Neodjuvant Nivolumab and Lirilumab, Followed by Surgery, Followed by Adjuvant Nivolumab and Lirilumab, in Patients With Relapsed, Resectable Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Dana-Farber Cancer Institute

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NCI Protocol #: N/A
DF/HCC Protocol #: 17-411
Title:  Neoadjuvant nivolumab and lirilumab followed by surgery followed by adjuvant 
nivolumab and lirilumab in SCCHN
Coordinating Center: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215
Principal Investigator (PI): 
Glenn Hanna, MD
Head & Neck Oncology
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
gjhanna@partners.org
Other Investigators:
Study Agents: Nivolumab and lirilumab; supplied by Bristol-Myers Squibb
IND #:  
IND Sponsor: Glenn Hanna, MD
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            SCHEMA
Patients who received any definitive 
treatment (any initial stage) for 
squamous cell carcinoma of the head & 
neck
Key Eligibility:
•
must have locoregional recurrence
•
regardless of HPV or smoking 
status
•
documented disease-free interval > 
8 weeks after initial therapy
•
no prior immunotherapy
•
ECOG PS ≤ 2
B
I
O
P
S
Y
*
Nivolumab
+
Lirilumab
(1 dose, 7-21 days 
prior to surgery)
Cycles 1-3: 
Nivolumab on Days 1, 15
Lirilumab on Day 1
Cycles 4-6 & beyond: 
Nivolumab & Lirilumab on 
Day 1
To begin 3-8 weeks from the 
surgical date (of a 28 day long 
cycle, for a maximum of 6 
cycles or until disease 
progression or recurrence)
* Tumor tissue and blood will be collected at the time of biopsy and surgery for 
correlative studies to include: tumor multiparametric flow cytometry, 
genomics, immunohistochemistry and circulating immune profiling
** Imaging is required prior to immunotherapy and 1-4 days prior to surgery
Mandatory
S
U
R
G
E
R
Y
*
Hypothesis: Adjuvant combined immune checkpoint therapy will decrease 
or delay recurrences and improve survival
Primary endpoint: disease-free survival (DFS^) at 1-year
Secondary endpoints: DFS at 2-years, overall survival at 3-years, immune and 
genomic correlatives, radiologic response
^ DFS = disease-free survival from date of salvage surgery

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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 .................................................................................................................5
2.1
Study Disease(s).......................................................................................................5
2.2
IND Agents..............................................................................................................6
3.
PARTICIPANT SELECTION...........................................................................................15
3.1
Inclusion Criteria ...................................................................................................15
3.2
Exclusion Criteria ..................................................................................................16
3.3
Inclusion of Women and Minorities ......................................................................17
4.
REGISTRATION PROCEDURES ...................................................................................17
4.1
General Guidelines for DF/HCC Institutions ........................................................17
4.2
Registration Process for DF/HCC Institutions.......................................................17
4.3
General Guidelines for Other Investigative Sites ..................................................18
4.4
Registration Process for Other Investigative Sites.................................................18
5.
TREATMENT PLAN........................................................................................................18
5.1
Pre-Treatment Criteria ...........................................................................................18
5.2
Treatment Regimen................................................................................................18
5.3
Agent Administration.............................................................................................19
5.4
Pharmaceutical Properties and Formulation for Lirilumab: ..................................19
5.5
Pharmaceutical Properties and Formulation for Nivolumab: ................................20
5.6
General Concomitant Medication and Supportive Care Guidelines......................21
5.7
Criteria for Taking a Participant Off Protocol Therapy.........................................22
5.8
Duration of Follow Up...........................................................................................23
5.9
Criteria for Taking a Participant Off Study ...........................................................23
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................23
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................24
7.1
Adverse Event Characteristics:..............................................................................24
7.2
Serious Adverse Events .........................................................................................25
7.3
Expected Toxicities................................................................................................25
7.4
Routine Adverse Event Reporting .........................................................................26
7.5
Serious Adverse Event Collection and Reporting .................................................27
7.6
Expedited Adverse Event Reporting to Overall PI................................................27
7.7
DF/HCC Expedited Reporting Guidelines.............................................................28
7.8
Expedited Adverse Event Reporting to the Food and Drug Administration 
(FDA).....................................................................................................................28
7.9
Expedited Adverse Event Reporting to Hospital Risk Management.....................29

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7.10
Expedited Adverse Event Reporting to BMS........................................................29
8.
PHARMACEUTICAL INFORMATION..........................................................................29
8.1
Storage and Stability..............................................................................................30
8.2
Handling.................................................................................................................30
8.3
Availability ............................................................................................................30
8.4
Ordering.................................................................................................................30
8.5
Accountability........................................................................................................30
8.6
Destruction and Return ..........................................................................................31
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................31
10.
STUDY CALENDAR .......................................................................................................33
11.
MEASUREMENT OF EFFECT .......................................................................................36
11.1
Antitumor Effect – Solid Tumors ..........................................................................36
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................43
12.1
Data Reporting.......................................................................................................44
12.2
Data Safety Monitoring..........................................................................................44
12.3
Multicenter Guidelines...........................................................................................44
13.
STATISTICAL CONSIDERATIONS...............................................................................44
14.
PUBLICATION PLAN .....................................................................................................45
15.
REFERENCES ..................................................................................................................46
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................51
APPENDIX B            GUIDANCE ON CONTRACEPTION......................................................51
APPENDIX C            MANAGEMENT ALGORITHMS............................................................54
APPENDIX D            DSMP.........................................................................................................62

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1. OBJECTIVES
1.1
Study Design
This is a phase II, open label, non-randomized, multi-institutional study of nivolumab (anti-PD-
1) and lirilumab (anti-KIR) in patients with relapsed, resectable, squamous cell carcinoma of the 
head and neck (SCCHN). Approximately 58 patients with confirmed locoregionally recurrent 
squamous cell carcinoma of the head and neck (including any primary site), who are candidates 
for salvage surgery will be enrolled in this study. A single dose of both study drugs will be given 
during a window of opportunity phase, before salvage surgery, followed by treatment with both 
study drugs in the adjuvant setting. Treatment in the adjuvant phase will continue for a maximum 
of 6 cycles or until disease progression or recurrence. The aim of this study is to improve 
disease-free survival in this critical SCCHN population. Primary endpoint is to evaluate disease-
free survival at 1-year from the time of salvage surgery. Secondary endpoints will include 
disease-free survival at 2-years, and overall survival at 3-years. 
The window phase of this study (from biopsy to surgical salvage) would allow administration of 
initial doses of immune checkpoint inhibitors facilitating assessment of toxicity and evaluation of 
early radiologic and clinicopathologic response, as well as immune and molecular correlates. 
We hypothesize that the combination of nivolumab and lirilumab used as adjuvant therapy in 
patients with locoregionally recurrent, resectable SCCHN will improve 1-year disease-free 
survival compared with standard observation in this high-risk population.
1.2
Primary Objectives
•
To estimate disease-free survival (DFS) at 1-year from the time of salvage surgery
1.3
Secondary Objectives
•
To evaluate toxicity; radiologic and clinicopathologic responses
•
To estimate DFS  from the time of salvage surgery
•
To estimate overall survival (OS)  from the time of salvage surgery
•
To characterize distinct tumor immunophentoypes and correlate these findings with 
outcomes
2. BACKGROUND
2.1
Study Disease(s)
Locoregional recurrence is a major cause of death in patients with squamous cell carcinoma of 
the head and neck (SCCHN), affecting up to 50% of patients treated with definitive therapy, 
which may include upfront surgical resection followed by adjuvant therapy or concurrent 
chemoradiotherapy [1]. Survival outcomes are generally poor for patients with locoregionally 

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recurrent disease and therapeutic options are limited by prior treatments (radiation and/or 
chemotherapy) [2]. When possible, salvage surgery is considered in these patients and frequently 
represents their only remaining chance at possible cure or long-term survival. Retrospective 
historical data have estimated 3-year overall survival (OS) at 37% among all surgically salvaged, 
recurrent SCCHN patients [3], with variability based on primary site of disease and interval of 
disease recurrence [4]. In a prospective single-institution observational cohort of 109 patients 
who underwent surgical salvage, 2-year disease-free survival (DFS) was 44% for all patients and 
correlated with stage (stage I, II 67-73%; stage III, IV 22-33%; p = 0.0005) and by site of 
recurrent disease (pharynx: 28%, oral cavity 47%, larynx: 58%, neck: 25%; p = 0.0645) [3]. 
Aside from salvage surgery or reirradiation in select patients, therapeutic options are limited and 
the standard of care is active surveillance following any salvage approach. A trial of 130 patients 
with locoregionally recurrent, operable SCCHN randomized patients to receive full-dose 
reirradiation and concurrent chemotherapy vs. active surveillance following re-resection and 
demonstrated improved rates of locoregional control (16 vs. 32 events, HR 2.73, 95% CI 1.66-
4.51, p < 0.0001) in the reirradiation arm but without an improvement in OS (p = 0.50) [5] – with 
an increase in acute and late toxicities observed in the chemoradiotherapy arm. Given these 
considerations, there is an urgent need to evaluate additional therapies in this critical population.
2.2
IND Agents
2.2.1
Nivolumab
2.2.1.1 Mechanism of action and pharmacology
It has become evident that tumor progression is promoted by immune evasion and abrogation of 
an effective immune response against cancer cells [6]. Mechanisms of tumor evasion include the 
development of T cell tolerance, modulation of inflammatory and angiogenic cytokines, 
downregulation of antigen-processing machinery, and changes in immune checkpoint receptor 
ligands or receptors that can all facilitate tumor immune evasion [7-9]. These mechanisms serve 
to define immunotherapy targets for clinical development. Immune checkpoint receptors block 
normal T cell activation and costimulation to maintain a homeostatic immune response [10]. 
Programmed cell death protein-1 (PD-1, CD279), one such receptor, is expressed on the surface 
of immune cells and interact with its cognate ligands on antigen-presenting or tumor cells. High 
tumor expression of the ligands of PD-1 (PD-L1 or B7-H1/CD274 and PD-L2 or B7-DC/CD273) 
and/or PD-1 expression by T lymphocytes can attenuate T cell activation and drive T cell 
exhaustion to favor tumor immune evasion [11]. By modulating these inhibitory immune 
receptor-ligand interactions, the goal is to overcome tumor mediated immunosuppression and 
facilitate an anti-tumor response. Preclinical evidence to support the negative regulatory effects 
of PD-1 comes from murine models. PD-1 knockout mice develop organ-specific autoimmunity 
which can mimic known autoimmune disease, such as systemic lupus erythematosus and acute 
graft versus host disease (GVHD) – but this can present at various time points and relies on host 
genetic factors [12]. Beyond PD-1 deficient models, antibody blockade in several mouse models 
have demonstrated the emergence of similar autoimmune phenomena [13]. These findings 
strengthen the argument that PD-1 inhibition permits enhancement of antigen-specific T cell 
response, but also indicate that responses can be variable and depend largely on underlying host 
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Efforts have focused on understanding PD-1/L1 expression patterns among various tumor types, 
in order to predict benefit from PD-1 blocking mechanisms. While estimates of tumor cell PD-
L1 expression vary considerably based on tumor type [14, 15], studies have estimated PD-L1 
expression in SCCHN at 30–70% with human papillomavirus (HPV) positive tumors more 
frequently harboring infiltrating immune cells that express PD-1 [16, 17]. Upregulation of PD-L1 
expression by tumor cells may offer a strategy for evasion and protect the cell from apoptotic 
demise mediated by T cells, and itself may facilitate T cell apoptosis [18]. Additionally, elevated 
PD-L1 expression levels correlate with a poor prognosis in some solid tumor malignancies [19]. 
However, several studies have demonstrated that even tumors with minimal PD-L1 expression 
may respond to PD-1 focused inhibitory mechanisms, and thus PD-1:L1 interactions are only one 
component that dictate response to these inhibitory immune signals in a complex tumor immune 
microenvironment [20, 21]. 
Nivolumab (BMS-936558, MDX-1106) is a fully human monoclonal antibody targeting the PD-
1 or CD279 cell surface receptor that binds to PD-1 with nanomolar affinity and a high degree of 
specificity. This therefore precludes binding to cognate ligands, PD-L1 or PD-L2 [22]. In chronic 
simian immunodeficiency virus (SIV) infection in macaques, studies have shown that PD-1 
blockade using an antibody to PD-1 was well tolerated and resulted in rapid expansion of virus-
specific CD8 T cells [23]. PD-1 blockade also resulted in proliferation of memory B cells and 
increases in SIV envelope-specific antibody. These improved immune responses were associated 
with significant reductions in plasma viral load and also prolonged the survival of SIV-infected 
macaques. In vitro assays have demonstrated the ability of nivolumab to potently enhance T-cell 
response and cytokine production (such as interferon alpha release); when later given to 
cynomolgus macaques at high concentrations, there were no adverse immune-related events, 
independent of circulating levels of anti-nivolumab antibodies [24]. In intravenous (IV) repeat-
dose toxicology studies in cynomolgus macaques, 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.
The pharmacokinetics of nivolumab have been reported in human subjects over a dose range of 
0.1 to 10 mg/kg administered as a single dose or as subsequent doses at 2 or 3 week intervals. 
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 every 2 weeks 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 population pharmacokinetic (PPK) analysis suggested that the 
following factors had no clinically meaningful effect on the clearance of nivolumab: age (29 to 
87 years), gender, race, baseline LDH, and PD-L1 expression. Although patient performance 
status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild hepatic 
impairment did have a mild effect on nivolumab clearance, the effect was not clinically 
meaningful [22]. Additionally, PPK and exposure response analyses have been performed to 
support the use of 240 mg IV flat dosing every 2 weeks in addition to the 3 mg/kg every 2 week 
regimen. Using the PPK model, exposure to nivolumab at 240 mg IV flat dose was identical to a 

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dose of 3 mg/kg for subjects weighing 80 kg.
2.2.1.2 Clinical safety
In an early phase I study investigating a single IV infusion of anti-PD-1 (MDX-1106) in dose-
escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort 
at 10 mg/kg (for a total of 39 patients), treatment was well tolerated. There was one serious 
adverse event, inflammatory colitis, observed in a patient with melanoma who received five 
doses at 1 mg/kg [25]. 
In a large registration trial which randomized advanced, platinum-refractory SCCHN patients to 
either nivolumab or single-agent standard chemotherapy, treatment-related grade 3 or 4 adverse 
events occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the 
standard arm [26]. In the nivolumab treated group, the most common adverse events were 
fatigue, nausea, rash, decreased appetite, and pruritis. Gastrointestinal events were less common 
than with standard chemotherapy. Pneumonitis was observed in 2.1% of nivolumab-treated 
patients and two treatment-related deaths occurred (one from hypercalcemia and one from 
pneumonitis). 
The overall safety experience with nivolumab as monotherapy is based on experience from more 
than 8,000 subjects treated to-date in patients with varied cancer types. The safety profile appears 
similar across cancer types [27, 28]. Treatment-related adverse events of grade 3 or 4 were 
reported in 7% of patients treated with nivolumab in advanced non-small cell lung cancer 
(NSCLC) of squamous histology and in 16.3% of unresectable, advanced stage melanoma 
patients. 
2.2.1.3 Clinical efficacy
Results from an early phase I trial demonstrated a wide range of clinical activity, including 
complete, partial and mixed response rates in advanced solid tumor patients; including 
individuals with colorectal cancer, NSCLC, melanoma, and renal cell carcinoma (RCC) [25]. 
Thirty-nine patients received a single IV infusion of anti-PD-1 (MDX-1106) in dose-escalating 
six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 
mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. 
One durable complete response (CR) and two partial responses (PRs; melanoma, RCC) were 
observed. Two additional patients (melanoma, NSCLC) had significant tumor regression not 
meeting defined PR criteria. Following this early signal, numerous clinical trials emerged to 
investigate the clinical efficacy of nivolumab in advanced solid tumor and hematologic 
malignancies – with nivolumab (Opdivo™) now approved in six cancer types owing to its 
demonstrated clinical efficacy.
In a randomized phase III study (Checkmate-141) of patients with recurrent or metastatic, 
platinum-refractory SCCHN, 361 patients were assigned to nivolumab or standard chemotherapy 
in a 2:1 ratio with a primary endpoint of overall survival (OS) [26]. Nivolumab (at a dose of 3 
mg/kg body weight IV) every 2 weeks or standard, single-agent systemic therapy (methotrexate, 
docetaxel, or cetuximab) was administered. Additional end points included progression-free 

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survival (PFS), objective response rate (ORR), safety, and patient-reported quality of life (QOL). 
The median OS was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab 
group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. OS 
was significantly longer with nivolumab than with standard therapy (hazard ratio [HR] for death, 
0.70; 97.73% CI, 0.51 to 0.96; p = 0.01), and the estimates of the 1-year survival rate were 
approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% 
vs. 16.6%). Median PFS was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months 
(95% CI, 1.9 to 3.1) with standard therapy (HR for disease progression or death, 0.89; 95% CI, 
0.70 to 1.13; p = 0.32). The rate of PFS at 6 months was 19.7% with nivolumab versus 9.9% 
with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the 
standard-therapy group. Additionally, individuals in the study who were PD-L1 (≥ 1% of tumor 
or immune cells by immunohistochemistry [IHC]) or HPV positive appeared to have improved 
outcomes. This study led to the approval of nivolumab in this setting in April of 2016.
2.3.1 Lirilumab
2.3.1.1 Mechanism of action and pharmacology
IPH-2101 (1-7F9) is a first in class fully human anti-KIR monoclonal antibody that was 
developed by Innate Pharma. Lirilumab (BMS-986105) is the second anti-KIR antibody and will 
be the antibody used in this protocol [22]. While lirilumab and IPH-2101 bind to the same KIR 
subtypes and have similar affinity there are several differences between the two products: IPH-
2101 is a non-recombinant protein that is produced by a murine hybridoma cell line, whereas 
lirilumab is a recombinant product produced in Chinese hamster ovary cells; lirilumab has a 
single amino acid substitution of a serine to a proline at position 231 of the immunoglobulin-4 
heavy chain resulting in greater stability of the compound. Most available preclinical data has 
utilized IPH-2101, which is a fully human monoclonal anti-KIR antibody that binds specifically 
and with high affinity to KIR2DL-1, 2 and 3 and KIR2DS-1 and 2, thus preventing interaction 
between KIR and human leukocyte antigen (HLA)-C. IPH-2101 has been shown to augment NK 
cell-mediated lysis of HLA-C-expressing tumor cells, including autologous leukemic blasts in 
vitro, but did not induce killing of normal peripheral blood mononuclear cells, suggesting 
preferential enhancement of NK-cell cytotoxicity against malignant target cells [29] – and all in 
vivo treated mice in the experiment survived by day 75 of the study (p < 0.01). 
Early phase trials evaluating the pharmacokinetic parameters for single-agent IPH-2101 have 
suggested a half-life of 12-14 days at doses higher than 0.3 mg/kg [30]. At a dose of 0.075 
mg/kg, full KIR occupancy (above 90%) was seen for less than 7 days. At a dose of 0.3 mg/kg, 
KIR occupancy decreased to less than 90% beginning on day 28. Sustained full KIR occupancy 
(above 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was clear correlation 
between anti-KIR antibody exposure and KIR occupancy.
2.3.1.2 Clinical safety
A phase I study of IPH-2101 in 23 elderly patients with acute myeloid leukemia (AML) in first 
complete remission was recently reported. Patients received escalating doses: 0.0003, 0.003, 
0.015, 0.075, 0.3, 1 and 3 mg/kg, but a maximally tolerated dose was not reached. At the highest 

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dose levels (0.3, 1, and 3 mg/kg), transient increases in tumor necrosis factor-alpha (TNF-α) 
serum concentrations and NK cell CD69 expression were observed. Grade 3 and 4 adverse 
events were limited to one patient who experienced a transient lipase elevation that resolved 
spontaneously. The most frequently reported treatment-related effects included pruritis (17%), 
rash (17%), and fever (13%). A similar trial in 32 patients with relapsed, refractory multiple 
myeloma used IPH-2101 administered IV every 28 days in 7 dose-escalated cohorts (0.0003 to 3 
mg/kg) for up to 4 cycles. Again the highest dose was tolerated without achieving a maximally 
tolerated dose [31]. In the relapsed, refractory myeloma setting there was one severe adverse 
event reported (acute renal failure requiring hemodialysis), with no evidence of autoimmunity 
noted. In the expanded cohort of this trial, the most commonly observed treatment-related effects 
included fatigue, chills, non-cardiac chest pain and pyrexia.
IPH-2101 has also been evaluated in combination with lenalidomide in the treatment of relapsed, 
refractory multiple myeloma [32]. In a phase I trial that enrolled 15 patients in three cohorts 
lenalidomide was given at a standard 10 mg dose in cohort 1 and 25 mg in cohorts 2 and 3 on 
days 1 to 21 of a 28 day cycle in combination with IPH-2101 given IV on day 1 of each cycle at 
0.2 mg/kg in cohort 1, 1 mg/kg in cohort 2, and 2 mg/kg in cohort 3. The biologic endpoint of 
full KIR occupancy was achieved across the IPH-2101 dosing interval. Pharmacokinetic data of 
IPH-2101 with lenalidomide were similar to data from a prior single-agent IPH-2101 trial. Five 
serious adverse events were reported along with five objective responses; with no autoimmunity 
reported. Grade 3 and 4 adverse events most often included neutropenia and lymphopenia, along 
with a cytokine release syndrome with elevation in pro-inflammatory cytokines in two patients. 
After completion of the study, one patient developed therapy-related myelodysplasia.
2.3.1.3 Clinical efficacy
In the above early study utilizing IPH-2101 in elderly, advanced AML patients, overall and 
relapse-free survival rates compared favorably to reports in comparable patient populations [30]. 
Twenty evaluable patients had relapse with a median PFS of 7.7 months (95% confidence 
interval [CI], 1.8-9.5) and a median OS of 12.7 months (95% CI, 10.9-24.2). The 6 patients 
treated at dose levels 1 and 3 mg/kg showed a significantly improved OS compared with the 16 
patients on the previous dose levels (< 0.3 mg/kg): 29.7 months compared with 11.8 months, 
respectively (p = 0.03). In the early phase study of IPH-2101 in relapsed, refractory multiple 
myeloma, no objective responses were observed while eleven (34%) patients achieved a best 
response of stable disease [31]. In the combined IPH-2101 and lenalidomide study mentioned 
above, there were five objective responses: two very good partial responses (VGPR) and three 
partial responses (PR); out of these, objective responses occurred in 3 patients who had received 
prior lenalidomide and dexamethasone. The PFS was 24 months (95% CI, 2.5 to not reached). 
2.3.2 Nivolumab combined with lirilumab
2.3.2.1 Clinical safety
Across a phase I/II study of the combination of nivolumab and lirilumab in advanced solid tumor 
patients, treatment-related adverse events of all grades were reported in 71.7% of patients, which 
was similar to rates observed with anti-PD-1 monotherapy [33]. The most common events 

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included fatigue (20.8%), pruritis (18.9%), infusion-related reactions (17.6%) and rash (16.4%). 
Grade 3 and 4 toxicities were observed in 15.1% of patients, with only 2.5% discontinuing 
treatment.
2.3.2.2 Clinical efficacy
Preclinical studies have evaluated the hypothesis that the combination of anti-KIR and anti-PD-1 
would potentiate anti-tumor response in solid tumor models. The rationale was to utilize 
pharmaceutical manipulation to regulate innate and adaptive immunity and recapitulate what has 
been observed in post-allogeneic stem cell transplant patients who demonstrate KIR mismatch 
[34]. Nivolumab and lirilumab are both fully human monoclonal antibodies, and therefore 
murine specific PD-1 antibody and anti-Ly49 antibody (an F(ab)2 that recognizes Ly49C/I which 
is the KIR homologue in mice) were utilized. Syngeneic MC38 murine colon carcinoma cell line 
models were used and mice randomized to one of four cohorts to receive control 
immunoglobulin (IgG), anti-Ly49 antibody, anti-PD-1 antibody, or both antibodies. Mice treated 
with a control IgG antibody had rapid tumor growth. While mice treated with anti-Ly49 antibody 
did not differ significantly from controls, those treated with a murine anti-PD-1 antibody showed 
latency in tumor progression and 30% of mice continued to be free of tumor. Those treated with 
both antibodies also had latency in tumor progression and 60% of mice had regression of tumor 
bulk (referenced from protocol 12-487, DFCI).
In a phase I/II study of 29 patients with advanced SCCHN treated with the combination of 
nivolumab (3 mg/kg IV every 2 weeks) and lirilumab (in doses ranging from 0.1 to 3 mg/kg IV 
every 4 weeks – with a phase II established dose of 3 mg/kg IV every 4 weeks) until disease 
progression, an ORR of 24.1% was observed [33]. Three CRs were reported (10.3%) along with 
4 additional PRs (13.8%), of which 2 were near-complete responses with ≥ 80% reduction in the 
size of tumor burden. Additionally, eight patients had stable disease (overall disease control rate 
of 51.7%). Six-month OS for the combination was 90% and the 1-year OS rate was 60%. Deep 
and durable responses were observed in some patients, particularly in PD-L1 positive tumors. 
Higher levels of PD-L1 expression as measured by IHC resulted in modest increases in ORR (≥ 
5%, 54.5%; ≥ 50%, 57.1%). All patients had progressed or were intolerant of at least 1 or more 
lines of prior therapy. 
In addition to head and neck cancer and other solid tumors, lirilumab is being investigated in 
combination with nivolumab, as well as with azacitidine and rituximab in certain hematologic 
malignancy subtypes.
2.4 Rationale
Locoregionally recurrent SCCHN imparts significant morbidity on afflicted patients and results 
in poor long-term disease outcomes, representing an important population where novel 
treatments are needed. Mortality rates in this setting approach 50% [1], and it is often very 
challenging to treat these patients owing to the multifocal and an infiltrative burden of disease. 
This is further complicated by the fact that prior chemotherapy and radiation treatments may 
limit potential therapeutic options. The interval in which disease recurs if often of prognostic 
value: as those with a disease-free interval less than 6 months have poorer outcomes [35]. Also 

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an important consideration, the site of disease recurrence often dictates available retreatment 
options and prognosis: laryngeal recurrence can sometimes be salvaged with total laryngectomy 
(5-year OS approaches 60%) as compared with oropharyngeal or hypopharyngeal tumors (5-year 
OS in the 16-44% range) which are more difficult to resect [36]. Post-salvage positive resection 
margins and extracapsular spread of disease also have been reported as predictors of poor 
outcome [37]. Patient-specific factors also play heavily into decision-making, as prior therapy 
may have contributed to poor cardiopulmonary or renal reserve, cognitive issues, tobacco and 
alcohol exposure may be ongoing, and there remain significant quality of life concerns with re-
resection. While the morbidity associated with salvage surgery can be substantial depending on 
the site and extent of disease, it often represents the best therapeutic option for operable patients 
[38]. For the above reasons, capturing outcomes in this heterogeneous population can be 
difficult. In a single-center retrospective series of 109 patients undergoing salvage surgery for 
recurrent SCCHN, 5-year OS was 42% compared with a 5-year DFS of 47% for all patients [36]. 
Accounting for specific disease sites, 3-year OS in surgically salvaged oropharyngeal tumors has 
been estimated at 48.7% [39], whereas 5-year OS in laryngeal and hypopharyngeal recurrence 
treated with surgical salvage is 27-57% [40, 41]. A large multicenter meta-analysis that included 
over 1000 patients reported a 5-year OS of 39%. Of note, these studies included patients 
receiving salvage surgery with or without additional ‘adjuvant’ chemotherapy and/or radiation—
the benefit of which remains controversial. Investigating alternative therapeutic strategies that 
incorporate novel treatment mechanisms is warranted. 
It is now widely recognized that tumor cells harbor immune checkpoint receptors to evade 
immune recognition [11]. Immune checkpoint inhibitors that block inhibitory immune cell 
signaling have demonstrated efficacy in platinum-refractory and advanced SCCHN [26, 42, 43] 
prompting clinical trials to explore their potential in various other head and neck cancer 
populations. Aside from T cells, recent data aimed at understanding the tumor microenvironment 
has suggested that natural killer (NK) cells are heavily infiltrated in SCCHN tumors and also 
express immune checkpoint receptors like programmed cell death protein-1 (PD-1) and the killer 
cell immunoglobulin-like receptor (KIR) [44, 45]. NK cells comprise 15% of peripheral 
circulating lymphocytes and are crucial in innate immune function: they bind to target via 
receptors that promote tyrosine kinase phosphorylation and signaling cascades to release 
preformed perforin and granzyme-containing granules to kill target cells [46]. They also 
concurrently release chemokines into the surrounding microenvironment to recruit other immune 
effector cells. While NK cells can mediate cytotoxic activity, they also contain another receptor 
set that binds major histocompatibility complex (MHC) class I molecules. Binding of human 
leukocyte antigen (HLA)-A, B or C to KIR leads to downstream signaling which suppresses 
normal NK cell activation – this KIR:HLA interaction impairs NK cell responsiveness [34]. 
Additionally, there are seven inhibitory KIRs with some receptors expressed on NK T cells 
which has implications for activating NK cells via KIRs. Early data about NK cell involvement 
in anti-tumor response arose from hematopoietic stem cell transplant studies, where leukemia 
patients transplanted with KIR mismatched donor NK cells (recalling that KIR interacts with 
specific HLA ligands) had lower rates of relapse [47]. In fact, NK cell activation has been shown 
to eradicate tumor in the presence of interleukin-15 (IL-15) released by tumor cells in murine 
models [48]. Moreover, recently published data has suggested higher rates of NK cell presence 
among SCCHN tumors [44], and our own data suggests higher NK cell abundance among 
immunologically rich SCCHN tumors [49].

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The combination of the KIR inhibitor lirilumab and the PD-1 inhibitor nivolumab resulted in an 
objective response rate of 24.1% in a phase I/II study that included advanced SCCHN patients – 
as presented recently in abstract form (NCT01714739) [33]. Among 29 patients, 3 demonstrated 
a complete response (10.3%) with an additional 4 patients (13.8%) having a partial response – 
yielding a 1-year overall survival rate of 60% in this cohort. Of the 4 partial responders, half 
were near-complete responses with > 80% reduction in tumor size. Nivolumab was administered 
at a standard dose of 3 mg/kg every 2 weeks, while the phase II dose of lirilumab was established 
at 3 mg/kg every 4 weeks. Treatment-related adverse events of all grades in this group were 
similar to those with nivolumab monotherapy. These preliminary findings warrant further 
investigation using this combination in other SCCHN populations, as these patients were often 
heavily pre-treated and observed responses were usually durable. 
Administering systemic therapy prior to surgical re-resection (so-called neoadjuvant treatment) 
could offer several advantages, including downstaging of tumor burden and nodal disease to 
decrease the morbidity of salvage surgery and decrease the likelihood of a positive surgical 
margin. Early systemic therapy may address the risk of distant metastatic spread, and facilitate 
early evaluation of biomarkers of response to neoadjuvant therapy. The concept of induction 
therapy in the form of neoadjuvant treatment (prior to surgical resection) has previously been 
explored in SCCHN in the initial treatment setting. Three cycles of a platinum-based 
combination followed by surgery in a resectable, locoregionally advanced oral cavity SCCHN 
population did not improve OS compared with standard resection, but seemed to result in tumor 
downstaging resulting in fewer patients requiring mandibulectomy and adjuvant radiation [50]. A 
similar study combining platinum-based therapy with a taxane prior to resection in advanced oral 
cancer patients failed to improve 5-year OS rates [51]. Recognizing their clinical benefit and 
favorable toxicity profile in SCCHN, an exciting next step is to investigate neoadjuvant 
immunotherapeutic approaches to treat resectable SCCHN – and such trials are now underway.
Capitalizing on the window phase of treatment prior to initial surgical resection in SCCHN, 
several accruing trials using the anti-PD-1 inhibitors pembrolizumab and nivolumab with or 
without the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab are 
active [NCT02296684, NCT02641093, NCT02919683, NCT02488759, NCT03021993]. These 
trials can be distinguished by the number of pre-operative doses of immunotherapy (ranging 
from one to four) and whether or not adjuvant immunotherapy is continued following resection. 
Preliminary efficacy and response assessments are eagerly anticipated for these studies to inform 
future neoadjuvant immunotherapeutic trial designs. Extrapolating from a related disease, non-
small cell lung cancer, a neoadjuvant study of two doses of nivolumab prior to definitive surgical 
resection for resectable non-small cell lung cancer recently reported preliminary results [52]. 
Seven of 18 (38.8%) evaluable patients had major pathologic regression (defined as < 10% 
viable tumor remaining at the time of resection) with 1 patient experiencing a pathologic 
complete response, and all with dense immune cell infiltrates observed on pathology. 
Importantly, only 1 patient withdrew from the study due to toxicity but there were no delays to 
surgery. This latter trial indicates that neoadjuvant immunotherapy treatment strategies prior to 
resection appear feasible and safe. 
Recently, an open-label phase II study of pembrolizumab in relapsed, locally recurrent SCCHN 

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opened with a primary endpoint of 1-year DFS (NCT02769520). The study includes a window of 
opportunity phase which randomizes patients 3:1 to pembrolizumab and placebo for a maximum 
of 2 doses prior to salvage surgery. Following surgery, pembrolizumab (or placebo) at standard 
dosing will be administered every 3 weeks up to 12 months or until disease progression. Given 
the favorable preliminary response signal observed with combined anti-PD-1 and anti-KIR 
immunotherapy in an advanced SCCHN cohort, studies utilizing this regimen in the neoadjuvant 
and/or adjuvant treatment setting are warranted. Here we propose a single arm, non-randomized 
phase II study for patients with relapsed, resectable SCCHN using the combination anti-KIR and 
anti-PD-1 therapy both in a window of opportunity phase prior to resection and in the adjuvant 
setting following salvage surgery in hopes of improving the 1-year DFS in this critical 
population. The use of this novel neoadjuvant combination of immune checkpoint inhibition 
offers early systemic therapy with a favorable side effect profile in a high-risk population in 
hopes of downstaging tumor burden and addressing the risk of distant disease spread, while 
permitting a window phase in which to explore immune correlatives. Additionally, the adjuvant 
phase of therapy seeks to continue immune checkpoint inhibition exposure post-resection to 
potentially address remaining microscopic disease and improve both disease-free and overall 
survival while minimizing toxicity.
2.5 Correlative Studies Background
Given that response rates to PD-1 blockade in the advanced, platinum-refractory SCCHN setting 
approach 20%, there is strong interest in identifying biomarkers that predict clinical benefit. In a 
NSCLC population, PD-L1 expression in at least 50% of tumor cells yielded a response rate of 
45.2%, compared with an objective response rate of 19.4% among all treated patients [53]. More 
recently, whole-exome sequencing of NSCLC tumors treated with PD-1 blockade revealed that 
higher mutational burden correlated with improved objective response rates [54]. Somatic 
alterations in tumor cells yield neoantigens which are thought to facilitate antigen-specific CD8+ 
T cell responses – suggesting that the genomic landscape of the tumor impacts PD-1 response. In 
SCCHN, stromal or tumor PD-L1 expression does appear to partially impact response, but even 
PD-L1 negative patients may respond to treatment – suggesting important mechanisms beyond 
PD-1:L1 interactions [42, 43]. Moreover, NK cell infiltration is thought to be increased among 
SCCHN tumors, and our own work has suggested that NK cell populations may be higher in 
immunologically rich SCCHN tumors [44, 49]. 
More recent work has sought to use more comprehensive immune-based metrics to characterize 
the tumor microenvironment. Cytometric profiling has identified immunologically ‘hot’ and 
‘cold’ immunophenotypes which may identify tumors more likely to respond to 
immunotherapies [55, 56]. Studies confirming these findings in head and neck cancer patients 
are not yet published, although our own preliminary work has shown that a robust CD8+ T cell 
infiltrate and pattern of immune checkpoint co-expression may predict clinical benefit to PD-1 
blockade in an advanced SCCHN population [57]. The window phase of treatment proposed in 
this study will allow evaluation of pre- and post-immunotherapy tumor samples, permitting 
investigation of immune microenvironment alterations to potentially identify mechanisms of 
response and resistance. Additionally, whether the circulating peripheral immune environment 
recapitulates the tumor immune microenvironment remains an unanswered question. By 
evaluating both the tumor and circulating immune profile, we hope to evaluate whether early 

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peripheral blood changes in immune parameters could parallel an early indication of treatment 
response, avoiding the cost and risk of sequential tumor biopsies. Understanding the genomic 
determinants which drive immunophenotype appear crucial and therefore whole exome and bulk 
RNA sequencing are also planned. Finally, we will attempt to correlate changes in tumor and 
lymph node radiologic measurements with immune microenvironment alterations and circulating 
immune parameters. 
3. PARTICIPANT SELECTION
Participants must meet the following eligibility criteria on screening examination to be eligible to 
participate in the study:
3.1
Inclusion Criteria
3.1.1
Subject must have histologically or cytologically confirmed locoregionally recurrent 
squamous cell carcinoma of the head and neck (including any primary site, such as oral 
cavity, oropharynx, larynx or hypopharynx, and nasopharynx carcinoma)
3.1.2
Must be a candidate for salvage surgery
3.1.3
Willing to provide blood and tissue from diagnostic biopsy and at the time of surgery
3.1.4
Has documented disease-free interval (DFI) > 8 weeks after completion of initial therapy; 
DFI is from the time of completion of initial treatment (from date last known disease-free 
at end of initial treatment) to the diagnosis of local or locoregional recurrence
3.1.5
Any HPV status or smoking history is permitted. Oropharyngeal cancer patients are 
required to undergo HPV testing with p16 immunohistochemistry and/or confirmatory 
HPV PCR or ISH testing
3.1.6
Age 18 years or older
3.1.7
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
3.1.8
Participant must have normal organ and marrow function as defined below within 21 
days prior to study registration:
−
leukocytes
≥3,000/mcL
−
absolute neutrophil count
≥1,500/mcL
−
platelets
≥100,000/mcL
−
total bilirubin
≤2.0 g/dL 
−
AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal
−
creatinine
within normal institutional limits
OR
−
creatinine clearance
≥60 mL/min/1.73 m2 (calculated using the Cockcroft-

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Gault equation) for participants with creatinine levels 
above institutional normal
3.1.9
Ability to understand and the willingness to sign a written informed consent document
3.1.10 Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of 
contraception. WOCBP should plan to use an adequate method to avoid pregnancy for 5 
months (30 days plus the time required for nivolumab to undergo five half-lives) after the 
last dose of investigational drug 
3.1.11 Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 iu/l or equivalent units of hcg) within 24 hours prior to the start 
of nivolumab
“Women of childbearing potential (WOCBP)” is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. In addition, to be defined as menopausal, women under the age of 
55 must have a documented serum follicle stimulating hormone (FSH) level greater than 
40 mIU/mL.
3.1.12 Men who are sexually active with WOCBP must agree to use any contraceptive method 
with a failure rate of less than 1% per year. Men who are sexually active with WOCBP 
will be instructed to adhere to contraception for a period of 7 months 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
See Appendix B for further guidance on contraception.
3.2
Exclusion Criteria
3.2.1
Existing significant autoimmune conditions. Patients with a history of Hashimoto 
thyroiditis who are stable on replacement hormone therapy are not excluded. Patients 
cannot be on long-term (> 4 weeks) corticosteroids at doses exceeding prednisone 20 mg 
(or its equivalent) prior to enrollment. Short-term corticosteroid dosing is permitted as 
long as steroids are discontinued within 2 weeks of study enrollment.
3.2.2
Subject who has had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier.

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3.2.3
Subject who has been treated with immunotherapy. This includes prior treatment with 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways
3.2.4
Subject with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
However, baseline brain imaging is not required prior to enrollment in the study if 
patients are asymptomatic.
3.2.5
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.
3.2.6
Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency. Any 
positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, 
eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
3.2.7 Known non-infectious pneumonitis or any history of interstitial lung disease.
3.2.8 Receipt of a live vaccine within 30 days of start of study treatment.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this study.
4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Eligible subjects will be registered by a member of the study team in the Clinical Trials 
Management System (CTMS) “OnCore”. Registrations must occur prior to the initiation of 
protocol therapy. Any subject not registered to the protocol before protocol therapy begins will 
be considered ineligible and registration will be denied.
Following registration, 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. 

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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
See DSMP appendix
4.4
Registration Process for Other Investigative Sites
See DSMP appendix
5. TREATMENT PLAN
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than nivolumab (BMS-936558) and lirilumab (BMS-986015) may be 
administered with the intent to treat the participant’s malignancy during the course of treatment.  
5.1
Pre-Treatment Criteria
Eligibility and exclusion criteria are provided in Section 3.  These criteria will be assessed 21 
days prior to study registration 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.  
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, and medical histories. 
5.2
Treatment Regimen
Patients will be premedicated with diphenhydramine, famotidine, and acetaminophen before 
lirilumab doses unless otherwise directed by treating investigator. Each treatment cycle will be 
28 days long. On the days when both nivolumab and lirilumab are administered, nivolumab will 
be administered first, followed by lirilumab, with a 30-minute minimum duration time between 
the administration of nivolumab and lirilumab. Nivolumab infusion must be promptly followed 
by a saline flush to clear the line of nivolumab before starting the lirilumab infusion. Participants 
should be carefully monitored for infusion reactions during nivolumab and lirilumab 
administration. If an acute infusion reaction is noted, participants should be managed according 
to the algorithm described in Appendix C or in Nivolumab IB. 

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Nivolumab infusion time should be 30 (+/-10) minutes. A volumetric pump with a 0.2 - 0.22 
micron in-line filter through an IV transfer set will be used.
Lirilumab infusion time should be 60 (+/-15) minutes. A volumetric pump with a 0.2 micron in-
line filter through an IV transfer set will be used.
Window phase: Seven to twenty-one days prior to salvage surgical resection, a single dose of 
each study drug will be administered. Nivolumab 240 mg IV flat dosing will be administered 
through IV infusion, followed by lirilumab 240 mg IV flat dosing.
Salvage surgical resection: Each participant should be a candidate for salvage surgical resection 
to be able to participate in this study. Surgery should be performed no later than 4 weeks after 
study enrollment. Patients remain eligible to continue on study regardless of post-salvage surgery 
excisional margin status. Following salvage surgery, re-irradiation or additional chemotherapy is 
not permitted during the study period.
Adjuvant phase: Three to eight weeks after salvage surgery, treatment will restart. If additional 
surgery is required after the initial salvage surgery (e.g., for completion, reconstruction), 
treatment will restart after the additional surgery. In Cycle 1-3: Nivolumab will be administered 
on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle.  In 
Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day 
long cycle. Treatment with both study drugs will continue for a maximum of 6 cycles or until 
disease progression or recurrence, unacceptable toxicity or withdrawal of consent. Nivolumab 
240 mg IV flat dosing will be administered through IV infusion, followed by lirilumab 240 mg 
IV flat dosing.
5.2.1
Cycle 1, Day 1
If screening assessments occur within a week 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. Laboratory 
evaluations do not need to be repeated to meet eligibility criteria on cycle 1 day 1, if they were 
done within 3 days of the first treatment dose.
5.3
Pharmaceutical Properties and Formulation for Lirilumab:
5.3.1
Description of the Dosage Form
Lirilumab Injection 100 mg/Vial (10 mg/mL): Lirilumab injection has been developed to be used 
as an intravenous (IV) infusion for clinical studies. The drug product is a clear to opalescent, 
colorless liquid, which may contain few particles.
The 100-mg/vial presentation is contained in a 10-cc Type I flint glass vial, closed with 20-mm 
stoppers, and sealed with aluminum seals. Each vial of the drug product contains the labeled 
amount of lirilumab drug substance, sucrose, sodium phosphate monobasic, sodium phosphate 
dibasic, polysorbate 80 (PST), and water for injection. Diluted sodium hydroxide and/or 
hydrochloric acid solution may be added to adjust the pH to 7.0. A sufficient overfill is included 
in each vial to account for vial, needle, and syringe holdup.

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5.3.2
Drug Product Preparation
Lirilumab injection is administered IV either undiluted (10 mg/mL) or diluted in NS to lirilumab 
concentrations as low as 0.5 mg/mL. The dosing solution is to be infused using a volumetric 
pump at the protocol-specific dose(s) and rate(s) through a non-di-2-ethylhexyl phthalate 
(DEHP) or DEHP IV infusion set with a 0.2 micron polyethersulfone in-line filter. The drug 
product is not to be administered as an IV push or bolus injection.
Care must be taken to ensure the sterility of the prepared solutions, as the drug product does not 
contain anti-microbial preservatives or bacteriostatic agents. 
5.3.3
Recommended Storage and Use Conditions
Lirilumab injection should be stored refrigerated at 2°C to 8°C and protected from light and 
freezing. The administration of lirilumab infusions must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored in a refrigerator at 2°C 
to 8°C (36°F to 46°F) for up to 20 hours, and at room temperature (20°C to 25°C, 68°F to 77°F) 
and room light for a maximum of 4 hours. The maximum 4-hour period under room temperature 
and room light conditions includes the product administration period. The solution in IV bag 
(diluted or undiluted) should not be shaken or frozen. Equilibration to room temperature is 
recommended for the infusion bag, drug product, or their combination prior to administration.
5.4
Pharmaceutical Properties and Formulation for Nivolumab:
5.4.1
Description of the Dosage Form
Nivolumab injection, 100 mg/10 mL (10 mg/mL): Nivolumab injection, 100 mg/10 mL (10 
mg/mL) is a clear to opalescent, colorless to pale yellow liquid, which may contain light (few) 
particulates. The drug product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution 
formulated 
at 
10 
mg/mL 
in 
sodium 
citrate, 
sodium 
chloride, 
mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (Tween 80), at pH 6.0 and 
includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I 
flint glass vials, stoppered with butyl rubber stoppers and sealed with aluminum seals. The only 
difference between the two drug product presentations is the vial fill volume.
5.4.2
Drug Product Preparation
Nivolumab Injection, 100 mg/10 mL (10 mg/mL): Nivolumab injection is to be administered 
as an IV infusion through a 0.2 - 0.22 micron pore size, low-protein binding (polyethersulfone 
membrane) in-line filter at the protocol-specified doses and infusion times. It is not to be 
administered as an IV push or bolus injection. When the dose is based on patient weight (ie, 
mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 
mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection 
can be infused undiluted or diluted so as not to exceed a total infusion volume of 120 mL.
During drug product preparation and handling, vigorous mixing or shaking is to be avoided.
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with 

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polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and glass bottles.
5.4.3
Recommended Storage and Use Conditions
Nivolumab Injection, 100 mg/10 mL (10 mg/mL): Vials of nivolumab injection must be stored 
at 2°C to 8°C (36°F to 46°F) and protected from light and freezing.
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container: The 
administration of nivolumab infusion must be completed within 24 hours of preparation. If not 
used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum of 8 hours under 
room temperature and room light conditions includes the product administration period.
5.5
General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of IND Agents with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Overall PI should 
be alerted if the participant is taking any agent known to affect or with the potential to affect 
CYP450 isoenzymes. 
5.5.1
Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids 
•
Any 
concurrent 
anti-neoplastic 
therapy 
(ie, 
chemotherapy, 
hormonal 
therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents for treatment of NSCLC)
5.5.2
Other Restrictions and Precautions 
Participants with a condition requiring systemic treatment with either corticosteroids (> 20 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first 
dose of study treatment are excluded. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 20 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
5.5.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.

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5.6
Criteria for Taking a Participant Off Protocol Therapy
The following stopping rule will be used to monitor delays in salvage surgery due to excessive 
nivolumab and/or lirilumab-related toxicity: if 3 or more of the first 10 patients who begin 
protocol treatment experience treatment related toxicities which cause delays in definitive 
surgery, accrual to the trial will be suspended to further evaluate the events and decisions made 
regarding the overall status of the trial. If the true delay in surgery rate due to toxicity is 10% 
then the probability of suspending accrual is 7%; if the true rate is 20%, then the probability of 
suspending accrual is 32.2%; if the true delay in surgery rate due to toxicity is 30% then the 
probability of suspending accrual is 62%. Adverse events will be continuously monitored 
throughout the trial by the study team with decisions made accordingly regarding the study status 
and patient entry throughout the duration of the trial.
Any adverse event(s) (as outlined in Section 6.1) attributed to the study medication that result in 
a delay in the planned date of salvage surgery exceeding 14 days warrants removal of the patient 
from the study protocol treatment. Otherwise, therapy can be resumed in the adjuvant phase at 
the discretion of the treating physician or PI. Duration of therapy will depend on individual 
response, evidence of disease progression or recurrence and tolerance. In the absence of 
treatment delays in the adjuvant phase due to adverse event(s), treatment may continue for six 
cycles or until one of the following criteria applies:
•
Disease progression or recurrence
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s) (see Section 6.2)
•
Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements
•
Participant decides to withdraw from the protocol therapy
•
General or specific changes in the participant's condition rendering the participant 
unacceptable for further treatment in the judgment of the treating investigator
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.
An ODQ Treatment Ended Form will be filled out when a participant is removed from protocol 
therapy. 
This 
form 
can 
be 
found 
on 
the 
DF/HCC 
website 
at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/.

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In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Glenn Hanna, MD at 617-632-3696 or 617-632-3090.
5.7
Duration of Follow Up
Participants, regardless if they receive the adjuvant therapy, will be followed for response (at the 
end of the window phase of the trial) and until first disease progression/recurrence and for 
survival for 5 years from point of salvage surgery (or from study registration if no salvage 
surgery was performed). Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event.
5.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
•
Patient completed required follow-up
•
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).
For “Centralized Subject Registrations”, the research team submits a completed Off Study form 
to ODQ when a participant comes off study. This form can be found on the ODQ website or 
obtained from the ODQ registration staff. 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
6. DOSING DELAYS/DOSE MODIFICATIONS
There will be no dose reductions for nivolumab or lirilumab permitted. Doses of nivolumab or 
lirilumab may be interrupted, delayed, or discontinued depending on how well the participant 
tolerates the treatment. If a lirilumab dose is delayed beyond four weeks from the prior lirilumab 
dose, then subsequent lirilumab doses should be rescheduled, if needed, such that the patient 
receives both nivolumab and lirilumab at next visit
6.1
Administration both study drugs should be delayed for the following adverse events: 
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥ 3 AST, ALT, Total Bilirubin will require dose discontinuation 

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•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Note: see Appendix C for guidelines on managing immune-related toxicities
Participants who require delay of nivolumab or lirilumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab or lirilumab dosing when re-treatment 
criteria (as described below) are met. Participants with a delay in dosing beyond 8 weeks should 
be considered for discontinuation of protocol treatment and discussed with the Overall PI.
Subsequent dosing may be re-started if subjects continue to meet laboratory criteria (baseline 
values). The investigator will determine if subsequent dosing is appropriate for subjects who 
have laboratory or clinical abnormalities that do not meet dose discontinuation criteria (described 
below). All related grade 2 toxicities should be discussed with the Overall PI, prior to subsequent 
dosing.
6.2
Administration of both study drugs should be permanently discontinued for the 
following adverse events: 
•
A grade 3 pneumonitis and grade 3 uveitis will require permanent discontinuation.
•
Any grade 4 adverse event will require permanent discontinuation with the following
exceptions:
−
Grade 4 electrolyte abnormalities that < 72 hours in duration
−
Grade 4 neutropenia < 5 days in duration
−
Grade 4 increase in amylase or lipase that is not associated with clinical or radiographic 
evidence of pancreatitis
−
Grade 4 lymphopenia < 5 days in duration
The consideration to re-initiate study therapy under these exceptions will be made on a case by
case basis after considering the overall benefit/risk profile and in consultation with the Overall 
PI.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
7.1
Adverse Event Characteristics: 
•
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.
•
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.

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-
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.
7.2
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe)
•
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect 
•
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) 
•
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs.
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
7.3
Expected Toxicities
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 in the Investigator’s Brochure or is 
included in the informed consent document as a potential risk. Most common adverse events or 
expected toxicities are listed below. Details are found in the respective IBs. Management of 
expected toxicities is described in Appendix C.
Most common adverse reactions (>20%) related to nivolumab alone were: fatigue, rash, 
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, 
decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia.

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The most common adverse reactions (>5%) related to lirilumab alone were: asthenia, fatigue, 
pruritus, infusion-related reaction, chills, and neutropenia.
The most common adverse reactions (>10%) related to nivolumab in combination with lirilumab 
were: fatigue, pruritus, infusion-related reaction, and rash.
The following hospitalizations are not considered SAEs in BMS supported clinical studies: 
−
A visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
Elective surgery, planned prior to signing consent
−
Admissions as per protocol for a planned medical/surgical procedure
−
Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.
−
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAES 
7.4
Routine Adverse Event 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.
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 

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IRB, FDA, etc.) must also be reported in routine study data submissions.
7.4.1
Routine Adverse Event Reporting to BMS 
Adverse Events that are routinely collected according to GCP shall be submitted to BMS every 
three (3) months by the last working day of the third month.  
The Adverse Event information required to be sent to BMS is noted in the ‘Bristol-Myers Squibb 
Early Asset Investigator Sponsored Research (ISR) Import Plan’ spreadsheet and submitted to 
BMS via the mailbox: MG-RD-GPVE-PHARMACOVIGILANCE@bms.com
When the file is submitted to BMS, it must be noted that the file contains all “Non Serious 
Adverse Events” (only adverse events not previously submitted to BMS within the 3 months)
Sites other than Dana-Farber must fill out the ISR spreadsheet to Dana-Farber every three 
months and Dana-Farber will include information from other sites in their submissions to BMS.
7.5
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur within 100 days of 
discontinuation of dosing. All SAEs should be followed to resolution or stabilization.
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy).  The 
sponsor-investigator should report any SAE that occurs after these time periods that is believed 
to be related to study drug or protocol-specified procedure. 
The sponsor-investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms). Frequency of 
reconciliation should be every 3 months and prior to the database lock or final data summary. 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation report. 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data elements 
listed on the GPV&E reconciliation report will be used for case identification purposes. If the 
Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS.
7.6
Expedited Adverse Event Reporting to Overall PI
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
following the subject’s written consent, during treatment, or within 100 days of the last dose of 
treatment on the local institutional SAE form. 
In the event of an unanticipated problem or life-threatening complications, treating investigators 
must immediately notify the overall PI.

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Investigators will report AEs directly to the DFCI Office for Human Research Studies (OHRS) 
per the DFCI IRB reporting policy, using the local institutional SAE form.
7.7
DF/HCC Expedited Reporting Guidelines
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. 
7.8
Expedited Adverse Event Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria below for expedited reporting:
Report any unexpected fatal or life-threatening suspected adverse reactions no later than 7 
calendar days after initial receipt of the information. Submit 7-day reports by a rapid means of 
communication (preferably fax). Each submission should be address to the Regulatory Project 
Manager and/or to the Chief, Project Management Staff.
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/.  Send the SAE forms as follows:
By fax: 
301-796-9849

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OR
By mail:
MEDWATCH
5600 Fishers Lane
Rockville, MD 20852-9787
Fax: 1-800-FDA-0178 (1-800-332-0178)
http://www.accessdata.fda.gov/scripts/medwatch/
7.9
Expedited Adverse Event Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.10
Expedited Adverse Event Reporting to BMS
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a 
Pregnancy Surveillance Form.
SAE Email Address:  Worldwide.Safety@BMS.com
SAE Facsimile Number:  609-818-3804
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
7.11
Multi-Center Trial Specifications
For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each 
participating institution must abide by the reporting requirements set by the DF/HCC. This 
applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable 
or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of study 
phase or attribution.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in section 7.3.

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8.5
Accountability
Accountability for investigational agents at the study site is the responsibility of the sponsor-
investigator. Study drug will be dispensed only to eligible patients by Dana-Farber Research 
Pharmacy. The appropriate study personnel will maintain records of study drug receipt and 
dispensing at Dana-Farber Research Pharmacy. A careful record of the inventory and disposition 
of the agent will be maintained, using the NCI Drug Accountability Record Form (DARF).
8.6
Destruction and Return
Unused supplies and expired supplies of the investigational agents will be destroyed on site, by 
the Dana-Farber Research Pharmacy, per institutional SOP.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Correlative studies are planned as part of this study. At the time of biopsy to demonstrate 
recurrence, tumor tissue will be sent for multiparametric flow cytometry (Belfer Center for 
Applied Cancer Science, DFCI), a portion of fresh-frozen, paraffin-embedded (FFPE) tissue will 
be obtained for genomic sequencing and for immunohistochemistry (IHC) for immune marker 
staining (e.g. PD-1, PD-L1/L2) and/or multiplexed immunofluorescence (MIF). Flow cytometry, 
sequencing and IHC/MIF data will be gathered to characterize distinct tumor immunophentoypes 
and these findings will be correlated with outcomes.
9.1 Biomarker Studies
Biopsy confirmed squamous cell carcinoma of the head and neck is a requirement to be enrolled 
on this study. A separate, fresh research biopsy is mandatory prior to starting treatment on study 
if tumor is accessible, otherwise archival tissue will be accepted. At the time of definitive 
surgical resection, after adequate tumor for pathological assessment has been harvested as 
deemed appropriate 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 research 
purposes.
Tumor biopsies and/or surgery should not generally be performed on Friday afternoons, as there 
may not be time for processing of fresh tissue samples. If a biopsy or surgical resection is 
performed on Friday morning, Dr. Patrick Lizotte of the Belfer Center for Applied Cancer 
Science should be notified ahead of time to ensure that there will be adequate time for processing 
fresh tissue or serum samples, since these should not be stored over the weekend.
Each tumor and blood 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 laboratory 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 

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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.
At the time of blood sample collection (see Study calendar), 2 tubes are requested:
1. 2 tubes drawn in 8 mL whole blood, purple top tubes for circulating immune profiling
2. 2 tubes drawn in 8 mL whole blood, purple top tubes for neoantigen T cell profiling
Multiparametric flow cytometry
At the time of pre-treatment biopsy and surgical resection, two cores of fresh tissue will be 
allocated to two 1.5 mL centrifuge tubes (one core in each tube) in RPMI containing 10% fetal 
bovine serum (FBS). Additionally, at the time of pre- and post-treatment biopsy and at specified 
time points during and after treatment, two tubes of peripheral blood (obtained at a minimum of 
3 time points during the study) will be obtained per standard collection protocols – drawn in 
phlebotomy or clinic and captured in 8 mL whole blood, purple top tubes. The volume of blood 
to be collected per blood draw for study purposes will not exceed 40 mL. All specimens will be 
de-identified and labeled with the participant’s initials, study ID number and the date of 
acquisition. After collection, the tissue and blood collection tubes should be delivered 
immediately to the lab of Dr. Patrick Lizotte and Megan Cavanaugh [office: LC-4315J, Robert 
and Renee Belfer Center for Applied Cancer Science, 360 Longwood Avenue, Boston, MA 
02215, phone: 207-423-0958 or 631-487-6573]. The specimen must arrive in a timely fashion to 
facilitate processing for evaluation of immune cells. Tissue will be prepared as a cell suspension 
that will be stained using fluorescently-conjugated antibody cocktails for human immune 
markers (surface antibodies include: CD45, CD3, CD4, CD8, CD69, CD38, CCR7, LAG-3, 
TIM-3, PD-1, CD45RA, HLA-DR, CTLA-4, CD16, CD56, CD31, CD33, PD-L1, PD-L2, GITR, 
CD15, CD19, and CD14). Cells will be analyzed within 72 hours of fixation on a BD Fortessa 
cell analyzer with FACSDiva software v8.0.1 (BD Biosciences) and gated using FlowJo software 
v10.
Immunohistochemistry
At the time of pre-treatment biopsy and surgical resection, one core of fresh tissue will be 
allocated to a standard orange-top specimen cup containing 10% neutral buffered formalin. The 
specimen will be labeled with the participant’s initials, medical record number and the date of 
acquisition. After collection, the specimen will be sent to the Brigham & Women’s Hospital 
(BWH) pathology division for processing. Following standard tissue processing, sectioning and 
slide preparation for histopathologic review, the specimen will be stored in accordance with 
BWH protocols (both tissue blocks and tissue slides). At a later time, we will then request tissue 
block retrieval through the Pathology Specimen Locator Core with preparation of 5 unstained 
slides through the Specialized Histopathology (SHP) Core service at BWH. SHP will then 
prepare 1 stained hematoxylin & eosin slide, 1 slide stained for PD-1, 1 slide stained for PD-L1 
and 2 unstained slides will be stored for additional studies. These slides will be retrieved from 
the SHP in Thorn Building, 6th floor, room 603 at the BWH by the study principal investigator.  
In collaboration with an oral histopathologist, Dr. Sook-Bin Woo of the BWH Department of 
Oral Medicine and Dentistry, the slides will be analyzed and scored based on stained immune 
parameters.

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Genomic sequencing
At the time of pre-treatment biopsy and surgical resection, one core of fresh tissue will be 
allocated to 5 mL of RPMI media in a 15 mL conical tube for the purposes of DNA and RNA 
sequencing efforts. Once prepared, aliquoted core material for sequencing will be delivered 
immediately to the laboratory of Dr. Ravindra Uppaluri at the DFCI [Dana Building, 8th floor, 
room 819, 450 Brookline Avenue, Boston, MA 02215, office: 617-632-3091].
9.2 Multi-center Guidelines
Non-DF/HCC sites will be responsible for shipping samples to Dana-Farber on the day of 
collection.  Specific shipping instructions will be provided separately.

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10. STUDY CALENDAR
Screening evaluations are to be conducted within 3 weeks prior to study registration.  Procedures 
done within a week of study registration don’t need to be repeated to establish baseline. Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  Laboratory evaluations do not 
need to be repeated to meet eligibility criteria on cycle 1 day 1, if they were done within 3 days 
of the first treatment dose. In an 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. 
Each treatment cycle in this study is 28 days long.
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.
Screening
Window 
Phase
Pre-
surgery
Adjuvant phase
End of 
Treatment  
Follow 
up visit 
30 days 
after 
last 
dose 
Cycle 
1
Cycle
 2
Cycle 
3
Cycle 
4-6
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Informed consent
X
Medical History
X
Concomitant 
Medicines
X  
Physical exam (Ht, 
Wt, VS, PS) a 
X  
X
X
X
X
X
X
X
X
X
X
Routine labs b
X  
X
X
X
X
X
X
X
X
X
X
FSH (if female <55 
years old)
X
HPV testing (oro-
pharyngeal only)
X
B-HCG 
(WOCBP only) c
X
X
X
ECG
X
Surgery
X
X

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a)
Physical exam is symptom directed. Height measured at screening only.
b)
Routine labs include: CBC, LFTs, CMP, Mg, TSH, Free T4. Baseline HCV antibody, hepatitis B surface antigen, hepatitis 
B surface antibody, and hepatitis B core antibody testing is required. TSH and free T4 are required less frequently 
according to the following schedule: screening, window phase (D1 of pre-surgery immunotherapy dosing), D1 of each 
adjuvant cycle, and at the 30-day post protocol treatment visit.
c)
Serum or urine within 24 hours prior to first dose. 
d)
PET-CT or contrast-enhanced CT imaging of the chest, abdomen and pelvis will be obtained at baseline to rule out distant 
disease. Contrast-enhanced neck CT or MRI at the time of screening or registration and will be repeated 1-4 days prior to 
salvage surgery. Interval scans (contrast-enhanced neck CT or MRI) will be performed every 8 weeks following salvage 
surgery or as clinically indicated while on treatment. Follow-up imaging will be performed at the end of treatment (see 
footnote g). 
e)
Archival tissue is acceptable. Some of this tissue will also be used for correlative study.
f)
Fresh biopsy is mandatory if tumor is accessible. Fresh tissue is also collected at the time of surgery. Biopsy will also be 
obtained at the time of progression or recurrence, if safe to perform.
g)
Participants, regardless if they receive the adjuvant therapy, will be followed for response (at the end of the window phase 
of the trial) until first disease progression or recurrence and for survival throughout the trial for a total of 5 years from time 
of salvage surgery (or from study registration if no salvage surgery was performed). Post-end of protocol treatment, if first 
disease progression or recurrence has not been confirmed, tumor assessments (contrast-enhanced neck CT or MRI and 
PET-CT) are to continue every 3 months (+/- 1 month) until first disease progression or recurrence, death, or 2 years post-
date of salvage surgery (or from study registration if no salvage surgery was performed), then every 6 months until 5 years 
post-date of salvage surgery (or from study registration if no salvage surgery was performed). After first disease 
progression or recurrence has been confirmed, patients will be followed for survival by phone only, every 3 months (+/- 1 
month) until death or 5 years post-date of salvage surgery (or from study registration if no salvage surgery was performed), 
whichever occurs first.
h)
Recommended in the setting of disease recurrence or progression only.
i)
Screening correlative blood collection may occur at screening or at pre-surgery. Pre-surgery correlative blood collection 
may occur any time from the day following neoadjuvant drug administration until surgery. EOT blood draw may occur 
after the EOT visit.
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for recurrence every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained (not less than 4) weeks 
following initial documentation of objective response. Timelines are described in section 10. 
Radiologic 
evaluation d, g
X
X
X
Biopsy sample e, f
X
Xh
Correlative biopsy f
X
Xh
Correlative blood i
Xi
X
X
Nivolumab
X
X
X
X
X
X
X
X
Lirilumab
X
X
X
X
X
Adverse event 
evaluation  
X
X
X
X
X
X
X
X
X
X

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Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/lung parenchymal inflammation, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic 
lesions are all considered non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 

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since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, 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), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 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, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a 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 unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
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Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 

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measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
MIBG (meta-iodobenzylguanidine). The following is recommended, to assure high 
quality images are obtained. 
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds. 
Images from the head to the distal lower extremities should be obtained. 
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images. 
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred. 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity.
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 

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pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.4 Response Criteria (for the window phase of the study)
11.1.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 

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short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.1.4.3
Evaluation of New Lesions (for the window phase and adjuvant phase)
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 (for example, some ‘new’ bone lesions may be simply 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.
11.1.4.4
Evaluation of Best Overall Response (for the window phase of the study)
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
>4 wks Confirmation**

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PR
Non-CR/Non-
PD/not 
evaluated
No
PR
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
∗
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
∗
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.5 Duration of Response (for the window phase of the study)
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
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 progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.

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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, including the baseline measurements. 
11.1.6 Disease-Free Survival and Overall Survival
Overall Survival: Overall Survival (OS) is defined as the time from salvage surgery (or 
from study registration if no salvage surgery was performed) to death due to any cause, or 
censored at date last known alive.
Disease-Free Survival: Disease-Free Survival (DFS) is defined as the time from salvage 
surgery (or from study registration if no salvage surgery was performed) to first 
progression or recurrence or invasive non-head-and-neck second primary or death from 
any cause, whichever occurs first. Participants alive without disease progression or 
recurrence are censored at date of last disease evaluation.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study.
12.1.2 Responsibility for Data Submission
Study team is responsible for entering data in the eDC system (InForm), within the 
timeframe, in accordance with DF/HCC SOPs.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. 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 Overall PI and study 
team.
The DSMC will review each protocol up to four times a year 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 with 30 

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days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; 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
Multicenter Guidelines
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 B.
•
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.
12.4
Data Sharing Agreement
Data are planned to be transferred to BMS a the following 2 proposed timepoints:
1) When n=27 patients (50% of the total sample size) have been accrued and undergone the 
response assessment during the window phase and proceeded to salvage surgery.
2) When those same n=27 patients have first disease progression or date last know disease-
free and/or follow up information to 1 year post salvage surgery.
To be compliant with HIPAA:
a) Variables such as age will be transferred as needed rather than patient identifying 
information such as names, date of birth, etc
b) Patient specific dates will be replaced with times in days or months from date of salvage 
surgery to date of progression/date last know disease-free and/or to date of most recent 
follow-up.
c) The case number from the trial database will be replaced with a unique case identifier and 
will be the only assigned identifier in the dataset(s) upon transfer (note the study 
statistician generates this random number and keeps a mapping of this identifier to the 
original case number).
Closer to data transfer itself, decisions will be made as to whether the study statistician or 
ODQ staff (or a combination) prepare the dataset(s) and BMS preference to receive excel or 
SAS dataset(s). Documentation will also be included with the dataset(s) (i.e. variables names 
with corresponding descriptions and/or definition). Once the dataset(s) is prepared, it will be 
reviewed by the study statistician (if they did not prepare it) and the study chair, data will be 
archived and then transferred (by study statistician or ODQ) in a secure manner (method to 
be determined at time of transfer).

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No party may report and/or publish on outcome data while the trial is ongoing. After closure 
of trial the usual follow up and preparation of reports and/or manuscript will resume.
13. STATISTICAL CONSIDERATIONS
This is a one arm phase II trial. The primary endpoint is 1-year disease-free survival (DFS) from 
point of salvage surgery. A 1-year DFS of 57% [36, 39-41] is the basis of the null hypothesis. 
Based on a 1-year DFS of 57%, the hazard is .5621 DFS events/person-year of follow up. A 30% 
reduction in that hazard would lead to a hazard of .3935. When 37 DFS events are observed 
among n=54 patients who receive salvage surgery and begin adjuvant treatment, this design has 
81% power to detect a 30% reduction in the DFS hazard (using a one-sided 10% type I error rate, 
Wald's test). Assuming an exponential distribution, this corresponds to improving 1-year DFS 
from 57% to approximately 67.5% from using the adjuvant treatment.
Allowing for patients who may fail prior to salvage surgery, not receive the adjuvant portion of 
treatment, or for patients who are declared ineligible, n=58 patients will be registered to the trial.
The primary efficacy population includes all eligible patients who receive salvage surgery and 
begin adjuvant treatment. The Kaplan-Meier method will be used to estimate time-to-event 
endpoints. 
For secondary objectives: Best overall response (at the end of the window phase of the trial) will 
be summarized as a proportion with a corresponding exact 95% confidence interval (CI) (noting 
that a ‘modified’ version (no confirmation of initial CR or PR) of RECIST will be used for 
patients whose disease initially achieves a CR or PR: the patients’ tumor will be resected prior to 
confirming the CR or PR at least 4 weeks after initial response). Adverse events will be 
classified and graded according to the CTCAE v.4.0. Frequencies of adverse events will be 
summarized. The distributions of n-year DFS and survival will be estimated using a Kaplan-
Meier method with corresponding 95% confidence intervals for time-specific event time. Several 
correlative studies are also planned. Given the small sample size of this trial, these studies are 
exploratory. Samples will be collected at baseline and at post-baseline timepoints as outlined in 
the protocol. Markers from the samples (cluster differentiation markers from both tumor and 
circulating peripheral blood, see Section 9.1) will be summarized descriptively and graphically. 
Within subject changes in markers will also be analyzed. Assuming n=50 patients with useable 
baseline and post baseline markers, there is 81% power to detect .42 SD mean difference 
(Wilcoxon sign rank test two-sided 0.05 alpha level.
The following stopping rule will be used to monitor delays in salvage surgery due to excessive 
nivolumab and/or lirilumab-related toxicity: if 3 or more of the first 10 patients who begin 
protocol treatment experience treatment related toxicities which cause delays in definitive 
surgery, accrual to the trial will be suspended to further evaluate the events and decisions made 
regarding the overall status of the trial. If the true delay in surgery rate due to toxicity is 10% 
then the probability of suspending accrual is 7%; if the true rate is 20%, then the probability of 
suspending accrual is 32.2%; if the true delay in surgery rate due to toxicity is 30% then the 
probability of suspending accrual is 62%. Adverse events will be continuously monitored 

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throughout the trial by the study team with decisions made accordingly regarding the study status 
and patient entry throughout the duration of the trial.
Assuming accrual of approximately 2.2 patients per month, 2 years of accrual and 2 years of 
follow up are needed for the operating characteristics for the primary endpoint. Analysis of 
primary endpoint is estimated to take place therefore approximately 4 years after the trial opens 
to accrual (approximately 2 years of accrual and 2 years follow up) or when 38 DFS events have 
been observed. Due to possible delays in initiation of approval at other sites, in initiation of 
accrual itself, the accrual period could take longer and due to possible delays in data submission 
and processing, the actual analysis time for the primary endpoint could be later. Analysis of 
secondary endpoints will require more follow-up. Assuming that the stated accrual assumptions 
hold, if at any time within 4 years >37 DFS events are observed, the study will not have met its 
primary endpoint.
See also Data Sharing Agreement in section 12.
14. PUBLICATION PLAN
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 to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 
15. REFERENCES
1.
Brockstein B, H.D., Rademaker AW, Kies MS, Stenson KM, Rosen F, Mittal BB, Pelzer 
H, Fung BB, Witt ME, Wenig B, Portugal L, Weichselbaum RW, Vokes EE, Patterns of 
failure, prognostic factors and survival in locoregionally advanced head and neck cancer 
treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional 
experience. Ann Oncol, 2004. 15(8): p. 1179-86.
2.
Ho AS, K.D., Ganly I, Lee NY, Shah JP, Morris LG, Decision making in the 
management of recurrent head and neck cancer. Head Neck, 2014. 36(1): p. 144-51.
3.
Jr, G.W., Salvage surgery for patients with recurrent squamous cell carcinoma of the 
upper aerodigestive tract: when do the ends justify the means? Laryngoscope, 2000. 
110(3 Pt 2 Suppl 92): p. 1-18.
4.
M, Z., Surgical salvage of recurrent cancer of the head and neck. Curr Oncol Rep, 2014. 
16(5): p. 386.
5.
Janot F, d.R.D., Benhamou E, Ferron C, Dolivet G, Bensadoun RJ, Hamoir M, Géry B, 
Julieron M, Castaing M, Bardet E, Grégoire V, Bourhis J, Randomized trial of 
postoperative reirradiation combined with chemotherapy after salvage surgery compared 
with salvage surgery alone in head and neck carcinoma. J Clin Oncol, 2008. 26(34): p. 

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5518-23.
6.
Galon J, C.A., Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, 
Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, 
Fridman WH, Pagès F, Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4.
7.
Duffy SA, T.J., Terrell JE, Islam M, Li Y, Fowler KE, Wolf GT, Teknos TN, Interleukin-
6 predicts recurrence and survival among head and neck cancer patients. Cancer, 2008. 
113(4): p. 750-7.
8.
M, S., Immunobiology of HPV and HPV vaccines. Gynecol Oncol, 2008. 109(2 Suppl): p. 
S15-21.
9.
O'Brien PM, S.C.M., Evasion of host immunity directed by papillomavirus-encoded 
proteins. Virus Res, 2002. 88(1-2): p. 103-17.
10.
AG, R., Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell 
immunity. Br J Haematol, 2013. 162(3): p. 313-25.
11.
Leach DR, K.M., Allison JP, Enhancement of antitumor immunity by CTLA-4 blockade. 
Science, 1996. 271(5256): p. 1734-6.
12.
Nishimura H, N.M., Hiai H, Minato N, Honjo T, 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.
13.
Blazar BR, C.B., Panoskaltsis-Mortari A, Carter L, Iwai Y, Yagita H, Nishimura H, 
Taylor PA, 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.
14.
Cooper WA, R.P., Cherian M, Duhig EE, Godbolt D, Jessup PJ, Khoo C, Leslie C, 
Mahar A, Moffat DF, Sivasubramaniam V, Faure C, Reznichenko A, Grattan A, Fox SB, 
Intra- and Inter-Observer Reproducibility Assessment of PD-L1 Biomarker in Non-Small 
Cell Lung Cancer (NSCLC). Clin Cancer Res, 2017. Apr 18. pii: clincanres.0151.2017. 
doi: 10.1158/1078-0432.CCR-17-0151([Epub ahead of print]).
15.
Powles T, S.K., Stenzl A, Bedke J, Immune Checkpoint Inhibition in Metastatic 
Urothelial Cancer. Eur Urol, 2017. Apr 13. pii: S0302-2838(17)30278-6. doi: 
10.1016/j.eururo.2017.03.047([Epub ahead of print]).
16.
Feldman R, G.Z., Knezetic J, Reddy S, Nathan CA, Javadi N, Teknos T, Molecular 
profiling of head and neck squamous cell carcinoma. Head Neck, 2016. 38(Suppl 1): p. 
E1625-38.
17.
Lyford-Pike S, P.S., Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon 
JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai SI, Evidence 
for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and 
neck squamous cell carcinoma. Cancer Res, 2013. 73(6): p. 1733-41.
18.
Azuma T, Y.S., Zhu G, Flies AS, Flies SJ, Chen L, B7-H1 is a ubiquitous antiapoptotic 
receptor on cancer cells. Blood, 2008. 111(7): p. 3635-43.
19.
Hino R, K.K., Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y, Tumor cell 
expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant 
melanoma. Cancer, 2010. 116(7): p. 1757-66.
20.
Iwai Y, I.M., Tanaka Y, Okazaki T, Honjo T, Minato N, 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 USA, 2002. 99(19): p. 12293-7.

NCI Protocol #: N/A
DF/HCC Protocol #: 17-411
Protocol Version Date: Amendment 9/August 16, 2019
48
21.
Strome SE, D.H., Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, 
Hirano F, Lin W, Kasperbauer JL, Ballman KV, Chen L, B7-H1 blockade augments 
adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res, 2003. 63(19): 
p. 6501-5.
22.
Brochure, B.-a.-K.a.I.s.
23.
Velu V, T.K., Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, 
Silvestri G, Freeman GJ, Ahmed R, Amara RR, Enhancing SIV-specific immunity in vivo 
by PD-1 blockade. Nature, 2009. 458(7235): p. 206-10.
24.
Wang C, T.K., Han M, Wang XT, Huang H, Feingersh D, Garcia C, Wu Y, Kuhne M, 
Srinivasan M, Singh S, Wong S, Garner N, Leblanc H, Bunch RT, Blanset D, Selby MJ, 
Korman AJ, 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.
25.
Brahmer JR, D.C., Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons 
A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen 
L, Korman AJ, Pardoll DM, Lowy I, Topalian SL, Phase I study of single-agent anti-
programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75.
26.
Ferris RL, B.G.J., Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, 
Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, 
Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML, 
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J 
Med, 2016. 375(19): p. 1856-67.
27.
Brahmer J, R.K., Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski 
A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, 
Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, 
Harbison CT, Lestini B, Spigel DR, Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(2): p. 123-35.
28.
Larkin J, C.-S.V., Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, 
Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio 
M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, 
Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, 
Wolchok JD, Combined Nivolumab and Ipilimumab or Monotherapy in Untreated 
Melanoma. N Engl J Med, 2015. 373(1): p. 23-34.
29.
Romagné F, A.P., Spee P, Zahn S, Anfossi N, Gauthier L, Capanni M, Ruggeri L, 
Benson DM Jr, Blaser BW, Della Chiesa M, Moretta A, Vivier E, Caligiuri MA, Velardi 
A, Wagtmann N, Preclinical characterization of 1-7F9, a novel human anti-KIR receptor 
therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood, 
2009. 114(13): p. 2667-77.
30.
Vey N, B.J., Boissel N, Bordessoule D, Prebet T, Charbonnier A, Etienne A, Andre P, 
Romagne F, Benson D, Dombret H, Olive D, A phase 1 trial of the anti-inhibitory KIR 
mAb IPH2101 for AML in complete remission. Blood, 2012. 120(22): p. 4317-23.
31.
Benson DM Jr, H.C., Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, 
Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, Farag SS, A phase 1 trial of the 
anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. 
Blood, 2012. 120(22): p. 4324-33.

NCI Protocol #: N/A
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49
32.
Benson DM Jr, C.A., Jagannath S, Munshi NC, Spitzer G, Hofmeister CC, Efebera YA, 
Andre P, Zerbib R, Caligiuri MA, A Phase I Trial of the Anti-KIR Antibody IPH2101 and 
Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res, 
2015. 21(18): p. 4055-61.
33.
Leidner R, K.H., Haddad R, et al, Preliminary efficacy from a phase 1/2 study of the 
natural killer cell–targeted antibody, lirilumab, in combination with nivolumab in 
squamous cell carcinoma of the head and neck. Presented at: 2016 SITC Annual 
Meeting. 2016: p. November 9-13, 2016; National Harbor, MD. Abstract 456.
34.
Murphy WJ, P.P., Miller JS, NK cells--from bench to clinic. Biol Blood Marrow 
Transplant, 2012. 18(1 Suppl): p. S2-7.
35.
Spencer SA, H.J., Wheeler RH, Machtay M, Schultz C, Spanos W, Rotman M, Meredith 
R, Ang KK, Final report of RTOG 9610, a multi-institutional trial of reirradiation and 
chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. 
Head Neck, 2008. 30(3): p. 281.
36.
Hamoir M, H.E., Ambroise J, Lengelé B, Schmitz S, Salvage surgery in recurrent head 
and neck squamous cell carcinoma: Oncologic outcome and predictors of disease free 
survival. Oral Oncol, 2017. 67(Epub 2017 Jan 28): p. 1-9.
37.
Tan HK, G.R., Auperin A, Bourhis J, Janot F, Temam S, Salvage surgery after 
concomitant chemoradiation in head and neck squamous cell carcinomas - stratification 
for postsalvage survival. Head Neck, 2010. 32(2): p. 139-47.
38.
Jr, G.W., Salvage surgery for patients with recurrent squamous cell carcinoma of the 
upper aerodigestive tract: when do the ends justify the means? Laryngoscope, 2000. 
110(3 Pt 2 Suppl 93): p. 1.
39.
Zafereo ME, H.M., Rosenthal DI, Sturgis EM, Lewin JS, Roberts DB, Weber RS, The 
role of salvage surgery in patients with recurrent squamous cell carcinoma of the 
oropharynx. Cancer, 2009. 115(24): p. 5723-33.
40.
Putten L, B.R., Doornaert PA, Buter J, Eerenstein SE, Rietveld DH, Kuik DJ, Leemans 
CR, Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: 
outcome and review. Acta Otorhinolaryngol Ital, 2015. 35(3): p. 162-72.
41.
Sandulache VC, V.L., Skinner HD, Cata J, Hutcheson K, Fuller CD, Phan J, Siddiqui Z, 
Lai SY, Weber RS, Zafereo ME, Salvage total laryngectomy after external-beam 
radiotherapy: A 20-year experience. Head Neck, 2016. 38 Suppl 1: p. E1962-8.
42.
Chow LQ, H.R., Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness 
B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, 
Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY, Antitumor Activity of 
Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic 
Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 
Expansion Cohort. J Clin Oncol, 2016. [Epub ahead of print].
43.
Seiwert TY, B.B., Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, 
Lunceford J, Gause C, Cheng JD, Chow LQ, Safety and clinical activity of 
pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the 
head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet 
Oncol, 2016. 17(7): p. 956-65.
44.
Mandal R, S.Y., Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, Ganly I, Hakimi 
AA, Chan TA, Morris LG, The head and neck cancer immune landscape and its 
immunotherapeutic implications. JCI Insight, 2016. 1(17): p. e89829.

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45.
Norris S, C.A., Kuri-Cervantes L, Bower M, Nelson M, Goodier MR, PD-1 expression 
on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral 
Immunol, 2012. 25(4): p. 329-32.
46.
Purdy AK, C.K., Natural killer cells and cancer: regulation by the killer cell Ig-like 
receptors (KIR). Cancer Biol Ther, 2009. 8(23): p. 2211-20.
47.
Ruggeri L, M.A., Capanni M, Urbani E, Carotti A, Aloisi T, Stern M, Pende D, Perruccio 
K, Burchielli E, Topini F, Bianchi E, Aversa F, Martelli MF, Velardi A, Donor natural 
killer cell allorecognition of missing self in haploidentical hematopoietic transplantation 
for acute myeloid leukemia: challenging its predictive value. Blood, 2007. 110(1): p. 433-
40.
48.
Liu RB, E.B., Arina A, Schreiber K, Hyjek E, Schietinger A, Binder DC, Butz E, Krausz 
T, Rowley DA, Jabri B, Schreiber H, Densely granulated murine NK cells eradicate 
large solid tumors. Cancer Res, 2012. 72(8): p. 1964-74.
49.
Hanna GJ, L.H., Jones RE, Bacay AF, Lizotte PH, Ivanova EV, Bittinger MA, 
Cavanaugh ME, Rode AJ, Schoenfeld JD, Chau NG, Haddad RI, Lorch JH, Wong KK, 
Uppaluri R, Hammerman PS, Defining an inflamed tumor immunophenotype in 
recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol, 2017. 
67: p. 61-69.
50.
Licitra L, G.C., Guzzo M, Mariani L, Lo Vullo S, Valvo F, Quattrone P, Valagussa P, 
Bonadonna G, Molinari R, Cantù G, Primary chemotherapy in resectable oral cavity 
squamous cell cancer: a randomized controlled trial. J Clin Oncol, 2003. 21(2): p. 327-
33.
51.
Zhong LP, Z.C., Ren GX, Guo W, William WN Jr, Sun J, Zhu HG, Tu WY, Li J, Cai YL, 
Wang LZ, Fan XD, Wang ZH, Hu YJ, Ji T, Yang WJ, Ye WM, Li J, He Y, Wang YA, 
Xu LQ, Wang BS, Kies MS, Lee JJ, Myers JN, Zhang ZY, 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.
52.
Forde PM, S.K., Chaft JE, Hellmann M, Merghoub T, Wolchok JD, Yang SC, 
Battafarano RJ, Gabrielson E, Georgiades CS, Verde F, Rosner GL, Naidoo J, Cottrell 
TR, Taube JM, Anagnostou V, Velculescu VE, Topalian SL, Pardoll DM, Brahmer JR 
Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer. 
Ann Oncol, 2016. 27(6): p. 1-36.
53.
Garon EB, R.N., Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, 
Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, 
Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, 
Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 
Investigators, Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J 
Med, 2015. 372(21): p. 2018-28.
54.
Rizvi NA, H.M., Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, 
Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, 
Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher 
TN, Chan TA, Cancer immunology. Mutational landscape determines sensitivity to PD-1 
blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.
55.
Gajewski TF, S.H., Fu YX, Innate and adaptive immune cells in the tumor 
microenvironment. Nat Immunol, 2013. 14(10): p. 1014-22.

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56.
Lizotte PH, I.E., Awad MM, Jones RE, Keogh L, Liu H, Dries R, Almonte C, Herter-
Sprie GS, Santos A, Feeney NB, Paweletz CP, Kulkarni MM, Bass AJ, Rustgi AK, Yuan 
GC, Kufe DW, Janne PA, Hammerman PS, Sholl LM, Hodi FS, Richards WG, Bueno R, 
English JM, Bittinger MA, Wong KK, Multiparametric profiling of non–small-cell lung 
cancers reveals distinct immunophenotypes. JCI Insight, 2016. 1(14): p. e89014.
57.
Hanna GJ, L.H., Jones RE, Bacay AF, Lizotte PH, Ivanova EV, Bittinger MA, 
Cavanaugh ME, Rode AJ, Schoenfeld JD, Chau NG, Haddad RI, Lorch JH, Wong KK, 
Uppaluri R, Hammerman PS, Defining an inflamed tumor immunophenotype in 
recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol, 2017. 
Apr;67:61-69. doi: 10.1016/j.oraloncology.2017.02.005. Epub 2017 Feb 14.

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
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          GUIDANCE ON CONTRACEPTION
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. 
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
For WOCBP
Highly effective methods of birth control include the following:
• Progestogen only hormonal contraception associated with inhibition of ovulation
• Hormonal methods of contraception including oral contraceptive pills
(combination of estrogen and progesterone), vaginal ring, injectables, or implants
• Intrauterine devices (IUDs) (hormonal or non-hormonal)
• Intrauterine Hormone-releasing System (IUS)
• Bilateral tubal ligation
• Vasectomy
• Complete abstinence (complete avoidance of heterosexual intercourse)
For male subjects with partners that are WOCBP
• Condom
All male subjects who have partners who are WOCBP must use condoms as their second method 
of contraception.
Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to 
contraception for a period of 7 months after the last dose of investigational product. Men 
receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to 
contraception for a period of 7 months after the last dose of investigational product. These 
durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and 
are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 
days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 
days after the last dose of nivolumab.

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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

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DFCI IRB Protocol #: 17-411
APPENDIX D
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan

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3
3

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