strongly 
recommended – this can be a core biopsy of a lymph node or an in office biopsy. At the time of 
definitive surgical resection, after adequate tumor for pathological assessment has been harvested as 
deemed by the surgeon, remaining tissue will also be obtained for research purposes. If relevant, tissue 
may also be obtained at the time of first recurrence after surgery for study. 
Biopsies/surgery should not generally be performed on Friday afternoons, as there may not be time 
for processing of tissue. However, specimens in formalin may be stored over the weekend and 
transported on Monday. Specimens in formalin should be stored at room temperature until 
shipment. Other investigative sites should follow institutional procedures for collecting and 
processing biopsy specimens.
When archival tissue is used for the pretreatment tissue specimen, formalin-fixed paraffin 
embedded block(s) and or unstained/unbaked slides (15-20 recommended, although fewer are 
acceptable), stored at room temperature and tissue scrolls should be obtained to facilitate 
correlative analyses.
In the case of fresh biopsies / surgical specimens, ideally at least 2-4 core biopsies / pieces of tumor 
tissue will be obtained:
Half of the cores / specimens should be placed in 10% neutral buffered formalin tube.
Half of the cores / specimens should be processed fresh for molecular analyses in media, snap 
frozen or frozen in RNAlater. 
After being obtained, processing of the specimens is as follows:
All samples should be de-identified and labeled with the Participant initials, Participant Study 
ID number, anatomical location from which tissue was obtained (e.g. lymph node, primary oral 
cavity tumor) and date of procedure.
Specimens in formalin should be should be transferred to a pathology laboratory, placed in 
fixative at a 10:1 ratio and fixed for at least 24-48 hours. Thicker tissue samples may require longer 
fixation to create a formalin-fixed, paraffin embedded block. 
Specimens to be processed immediately for molecular analyses should be transferred to the lab 
of Ravindra Uppaluri, MD PhD or Kai Wucherpfennig PhD with 1.5 hours of collection.  
Snap frozen or specimens in RNA later should frozen in liquid nitrogen and then stored at -70 
to -80. 
Slides / tissue blocks will then be sent to / collected by: 
Shana Criscitiello | Clinical Research Coordinator
Department of Radiation Oncology
Brigham and Women’s Hospital/Dana-Farber Cancer Institute
E-mail: scriscitiello@bwh.harvard.edu
Phone: (617) 582-8919

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Fax: (617) 582-8911
Pager: BWH 33150 
Location: Dana L1, Room 51
If slides / blocks are shipped, a specimen inventory including the Participant initials, Participant 
Study ID number, anatomical location from which tissue was obtained (e.g. lymph node, primary 
oral cavity tumor) and date of procedure should be included with all samples and also emailed to 
scriscitiello@bwh.harvard.edu with shipment tracking number.  Site specific shipping policies 
should be observed to ensure safe handling, travel and arrival. 
  
Frozen / RNAlater samples can be batched and shipped overnight on dry ice to  the lab of Mariano 
Severgnini at: 
Center for Immuno-Oncology
Dana-Farber Cancer Institute
450 Brookline Ave, JF0406
Boston, MA 02215
Phone: (617) 632-2421
DFCI pager: 617-632-3352 pager: 42093
Email: mariano_severgnini@dfci.harvard.edu
If frozen specimens are shipped, a specimen inventory including the Participant initials, Participant 
Study ID number, anatomical location from which tissue was obtained (e.g. lymph node, primary 
oral cavity tumor) and date of procedure should be included with all samples and also emailed to 
mariano_severgnini@dfci.harvard.edu with shipment tracking number.  Site specific shipping 
policies should be observed to ensure safe handling, travel and arrival. 
We will perform comprehensive immune profiling on all tissue obtained in the context of this trials as 
allowed by the amount of tissue obtained.  The purpose of these analyses will be to analyze the 
expression select biomarkers (PD-L1, PD-L2, PD1, CD3, CD68, CD8, Ki67) and to determine the p16 
status from samples collected from patients with oral cavity cancer treated with nivolumab with or 
without ipilimumab and analyze the effect of treatment on these parameters. These analyses will 
include, H&E stain, immunohistochemistry and multiplex immunofluorescence to evaluate 
multiple biomarkers in tandem. 
Additional tissue, if available, will be used to stain for additional markers including other checkpoint 
ligands and receptors, RNA analyses including RNA profiling, whole exome sequencing to determine 
mutational burden and neoantigen detection, T-cell receptor sequencing to determine intratumoral 
TCR diversity (in conjunction with Adaptive Biotechnology) mouse xenograft studies, and flow 
cytometry to quantify immune populations. De-identified specimens be processed and analyzed by 
outside facilities as appropriate to perform these analyses.
Peripheral blood samples will be collected for use in studies by the study team and Adaptive 
Biotechnology to investigate immune functioning and anti-tumor immunity before and after window 

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treatment and then again after surgery and before adjuvant treatment, if indicated.  The volume of 
blood to be collected per blood draw for study purposes will not exceed 40 cc.  
Each sample obtained will be assigned a unique coded identifier in order to preserve the 
confidentiality of the participant. The coded samples will be linkable to the participant, but the key 
that links that person to the unique identifier will be stored in a database housed on a server at the 
DFCI. Access to participant identity will be provided only to the principal investigator and study 
staff (not lab staff). There are multiple firewalls and passwords protecting the data from unwanted 
viewers. Patient privacy will be maintained by strictly curtailing access to the electronic file via 
passwords and firewalls. The coded samples will be cryopreserved and stored in secure locked 
freezers. Once all research is complete, the link between the coded samples and patient identifiers 
will be destroyed.
Research blood samples will be drawn in phlebotomy and will be captured in three 8-cc whole 
blood or EDTA tubes, and 1 red top tubes.
Blood samples will be processed by the lab of Kai Wucherpfennig PhD, the Center for Immuno 
Oncology laboratory at the Dana-Farber Cancer Institute, or at other investigative sites. Two 
components will be stored from the tubes: serum/plasma and mononuclear cells. Each red tube 
should yield about 3 cc of serum. Blood for serum will be spun (3000 g x 10 minutes at 4C) within 
5 hours of collection and serum removed by pipetting. Serum will be maintained in 1-cc aliquots 
in vials at -80C. Isolation of mononuclear cells and plasma will be collected from whole blood 
tubes after centrifugation at 1500 RCF for 20 minutes or by using similar standard institutional 
protocols. Plasma will be removed by pipetting and maintained in 1-cc aliquots in vials at -80C. 
Mononuclear cells will be pipetted into a 15 mL centrifuge tube and washed twice with PBS, 
spinning the cells at 300 RCF and aspirating the PBS in between each wash. The resulting cell 
pellet will be resuspended in 10% DMSO-containing media and stored in cryovials at -80C.  
Sites other than the DFCI may either process PBMCs on site, following standard protocols and 
ship frozen pellets and plasma separately (preferred method) or immediately express ship 
unprocessed vacutainer tubes using an overnight courier, ex. Fed Ex. The integrity of the blood 
samples requires they be processed within 24 hours of collection.
Shipping information from sites other than DFCI: 
-
Unprocessed tubes must be shipped on the day of collection. Samples are to be 
shipped overnight Mon-Thurs ONLY, at ambient temperature by overnight 
carrier such as FedEx or UPS
-
Processed samples – it is suggested to batch ship these samples at a time agreed 
by the collection site and DFCI. 
o
Plasma/ Serum: Ship overnight, Monday-Thursday ONLY, using a 
styrofoam box containing dry ice, using appropriate labels, following 
all safety/shipping regulations. Shipments must be made by an 
overnight carrier, such as FedEx or UPS.
o
PBMCs: ship overnight, Monday-Thursday ONLY, using cryotanks 
containing liquid nitrogen, using appropriate labels, following all 
safety/shipping regulations. Shipments must be made by an overnight 
carrier, such as FedEx or UPS.  Cryotanks have temperature monitors 

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connected to an alarm system at Cryoport headquarters.  Shipping 
temperature should be around -150C. 
Cryoport, Inc
17305DaimlerSt.
Irvine, CA 92614 
 +1 949.470.2300
cs@cryoport.com
All blood samples will be shipped to the lab of Mariano Severgnini at: 
Center for Immuno-Oncology
Dana-Farber Cancer Institute
450 Brookline Ave, JF0406
Boston, MA 02215
Phone: (617) 632-2421
DFCI pager: 617-632-3352 pager: 42093
Email: mariano_severgnini@dfci.harvard.edu
When specimens are shipped, a specimen inventory including the Participant initials, Participant 
Study ID number, and date of collection should be included with all samples and also emailed to 
mariano_severgnini@dfci.harvard.edu with shipment tracking number.  Site specific shipping 
policies should also be observed to ensure safe handling, travel and arrival. 
Once collected, samples will be coded to maintain patient confidentiality and then transferred to 
the center for Immuno Oncology at the DFCI for use in studies of immune functioning. 
Studies of immune function performed on blood will include: 
-Analysis of antibody response (both quantitative antibody titer and qualitative antibody binding 
and functionality)
-Study of T-cell composition and functioning
-Analysis of cytokine response
-Identification of circulating antigen, DNA or tumor cells 
-Comparison of immune responsiveness in serum
-Analysis of blood cell composition using flow cytometry
-Effect of immune status on circulating tumor cells 
-Analysis of genomic or protein polymorphisms that may affect immune functioning and 
inflammation 
-Analysis of inflammatory status in correlation to toxicity response 
-Analysis of intracellular signaling pathways
Blood will be collected according to standard clinical protocol. Blood samples will only be 
requested during a regularly scheduled clinic visit, and no more than 40 cc will be collected during 
a single visit, and no more than 80 ml in a four-week period.  Patient identifiers will be removed 
from patient samples, and each sample will be given a unique identifier.  Discarded samples will 
be completely de-identified, and all samples will be de-identified at the end of the study.  Samples 
should be stored in a locked freezer.  

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Standard imaging (CT neck and/or PET/CT or CT chest) will be performed before and after 
window treatment. Although not required – a before and after PET/CT is strongly encouraged in 
all patients. In addition to monitoring response and correlating with pathologic response, we will 
analyze various radiologic parameters [46] to correlate with pathologic response, outcome as well 
as immunologic parameters such as degree of lymphocyte infiltration.  
8.
 PHARMACEUTICAL INFORMATION
 
Drug Ordering
Free of cost, investigational supply of nivolumab and ipilimumab will be provided by Bristol-
Myers Squibb.  
Product information
PRODUCT INFORMATION TABLE 2: Please also see respective Product Investigator Brochures
Product Description
Product 
Description and 
Dosage Form
Potency
Primary 
Packagin
g
(Volume)/ 
Label 
Type
Secondary 
Packaging
(Qty) /Label 
Type
Appearance
Storage Conditions
(per label)
Nivolumab BMS-
936558-01 
Solution for 
Injection*
100 mg (10 
mg/mL)
10 mL 
vial
5-10 vials per 
carton/ Open-
label
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2 to 8°C. Protect 
form light and 
freezing
Ipilimumab 
Solution for 
Injection
200 mg (5 
mg/mL)
40 mL 
vial
4 vials per 
carton/Open-
label
Clear, colorless to 
pale yellow liquid. 
May contain 
particles
2 to 8°C. Protect 
from light and 
freezing.
*Nivolumab may be labeled as BMS-936558-01 Solution for Injection
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab and ipilimumab include laboratory coats and 
gloves.
For additional details on prepared drug storage and use time of nivolumab or ipilimumab under 
room temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) and 
Ipilimumab Investigator Brochure section for “Recommended Storage and Use Conditions” 
Dose calculations and administration
The first dose of nivolumab with or without ipilimumab will be administered week 1 of the study 
treatment. Preparation and administration details are described in the investigational brochure. 
Nivolumab and ipilimumab will be given together week 1 for subjects enrolled in cohort 2. 

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Nivolumab dose = 3 mg/kg
Ipilimumab dose = 1 mg/kg
When study drugs (ipilimumab or nivolumab) are to be administered on the same day, separate 
infusion bags and filters must be used for each infusion. It is recommended that nivolumab be 
administered first. The second infusion will always be ipilimumab, and will start approximately 
30 minutes after completion of the nivolumab infusion.
BMS-936558 (nivolumab) is to be administered as a 60 (+/- 15) minute IV infusion. Ipilimumab 
should be administered as a 90 (+/- 15) minute IV infusion following.
Ipilimumab and nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. 
Pharmacy is allowed to follow the DFCI dosing weight practice which is to use the weight from 
baseline or the previous dose if it has not changed more than ≥ 5%. All doses should be rounded 
up or to the nearest milligram per institutional standard. 
Cohort 1 patients will receive a total of two nivolumab doses (Week 1 and 3). Cohort 2 patients 
will receive a total of two nivolumab doses (Week 1 and 3) and one ipilimumab dose (Week 1). 
Following the first dose of nivolumab with or without  ipilimumab, nivolumab will be given on 
week 3 at a dose of 3mg/kg. Patients may not be dosed with nivolumab less than 12 days apart; 
and may be dosed up to 3 days after the scheduled date, if necessary.
Dose Modifications
There will be no dose modifications permitted. Dose reductions or dose escalations are not 
permitted.
9.
STUDY CALENDAR
Baseline evaluations are to be conducted within 3 weeks prior to start of protocol therapy 
(except for pregnancy test and baseline tumor biopsy, as detailed). If these screening assessments 
occur within 3 days before start of study treatment, then they may serve as the baseline cycle 1 day 
1 values. Each treatment cycle will be 14 days long. Subjects may be dosed no less than 12 days 
between doses. 
As detailed in the Study Calendar, a negative pregnancy test in women of child-bearing potential 
must be documented within 24 hours before the first dose of study medication.
Correlative tissue collection obtained before starting protocol therapy, should be performed if 
archival tissue is not available.
In the event that the participant’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy.

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Assessments must be performed prior to administration of any study agent. Study assessments and 
agents should be administered within + 3 days of the protocol-specified date, unless otherwise 
noted.
Scans must be done <4 weeks prior to the registration. 

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Screeni
ng
Wee
k 1
Wee
k 3
Presurgery/surg
ery (week 3-4)
Wee
k 
10-
20
3 
months 
after all 
treatme
nt
3 
mont
hs to 
1 
yearl
1 
year 
visit
l
Surviv
al 
follow 
up by 
phone
m
Informed 
consent
X
Medical 
History
X
Physical exam 
(Ht, Wt, VS, 
PS) a
X
X
X
Xi
Xi
X
i
B-HCG b
X
Routine labs, d
X
X c
X
X
Xi
Screening 
labs/ECG e
X
Adverse event 
evaluation f
X
X
X
Xi
Xi
Radiologic 
evaluation g
X
X
Correlative 
blood 
collection h
X
X
X 
X
X
Correlative 
tissue 
collection
Xj
X k
Study Agent -
Nivolumab
X
X
Study Agent - 
Ipilimumab(co
hort 2 only)
X
a.
Height is taken only at screening. 
b.
Serum or urine pregnancy test (women of childbearing potential), within 24 hours of the first 
dose of nivolumab.
c.
Not needed if pre-study labs performed within 3 days of Day 1. 
d.
CBC with differential, comprehensive chemistry panel including LDH, AST, ALT, ALP, 
T.Bili, BUN or serum urea, Cre, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, phosphorus, 
albumin, and total protein as well as TSH, Free T4, and Free T3.
e.
Routine labs as per D, and also HBVsAg, HCV Ab or HCV RNA. EKG is required only at 
screening and as clinically indicated. If patient is not high risk, negative tests results don’t need 
to be resulted for study enrollment.
f.
In addition to specified time points, adverse effects will also be continuously monitored. 

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g.
Imaging will include CT neck/chest and/or PET-CT. MRI neck may be performed instead of 
CT neck. 
h.
Correlative blood collections will be timed to coincide with blood drawn for other reasons, but 
will in general be scheduled at baseline, week 3-4 and then after surgery and before adjuvant 
treatment (week 10-20), if indicated. Additional optional research blood draws may be taken 
during routine follow up to year 3. 
i.
Not performed if patient receiving care at outside institution.  All efforts will be made to obtain 
outside medical records. 
j.
Archival tissue may be used. 
k.
Obtained at the time of surgery (week 3-4).  
l.
Visits will occur approximately every 2-3 months over the first year. Medical records from 
local evaluations may be provided if patient is unable to follow up at study site. 
m. 1 year after enrollment (+/-2 weeks), patients will be restaged with a clinical exam, CT 
neck/chest and/or PET-CT as per standard of care. This is optional, but highly encouraged. 
Medical records from local evaluations may be provided if patient is unable to follow up at 
study site.
n.
After the 1 year visit, follow up for survival will continue by phone. Patients will be contacted 
by phone, every 3 +/- 1 month, for up to 3 years from enrollment.

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10. MEASUREMENT OF EFFECT 
The main focus of this trial is to determine safety and response in the window period where 
the two investigational agents will be investigated. Thus patients will be examined and staged 
as part of the screening process and then again following window treatment prior to surgery.  
Pathologic evaluation will also be performed at the time of surgery.  Following surgery (and 
adjuvant therapy, if indicated), follow up will be as per standard of care, with an emphasis on 
monitoring of disease-free and overall survival. 
10.1 Antitumor Effect– Solid Tumors
For the purposes of this study, participants should be re-evaluated for response at week 3-4 
following window treatment and prior to definitive surgery.
There is currently some uncertainty about how best to monitor response to immunotherapy [47], 
as well as how best to monitor response in the preoperative window setting [48, 49]. 
Additionally, assessing radiologic response in the oral cavity can be complicated by dental 
artifact and head position. Therefore, response will be assessed in multiple ways using clinical, 
radiologic and pathologic data. Thus, although our primary endpoint will utilize volumetric 
measurements (obtained either radiologically, clinically or pathologically) that have been 
previously investigated in this setting [48], international RECIST criteria will also be measured 
as a secondary endpoint. Changes in the diameter (unidimensional axial measurement) of the 
tumor lesions are used in the RECIST criteria. We will also evaluate pathologic response 
defined below. 
10.1.1
Definitions
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment.
Evaluable for objective response. Only those participants who have measurable disease present at 
baseline (either by clinical exam or imaging), have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. These participants 
will have their response classified according to the definitions stated below. (Note: Participants 
who exhibit objective disease progression or die prior to the end of treatment will also be 
considered evaluable.)
10.1.2
Disease Parameters
Measurable disease. Measurable disease is the presence of at least one lesion that can 
be accurately measured in at least one dimension with longest diameter >20 millimeters (mm) 
using conventional techniques (CT, MRI, x-ray, PET-CT or clinical exam) or  >10 mm with 
spiral CT scan. Measurable lesions must be at least 2 times the slice thickness in mm. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).  In the oral 
cavity, imaging modalities may be obscured by dental artifact, or normal mucosa; therefore, 
clinical exam or pathologic measurements may suffice. 

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Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease.
Target lesions. All measurable lesions up to a maximum of 10 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as the reference by which to characterize the RECIST objective tumor 
response.  Volumetric measurements may also be made using imaging software using contouring 
software or by obtaining measurements in at least 2 dimensions or by multidimensional 
measurements obtained from clinical exam. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and 
above the 10 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence of each 
should be noted at each follow-up. 
10.1.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment.
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial or 
mucosal (e.g., skin nodules, oral cavity primaries and palpable lymph nodes). In these cases, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously. 
10.1.4
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans 
should follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response (L.K. 
Shankar, J.M. Hoffman, S. Bacharach, M.M., et al. Consensus recommendations for the use of 18F-
FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J 
Nucl Med, 47(6):901-903, 2006 or  http://www.ncbi.nlm.nih.gov/pubmed/16741317).  Patients 
should avoid strenuous exercise and be on a low carbohydrate diet for 24 hours prior to the scan. 
Patients should fast for 4 hours or longer prior to the FDG injection and should have a serum glucose 

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of less than 200 mg/dL at the time of FDG injection. A 10-20 mCi dose of FDG should be injected 
for typical adult patients. 
10.1.5
Response Criteria 
10.1.5.1
Evaluation of Target Lesions
Volumetric Analysis
As previously described [48], volumetric response will be determined by measuring measurable 
and non measurable primary and nodal disease in at least two dimensions as determined by scan, 
clinical exam or pathology. If measurement in two dimensions is not possible due to irregular 
shape of the lesion, comparison of the single largest dimension measured may be used. In all cases, 
serial photographs are strongly recommended to help assess response.  Responders will have 
demonstrated any decrease in overall tumor volume. Primary and nodal volume will also be 
assessed separately in terms of response. 
RECIST Criteria
Complete Response (CR): Disappearance of all target lesions.
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD.
Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target 
lesions, taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions  (new lesions must be > slice thickness). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started.
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given.
Note: If tumor response data is missing for target lesions, the overall assessment must be UN 
unless there is new disease that would result in an overall assessment of PD. However, if there is 
missing or unevaluable data for non-target lesions, but data is available for all target lesions, the 
overall response for that time point will be assigned based on the sum LD of all target lesions. 
Additionally, the assessment of CR cannot be made if there is missing or unevaluable data for 
non-target lesions. In this case, the overall assessment would be PR.
10.1.5.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions. 

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Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions* (new lesions must be > 
slice thickness) and/or unequivocal progression of existing non-target lesions.
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given.
Note: Although a clear progression of "non-target" lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed at a later time by review of the Principal Investigator. Additionally, the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment is mandatory to differentiate between stable and progressive disease.
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e., not due to 
difference in scanning technique, imaging modality, or findings thought to represent something 
other than tumor (ex: new bone lesions may be healing or flare of pre-existing lesions). However, 
a lesion identified on a follow-up scan in an anatomical location that was not scanned at baseline 
is considered new and will indicate PD. If a new lesion is equivocal (because of small size, etc.), 
follow-up evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion was 
discovered.
 
10.1.6
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started.
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is 
objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started.
10.1.7
Local failure is defined as the presence of biopsy-proven recurrent cancer at the 
original site of the primary tumor or radiologic scans that demonstrate progression at that site. Local 
progression-free survival (LPFS) is defined as the duration of time from enrollment to time of local 
failure or death.
10.1.8
Regional failure is defined as the presence of biopsy-proven recurrent cancer within 
the head and neck region outside of the area of the primary lesion or radiologic scans that 

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demonstrate progression at that site. Regional progression-free survival (RPFS) is defined as the 
duration of time from enrollment to time of regional failure or death.
10.1.9
Disease-free survival is defined as the time between first study treatment and either 
recurrent disease or death. Recurrent disease includes a local failure, regional failure, or distant 
metastasis.
10.1.10
Response Review
Central review is not going to be performed.
10.2 Other Response Parameters
Pathologic response should be assessed qualitatively and quantitatively (e.g. percent viable cells) [36, 
37] when possible.  This will take into account immune infiltration with or without tertiary lymph node 
structures, evidence of tumor death and subsequent tissue repair – these features should be documented 
and recorded when observed. 
 Pathologic staging will also be compared with clinical staging performed at study entry. 
For patients that have a PET performed before and after treatment, the maximum SUV of the primary 
lesion and of the most avid nodal disease with in the neck should be recorded before and after study 
therapy. 
11. ADVERSE EVENT REPORTING REQUIREMENTS
11.1
Definitions
11.1.1
Adverse Event (AE)
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests. 
11.1.2
Serious adverse event (SAE)
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 

Results in death

Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form.

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
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry, are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). Surgery 
to remove the primary oral cavity lesion and/or nodal disease, or any additional surgery 
performed as a result of this surgery is also not considered an SAE.

Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. This does not 
include expected side effects of planned surgery. 

Is a congenital anomaly or birth defect; or

Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
Events not considered to be serious adverse events are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not worsen

emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

respite care
11.1.3
Expectedness
Adverse events can be 'Expected' or 'Unexpected.' 
11.1.3.1
Expected adverse event
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the package insert or 
is included in the informed consent document as a potential risk.  
11.1.3.2
Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, or the package insert or when it is not included in the informed consent 
document as a potential risk.  
11.1.4
Attribution

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Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment.

Possible – The AE may be related to the study treatment. 

Unlikely - The AE is doubtfully related to the study treatment.

Unrelated - The AE is clearly NOT related to the study treatment.
11.2
Procedures for AE and SAE Recording and Reporting
Investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points 
during the study.
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded in 
the participant’s medical record and on the appropriate study-specific case report forms. 
The descriptions and grading scales found in the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE version 4.0) will be utilized for AE reporting. 
The CTEP Active Version of the CTCAE version 4.0 is identified and located on the CTEP website 
at:
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of 
CTCAE.
11.3
Reporting Requirements for Participating Investigators
Each participating investigator is required to abide by the reporting requirements set by the 
DF/HCC. The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator. 
It is the responsibility of each participating investigator to report adverse events within 48 hours to the 
Overall PI, Dr. Jonathan Schoenfeld, MD, MPH (at the contact given below), or representative 
personnel; and submit to DFCI IRB within 10 working days. 
Jonathan Schoenfeld, MD, MPH
617-632-3591
jdschoenfeld@partners.org
11.4
Reporting Requirements for DFCI IRB

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Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
(C2D1) on the local institutional SAE form. 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.
.
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
The overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events.
11.5
      Expedited Reporting to Hospital Risk Management
Participating investigators will report to DFCI Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy. 
11.6
Reporting Requirements for FDA
   There will be no submissions to the FDA as this protocol is deemed IND exempt.
11.7
 Reporting Requirements for BMS
    The Overall PI, or representative personnel; as soon as possible under the circumstances, will notify 
BMS of any serious adverse events (within 48 hours of learning about the event). 
A report will be sent for any serious adverse event (SAE) that occurs after the initial dose of 
study treatment, during treatment, or within 30 days of the last dose of treatment (C2D1).

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    BMS contact for SAE reports:
    Email: Worldwide.Safety@BMS.com
    Fax: +01-609-818-3804
11.8
Monitoring of Adverse Events and Period of Observation
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention through the study intervention period and up to 30 days after the last study 
intervention (C2D1) should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be irreversible, or 
the participant is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) 
should be documented on the appropriate case report form and recorded in the participant’s 
medical record to facilitate source data verification. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring 
visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to the 
study.  
12. DATA AND SAFETY MONITORING
12.1
Data Reporting
12.1.1
Method 
The ODQ will collect, manage, and monitor data for this study. 
Note: All adverse events that have occurred on the study, including those reported through 
AdEERS, must be reported via CTMS or CDUS.
12.1.2
Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) to the ODQ 
is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to enrollment with ODQ
On Study Form
Within 21 days of enrollment

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Baseline Assessment Form
Within 21 days of enrollment
Treatment Form
Within 14 days of the last day of the cycle
Adverse Event Report Form
Within 14 days of the last day of the cycle
Response Assessment Form
Within 14 days of the completion of the cycle 
required for response evaluation
Off 
Treatment/Off 
Study 
Form
Within 21 days of completing treatment or 
being taken off study for any reason
Follow up/Survival Form
Within 21 days of the protocol defined follow 
up visit date or call
12.2
Safety Meetings
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Principal Investigator and study team.
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring within 30 days for Phase I or II protocols; 
any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
12.3
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant enrollment and will continue 
during protocol performance and completion. 
12.4
Multi-Center Guidelines

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This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix D. 

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.

Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center.
13. REGULATORY CONSIDERATIONS
13.1
Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB governing 
each study location. 
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. 
The DF/HCC Overall Principal Investigator will disseminate protocol amendment information 
to all participating investigators. 
All IRB decisions concerning the conduct of the study must be made in writing.
13.2
Informed Consent
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained before 
the participant is involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and by the person 
obtaining the consent. The participant must be given a copy of the signed and dated consent 
document. The original signed copy of the consent document must be retained in the medical 
record or research file. 
13.3
Ethics and Good Clinical Practice (GCP)

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This study is to be conducted according to the following considerations, which represent good 
and sound research practice:

E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf 

US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki

Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html

Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 

Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 

Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 

Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 

State laws

DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/ 
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy. 
13.4
Study Documentation
The investigator must prepare and maintain adequate and accurate case histories designed to record 
all observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified.
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. 
13.5 Records Retention

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All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
14. STATISTICAL CONSIDERATIONS 
This sequential biomarker driven screening design is designed to identify promising treatments 
worthy of additional study. 
Co Primary Endpoint
The primary endpoints for this trial is safety and tolerability defined as the number of DLTs and 
volumetric response as defined in section 10.1. 
Secondary Endpoints: 
Secondary endpoints include disease response according to RECIST 1.1, pathologic response, 
local failure rate, regional failure rate, local and regional progression free survival, disease-free 
survival, and overall survival.  All are defined in Section 10.1. 
Sample Size and Study Duration: 
Because the use of nivolumab with or without ipilimumab is relatively novel in this setting, we 
will complete a safety run-in prior in each cohort prior to enrolling additional patients. If a single 
patient in either cohort is permanently unable to undergo surgery as a result of investigational 
treatment, enrollment to that cohort will close other DLTs are defined in Section 5.4. If this occurs 
in the nivolumab cohort then the study will close.  The safety run in will begin and complete for 
nivolumab cohort before enrollment begins on the safety-run in ipilimumab cohort. Once both 
safety run-ins are complete, patients will be randomizedrandomized to one of the two cohorts. If 
at any point during the study only one cohort is open for enrollment, all patients will be assigned 
to that cohort. 
The safety run in for each cohort will follow a typical 3+3 design in each cohort. Initially 3 patients 
will be entered. If 0 out of 3 patients experiences dose-limiting toxicity (DLT), the safety run in 
will end and the study will proceed. If exactly 1 out of 3 patients has a DLT, an additional 3 patients 
will be entered in the safety run in. If none of the next 3 patients experiences a DLT, the study will 
proceed. If at any time 2 (or more) patients experience DLT, the study will terminate.  Either arm 
will be considered promising if the safety run in is successfully completed. 
Additionally, either arm (nivolumab or nivolumab combined with ipilumumab) will be considered 
promising and worthy of further evaluation if there is strong evidence that the response rate  in 
either arm evaluated independently may be at least 15% (number of patients with volumetric 
response versus total number of patients treated in that arm).  Response rates will also be correlated 
with RECIST and pathologic response and changes in lymphocyte infiltration of primary tumor 
deposits. 
The decision rule will be based on the lower bound of the one-sided, 90% exact binomial 
confidence interval.  With this criteria, the treatment will be considered promising if 6 or more of 
the 20 patients (including patients in the safety-run in) in either arm demonstrate a response. This 

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would correspond to a lower confidence bound that is at least 15%. If none of the first 10 patients 
in either arm have a response, then enrollment will stop. Analyses of response rates will be 
presented by treatment arm within disease accompanied by exact 80% confidence intervals.  For a 
sample of size 20 per arm, each confidence interval will be no wider than 0.32.   We will also 
estimate an aggregated response rate for each treatment modality and present with 80% exact 
confidence intervals. 
Correlative studies will be largely exploratory in nature.  We will attempt to correlate PD-L1 
expression, mutational burden, T-cell infiltration and initial tumor burden with volumetric, 
RECIST and pathologic response. We will measure changes in radiologic and pathologic 
parameters and IHC staining over the course of therapy and correlate these with response and 
changes in immune markers present in the peripheral circulation. 
The accrual goal for this study is 40 patients. We anticipate enrolling approximately 2 patients per 
month.  Therefore, we expect to completely accrue to this study in approximately 20 months. The 
results should be made public within 24 months of reaching the end of the study. The end of the 
study is the time point at which the last data items are reported or after the outcome data are 
sufficiently mature for analysis, as defined above. 
Analysis of Endpoints: 
The primary endpoint is volumetric response, which will be assessed among all patients who 
initiate protocol therapy.  Response will be assessed as defined in section 10.1. The response rate 
will be reported with 90% exact confidence intervals. 
All patients who initiate protocol therapy will also be evaluated for response using RECIST v1.1, 
pathologic response at the time of surgery, safety and tolerability, local failure rate, regional failure 
rate, local and regional progression free-survival and overall survival.  PFS and OS will be 
analyzed using Kaplan–Meier product-limit estimates and will be plotted using Kaplan-Meier 
plots. PFS is defined as the time from study randomization to disease progression according 
RECIST 1.1, medical judgment or death due to any cause, whichever occurred first.  Patients alive 
without disease progression are censored at the date of last disease evaluation.  The hazard ratio 
for each time-to-event endpoint will be estimated with 95% confidence intervals derived from the 
Cox proportional hazard model, but no hypothesis testing will be conducted.  Other definitions are 
provided in section 10.1. 
All patients will be evaluable for toxicity from the time of their first treatment with any study 
agent. Toxicity will be graded according to NCI CTCAE, Version 4.0. Toxicities will be 
summarized by maximum grade and by treatment arm.  Incidence rate of each toxicity will be 
reported with 95% exact CI. 
15. PUBLICATION PLAN
We expect this study to produce at least 1 abstract that will be presented at a national meeting, as 
well as a publication reporting the final results of the study. We will plan on submitting the study 
results approximately 2 years after the accrual is complete, allowing additional time for toxicity.  

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16. REFERENCES 
1.
Freeman, G.J., et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 
family member leads to negative regulation of lymphocyte activation. J Exp Med, 2000. 
192(7): p. 1027-34.
2.
Latchman, Y., et al., PD-L2 is a second ligand for PD-1 and inhibits T cell activation. 
Nat Immunol, 2001. 2(3): p. 261-8.
3.
Carter, L., et al., PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells 
and is overcome by IL-2. Eur J Immunol, 2002. 32(3): p. 634-43.
4.
Sheppard, K.A., et al., PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004. 
574(1-3): p. 37-41.
5.
Nishimura, H. and T. Honjo, PD-1: an inhibitory immunoreceptor involved in peripheral 
tolerance. Trends Immunol, 2001. 22(5): p. 265-8.
6.
Nishimura, H., et al., Development of lupus-like autoimmune diseases by disruption of the 
PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999. 11(2): p. 
141-51.
7.
Nishimura, H., et al., Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient 
mice. Science, 2001. 291(5502): p. 319-22.
8.
Okazaki, T., et al., Autoantibodies against cardiac troponin I are responsible for dilated 
cardiomyopathy in PD-1-deficient mice. Nat Med, 2003. 9(12): p. 1477-83.
9.
Salama, A.D., et al., Critical role of the programmed death-1 (PD-1) pathway in 
regulation of experimental autoimmune encephalomyelitis. J Exp Med, 2003. 198(1): p. 
71-8.
10.
Blazar, B.R., et al., Blockade of programmed death-1 engagement accelerates graft-
versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol, 2003. 
171(3): p. 1272-7.
11.
Iwai, Y., S. Terawaki, and T. Honjo, PD-1 blockade inhibits hematogenous spread of 
poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int 
Immunol, 2005. 17(2): p. 133-44.
12.
Iwai, Y., et al., Involvement of PD-L1 on tumor cells in the escape from host immune 
system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A, 2002. 
99(19): p. 12293-7.
13.
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.
14.
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800.
15.
Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates 
cancer therapeutic immunity. Cancer Res, 2005. 65(3): p. 1089-96.
16.
Blank, C., et al., PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 
receptor (TCR) transgenic CD8+ T cells. Cancer Res, 2004. 64(3): p. 1140-5.
17.
Konishi, J., et al., B7-H1 expression on non-small cell lung cancer cells and its 
relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer 
Res, 2004. 10(15): p. 5094-100.

Window Study of Nivolumab with or without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity              
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63
18.
Ohigashi, Y., et al., Clinical significance of programmed death-1 ligand-1 and 
programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res, 
2005. 11(8): p. 2947-53.
19.
Tsushima, F., et al., Predominant expression of B7-H1 and its immunoregulatory roles in 
oral squamous cell carcinoma. Oral Oncol, 2006. 42(3): p. 268-74.
20.
Thompson, R.H., et al., B7-H1 glycoprotein blockade: a novel strategy to enhance 
immunotherapy in patients with renal cell carcinoma. Urology, 2005. 66(5 Suppl): p. 10-
4.
21.
Thompson, R.H., et al., Costimulatory molecule B7-H1 in primary and metastatic clear 
cell renal cell carcinoma. Cancer, 2005. 104(10): p. 2084-91.
22.
Dong, H. and L. Chen, B7-H1 pathway and its role in the evasion of tumor immunity. J 
Mol Med (Berl), 2003. 81(5): p. 281-7.
23.
Azuma, T., et al., B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood, 
2008. 111(7): p. 3635-43.
24.
Hino, R., et al., Tumor cell expression of programmed cell death-1 ligand 1 is a 
prognostic factor for malignant melanoma. Cancer, 2010. 116(7): p. 1757-66.
25.
Velu, V., et al., Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature, 
2009. 458(7235): p. 206-10.
26.
Wang, C., et al., In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-
936558, and in vivo toxicology in non-human primates. Cancer Immunol Res, 2014. 2(9): 
p. 846-56.
27.
Habicht, A., et al., A link between PDL1 and T regulatory cells in fetomaternal tolerance. 
J Immunol, 2007. 179(8): p. 5211-9.
28.
Schoenfeld, J.D., Immunity in head and neck cancer. Cancer Immunol Res, 2015. 3(1): p. 
12-7.
29.
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells 
and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl 
Acad Sci U S A, 2010. 107(9): p. 4275-80.
30.
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 
2013. 369(2): p. 122-33.
31.
Larkin, J., et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated 
Melanoma. N Engl J Med, 2015. 373(1): p. 23-34.
32.
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med, 2010. 363(8): p. 711-23.
33.
Bernier, J., et al., Postoperative irradiation with or without concomitant chemotherapy 
for locally advanced head and neck cancer. N Engl J Med, 2004. 350(19): p. 1945-52.
34.
López-Cedrún, J.L. and J. Andrés de Llano, A 22 years survival and prognostic factors 
analysis in a homogeneous series of 64 patients with advanced cancer of the tongue and 
the floor of the mouth, in J Craniomaxillofac Surg. 2015. p. 376-81.
35.
Metcalfe, C.W., D. Lowe, and S.N. Rogers, What patients consider important: temporal 
variations by early and late stage oral, oropharyngeal and laryngeal subsites. J 
Craniomaxillofac Surg, 2014. 42(5): p. 641-7.
36.
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.

Window Study of Nivolumab with or without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity              
June 14, 2019
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This document is confidential. Do not disclose or use except as authorized.
64
37.
Zhong, L.P., et al., Long-term results of a randomized phase III trial of TPF induction 
chemotherapy followed by surgery and radiation in locally advanced oral squamous cell 
carcinoma. Oncotarget, 2015. 6(21): p. 18707-14.
38.
Schadendorf, D., et al., Pooled Analysis of Long-Term Survival Data From Phase II and 
Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol, 
2015. 33(17): p. 1889-94.
39.
Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med, 2015. 372(21): p. 2018-28.
40.
Feldman, R., et al., Molecular profiling of head and neck squamous cell carcinoma. Head 
Neck, 2015.
41.
Garon, E.B., et al., Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer, in 
N Engl J Med. 2015.
42.
Topalian, S.L., et al., Survival, durable tumor remission, and long-term safety in patients 
with advanced melanoma receiving nivolumab. J Clin Oncol, 2014. 32(10): p. 1020-30.
43.
Van Allen, E.M., et al., Genomic correlates of response to CTLA-4 blockade in 
metastatic melanoma. Science, 2015. 350(6257): p. 207-11.
44.
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to 
PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.
45.
Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody 
MPDL3280A in cancer patients. Nature, 2014. 515(7528): p. 563-7.
46.
Aerts, H.J., et al., Decoding tumour phenotype by noninvasive imaging using a 
quantitative radiomics approach. Nat Commun, 2014. 5: p. 4006.
47.
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20.
48.
Li, J., et al., Cetuximab ameliorates suppressive phenotypes of myeloid antigen 
presenting cells in head and neck cancer patients. J Immunother Cancer, 2015. 3: p. 54.
49.
Patil, V., et al., Is There a Limitation of RECIST Criteria in Prediction of Pathological 
Response, in Head and Neck Cancers, to Postinduction Chemotherapy? ISRN Oncol, 
2013. 2013: p. 259154.
50.
Zhong, L.P., et al., Randomized phase III trial of induction chemotherapy with docetaxel, 
cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally 
advanced resectable oral squamous cell carcinoma. J Clin Oncol, 2013. 31(6): p. 744-51.

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

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Appendix B: Methods of Contraception
At a minimum, subjects must agree to use one highly effective OR one less effective method of 
contraception as listed below:
Highly Effective Methods Of Contraception
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use 
one of the highly effective methods of contraception listed below. Male subjects must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as follows:
1. Progestogen only hormonal contraception associated with inhibition of ovulation.
2. Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) such 
as Mirena®
3. Nonhormonal IUDs, such as ParaGard®
4. Bilateral tubal occlusion
5. Vasectomised partner with documented azoospermia 90 days after procedure
Vasectomised partner is a highly effective birth control method provided that partner is the sole 
sexual partner of the WOCBP trial participant and that the vasectomised partner has received 
medical assessment of the surgical success.
6. Intrauterine hormone-releasing system (IUS).
7. Complete abstinence
Complete abstinence is defined as the complete avoidance of heterosexual intercourse. 
Complete abstinence is an acceptable form of contraception for all study drugs and must be used 
throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 
days).
It is not necessary to use any other method of contraception when complete abstinence is elected.
Subjects who choose complete abstinence 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.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the subject.
Less Effective Methods Of Contraception
1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
4. Male or female condom with or without spermicide*
5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action
* A male and a female condom must not be used together.
Unacceptable Methods Of Contraception
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2. Withdrawal (coitus interruptus)
3. Spermicide only

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4. Lactation amenorrhea method (LAM)

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Appendix C: Management Algorithms

These general guidelines constitute guidance to the Investigator. The guidance applies to 
all immuno-oncology (I-O) 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
Investigators should refer to the most current version of the nivolumab or ipilimumab IB for 
current recommendations for management of a specific Adverse Event of interest.
I-O Safety 
Algorithm_GI.pdf
I-O Safety Algorithm 
Renal.pdf
I-O Safety 
Algorithm_Pulm.pdf
IO Safety 
Algorithm_Hepatic.pd
I-O Safety 
Algorithm_Endocrine.
I-O Safety 
Algorithm_Skin.pdf
I-O Safety 
Algorithm_Neuro.pdf

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Appendix D: 
          
MULTICENTER GUIDELINES
Appendix D
Dana-Farber/Harvard Cancer Center
 Multi-Center Data and Safety Monitoring Plan
TABLE OF CONTENTS
1.
OBJECTIVES......................................................................................................................................................5
1.1
Study Design.....................................................................................................................................................5
1.2
Primary Objectives...........................................................................................................................................5
1.3
Secondary Objectives .......................................................................................................................................5
2.
BACKGROUND..................................................................................................................................................6
2.1
Study Agents .....................................................................................................................................................6
2.1.1
Nivolumab...............................................................................................................................................6
Cancer immunotherapy is based on the premise that the body’s immune system can recognize a tumor as 
foreign and mount an effective antitumor response capable of eliminating that tumor. This likely requires 
immune recognition of specific tumor antigens, but also effective functioning of activated T-cells capable of 
eliminating tumor cells as they arise and causing tumor shrinkage where existing tumor deposits are present. 
Conversely, tumor progression is likely intimately intertwined with mechanisms by which tumors evade 
immune recognition and attack. ............................................................................................................................6
One mechanism by which tumors may evade immune attack is by coopting inherent immune checkpoints that 
function under normal circumstances to maintain immune homeostasis and prevent harmful autoimmunity. 
Thus, one strategy that exists for cancer immunotherapy is to modulate these regulatory immune checkpoints 
that largely exist on the surface of T-cells.  This can ideally overcome tumor mediated immune suppression, 
and potentiate nascent antitumor immune responses that might otherwise have been unable to lead to 
meaningful tumor regression.................................................................................................................................6
Programmed death receptor-1 (PD-1, CD279), is a 55 kD type I transmembrane protein is a member of the 
CD28 family of T-cell constimulatory molecules that also includes CD28, CTLA-4, ICOS, and BTLA [1]. 
PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a 
membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Two ligands specific for PD-1 have 
been identified: PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273) [2]. PD-L1 and PD-L2 have been shown 
to down-regulate T-cell activation upon binding to PD-1 in both murine and human systems [2, 3]. PD-1 
delivers a negative signal by the recruitment of SHP-2 to the phosphorylated tyrosine residue in the ITSM in 
its cytoplasmic region [4, 5]. PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells [5]..6
Further evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. PD-1-
deficient mice develop various autoimmune phenotypes, including dilated cardiomyopathy, a lupus-like 
syndrome with arthritis and nephritis, and accelerated diabetes mellitus [6-8]. The emergence of these 
autoimmune phenotypes is dependent upon the genetic background of the mouse strain and many of these 
phenotypes emerge at different times and show variable penetrance. In addition to the phenotypes of null 
mutations, PD-1 inhibition by antibody-mediated blockade in several murine models has been found to play a 
role in the development of autoimmune diseases such as encephalomyelitis, graft-versus-host disease, and type 
I diabetes[9, 10]. Taken together, these results suggest that PD-1 blockade has the potential to activate anti-
self T-cell responses, but these responses are variable and dependent upon various host genetic factors. Thus, 
PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-antigens....................6
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies (mAbs) can 
enhance the anti-tumor immune response and result in tumor rejection. Antitumor activity by PD-1 blockade 
functions in PD-L1-positive tumors as well as in tumors that are negative for the expression of PD-L1[11-16]. 

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This suggests that host mechanisms (ie, expression of PD-L1 in antigen-presenting cells) limit the antitumor 
response. Consequently, both PD-L1 positive and negative tumors may be targeted using this approach. In 
humans, constitutive PD-L1 expression is normally limited to macrophage-lineage cells, although expression 
of PD-L1 can be induced on other hematologic cells as well, including activated T cells. However, aberrant 
expression of PD-L1 by tumor cells has been reported in a number of human malignancies [17-22]. PD-L1 
expressed by tumor cells has been shown to enhance apoptosis of activated tumor-specific T cells in vitro [5]. 
Moreover, the expression of PD-L1 may protect the tumor cells from the induction of apoptosis by effector T 
cells[23]. Retrospective analyses of several human tumor types suggest that tumor over-expression (as 
measured by IHC) of PD-L1 may permit immune evasion by tumors. In renal cell carcinoma, high surface 
expression levels of PD-L1 on tumor cells are related to tumor aggressiveness [20, 21].  Subjects with high 
tumor and/or lymphocyte PD-L1 levels are 4.5 times more likely to die from their cancer than subjects 
exhibiting low levels of PD-L1 expression. In addition, in multivariate analysis, high expression of PD-L1 is 
correlated to have a worse overall survival rate compared to low expression levels of PD-L1[24].....................6
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (HuMAb; 
immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 279 
(CD279) cell surface membrane receptor. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and 
is produced using standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. .............................................................7
OPDIVO™ (nivolumab) is approved for use in multiple countries including the United States (US, Dec-2014), 
the European Union (EU, Jun-2015), and Japan (Jul-2014). ................................................................................7
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related members of the 
CD28 family. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in 
enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro [25]. Nivolumab binds with high 
affinity to activated human T-cells expressing cell surface PD-1 and to cynomolgus monkey PD-1. In a mixed 
lymphocyte reaction (MLR), nivolumab promoted a reproducible concentration-dependent enhancement of 
IFN-α release [26]. ................................................................................................................................................7
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well tolerated at 
doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, administered twice 
weekly for 27 doses. While nivolumab alone was well tolerated in cynomolgus monkeys, combination studies 
have highlighted the potential for enhanced toxicity when combined with other immunostimulatory agents.....7
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys 
with nivolumab was conducted. Administration of nivolumab at up to 50 mg/kg 2QW was well tolerated by 
pregnant monkeys; however, nivolumab was determined to be a selective developmental toxicant when 
administered from the period of organogenesis to parturition at <=10 mg/kg (area under the concentration-time 
curve [AUC] from time zero to 168 hours [AUC (0-168 h)] 117,000 g  h/mL). Specifically, increased 
developmental mortality (including late gestational fetal losses and extreme prematurity with associated 
neonatal mortality) was noted in the absence of overt maternal toxicity. There were no nivolumab-related 
changes in surviving infants tested throughout the 6-month postnatal period. Although the cause of these 
pregnancy failures was undetermined, nivolumab-related effects on pregnancy maintenance are consistent 
with the established role of PD-L1 in maintaining fetomaternal tolerance in mice [27]......................................7
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with non-small cell lung 
cancer (NSCLC), melanoma, and clear-cell renal cell carcinoma (RCC) in addition to other tumor types. 
Please refer to the 2015 IB for specific details. Nivolumab is being investigated both as monotherapy and in 
combination with chemotherapy, targeted therapies, and other immunotherapies...............................................8
Nivolumab is approved in multiple countries including the US for treatment of previously treated, 
unresectable or metastatic melanoma, advanced renal cell carcinoma and previously treated, metastatic 
squamous NSCLC, the EU for treatment of previously treated, unresectable or metastatic melanoma, and 
Japan for treatment of unresectable melanoma. Please see the IB for more details..............................................8
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 10 mg/kg 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric mean (% 
CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) was 
8.0 L (30.4%), and geometric mean elimination half-life (t1/2) was 26.7 days (101%). Steady-state 
concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, and systemic 
accumulation was approximately 3-fold. The exposure to nivolumab increased dose proportionally over the 
dose range of 0.1 to 10 mg/kg administered every 2 weeks. The clearance of nivolumab increased with 
increasing body weight. The PPK analysis suggested that the following factors had no clinically important 

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effect on the CL of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK analysis 
suggested no difference in CL of nivolumab based on age, gender, race, tumor type, baseline tumor size, and 
hepatic impairment................................................................................................................................................8
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild hepatic 
impairment had an effect on nivolumab CL, the effect was not clinically meaningful. When nivolumab is 
administered in combination with ipilimumab, the CL of nivolumab was increased by 24%, whereas there was 
no effect on the clearance of ipilimumab. Additionally, PPK and exposure response analyses have been 
performed to support use of 240 mg Q2W dosing in addition to the 3 mg/kg Q2W regimen. Using the PPK 
model, exposure of nivolumab at 240 mg flat dose was identical to a dose of 3 mg/kg for subjects weighing 80 
kg, which was the approximate median body weight in nivolumab clinical trials (please see 2015 IB for more 
details). ..................................................................................................................................................................8
2.1.2
Nivolumab combined with ipilimumab ................................................................................................11
2.2
Study Disease..................................................................................................................................................16
2.3
Rationale.........................................................................................................................................................16
2.4
Correlative Studies Background.....................................................................................................................17
3.
PARTICIPANT SELECTION.........................................................................................................................18
3.1
Eligibility Criteria ..........................................................................................................................................18
1.
Pathologically confirmed squamous cell carcinoma of the oral cavity. Clinical stage >=T2 (primary 
tumor greater than 2 cm in size) and/or evidence of regional nodal involvement by clinical exam or imaging 18
2.
Only patients 18 years and older are eligible. There is no upper age limit but the patients must be able to 
medically tolerate the regimen. Adverse event data are currently unavailable on the use immune checkpoint 
blockade for participants < 18 years of age, and thus children are excluded from this study ............................18
3.
ECOG performance status <=1 (see Appendix A) ....................................................................................18
4.
Patients much be a surgical candidate (e.g. their disease must be considered resectable before any 
treatment and must have no serious medical contraindications that definitively preclude undergoing general 
anesthesia) ...........................................................................................................................................................18
Ability to understand and the willingness to sign a written informed consent document ..................................18
5.
Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of contraception 
(see Appendix B). 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. WOCBP 
is defined as any woman or adolescent who has begun menstruation and is not post- menopausal. A post-
menopausal woman is defined as a woman who is over the age of 45 and has not had a menstrual period for at 
least 12 months....................................................................................................................................................18
6.
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) to be scheduled within 24 hours prior to the start of nivolumab
19
7.
Men who are sexually active with WOCBP must agree to use any contraceptive method (see Appendix 
B) with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with 
WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of 
investigational product Women who are not of childbearing potential (ie, who are postmenopausal or 
surgically sterile as well as azoospermic men do not require contraception) .....................................................19
8.
Participants must have normal organ and marrow function as defined below:.........................................19
Laboratory parameters: WBC ≥ 2000/uL, Absolute neutrophil count (ANC) ≥ 1500/mm3; Platelets ≥ 
100,000/mm3; Hemoglobin (Hgb) ≥ 9 g/dL; Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3 × upper limit of normal (ULN); Bilirubin ≤ 2.5 × ULN (≤ 4 × ULN for subjects with Gilbert’s 
disease); Alkaline phosphatase ≤ 2.5 × ULN; Creatinine ≤ 1.5 × ULN .............................................................19
3.2
Exclusion Criteria........................................................................................................................................19
1.
Pathologically proven, radiologic or clinical evidence of distant metastatic disease (this includes all 
disease below the clavicles, as well as disease metastatic to the bone, brain, or in the spinal canal).................19
2.
Any prior immunologic cancer therapy with systemic inhibitors of the PD-1 or CTLA-4 pathway ........19

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3.
Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that would limit compliance with study requirements ........................................................................................19
4.
Individuals with a history of a different malignancy are ineligible except for the following 
circumstances: if they have been disease-free for at least 2 years and are deemed by the investigator to be at 
low risk for recurrence of that malignancy; or if diagnosed and treated within the past 2 years for cervical 
cancer in situ or basal cell or squamous cell carcinoma of the skin....................................................................19
5.
Prior radiation to the head and neck region...............................................................................................19
6.
Prior chemotherapy within the last 2 years................................................................................................19
7.
History of pneumonitis or interstitial lung disease....................................................................................19
8.
Has evidence of active, noninfectious pneumonitis that required treatment with steroids. ......................20
9.
Active, suspected or prior documented autoimmune disease that has required systemic treatment in the 
last 2 years with immune modifying agents (e.g. replacement therapy such as thyroxine, insulin or physiologic 
corticosteroids is not an exclusion criteria). This does not include patients with vitiligo or type 1 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.....20
10.
The subject is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV 
RNA.These tests do not have to be resulted prior to registration if patient is low risk. .....................................20
11.
Lack of availability for follow up assessments..........................................................................................20
12.
Concurrent administration of other cancer specific therapy during the course of this study is not allowed
20
13.
Patients who require systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or 
topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease................................................................................................................20
14.
History of allergy to study drug components ............................................................................................20
15.
History of severe hypersensitivity reaction to any monoclonal antibody..................................................20
16.
The investigator’s belief that the subject is medically unfit to receive nivolumab, and/or ipilimumab or 
unsuitable for any other reason ...........................................................................................................................20
17.
Has received a live vaccine within 28 days of planned start of study therapy ..........................................20
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations..................................................20
4.
REGISTRATION/ENROLLMENT PROCEDURES ...................................................................................20
4.1
General Guidelines for DF/HCC and DF/PCC Institutions ..........................................................................20
4.2
Registration Process for DF/HCC Institutions ..............................................................................................21
4.3
General Guidelines for Other Investigative Sites...........................................................................................21
4.4
Registration Process for Other Investigative Sites.........................................................................................21
5.
TREATMENT PLAN .......................................................................................................................................22
5.1
Treatment regimen ........................................................................................................................................22
Treatment will be administered on an outpatient basis. Expected toxicities and potential risk as well as 
management of these toxicities are described in Appendix D and E. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the participant’s 
malignancy during the course of treatment..............................................................................................................22
5.2
Pre-treatment Criteria..................................................................................................................................23
5.2.1
Screening for trial eligibility.................................................................................................................23
5.2.2
On treatment visits................................................................................................................................24
5.2.3
Additional On-Treatment Assessments ................................................................................................25
5.3
Agent Administration ....................................................................................................................................26
5.3.1
Nivolumab.............................................................................................................................................26

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5.3.2
Ipilimumab............................................................................................................................................29
5.3.3
Standard of care treatment following window treatment with nivolumab with or without ipilimumab
30
5.4
Definition of Dose-Limiting Toxicity...........................................................................................................31
5.5
General Concomitant Medication and Supportive Care Guidelines .............................................................33
5.6
Duration of Therapy........................................................................................................................................34
5.7
Criteria for Taking a Participant Off Protocol Therapy................................................................................35
5.8
Duration of Follow Up ...................................................................................................................................35
5.8.1
The patient will be followed at least every other week during the window phase of this trial (weeks 1-
4)
35
5.8.2
First restaging will be performed after window treatment and prior to surgery (week 3 or week 4)...35
5.8.3
Following surgery on week 3 or 4, patients will be followed as per standard of care. This may include 
radiation with or without concomitant chemotherapy at the discretion of the treating physicians.  As per 
standard of care, patients will have restaging exam and scans between 10 and 16 weeks following the 
completion of all cancer directed therapy or earlier if clinically indicated. The scans at the 3 month follow up 
time point are optional, but highly encouraged...................................................................................................35
5.9
Criteria for Taking a Participant Off Study ...................................................................................................35
6.
DOSING DELAYS/DOSE MODIFICATIONS .............................................................................................36
6.1
Anticipated Toxicities .....................................................................................................................................36
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................................................................................................................................................................36
6.2
Toxicity Management .....................................................................................................................................36
6.3
Dose Modifications/Delays ............................................................................................................................38
6.3.1
Delays in nivolumab administration.....................................................................................................38
7.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................................38
8.
PHARMACEUTICAL INFORMATION....................................................................................................43
9.
STUDY CALENDAR........................................................................................................................................44
Week 3.................................................................................................................................................................46
Study Agent - Ipilimumab(cohort 2 only)...........................................................................................................46
10.
MEASUREMENT OF EFFECT......................................................................................................................48
10.1
Antitumor Effect– Solid Tumors ................................................................................................................48
10.1.1
Definitions........................................................................................................................................48
10.1.2
Disease Parameters ..........................................................................................................................48
10.1.3
Methods for Evaluation of Measurable Disease ..............................................................................49
10.1.4
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should follow the 
NCI Guidelines for using FDG PET as an indicator of therapeutic response (L.K. Shankar, J.M. Hoffman, S. 
Bacharach, M.M., et al. Consensus recommendations for the use of 18F-FDG PET as an indicator of 
therapeutic response in patients in National Cancer Institute Trials. J Nucl Med, 47(6):901-903, 2006 or  
http://www.ncbi.nlm.nih.gov/pubmed/16741317).  Patients should avoid strenuous exercise and be on a low 
carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or longer prior to the FDG 
injection and should have a serum glucose of less than 200 mg/dL at the time of FDG injection. A 10-20 mCi 
dose of FDG should be injected for typical adult patients. .................................................................................49
10.1.5
Response Criteria .............................................................................................................................50
10.1.6
Duration of Response.......................................................................................................................51

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10.1.7
Local failure is defined as the presence of biopsy-proven recurrent cancer at the original site of the 
primary tumor or radiologic scans that demonstrate progression at that site. Local progression-free survival 
(LPFS) is defined as the duration of time from enrollment to time of local failure or death..................................51
10.1.8
Regional failure is defined as the presence of biopsy-proven recurrent cancer within the head and 
neck region outside of the area of the primary lesion or radiologic scans that demonstrate progression at that 
site. Regional progression-free survival (RPFS) is defined as the duration of time from enrollment to time of 
regional failure or death. .....................................................................................................................................51
10.1.9
Disease-free survival is defined as the time between first study treatment and either recurrent 
disease or death. Recurrent disease includes a local failure, regional failure, or distant metastasis...................52
10.1.10
Response Review .............................................................................................................................52
10.2
Other Response Parameters ......................................................................................................................52
11.
ADVERSE EVENT REPORTING REQUIREMENTS................................................................................52
11.1
Definitions..................................................................................................................................................52
11.1.1
Adverse Event (AE).........................................................................................................................52
11.1.2
Serious adverse event (SAE)............................................................................................................52
11.1.3
Expectedness....................................................................................................................................53
11.1.4
Attribution........................................................................................................................................53
11.2
Procedures for AE and SAE Recording and Reporting.............................................................................54
11.3
Reporting Requirements for Participating Investigators ..........................................................................54
11.4
Reporting Requirements for DFCI IRB.....................................................................................................54
11.5
Expedited Reporting to Hospital Risk Management..................................................................................55
11.6
Reporting Requirements for FDA..............................................................................................................55
11.7
Reporting Requirements for BMS..............................................................................................................55
11.8
Monitoring of Adverse Events and Period of Observation........................................................................56
12.
DATA AND SAFETY MONITORING...........................................................................................................56
12.1
Data Reporting ..........................................................................................................................................56
12.1.1
Method .............................................................................................................................................56
12.1.2
Data Submission ..............................................................................................................................56
12.2
Safety Meetings..........................................................................................................................................57
12.3
Monitoring.................................................................................................................................................57
12.4
Multi-Center Guidelines............................................................................................................................57
13.
REGULATORY CONSIDERATIONS...........................................................................................................58
13.1
Protocol Review and Amendments ............................................................................................................58
13.2
Informed Consent.......................................................................................................................................58
13.3
Ethics and Good Clinical Practice (GCP) ................................................................................................58
13.4
Study Documentation.................................................................................................................................59
13.5
Records Retention......................................................................................................................................59
14.
STATISTICAL CONSIDERATIONS.............................................................................................................60
15.
PUBLICATION PLAN.....................................................................................................................................61
16.
REFERENCES..................................................................................................................................................62

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APPENDICES.............................................................................................................................................................65
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..........................................................................77
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. DF/HCC 
includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.......................................77
2.
GENERAL ROLES AND RESPONSIBILITIES ..........................................................................................78
2.1
DF/HCC Sponsor ...........................................................................................................................................78
2.2
Coordinating Center.......................................................................................................................................79
2.3
Participating Institution .................................................................................................................................79
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS........................................................80
3.1
Protocol Distribution......................................................................................................................................80
3.2
Protocol Revisions and Closures....................................................................................................................80
3.3
Informed Consent Requirements ....................................................................................................................80
3.4
IRB Documentation ........................................................................................................................................81
3.5
IRB Re-Approval ............................................................................................................................................81
3.6
Participant Confidentiality and Authorization Statement ..............................................................................81
3.7
DF/HCC Multi-Center Protocol Registration Policy.....................................................................................82
3.8
DF/HCC Protocol Case Number....................................................................................................................83
3.10
Safety Assessments and Toxicity Monitoring.............................................................................................84
3.11
Data Management .....................................................................................................................................84
4.
REQUISITIONING INVESTIGATIONAL DRUG ......................................................................................85
5.
MONITORING: QUALITY CONTROL .......................................................................................................85
5.1
Ongoing Monitoring of Protocol Compliance ...............................................................................................85
5.1.1
Remote Monitoring....................................................................................................................................85
DFCI CTO will virtually monitor sites throughout the study. On-site monitoring visits will be supplemented with 
virtual monitoring visits. The DF/HCC Lead Institution will request source documentation from Participating 
Institutions as needed to complete virtual monitoring activities. Participating Institutions will be asked to 
forward de-identified copies of participants’ medical record and source documents to the DF/HCC Lead 
Institution to aid in the source documentation verification process........................................................................85
5.1.2
On-Site Monitoring....................................................................................................................................86
5.2
Monitoring Reports ........................................................................................................................................86
5.3
Accrual Monitoring ........................................................................................................................................86
6.
AUDITING: QUALITY ASSURANCE..........................................................................................................86
6.1
Audit Plan: DF/HCC Sponsored Trials .........................................................................................................86
6.2
Audit Notification ...........................................................................................................................................86
6.3
Audit Reports..................................................................................................................................................87
6.4
Participating Institution Performance ...........................................................................................................87

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1.
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that 
will be participating in the research protocol.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.       
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol 
as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  
The Lead Institution is typically the home of the DF/HCC Sponsor. 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. FDA, OHRP, 
etc.). The DF/HCC Sponsor has ultimate authority over the protocol and is responsible for the 
conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC 
Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, both roles 
can be filled by two different people. 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.
   
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the 
DF/HCC Sponsor in order that he/she may fulfill the responsibilities outlined in the 
protocol document and DSMP, and as specified in applicable regulatory guidelines (i.e. 

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CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating 
Center for the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to 
use a CRO, the CRO will be deemed the Coordinating Center.  
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research.
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing 
clinical trial data.
2.
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Jonathan Schoenfeld, MD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed.

Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary language. 

Monitor progress and overall conduct of the study at all Participating Institutions. 

Require all DFCI and Participating Institution Institutional Review Boards’ (IRB), 
DF/HCC and other applicable (i.e. FDA) reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with FDA.

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor and as approved by Janssen.

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
Identify and qualify Participating Institutions and obtain accrual projections prior to 
extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
2.2
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).

Distribute protocol and informed consent document updates to Participating Institutions 
as needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the DF/HCC 
Sponsor for timely review and submission to the DFCI IRB, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring. 

Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites,  all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications.
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations, the 
protocol and HIPAA requirements. 
The general responsibilities for each Participating Institution may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB.

Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related 
activities. 

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
Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to local IRB per institutional requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings.
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol. 
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.   
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions.

Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 

Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to 
protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions 
will be implemented immediately followed by IRB request for approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 
will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures.
3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols.  This document will be provided separately to each Participating Institution.

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Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only 
attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug 
and/or device trials).  
3.4
IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB. 

Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 

Participating Institution’s IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.  
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 
the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, 
with the approval from the DFCI IRB will provide a consent template, with information 
regarding authorization for the use and disclosure of protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials. However, because of the nature of these trials, certain protected health information must 
be collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.
3.6.1
DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 

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de-identified. It is recommended that the assigned unique subject number (as described below) 
be used for all participant specific documents. Participant initials may be included or retained for 
cross verification of identification. 
3.7
DF/HCC Multi-Center Protocol Registration Policy
3.7.1
Participant Registration and Randomization 
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Coordinating Center or study coordinator:

Copy of screening test results, including imaging and pathology results

Signed participant consent form

HIPAA authorization form

Eligibility checklist

Clinic note, covering screening requirements and baseline AEs
The research nurse or data manager at the participating site will send the registration packet via 
email to the project manager at DFCI CTO.  To complete the registration process, the 
coordinator will follow DF/HCC Standard Operating Procedure for Human Subject Research 
Titled Subject Protocol Registration (SOP #: REGIST-101A) and register the participant on the 
protocol.  The coordinator will e-mail the participant study number and treatment assignment to 
the participating site. 
Subjects will be randomized by HCRN DF/HCC Office of Data Quality (ODQ) in a 1:1 ratio to 
either Cohort 1 or Cohort 2. Following registration and randomization, subjects may begin 
protocol treatment.  Issues that would cause treatment delays should be discussed with the 
sponsor-investigator.
Randomization can only occur during ODQ’s normal business hours, Monday through
Friday from 8:00 AM to 5:00 PM Eastern Time.
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
3.7.2
Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions. Treatment and other protocol-specific interventions may 
not be initiated until the Participating Institution receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified 
of any violations to this policy. 
3.7.3
Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below.

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3.8
DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.  
3.9
Protocol Deviations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB.
3.9.1
  Definition
Protocol Deviation: Any departure from the defined procedures set forth in the IRB approved 
protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g.
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB 
prior to its initiation or implementation. 
3.9.2
 Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol deviations occurring at their 
site. The DF/HCC Sponsor will also be responsible for ensuring that all protocol deviations are 
promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
is submitted to the Participating Institution IRB, per institutional policy. A copy of the 
Participating Institution’s IRB report and determination will be forwarded to the Coordinating 
Center within 10 business days after the original submission.  The deviation may not be 
implemented without all required approvals.

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All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations.
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. 
3.10
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.
Additional safety assessments and toxicity monitoring is outlined in the protocol.
3.10.1 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol Section 11.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB Adverse Event Reporting Policy IRB of record’s Adverse Event 
Reporting Policy.
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the protocol requirements.  Participating Institutions will review 
and submit to their IRB according to their institutional policies and procedures.
3.10.2  Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports 
are distributed to the Participating Institutions. Participating Institutions will review and submit 
to their IRB according to their institutional policies and procedures.
3.11
Data Management
Data will be handled and recorded in accordance with Section 12 of the protocol and from 
Section 3.10.1 of the DSMP.
Responses to all queries should be completed and submitted within 14 calendar days.  Responses 
may be returned on the written query or on an amended paper case report form, or in the case of 

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electronic queries, within the electronic data capture (eDC) system. In the case of a written query 
for data submitted on a paper case report form, the query must be attached to the specific data 
being re-submitted in response.       
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.
  
3.11.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. Participating 
Institutions are notified of their data submission delinquencies in accordance with the following:

All visits must be checked in and all data entered within 15 business days of the visit 
occurring.  Any visit data not entered within 15 business days is considered overdue.  
Sites will be notified of delinquent data in an escalating series of contacts until data is 
complete.  
4.
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol section 8.
5.
MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, 
provides quality control oversight for the protocol.
5.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institutions may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent procedures, 
adverse events and all associated documentation, review of study drug administration/treatment, 
regulatory files, protocol departures reporting, pharmacy records, response assessments, and data 
management. 
5.1.1
Remote Monitoring 
DFCI CTO will virtually monitor sites throughout the study. On-site monitoring visits will be 
supplemented with virtual monitoring visits. The DF/HCC Lead Institution will request source 
documentation from Participating Institutions as needed to complete virtual monitoring activities. 
Participating Institutions will be asked to forward de-identified copies of participants’ medical 

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record and source documents to the DF/HCC Lead Institution to aid in the source documentation 
verification process.
5.1.2
On-Site Monitoring
On-site monitoring will occur on an as-needed basis. Participating Institutions will be required to 
provide access to participants’ complete medical record and source documents for verification 
during on-site visits. Upon request, Participating Institutions should provide access to regulatory 
documents, pharmacy records, local policies related to the conduct of research, and any other 
trial-related documentation maintained by the Participating site. If there are protocol compliance 
concerns, issues that impact subject safety or the integrity of the study, or trends identified based 
on areas of need, additional monitoring visits may occur. 
5.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations.
5.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
The minimum accrual requirement is 3 patients per site annually because this is a Phase II trial. 
6.
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR).
6.1
Audit Plan: DF/HCC Sponsored Trials
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2 day period. If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. The DF/HCC Sponsor may request that an audit be 
performed by the ODQ if instances of serious non-compliance are found during routine 
monitoring.
6.2
Audit Notification
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 

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protocol. All institutions will forward a copy of final audit and/or re-audit reports and corrective 
action plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date. 
6.3
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan to the 
DFCI IRB as applicable.
6.4
Participating Institution Performance
The DF/HCC Sponsor, DFCI IRB is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol.
6.4.1
   Corrective Actions
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above.