Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)
Keywords: Nivolumab Stereotactic Body Radiotherapy (SBRT) 15-253
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
Nivolumab is an antibody (a type of human protein) that is designed to boost your body's immune system. It does this by allowing immune cells to grow and fight the cancer. Nivolumab has been approved by the FDA for the treatment of melanoma (a form of skin cancer) and lung cancer. It is currently under study for the treatment of head and neck squamous cell cancer.

Detailed description:

Arms:
arm 1: Nivolumab 3mg/kg IV every 2 weeks arm 2: Image Guided, Stereotactic Body Radiotherapy (27 Gy over 3 fractions given every other day) to a single lesion to start by study day 14 (study day 1 is day of first dose of Nivolumab).

Nivolumab 3mg/kg IV starting day 1 and then every 2 weeks thereafter. Treatment with Nivolumab will continue until progression or unacceptable toxicity.

Interventions: intervention 1: Nivolumab intervention 2: Stereotactic Body Radiation Therapy (SBRT)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 1 of 64 
 
 
 
 
A Phase II Randomized Controlled Screening Trial of Nivolumab with Image Guided, 
Stereotactic Body Radiotherapy (SBRT) versus Nivolumab Alone in Patients with Metastatic 
Head and Neck Squamous Cell Carcinoma (HNSCC) 
 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Sean M McBride, MD, MPH 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
Nancy Lee, MD 
Eric Sherman, MD 
Radiation Oncology 
Medicine 
Investigator(s)/Department: 
David G. Pfister, MD 
Afsheen Iqbal, MD 
Alan L. Ho, MD, PhD 
Alice Zervoudakis, MD 
Arlyn Apollo, MD 
Avni Desai, MD 
Han Xiao, MD 
Jahan Aghalar, MD 
Daniel McFarland, DO 
Jasmeet Chadha Singh, MD 
Jia Li, MD 
John Fiore, MD  
Juliana Eng, MD 
Kenneth Ng, MD 
Marina Shcherba, DO 
Pamela Drullinsky, MD 
Parisa Momtaz, MD 
Philip Caron, MD, PhD 
Sree Chalasani, MD 
Stephen Veach, MD 
Tiffany Troso-Sandoval, MD 
Zoe Goldberg, MD 
Lara Dunn, MD 
Janine Sun, NP 
Loren Michel, MD 
Jacqueline Bromberg, MD, PhD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Virginia Klimek, MD 
Neha Korde, MD 
Stuart Lichtman, MD 
Wanqing Iris Zhi, MD PhD 
Adriana Barison, PA 
Carla Hajj, MD 
Lior Braunstein, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
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Medicine 
Medicine 
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Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 


Page 2 of 64 
 
 
 
 
 
 
 
 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
Oncology 
 
 
 
cs 
Memorial Sloan Kettering Cancer 
Center IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-
2020 
Nadeem Riaz, MD 
Radiation 
Karen Borofsky, MD 
Radiation 
Preeti Parhar, MD 
Radiation 
Karen Schupak, MD 
Radiation 
Jillian Tsai, MD 
Radiation 
Marsha Reyngold, MD 
Radiation 
Richard Gewanter, MD 
Radiation 
Pinaki Dutta, MD 
Radiation 
Boris Mueller, MD 
Radiation 
Borys Mychalczak, MD 
Radiation 
Daphna Gelblum, MD 
Radiation 
Melissa Remis Zinovoy, MD 
Radiation 
Annemarie F. Shepherd, MD 
Radiation 
John Cuaron, MD 
Radiation 
Robert Young, MD 
Radiology 
Robert Lefkowitz, MD 
Radiology 
John Lyo, MD 
Radiology 
Zhigang Zhang, PhD 
Biostatisti 
Nora Katabi, MD 
Pathology 
Carly Osborne, APN 
Nursing 
Janice Terlizzi, APN 
Nursing 
Kathleen Leary, NP 
Nursing 
Carol Ann Milazzo, NP 
Nursing 
Lisa Cox, RN 
Nursing 
Colleen Foley, NP 
Nursing 
Sarah Ray, NP 
Nursing 
Consenting  Professional(s)/Department: 
Sean M. McBride, MD, MPH 
Radiation 
Nancy Lee, MD 
Radiation 
Nadeem Riaz, MD 
Radiation 
David G. Pfister, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Alan L. Ho, MD, PhD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Avni Desai, MD 
Medicine 
Eric Sherman, MD 
Medicine 
Han Xiao, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Jasmeet Chadha Singh, MD 
Medicine 
Daniel McFarland, DO 
Medicine 
John Fiore, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Philip Caron, MD, PhD 
Medicine 
Sree Chalasani, MD 
Medicine 
Stephen Veach, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Oncology 
Oncology 
Oncology 


Page 3 of 64 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
 
Alice Zervoudakis, MD 
Jia Li, MD 
Juliana Eng, MD 
Lara Dunn, MD 
Parisa Momtaz, MD 
Loren Michel, MD 
Jacqueline Bromberg, MD, PhD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Virginia Klimek, MD 
Neha Korde, MD 
Stuart Lichtman, MD 
Wanqing Iris Zhi, MD PhD 
Carla Hajj, MD 
Lior Braunstein, MD 
Karen Borofsky, MD 
Preeti Parhar, MD 
Karen Schupak, MD 
Jillian Tsai, MD 
Marsha Reyngold, MD 
Richard Gewanter, MD 
Pinaki Dutta, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Daphna Gelblum, MD 
Melissa Remis Zinovoy, MD 
Annemarie F. Shepherd, MD 
John Cuaron, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK  Sites 
Manhattan 
Basking Ridge 
Commack 
Rockville Centre 
Monmouth 
Westchester 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 4 of 64 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 8 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 14 
4.1 
Design................................................................................................................................. 14 
4.2 
Intervention .............................................................................................................................. 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 18 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 19 
6.1 
Subject Inclusion Criteria ..................................................................................................... 19 
6.2 
Subject Exclusion Criteria ................................................................................................... 21 
7.0 
RECRUITMENT PLAN .................................................................................................................... 23 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 24 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 28 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 30 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 41 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 48 
14.0 
BIOSTATISTICS ............................................................................................................... 50 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 52 
15.1  Research Participant Registration ....................................................................................... 52 
15.2 
Randomization .................................................................................................................... 52 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 52 
16.1 
Quality Assurance............................................................................................................... 53 
16.2 
Data and Safety Monitoring .................................................................................................... 53 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 54 
17.1 
Privacy ................................................................................................................................ 55 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 55 
17.2.1  ........................................................................................................................................  56 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 58 
19.0 
REFERENCES ....................................................................................................................... 59 
20.0 
APPENDICES ................................................................................................................... 61 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 5 of 64 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: A Phase II Randomized Controlled Screening Trial of Nivolumab with Image 
Guided, Stereotactic Body Radiotherapy (SBRT) versus Nivolumab Alone in Patients with 
Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC). 
Brief Background:  Nivolumab is a fully human monoclonal immunoglobulin G4 antibody 
that binds to programmed death-1 (PD-1) cell surface membrane receptor, a negative 
regulatory molecule expressed by activated T and B lymphocytes.  Inhibition of the 
interaction between PD-1 and its ligands (e.g. PD-L1) promotes immune responses and 
antigen-specific T cell responses to both foreign antigens as well as self antigens.[1] 
In early phase clinical trials in a variety of malignancies, including HNSCC, anti-PD-1 
antibodies have shown impressive objective response rates with a surprising number of 
patients experiencing durable, long-term complete or near complete remissions.  Still, 
these sustained responses have only been seen in a distinct minority of patients with 
HNSCC (20%) [2].   Accumulating pre-clinical evidence suggests a role for relatively high- 
dose-per-fraction radiotherapy in up-regulating adaptive immune response against 
established malignancies.  This can occur through a variety of mechanisms, including 
radiation-induced increases in tumor-antigen presentation by antigen presenting cells 
(ADCs), increases in tumor cell phagocytosis by dendritic cells, increases in secretion of 
“danger signals” such as HMGB1, and decreases in peripheral myeloid derived  
suppressor cells [3, 4].  Compared to conventional fractionated radiation therapy (1.8 Gy  
to 2 Gy per fraction), higher dose-per-fraction radiation therapy, delivered by conformal, 
image guided mechanisms has shown increased T- cell activity [5]. Even more tantalizing, 
recent evidence in patient-derived xenograft models have demonstrated potentially 
powerful synergy between high-dose radiotherapy and anti-PD-L1 antibody therapy 
(another mechanism of PD-1:PD-L1 signaling inhibition) [6].  The concomitant 
administration of radiation to a single metastasis and anti-PD-L1 therapy proved capable 
of dramatic reductions in non-irradiated metastases above and beyond the regression 
seen with anti-PD-L1 therapy alone.  This radiation-induced regression of non-irradiated 
systemic disease is termed the abscopal effect.  Multiple case reports have also now been 
published purportedly demonstrating the same phenomenon in patients who had initially 
progressed through checkpoint inhibitory therapy [7] . 
Research Hypothesis: The concomitant administration of SBRT with Nivolumab will 
result in a significant increase in objective response rate above and beyond Nivolumab 
alone in patients with metastatic HNSCC. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 6 of 64 
 
 
Schema: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
Arm 1: 
Nivolumab 
3mg/kg IV 
every 2 
weeks 
 
 
 
• Treatm 
ent 
until 
progre 
ssion 
or 
study 
drug 
discont 
inuatio 
n for 
any 
reason 
. 
 
• Option 
for 
treatm 
ent 
beyon 
d 
progre 
ssion 
in both 
arms. 
• Prim 
Endpoi 
nt: 
ORR 
per 
RECIS 
T 
• Secon 
d 
Endpoi 
nt: 
Page 7 of 64 
PFS, 
OS, 
ORR 
• Metasta 
tic 
HNSCC 
• N=60 
• 1:1 
randomi 
zation 
• Stratific 
ation 
based 
on HPV 
Arm 2: 
• Nivolu 
mab 
3mg/kg 
IV 
every 2 
weeks 
• SBRT 
9 Gy x 
3 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 8 of 64 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
 
Primary Objective: 
 
• 
To compare objective response rate (ORR) during the first 2 years of treatment as 
determined by the investigator using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria between patients receiving Nivolumab and SBRT to those 
receiving Nivolumab alone.  The ORR is defined as the number of patients 
randomized to a given arm with a best overall response (BOR) of complete 
response (CR) or partial response (PR) in non-irradiated lesions during the first 96 
weeks after treatment initiation divided by the total number of patients randomized 
to the given arm. 
Secondary Objectives: 
 
• 
To compare Overall Survival (OS) of Nivolumab and SBRT to Nivolumab alone. 
• 
To compare Progression Free Survival (PFS) of Nivolumab and SBRT to 
Nivolumab alone. 
• 
To compare duration of response (DOR) between the Nivolumab alone arm and 
Nivolumab + SBRT arm. 
• 
To compare treatment-related Adverse Events (tr-AE) of Nivolumab and SBRT to 
Nivolumab alone using Common Terminology Criteria for Adverse Events version 
4.0 (CTCAE v 4.0). 
• 
To evaluate cancer-specific health related quality-of-life using the EORTC-QLQ C- 
30. 
Exploratory Objectives: 
 
• 
Evaluation of tumor tissue PDL1 expression via IHC and its correlation with 
response. 
• 
Evaluate of peripheral blood mononuclear cell composition and its correlation with 
response 
• 
Evaluation of soluble PD-1 and PD-L1 and its correlation to response. 
• 
Evaluation of neo-antigen expression (optional) and its correlation to response. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Overall Study Rationale 
 
Substantial pre-clinical data has accumulated suggesting that higher-dose per fraction 
radiation therapy (SBRT) can enhance immune surveillance of extant tumors.  Over the 
past several years, early phase clinical trials involving  novel immunotherapies — 
specifically mono-clonal anti-body inhibitors of various immune checkpoints--have shown 
impressive tumor control outcomes.  Herein we outline a randomized, open label, Phase 2 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 9 of 64 
 
 
trial designed to determine whether clinically significant synergy exists between the 
immune checkpoint inhibitor Nivolumab and high dose per fraction, stereotactic body 
radiotherapy (SBRT) in patients with metastatic HNSCC. 
3.2 Current Standard of Care in Metastatic Head and Neck Squamous Cell 
Carcinoma (HNSCC) 
HNSCC is currently the fifth most common incident cancer worldwide.  Within the United 
States in 2013, 53,640 new cases of HNSCC were diagnosed, with approximately 11,500 
deaths attributed to this disease. The specific anatomic locations that fall under the 
HNSCC diagnostic umbrella include oral cavity, oropharynx, larynx, hypopharynx, 
nasopharynx, nasal cavity, and para-nasal sinuses [8].  Broadly speaking, HNSCC can be 
divided into tumors that arise from excessive toxic exposures, namely alcohol and 
tobacco, and those that arise as a result of viral infections, specifically the Epstein-Barr 
virus (EBV) in nasopharyngeal carcinoma, and the Human Papilloma Virus (HPV) in 
oropharynx cancer. 
At initial diagnosis, approximately 10% of patients with HNSCC will have metastatic (Stage 
IV-C) disease. For patients with locally advanced, non-metastatic HNSCC at diagnosis 
(Stage III-IVA/B),  approximately 50% treated with definitive surgery or concurrent chemo- 
radiotherapy will recur.  In recurrent disease with a metastatic component, median 
progression free survival (PFS) is ≤ 6 months [9]. 
Treatment of metastatic disease typically consists of cytotoxic chemotherapies (e.g. 
methotrexate, organoplatinum compounds, 5-fluorouracil (5FU), or taxanes) oftentimes in 
combination with the monoclonal anti-body inhibitor of the epidermal growth factor 
receptor (EGFR), Cetuximab.  Additionally,  it is not uncommon for patients to undergo 
palliative radiation therapy to synchronous loco-regional disease because of the high 
potential morbidity of continued progression in the head and neck region.  A Phase 3 trial 
by Vermorken, et al established the current chemotherapeutic standard of care for well 
performing patients with metastatic HNSCC [10].  Therein they found a significant 
improvement in overall survival (OS) comparing patients that received 5FU, a platinum 
agent, and Cetuximab to those who received 5FU and a platinum agent alone (10.1 
months versus 7.4 months).  A recent retrospective report on response rates to tri-modal 
treatment with 5FU, platinum, and cetuximab as a first line therapy in metastatic HNSCC 
showed an ORR of approximately 23.9% [11]. 
Tumor response rates in metastatic patients who have progressed through or recurred 
after a first-line platinum-containing therapy are even lower; a single arm, Phase 2 trial of 
Cetuximab monotherapy in patients who had failed a prior platinum-containing therapy 
showed an ORR of 13%.  In examining multiple studies of patients in this cohort, median 
OS is approximately 3-4 months, with survival at 1 year of approximately 5% [12]. 
In sum, response rates in both the 1st line and 2nd  line settings in metastatic HNSCC are 
underwhelming.  More broadly, chemotherapeutic options in this disease are limited.  The 
need for more potent therapies for these patients is clear. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 10 of 64 
 
 
3.3 Rationale for Use of Nivolumab in HNSCC 
 
3.3.1 Immunosurveillance in HNSCC 
 
Over the past decade, substantial evidence has accrued demonstrating the critical role  
that the immune system plays in the development and progression of HNSCC.  The two 
primary pathways by which HNSCC develops—chemical carcinogenesis and human 
papilloma virus (HPV) infection—both involve a failure of immune surveillance;  tumor cells 
escape cytotoxic T-lymphocyte-based adaptive immune destruction. 
HNSCC employs multiple mechanisms of immune escape [13].  Despite that fact that 
immunogenic tumor antigens (TA) exist in HNSCC along with their cognate TA-specific 
cytotoxic T-lymphocytes (CTLs specific for EGFR, E7 HPV oncoprotein, etc), these TA- 
specific  CTLs fail to eradicate their targets.  One evasive maneuver used by HNSCC to 
accomplish this escape is the down-regulation of human leukocyte antigen (HLA) 1, the 
MHC molecule required for interaction between TA and TA-specific CTLs.  Additionally,  it 
has been shown by multiple groups that HNSCC has developed the ability to 
downregulate its own antigen processing machinery (APM).  This deficiency also extends 
to nearby dendritic cells (DC), themselves critical intermediaries of antigen presentation. 
However, it is not just failure to present CTLs with viable tumor-specific targets that 
cripples the adaptive immune response to HNSCC, it is also the de-activation of the CTLs 
themselves that compounds the degree of suppression.  This deactivation occurs via an 
alteration in the balance of co-stimulatory (e.g. OX40 and 4-1BB) and co-inhibitory 
receptors (e.g. T-lymphocyte-associated antigen 4 (CTLA-4) and programmed-death 1 
(PD-1)) expressed by CTLs and their paired ligands (PD-L1, B7,etc), expressed by CD4+ 
helper T cells, DCs, myeloid derived suppressor cells (MDSCs), and tumor cells.  In the 
functioning immune system, expression of co-stimulatory receptors and ligands are 
requisite requirements for the successful activation of CTLs in the face of foreign antigen 
presentation.  Once an infectious threat has been eliminated, the binding of CTL, 
membrane bound co-inhibitory receptors, such as cytotoxic T-lymphocyte-associated 
antigen 4 (CTLA-4) and programmed-death 1, to their cognate ligands serves to dampen 
any further adaptive response and promote functional anergy.  In addition to CTLs, PD-1 
is also expressed by the immunosuppressive T-regulatory (Treg) cells where receptor 
engagement may be critical to the Treg cell’s suppressive function.  There is now 
mounting evidence that HNSCC has co-opted these co-signaling pathways in order to 
facilitate profound intra-tumoral immunosuppression [14, 15]. 
3.3.2 Programmed Cell Death 1 (PD-1) in HNSCC 
 
The data demonstrating the PD-1:PD-L1 pathway as a major mechanism of immune 
escape in HNSCC have become increasingly robust over the last few years.  A member of 
the CD28 family, PD-1 is a 55kD, type I transmembrane T-cell co-stimulatory receptor. 
The receptor contains an intracellular immunoreceptor inhibitor motif (ITIM)  and a 
membrane distal immunoreceptor tyrosine-based switch motif (ITSM). The two known 
ligands of PD-1 are PD-L1 and PD-L2 which, upon binding to PD-1, deactivate T cells. 
The down-regulation of T-cell activation is mediated via SHP-2 binding to the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 11 of 64 
 
 
phosphorylated tyrosine residue in the ITSM in the cytoplasmic region of PD-1.  PD-1 
deficient mice are prone to a variety of auto-immune ailments. Blockade of PD-1 with a 
mono-clonal antibody can bring about the same auto-immune phenotype. 
Several studies have shown high levels of PD-L1 expression in 46%-100% of tumors in 
treatment naïve primary, recurrent, and metastatic HNSCC [16].  Moreover,  there appears 
to be differential PD-L1 expression in HNSCC lesions depending upon etiology, with HPV- 
positive tumors having a statistically significant higher expression (49.2-65.2% vs 34.1%- 
40%).  In addition to tumor cells themselves, there are data suggesting that peripheral 
blood MDSCs, in-part responsible for suppression of T cell activation and migration, show 
increased PD-L1 expression in HNSCC; this up-regulation of PD-L1 expression is also 
seen in intratumoral Tregs in HNSCC.  This enhancement of PD-L1 on tumor cells, 
MDSCs, and Tregs is matched by a commensurate increase in PD-1 expression by both 
CD8+ T cells in the peripheral blood, and, to an even greater degree, CD8+ T cells in the 
tumors of HNSCC patients; this was seen in both HPV positive and negative patients. 
Moreover, in vitro blockade of PD-1 in these CD8+ T cells enhanced their adaptive 
function. 
The above pre-clinical data argue that the PD-1:PD-L1 axis plays an important role in both 
HPV positive and HPV negative HNSCC pathogenesis.  Because of the strength of the 
above pre-clinical data and the impressive results seen in other solid malignancies treated 
with anti-PD-1 therapy, Seiwert, et al devised, ran, and recently reported on a Phase Ib  
trial involving 60 recurrent/metastatic HNSCC patients with tumors positive for PD-L1 
treated with Pembrolizumab, a humanized monoclonal IgG4 antibody directed against PD- 
1.  They screened 104 patients for PD-L1 expression; 77.9% of patients were positive 
(defined as >=1% of cells in the tumor microenvironment staining for PD-L1); of the 
positive patients, sixty were eventually enrolled on the trial, 37 of which were HPV 
negative.  In total, the best overall response rate was 20%, a percentage that was identical 
regardless of HPV status.  Approximately 89% of the enrolled patients had undergone  
prior systemic treatment [2]. 
Although in the aforementioned study, patients were selected for inclusion only if their 
tumors expressed PD-L1, data from melanoma, non-small cell lung cancer, and renal cell 
carcinoma shows the potential for a still robust response in PD-L1 negative patients [17]. 
Therefore, in our own trial, we have chosen to include patients regardless of PD-L1 
expression status. 
3.3.3 Nivolumab Efficacy and Safety 
 
In our own trial, we will use Nivolumab as the anti-PD-1 agent.  Nivolumab is a fully human 
monoclonal immunoglobulin IgG4 antibody that binds to PD-1 cell surface membrane 
receptor.  A recently reported on Phase I open label, multiple dose escalation study 
investigated the safety and efficacy of Nivolumab in 304 patients with melanoma, renal cell 
carcinoma, non-small cell lung carcinoma (NSCLC), colorectal cancer, or hormone 
refractory prostate cancer [18].  Squamous NSCLC is the histology most biologically  
similar to HNSCC.  For NSCLC, the most active doses were 3 and 10 mg/kg, with a 
reported ORR of between 19% and 26%, with durable responses observed in both 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
Page 12 of 64 
 
 
squamous and non-squamous subtypes. There was no maximally tolerated dose identified 
in the above Phase I trial.  Drug-related adverse events occurring in >5% of subjects 
included, in order of most frequent to least frequent: fatigue, rash, diarrhea, pruritus, 
nausea, decreased appetite, decreased hemoglobin, and pyrexia.   Approximately 15% of 
patients experienced Grade 3 or 4 adverse events.  Those occurring in greater than >1% 
of research subjects included: fatigue (1.6%), lymphopenia (1.3%), abdominal pain (1%), 
diarrhea (1%), hypophosphatemia (1%) and pneumonitis (1%). Approximately 49% of 
patients on the Phase I study experienced a severe adverse event (SAE); 7.6% of patients 
experienced a Grade 3-4 SAE.  Drug-related SAEs occurred in 11.5% of patients.  Grade 
3-4 SAEs that occurred in 2 or more study subjects included: diarrhea (1%), pneumonitis 
(1%), pneumonia (0.7%), and increased lipase (0.7%).  Only 5.9% of patients had their 
treatment discontinued because of an SAE.  These SAEs included pneumonitis (4 
subjects) and hepatitis (2 subjects). There were 3 treatment-related deaths (1%), all 
related to pneumonitis. 
Siewert, et al recently updated their experience with Pembrolizumab (MK-3475) in an 
unselected group (both PDL1 positive and negative) of patients with recurrent/metastatic 
HNSCC.  In this expansion cohort of KEYNOTE 012, ORR (confirmed and unconfirmed) 
per RECIST 1.1 was 18.2% (95% CI, 11.1-27.2) [19]. 
3.4 Rationale for and Safety of Combining Nivolumab with Stereotactic Body 
Radiation Therapy (SBRT) 
The data examining the immune-modulatory effects of radiation are substantial.  Several 
groups have reported an up-regulation of pro-inflammatory cytokines in response to 
ionizing radiation, namely TNF, IL-1alpha,  and IL-1beta [20].  These inflammatory 
cytokines in turn promote the expression of critical leukocyte adhesion molecules (e.g. 
ICAM-1, VCAM-1, and E-selectin).   Given the above biology, it is not surprising that 
irradiation has been shown to enhance T-cell infiltration into the tumor microenvironment. 
Once intercalated into the microenvironment, radiation also serves to promote T-cell 
activation by increasing the expression of both tumor antigens and MHC Class I and II 
molecules [21].  In addition, several studies have demonstrated that radiation tends to 
results in immunogenic tumor cell death via necrosis and mitotic catastrophe [22]. The 
release of endogenous danger signals, such as HMGB1 and ATP, that accompany these 
types of tumor cell kill lead to the engagement of the innate immune system via the Toll- 
Like Receptors (e.g. TLR4) found on antigen presenting cells (APCs).   Activated APCs 
serve to further enhance anti-tumor T-cell response. 
Radiation-related induction of T-cell activity is not just incidental to but rather necessary for 
the anti-tumor effect of radiotherapy [23].  Indeed, several studies have shown that 
depletion of CD8+ T cells significantly hampers radiation-related retardation of local tumor 
growth.  But radiation alone rarely generates a systemic, immune-mediated anti-tumor 
response—the so called “abscopal effect”.  There has thus been great interest in 
combining radiotherapy with immune modulatory agents like Nivolumab in the hope that 
the synergy between the two therapies would result in substantial enhancement of anti- 
tumor immunity and subsequent regression of metastatic disease outside of the irradiated 


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field.  The abscopal effect would predict that this systemic disease response to radiation 
and Nivolumab at unirradiated sites should be in excess of the systemic response seen 
with Nivolumab monotherapy. 
Pre-clinical data and several case reports have hinted at the ability of such a combinatorial 
strategy to accomplish this. Deng, et al reported that 12Gy of ionizing radiation delivered to 
a mammary carcinoma established on the flank of a mouse in combination with an anti-PD- 
L1 antibody led to the sustained regression of tumors implanted on the contralateral flank 
of the animal, whereas no suchcontralateral responses were elicited when the animals were 
treated with either radiation or anti-PD-L1 alone [6]. A recently completed Phase I study 
combined SBRT (20 Gy per fraction) with IL-2, an older, established immune-modulatory 
agent, in patients with metastatic renal cell or melanoma. They reported CRs or PRs in 
66.6% of patients, rates far in excess of those expected with IL-2 alone [24].  More pertinent 
to our own study, Postow, et al, reported on a melanoma patient who, having had 
progressive disease while on Ipilimumab, a mono-clonal antibody directed against the 
checkpoint inhibitor CTLA-4, demonstrated dramatic tumor regression after receiving SBRT 
(8.5 Gy x 3) concurrent with Ipilimumab at both the irradiated site and multiple metastatic 
sites four months after irradiation [25].  A further, and perhaps more dramatic demonstration 
of synergy was reported by Golden, et al in a patient with metastatic lung adenocarcinoma, 
a histology that had demonstrated relatively unimpressive responses to single agent 
Ipilimumab. In their case report, a patient with widespread metastases received SBRT (6 
Gy x 5) to a liver lesion with infusion of Ipilimumab the day after the first fraction and 
continuing for 3 additional cycles. At 2.5 months post-treatment, dramatic regression was 
seen in both the irradiated lesion and in multiple osseous and hepatic metastases [26, 27]. 
Little data exists with regard to the safety of combined immunologic checkpoint inhibition 
and radiotherapy. However, Barker, et al recently reported on the Memorial Sloan Kettering 
institutional experience with Ipilimumab and non-brain radiotherapy [27]. They found no 
evidence of increased adverse effects compared to Ipilimumab alone. Many of the patients 
included in this retrospective report received SBRT with various dosing schemas. 
3.4.1 Rationale for Radiation Dose and Fractionation in Combination with Nivolumab 
 
Data with regards to appropriate dose per fraction is somewhat limited. Reits, et al 
examined MHC-1 up-regulation in response to variety of single dose radiation regimens 
[28]. They found that 1 Gy resulted in no increased expression, 4 Gy a slight increase, and 
10 Gy and 25 Gy a two-fold increase, with the 25 Gy dose resulting in a faster rate of 
increase. This increase in MHC-1 expression persisted for up to 11 days. Schaue, et al 
showed that doses of greater than 15 Gy per fraction resulted in dramatic increase in the 
immunosuppressive Treg population. Conversely, doses of 5 Gy or less failed to induce 
tumor-specific T-cells. They concluded that doses of 7.5 Gy per fraction were best able to 
generate anti-tumor immunity without increasing the proportion of T-regulatory cells. 
Addressing specifically the optimal fractionation in combination with checkpoint inhibitors, 
Dewan, et al evaluated three dose schemes [29]: 20 Gy x 1, 8 Gy x 3, and 6 Gy x 5. They 
found that the two fractionated regimens (8 Gy x 3 and 6 Gy x 5) resulted in more dramatic 
reductions in non-irradiated systemic disease compared to the single fraction dose in mouse 


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models of both  breast and  colorectal carcinoma.   The 8 Gy x 3 regimen proved  most 
effective, causing regression in 40% of tumors outside the irradiated field. This was nearly 
the same fractionation scheme used by Postow, et al in their seminal report. 
Given the above data, we have chosen a dose fractionation of 9 Gy x 3 for our study. 
 
3.4.2 Rationale for Timing of Radiotherapy and Nivolumab 
 
Although not completely analogous, Witek, et al reported on timing of radiotherapy relative 
to the administration of an adenoviral-mediated vaccine against the colorectal  cancer 
antigen GUCY2C in a murine subcutaneous tumor model using mouse CT26 colon cancer 
cells [30]. They found that T cell responses were enhanced and tumor eradication 
maximized when RT was administered prior to the vaccine. 
Deng, et al, in their study of anti-PD-L1 antibody in combination with RT delivered the 
therapies on the same day or with anti-PD-L1 given 1 day prior to RT administration. 
Golden, et al, in their report of an abscopal effect seen with the combination of Ipilimumab 
and radiation NSCLC-adenocarcinoma, delivered the RT one day prior to the Ipilimumab. 
Recognizing the paucity of data, but based on the aforementioned reports, this study will 
involve the administration of the first dose of Nivolumab one day before the first fraction of 
radiation. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a randomized (1:1), open label Phase 2 screening trial in subjects ≥ 18 years old 
with metastatic HNSCC.  Subjects will stratified based on viral status (p16+ OPC/EBER+ 
NPC vs others) and then randomized to either Nivolumab with interdigitated SBRT or 
Nivolumab alone. 
Subjects must undergo screening evaluations to determine eligibility within 28 days prior 
to randomization. 
Sixty (60) subjects will be randomized to one of the following arms: 
 
• 
Arm 1:  Nivolumab 3mg/kg IV every 2 weeks 
• 
Arm 2: 
o Image Guided, Stereotactic Body Radiotherapy (27 Gy over 3 fractions 
given every other day) to a single lesion to start by study day 14 (study day 
1 is day of first dose of Nivolumab). 
o Nivolumab 3mg/kg IV starting day 1and then every 2 weeks thereafter. 
• 
Treatment with Nivolumab will continue until progression or unacceptable toxicity. 
Key Inclusion Criteria: 


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1) Males and females ≥ 18 years of age. 
2) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
3) Histologically confirmed metastatic HNSCC, including nasopharynx WHO Type I-III 
histologies; patients can have simultaneous loco-regional disease. 
4) Subjects must have at least two lesions: 
o One lesion must be safely amenable to irradiation in the opinion of the treating 
radiation oncologist.  This can be a lesion that was previously irradiated as long 
as prior radiation preceded projected first fraction of SBRT by at least 6 
months. 
o At least one, not-to-be-irradiated lesion measurable by CT or MRI per RECIST 
1.1 criteria. 
5) Available  formalin fixed, paraffin-embedded (FFPE) tumor tissue block with unstained 
slides of tumor sample obtained via excisional, incisional, or core needle biopsy from a 
loco-regionally recurrent or metastatic lesion; FFPE tumor tissue block with unstained 
slides from the primary disease is acceptable with approval of principal investigator. 
6) Documentation of tumor viral status (p16 testing for oropharynx, EBER for 
nasopharynx).  Tests done on primary tumor specimens at outside institutions are 
sufficient to meet this criterion. 
7) Prior palliative or curative radiotherapy must be completed at least 14 days prior to 
randomization. 
Key Exclusion Criteria: 
 
1) Active brain metastases or leptomeningeal metastases are not allowed. 
2) Non-squamous histologies are not allowed; an exception is made for WHO Type I-III 
nasopharynx histologies. 
3) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. 
4) Prior active malignancy within the previous 3 years except for locally curable cancers 
such as basal or squamous skin cancer, superficial bladder, low risk prostate cancer, 
breast, or cervix cancer.  If other prior malignancy was active within prior 3 years, 
enrollment requires approval of a principal investigator. 
5) Subjects with active, known or suspected auto-immune disease.  Subjects with vitiligo, 
type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are eligible to 
enroll. 
6) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration.  Inhaled or topical steroids and adrenal replacement 
doses >10mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. 
Based upon an estimated ORR of 15% in the Nivolumab alone arm in a PD-L1 unselected 
population and an ORR of 45% in the Nivolumab and SBRT arm, the enrollment of 54 
patients will provide a one-sided alpha of 0.10 and a power of 0.80.  Assuming a 10% 
drop-out rate, we will seek to enroll 60 patients.  Patients will be randomized to the two 


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treatment arms in a 1:1 ratio (30 subjects in Arm 1 and 30 subjects in Arm 2).  Patients will 
be stratified based upon viral status (HPV/EBV+ vs not).  ORR will be assessed by the 
investigator using RECIST 1.1 criteria. Treatment with Nivolumab will continue until 
RECIST 1.1-defined progression, unacceptable toxicity, or withdrawal of consent. 
Nivolumab dose reductions will not be allowed. 
 
Because the toxicity of Nivolumab combined with SBRT is unclear, we have included an 
interim toxicity analysis for Arm 2 to occur after the first 20 patients have been randomized 
to this arm.  Using data from recently reported early phase trials of Nivolumab in NSCLC, 
we view 14% as an acceptable rate of acute (within 3 months of study initiation) >= Grade 
3 treatment-related adverse events; an unacceptable rate of acute >= Grade 3 treatment- 
related adverse events is 30%. If more than 5 (e.g. 6 or more) of the first 20 patients 
experience an acute >= Grade 3 treatment-related adverse event, the trial will be stopped 
early. If the true toxicity rate is 30%, the above boundary assures a 58% probability of 
stopping the trial at interim analysis; if the true toxicity rate is 40%, there is an 87% chance 
of stopping the trial early. If the true toxicity rate is 14%, the above boundary has only a  
5% probability of stopping the trial early. Of note, for radiation dermatitis, only Grade 4 
treatment-related events will be included in the interim analysis of toxicity. 
 
Study mandated follow-up for tumor assessment will conclude 96 weeks after the final 
patient is enrolled. 
The primary endpoint of the trial is the ORR as defined by RECIST 1.1 criteria. Analysis of 
ORR will occur 96 weeks after randomization of the final subject. 
The maximal total duration of the study from start of randomization to final analysis of 
ORR is expected to be 44 months, assuming an accrual of 3 patients per month.  Sample 
size estimate is 60 patients. 
 
 
4.2 
Intervention 
 
The study will consist of three phases:  screening, treatment, and follow-up. 
Screening Phase: 
• 
Establishment of initial eligibility and signing of the informed consent. 
• 
Confirmation that tumor tissue from a metastatic or loco-regionally recurrent lesion 
is available for biomarker analysis; if none is available and biopsy not an option, 
with the permission of the principal investigator, tumor tissue from the primary site 
at initial diagnosis is acceptable. 
• 
HPV status will be determined via p16 IHC staining or HPV ISH or PCR for all 
oropharynx primaries.  The p16 staining will be interpreted as positive if >70% 
strong and diffuse nuclear and cytoplasmic staining is specific to tumor cells. 
Status will be reported dichotomously as positive or negative.  EBER staining will 
be reported as well for patients with nasopharynx cancer.  For non-oropharynx and 
non-nasopharynx primaries, these tests are not required.  Tests previously 


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performed on primary tumor specimens from oropharynx or nasopharynx lesions at 
time of diagnosis are sufficient to meet this criterion. 
• 
Baseline tumor assessments will be performed within 28 days of randomization. 
• 
Eligibility assessment per timeframe outlined. 
• 
The screening phase will conclude with either randomization of the subject or with 
confirmation that the subject is a screen failure. 
 
Treatment Phase: 
 
• 
Nivolumab should begin within 14 days (+/-4 days) of randomization.  The first day 
of Nivolumab is designated as study Day 1. 
• 
Radiation will be delivered over 3 treatments (9 Gy per treatment) to a single 
lesion.  The first fraction must be administered by study day 14.  The remaining 2 
radiation treatments will be delivered over 10 business days at a frequency no 
greater than every other day. 
• 
All of the laboratories and vital signs will be collected prior to study drug dosing at 
the time points specified. 
• 
Adverse events will be documented at the time points specified. 
• 
Biomarker and immunogenicity samples will be obtained according to the outlined 
schedules. 
• 
EORTC QLQ-C-30: will be completed by Day 1 of treatment, and then, starting at 
week 8 (+/- 2 weeks), every 8 weeks (+/-2 weeks) for the first 48 weeks and every 
12 weeks (+/- 2 weeks) until either week 96 or disease progression (whichever 
occurs first). 
• 
Nivolumab is administered as an IV infusion every 14 days (+/- 2 days) until 
disease progression (or until discontinuation of Nivolumab in subjects receiving 
beyond progression), unacceptable toxicity, or withdrawal of consent. 
• 
Response is evaluated using RECIST 1.1 criteria. 
 
The first tumor assessment of non-irradiated lesions will occur at week 8 (+/- 2 weeks) 
after treatment initiation and then every 8 weeks (+/-2 weeks) for the first 48 weeks and 
then every 12 weeks (+/-2 weeks) until documented progression or week 96 whichever 
occurs first. CT or MRI images of chest, abdomen, pelvis, head, neck, and all known sites 
of disease should be obtained.  The same imaging modality that was used as baseline 
should be used at all subsequent evaluations. 
• 
After week 96 of treatment, patients will be contacted every 3 months for survival. 
This can be done by phone if the patient is unable to come into clinic for routine 
follow-up. 
• 
Treatment phase will conclude at the time of study drug discontinuation. 
• 
Imaging can continue per institutional preference past 96 weeks, however, 
RECIST reads are not required. 
 
Follow-Up Phase 
 
• 
Begins at the conclusion of Nivolumab therapy. 


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• 
Subjects will have one follow-up visit for safety within approximately 100 days from 
the last dose of Nivolumab. 
• 
Subjects who discontinue treatment for reasons other than tumor progression will 
continue to have tumor assessments per prior schedule (e.g. every 8 weeks for the 
first 48 weeks and then every 12 weeks until week 96). 
• 
Follow-up (phone or visit) will continue to occur every 3 months for survival 
information. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Nivolumab  (BMS-936558) 
 
Nivolumab is a fully human monoclonal immunoglobulin G4 antibody that binds to the 
programmed death-1 (PD-1) cell surface membrane receptor, a negative regulatory 
molecule expressed by activated T and B Lymphocytes. 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Nivolumab 
infusion concentration must be at or above the minimum allowable concentration of 0.35 
mg/mL. 
Nivolumab will be provided by BMS (Bristol-Myers Squibb) and shipped directly to the site 
where it is to be administered. 
Nivolumab (OPDIVO) is approved for the treatment of unresectable or metastatic 
melanoma in multiple countries including Japan, the US, and EU.  It is also approved for 
the treatment of metastatic squamous cell NSCLC in the US. 
5.1.1 Storage Conditions and Handling 
 
Nivolumab should be stored at between 2-8 degrees Celsius (36-46 degrees Fahrenheit), 
and protected from light, freezing, and shaken.  If any temperature excursions are 
encountered during storage, they should be reported to BMS.  As with all injectable drugs, 
care should be taken when handling and preparing Nivolumab.  Whenever possible, 
Nivolumab should be prepared in a laminar flow hood or safety cabinet using standard 
precautions for the safe handling of intravenous agents applying aseptic technique. 
Partially used vials should be disposed at the time following procedures for the disposal of 
anticancer drugs. 
5.1.2 Use Time/Stability 
 
Once transferred to IV bags, the solution may be stored for up to 20 hrs in a refrigerator at 
2-8 degrees Celsius and used within 4 hours at room temperature and under room light 
inclusive of administration time.  The maximum 4-hour period under room temperature and 
room light conditions for undiluted and diluted solutions of Nivolumab injection in the IV  
bag should be inclusive of the product administration period.  Please refer to the current 
Investigator Brochure for further details (Section 3). 
5.2  Image-Guided, High Dose Stereotactic Body Radiotherapy 


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Image-guided, stereotactic body radiotherapy allows for the deivery of  high-dose-per- 
fraction radiotherapy with exquisite precision whie excluding to a large degree normal 
tissue from being exposed to high-dose regions of irradiation.  Stereotactic radiotherapy is 
defined as the directing of therapy using beams of radiation along any trajectory in 3D 
space toward a target of known 3D coordinates.  The coordinate system is defined by 
reliable fiducial markers. For the purposes of this study, the tumor itself will serve as the 
fiducial.  Low-dose CT scans will be obtained at the time of treatment delivery, and 
intensity modulated radiotherapy planning (IMRT) will be utilized. 
IMRT is a sophisticated radiation planning and delivery technique that uses a computer 
controlled multi-leaf collimator to shape the intensity of each radiation treatment beam to 
optimally deliver the dose to the tumor and protect normal tissue.  The radiotherapy 
delivery systems that will be used in this trial are standard and FDA approved.  The dose 
fractionation scheme (9 Gy x 3) has been used routinely at MSKCC and other tertiary care 
centers. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
In order for a patient to be enrolled on trial, the following criteria need to be met: 
 
6.2 
Subject Inclusion Criteria 
 
1) Signed Written Informed Consent 
• 
Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. 
• 
Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other study obligations. 
 
2) Target Population 
• 
Males and females ≥ 18 years of age. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
• 
Histologically confirmed metastatic HNSCC, including nasopharynx WHO Type I-III 
histologies; patients can have simultaneous loco-regional disease. Central biopsy 
review at MSKCC is not required. 
• 
Subjects must have at least two lesions: 
o At least one lesion must be safely amenable to irradiation and likely to meet 
criteria delineated in Section 9.2.1 in the judgment of the treating radiation 
oncologist.  This can be a lesion that was previously irradiated as long as prior 
radiation was at least 6 months prior to projected first fraction of SBRT and as 
long as reirradiation dose constraints as outlined in appendix are being met. 
o A separate, not-to-be-irradiated lesion measurable by CT or MRI per RECIST 
1.1 criteria. 
• 
A formalin fixed, paraffin-embedded (FFPE) tumor tissue block or a minimum of 3 
unstained slides of tumor sample obtained via excisional, incisional, or core needle 
biopsy from a metastatic or loco-regionally recurrent lesion.  A new baseline biopsy 
does not need to be obtained for study purposes.  If 3 unstained are unavailable from 


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a metastatic or loco-regionally recurrent lesion, with permission of the PI, FFPE tumor 
tissue from the primary disease site at the time of original diagnosis is acceptable. 
• 
For oropharynx or nasopharynx primary lesions, documentation of viral status is 
required (e.g. high risk HPV sub-type PCR, p16 IHC, HPV ISH, EBER, etc). Tests 
done on primary tumor specimens from date of initial diagnosis at outside institutions 
are sufficient to meet this criterion. 
• 
Prior palliative or curative radiotherapy must be completed at least 14 days prior to 
randomization. 
• 
Immunosuppressive doses of systemic medication, such as steroids or absorbed 
topical steroids (doses >10mg/day prednisone or equivalent) must be discontinued at 
least 14 days prior to first Nivolumab administration. 
• 
Screening laboratory values must meet the following criteria (using CTCAE v4.0) and 
should be obtained within 28 days prior to randomization: 
o WBC >= 2 K/microliter 
o Neutrophils >= 1.5 K/microliter 
o Platelets >= 100 K/microliter 
o Hemoglobin >= 9.0 g/deciliter 
o Serum Creatinine <= 1.5 x ULN or creatinine clearance > 40ml/min using the 
Cockcroft-Gault formula. 
 
▪ 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
 
▪ 
Male CrCl = (140 - age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/dL 
o AST/ALT <= 3 x ULN (for subjects with liver metastases AST/ALT may be <=5 
x ULN). 
o Total bilirubin <1.5 x ULN (except subjects with Gilbert Syndrome who can 
have total bilirubin <3.0 mg/deciliter) 
o Calcium levels must be normalized and maintained within normal limits for 
study entry and while on treatment. 
o Subjects with an initial magnesium <0.5 mmol/liter (1.2 mg/deciliter) may 
receive corrective magnesium supplementation but should continue to receive 
either prophylactic weekly infusion of magnesium and/or oral magnesium 
supplementation. 
o Subjects must have a resting baseline O2 saturation by pulse oximetry of 
>=92% at rest. 
 
3) Reproductive Status 
• 
Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 28 days prior to 
randomization. 
• 
Women must not be breastfeeding 


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• 
Women of childbearing potential must agree to follow instructions for method(s) of 
contraception from time of enrollment for the duration of treatment with Nivolumab plus 
5 half- lives plus 30 days for a total of 23 weeks post treatment completion. 
• 
Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually 
active with WOCBP will be instructed to adhere to contraception for a period of 31 
weeks after the last dose of investigational product. 
• 
Women who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile as well as azoospermic men do not require contraception. 
• 
Azoospermic males and women of childbearing potential who are continuously not 
heterosexually active are exempt from contraceptive requirements. However, they still 
must have a pregnancy test. 
 
4) Insurance Approval 
• 
Insurance approval for SBRT should be obtained prior to randomization 
 
6.2 
Subject Exclusion Criteria 
 
Target Disease Exceptions 
 
• 
Active brain metastases (untreated brain metastases or growth on imaging as defined 
below) or leptomeningeal disease are not allowed.  Subjects with brain metastases are 
eligible if these have been treated and there is no MRI (or CT if MRI contraindicated) 
evidence of progression for at least 8 weeks after treatment for these metastases is 
complete and within 28 days prior to first study treatment. 
• 
Histologically confirmed non-squamous histologies are not allowed; an exception is 
made for WHO Type I-III  nasopharynx histologies. 
 
Medical History and Concurrent Diseases: 
 
• 
Any medical disorder that, in the opinion of the investigator, might increase the risk 
associated with study participation or interferes with the interpretation of study results. 
• 
Prior active malignancy within the previous 3 years except for locally curable cancers 
such as basal or squamous skin cancer, superficial bladder, low risk prostate cancer, 
breast, or cervix cancer. If other prior malignancy was active within prior 3 years, 
enrollment requires approval of a principal investigator. 
• 
Patients should be excluded if they have an active, known or suspected autoimmune 
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune 
condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger 
• 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration should be excluded. Inhaled or topical steroids and 
adrenal replacement doses >10mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 


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• 
As there is potential for hepatic toxicity with Nivolumab, drugs with a predisposition to 
hepatoxicity should be used with caution in patients treated with Nivolumab-containing 
regimen. 
• 
Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody. 
o NB-patients who have received prior anti-CTLA-4 antibody therapy are eligible 
assuming such therapy was discontinued within 28 days of enrollment. 
• 
Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 14 days of randomization. 
 
Physical and Laboratory Test Findings 
 
• 
Positive test for hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid 
indicating acute or chronic infection. 
• 
Known history of testing positive for HIV or known AIDS. 
• 
Any grade 4 laboratory abnormalities. 
Allergies and Adverse Drug Reaction 
• 
History of allergy to Nivolumab components 
• 
History of severe hypersensitivity reaction to any monoclonal antibody. 
Prohibited or Restricted Treatments 
The following medications are prohibited during the study: 
 
• 
Immunosuppressive agents (except to treat a drug-related adverse event). 
• 
Systemic corticosteroids > 10 mg daily prednisone equivalent save for exclusion 
outlined in the below paragraphs. 
• 
Any concurrent chemotherapy, hormonal therapy, immunotherapy, or investigational 
agents for treatment of cancer. 
Supportive care for disease-related symptoms may be offered to all subjects on the trial. 
 
Permitted Therapies During Study 
 
In either arm, if the investigator deems it medically necessary, non-target lesions can receive 
conventionally dosed, palliative radiation therapy. Palliative radiotherapy is not permitted within 24 
weeks of first study treatment.  Subjects receiving palliative radiation therapy will be considered to 
have had unequivocal progression of disease.  Administration of Nivolumab to subjects who 
received palliative radiation should follow guidelines specified for treatment beyond disease 
progression.  Any subsequent responses to therapy after the receipt of palliative radiation will not 
be counted towards the calculation of the primary endpoint, but patients who receive palliative 
radiation who remain on Nivolumab will have continued study-mandated scans until a 2nd 
progression event or 96 weeks, whichever occurs earlier. 
Other permitted therapies include topical, ocular, intra-articular intranasal and inhalational 
corticosteroids.  Adrenal replacement steroid doses including doses > 10 mg daily prednisone are 
also permitted. 


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7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s head and neck 
treatment team, the site protocol investigator, or research team at Memorial Sloan-Kettering 
Cancer Center (MSKCC).  If the investigator is a member of the treatment team, s/he will screen 
their patient’s medical records for suitable research study participants and discuss the study and 
their potential for enrolling in the research study.  Potential subjects contacted by their treating 
physician will be referred to the investigator/research staff of the study. 
The site principal investigator may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process.  The investigator/research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility.  They will use the information provided by 
the patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment team. 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log.  For these 
reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing 
medical records to identify potential research subjects and obtain information relevant to the 
enrollment process; (2) conversing with patients regarding possible enrollment; (3) handling of 
PHI contained within those records and provided by the potential subjects; and (4) maintaining 
information in a screening log of patients approached (if applicable). 
 
This limited waiver will apply only to MSK. 
8.0 
PRETREATMENT EVALUATION 
 
Screening Procedure Outline: 
 
Subjects will have a screening visit with the investigator and team.  The following will be 
assessed: 
8.1.1 Eligibility  Assessments 
 
o Informed consent signed 
o Assurance that inclusion and exclusion criteria are met 
o Medical History within 28 days prior to randomization 
o Sufficient tumor tissue for required biomarker analysis obtained before start of study from 
a metastatic lesion or loco-regionally recurrent site of disease. 
▪ 
Block or minimum of 3 slides obtained from core, punch, excisional biopsy; FNA 
insufficient. 
▪ 
Archival material is sufficient. 
▪ 
Material from bone is not sufficient as PD-L1 IHC cannot be done on bone. 


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▪ 
If no material is available from a metastatic or recurrent site, with permission of the 
principal investigator, material from the primary site of disease at the time of 
original diagnosis is acceptable. 
o HPV ISH, HPV PCR, p-16 expression testing, or EBER where for oropharynx and 
nasopharynx primary lesions, respectively.  If not done by an outside facility, this should 
be repeated at the trial site.  This testing could have been performed on primary lesion at 
time of initial diagnosis. 
8.1.2 Safety Assessments 
 
o Assessment of Signs and Symptoms within 28 days prior to randomization 
o Physical Examination within 28 days prior to randomization 
o Physical Measurements: weight within 28 days prior to randomization 
o Vital Signs and Oxygen saturation: blood pressure, heart rate, temperature, O2 saturation 
via pulse oximetry within 28 days prior to randomization 
o Performance status within 28 days prior to randomization 
o Prior medication collection:  data on all prior systemic therapy received to treat HNSCC 
within 28 days prior to randomization 
o Concomitant Medication Collection:  obtained within 28 days prior to randomization 
o Laboratory Tests (obtained within 28 days prior to randomization) 
o Complete Blood Count 
o Comprehensive Metabolic Panel ( AST, ALT, TBili, BUN, Creatinine, Ca, Mg, Na, 
K, Cl, Glucose, Amylase, Lipase) 
o TSH, Free T4, T3 
o Hepatitis B surface antigen, hepatitis C antibody 
o Pregnancy Test within 28 days prior to randomization. 
 
8.1.3 Efficacy Assessment 
 
o Screening/Baseline Tumor Assessment: CT or MRI of brain, neck, chest, abdomen, pelvis, 
and all other known sites of disease within 28 days prior to randomization. 
 
8.1.4 Patient Reported Outcome Assessment 
 
o EORTC QLQ-C-30 must be completed before administration of first dose of Nivolumab. 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Nivolumab should begin within 14 days (+/-4 days) of randomization.  The first day of Nivolumab 
is designated as study Day 1. 
Arm 1: On Day 1, patients will receive a one hour infusion of Nivolumab 3mg/kg and then every 
14 days (+/-2 days) until treatment progression per RECIST 1.1 criteria, unacceptable toxicity, or 
withdrawal of consent. 
Arm 2: After randomization, patients will complete CT simulation.  On Day 1 they will receive their 
first dose of Nivolumab (3mg/mg); they will receive their first radiation treatment (9 Gy) by study 
day 14. The additional 2 fractions of radiation (9 Gy per fraction) will be delivered within 10 
business days, no more frequently than every other day.  Nivolumab 3mg/kg will be administered 


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every 14 days (+/-2 days) until treatment progression per RECIST 1.1 criteria, unacceptable 
toxicity, or withdrawal of consent. 
9.2 Intervention: Nivolumab 
 
9.2.1 Preparation and Administration: 
 
• 
Nivolumab injection is to be administered using a volumetric pump with a 0.2/1.2 
micron pore size, low protein binding polyethersulfone membrane in-line filter at 
the protocol-specific doses. 
• 
The line should be flushed at the end of the infusion with sufficient quantity of 
normal saline per institution SOC. 
• 
Nivolumab is not to be administered as an IV push or bolus injection. 
• 
At the dose of 3mg/kg, the total dose needed will be diluted to a minimum total 
volume of 60 ml in 0.9% Sodium Chloride or 5% dextrose injection solution. 
• 
Care must be taken to assure sterility of the prepared solution as the produce not 
contain any anti-microbial preservative or bacteriostatic agent. 
• 
Nivolumab should be administered over a 1-hour period; infusions will be 
controlled by a volumetric pump. 
• 
Please refer to the current Investigator Brochure for further details. 
• 
Allow the appropriate number of vials of Nivolumab to stand at room temperature 
for approximately 5 minutes before preparation. 
• 
Ensure that Nivolumab solution is clear, colorless, and essentially free from 
particulate matter. 
• 
Aseptically withdraw the require volume of Nivolumab into a syringe and dispense 
into an IV bag. 
a. Add the appropriate volume of 0.9% Sodium Chloride injection solution. 
b. Mix by gently inverting several times. DO NOT shake. 
c. Record the Nivolumab expiration time and date on the IV bag label. 
d. Attach the IV bag containing the Nivolumab solution to the infusion set, in- 
line filter, and infusion pump. 
e. The infusion rate of the infusion pump should be adjusted to allow for a 
total infusion time of approximately 60 minutes. 
f. 
At the end of the infusion period, flush the line with a sufficient quantity of 
0.9% Sodium Chloride injection solution or 5% dextrose injection. 
• 
Pharmacy supplies required: 
a. Empty IV bags-50mg, 100mL, 200 mL 
b. 0.9% NaCl bags 
c. 0.2 or 0.22 micron in line filter and infusion tubing 
d. Volumetric infusion pumps. 
 
9.2.2 Selection and Timing of Dose for Each Subject 
 
Subjects randomized to Arm 1 or Arm 2 will receive Nivolumab as a 60 minute IV infusion 
on Day 1 of the study. Subjects randomized to Arm 2 will receive their first radiation 
fraction by study day 14.  Dose of Nivolumab is 3mg/kg and should be done based on the 


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body weight of the subject at the start of each cycle.   If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the original dose, the dose must 
be recalculated.  All doses should be rounded to the nearest milligram or as per 
institutional guidelines.   There are no pre-medications recommended for Nivolumab. 
9.2 Intervention: SBRT 
 
9.2.1 Target Selection 
 
• 
A single target lesion will be selected. 
• 
The lesion must be safely amenable to irradiation in the judgment of the treating 
radiation oncologist; approval of PI is not required. 
• 
Lesions must be located in one of the following eight locations: 
▪ 
Central Lung Tumors: GTVs within 2cm of the proximal bronchial tree 
(carina, right and left main bronchia, right and left upper lobe bronchi, 
intermedius bronchus, right middle lobe bronchus, lingular bronchus right 
and left lower lobe bronchi. 
▪ 
Lung Peripheral: metastases within the lung parenchyma with GTV outside 
of the proximal bronchial tree as described above. 
▪ 
Mediastinal Lymph Nodes: GTV arising within the anatomic space between 
the lungs, above the diaphragm, and below the thoracic inlet at the level of 
the top of the sterna notch. 
▪ 
Head and Neck: GTV occurring within cervical lymph node levels I-VI 
and/or retropharyngeal spaces, oral cavity, oropharynx, nasopharynx, 
hypopharynx, para-nasal sinuses, nasal cavity, and parotid gland/space. 
▪ 
Liver: GTV arising within the liver. 
▪ 
Spine: metastases will be assigned to the spinal/paraspinal site if the GTV 
arises within the vertebral bodies expanded by 1cm. 
▪ 
Osseous: GTV arising within an osseous structure, part of the axial 
skeleton, not included in the spinal definition. 
▪ 
Abdominal-Pelvic: GTV arising within the anatomic space defined by the 
diaphragm superiorly, the genitourinary diaphragm inferiorly include the 
peritoneal and retroperitoneal spaces, not including liver, osseous, or spinal 
metastases. 
 
• 
While no specific size constraint exists, the treating radiation oncologist must have 
a reasonable expectation that the dose constraints outlined in the appendix will be 
met; if, during planning, dose constraints to outlined normal tissue structures are 
exceeded, the treating radiation oncologist must receive permission of the study PI 
(Sean McBride) prior to proceeding with treatment. If permission is not obtained, 
the patient will be withdrawn from the study. 
• 
In instances where there is a metastatic or recurrent lesion that is either causing 
symptoms or on the precipice of doing so, the treating radiation oncologist should 
select this lesion for irradiation. 
• 
Every effort should be made to choose a target lesion outside of a previously 
irradiated site.  However, the treated lesion can be a lesion that was previously 


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irradiated as long as prior radiation was at least 6 months before the projected first 
fraction of SBRT and as long as re-irradiation dose constraints as outlined in 
appendix are met. In cases of re-irradiation, if the re-irradiation dose constraints 
outlined in the appendix are exceeded, the patient will be withdrawn from the 
study. 
9.2.2 Radiotherapy Simulation and Contouring Guidelines 
 
• 
All patients will undergo standard IMRT-based treatment planning (VMAT  allowed) 
prior to the first treatment using an appropriate immobilization device. 
o Begins with immobilization of the patient in a reproducible position in a 
custom-mold followed by acquisition of a CT scan in the treatment planning 
position.  Prior placement of fiducial markers and the use of 4D-CT 
acquisition is at the discretion of the treating radiation oncologist. 
o The use of intravenous, oral, or rectal contrast is at the discretion of the 
treating radiation oncologist. 
o The physician segments the tumor and critical normal tissues on the scan 
and also specifies the dosimetric goals. 
o For spinal cord lesions, MR fusion or CT myelogram prior to CT simulation 
will be required in order to ensure that the spinal cord is adequately 
segmented. 
• 
The definition of volumes will be in accordance with ICRU Report #50: Prescribing, 
Recording, and Reporting Photon Beam Therapy. 
o A gross tumor volume will be entered for the lesion (GTV), based on 
available imaging data. 
o The clinical target volume (CTV) should be the same as the GTV.  No 
margin is required for microscopic extension. 
o An internal target volume (ITV) can be used at the discretion of the treating 
radiation oncologist. 
o The planning target volume (PTV) should be the GTV (or ITV) plus 3 mm. 
o Each PTV will be treated to the prescribed dose of 9 Gy x 3. 
o Normal tissues contoured to determine dose volume histogram will incldue 
lungs, spinal cord, liver, kidney, heart, trachea, esophagus, rectum, 
bladder, and bowel, if applicable. 
9.2.3 Radiotherapy Planning and Treatment Delivery 
 
• 
Planning: 
o For IMRT-planning,  a physicist chooses the most favorable beam directions 
and inputs the treatment goals into a computer algorithm that designs the 
intensity patterns to best fulfill the goals of delivering the assigned dose to 
the target while keeping all relevant normal tissue structures to the limits 
set out in Appendix Normal Tissue Constraints.  The intensity patterns are 
then downloaded to the treatment machine to drive the multi-leaf collimator 
during treatment. 
• 
On Line Image-Guided  Localization and Treatment Delivery 


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o The patient immobilization device is itself fixed to the couch of the 
treatment machine. 
o Prior to each treatment, the position of the patient’s tumor is verified using 3 
dimensional kilovoltage cone beam CT imaging.  This is a high res olution 
CT scan taken of the patient and target structure of interest while the  
patient is immobilized on the treatment table. 
o The cone beam CT image is obtained and image registration between the 
cone beam CT and the planning CT is performed based on the location of 
the visible tumor abnormality noted in the CT. The image registration uses 
vendor-supplied software available at the treatment unit.  Thereafter, follow 
departmental filming policy. 
o The patient position is then adjusted to move the patient into the exact 
position corresponding to the designed IMRT treatment plan so that the 
prescription dose completely encompasses the target and the critical 
normal tissues are not within the high dose region. 
• 
Once the patient’s correct position is confirmed, the treatment will be delivered. 
During treatment the patient is monitored carefully to assure that there is no 
motion; if motion is noted, further imaging may be warranted. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 ASSESSMENTS DURING TREATMENT 
 
10.1.1 Safety Assessments 
 
o Targeted Physical Examination: Focused exam and history on AEs stemming from 
immune MOA.  This will occur on Day 1 of treatment and within 72 hours prior to 
Nivolumab administration at the following time points; 
o Every 2 weeks for the first month of treatment 
o Every 4 weeks for months 2-6 of treatment 
o Every 6 weeks until week 96 or progression 
o Vital Signs:  must include, at minimum, blood pressure on Day 1 of treatment and within 
72 hours prior to Nivolumab administration at the following time points; 
o Every 2 weeks for the first month of treatment 
o Every 4 weeks for months 2-6 of treatment 
o Every 6 weeks until week 96 or progression 
o Concurrent medication review on Day 1 of treatment and within 72 hours prior to 
Nivolumab administration at the following time points; 
o Every 2 weeks for the first month of treatment 
o Every 4 weeks for months 2-6 of treatment 
o Every 6 weeks until week 96 or progression 
o Physical Measurements: to include weight and performance status. This will occur on Day 
1 of treatment and within 72 hours prior to Nivolumab administration at the following time 
points; 
o Every 2 weeks for the first month of treatment 
o Every 4 weeks for months 2-6 of treatment 
o Every 6 weeks until week 96 or progression 


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o Adverse Event Assessment and attribution: This will occur on Day 1 of treatment and 
within 72 hours prior to Nivolumab administration at the following time points; 
o Every 2 weeks for the first month of treatment 
o Every 4 weeks for months 2-6 of treatment 
o Every 6 weeks until week 96 or progression 
o Laboratory Tests: CBC w/ differential, LFTs, BUN or serum urea level, creatinine, Ca, Mg, 
Na, K, Cl, Glucose, amylase, lipase, TSH (with reflexive Free T4 and T3) will occur within 
48 hours of 1st Nivolumab dose and within 72 hours prior to each subsequent dose of 
Nivolumab. 
 
 
10.1.2 Efficacy Assessments 
 
o Tumor Assessment:  tumor assessments of non-irradiated lesions via CT or MRI of all 
known sites of disease should occur 8 weeks after treatment initiation (day 1) (+/-2 weeks) 
and then every 8 weeks (+/- 2 weeks) for the first 48 weeks and every 12 weeks (+/- 2 
weeks) until progression or week 96 (whichever occurs first).  At each time-point, subjects 
should have CT/MR of neck, chest, abdomen, and pelvis with contrast.  Subjects with a 
history of brain metastasis should have surveillance MRI per the above schedule or  
sooner if clinically indicated.  If additional sites of disease not encompassed by the above 
imaging are noted, imaging of these lesions should also occur at the study mandated time 
points. 
Both MRI and contrast enhanced CTs are adequate imaging modalities for this study. CT with 
contrast or MR of the neck, chest, abdomen, pelvis, and all other known sites of disease are to be 
performed for tumor assessments per the timing above. 
CT scans should be acquired with 5mm slices with no intervening gap.  A non-contrast CT of the 
chest and a contrast enhanced MRI of the abdomen are acceptable if the patient has a 
contraindication to CT with contrast. 
PET/CT is acceptable so long as the CT component is of diagnostic quality. 
MRI brain scans during on-study treatment are required if there is a prior history of lesions 
present at screening, or as clinically indicated. 
 
10.1.3 Outcomes Research Assessment 
• 
EORTC QLQ-C-30: will be completed on or before Day 1 of treatment, and then, starting 
at week 8 (+/- 2 weeks), every 8 weeks (+/-2 weeks) for the first 48 weeks and every 12 
weeks (+/- 2 weeks) until either week 96 or disease progression (whichever occurs first). 
10.1.4 Exploratory Biomarker Testing 
 
o PBMC composition:  should be evaluated on blood drawn up to 7 days prior to treatment 
and then Days 14 (+/- 3 days)  and 28 (+/-3 days) and then upon progression (within 1 
week). 
o Soluble Biomarkers: can include PD-L1, and PD-1.  should be evaluated on blood drawn 
up to 7 days prior to treatment and then Days 14 (+/- 3 days)  and 28 (+/- 3 days)and then 
upon progression (within 1 week). 
10.2 Assessments During Follow-Up 


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There will be a single mandated follow-up visit: 
o Follow-Up Visit: occurs within 100 days from the last dose of Nivolumab (FU1) 
10.2.1 Safety Assessments at follow-up visit: 
o Targeted Physical Examination 
o Vital Signs: at a minimum, must include blood pressure. 
o Adverse events assessment 
o Review of concomitant medication 
10.2.2 Subject Status 
 
o Survival: at follow-up and then every 12 weeks thereafter (phone or visit 
acceptable). 
 
 
 
 
Note: baseline biopsy does not need to be obtained if sufficient biopsy material for required PD-L1 
testing from a metastatic or loco-regionally recurrent lesion already exists. If sufficient biopsy 
material is not available, efforts should be made to biopsy a recurrent/metastatic site.  If that is not 
feasible then, with the permission of the PI, material from the primary tumor specimen at initial 
diagnosis may be used.  Blood draw for PMBCs/soluble biomarkers are study mandated. 
11.0 
TOXICITIES/SIDE EFFECTS 


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An adverse event is defined as any new untoward medical occurrence or worsening of a pre- 
existing medical condition in a clinical investigation subject administered study drug and that does 
not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable or unintended sign, symptom, or disease temporally associated with the use of study 
drug/radiation or not considered related to the study drug/radiation. All AEs should be defined 
using the CTCAE v 4.0.  All grade 1-5 adverse events should be reported and attributed. 
The causal relationship to study drug is determined by the investigators and should be used to 
assess all AEs.  The causal relationships are defined as follows: 
• 
Related: there is a reasonable causal relationship between study drug/radiation 
administration and the AE. 
• 
Not related:  there is not a reasonable causal relationship between study drug/radiation 
administration and the AE. 
The common understood meaning of “reasonable causal relationship” is that there is evidence to 
suggest a causal relationship. 
 
 
11.1 Nivolumab Toxicity Management 
 
For Nivolumab monotherapy, the safety profile is similar across various tumor types.  
There is no pattern in the incidence, severity, or causality of AEs to Nivolumab dose level. 
In phase 3 controlled studies, the safety profile of Nivolumab monotherapy is acceptable in 
the context of the observed clinical efficacy, and manageable using the below mentioned 
safety guidelines.  Clinically relevant AEs typical of stimulation of the immune system were 
infrequent and manageable by delaying or stopping Nivolumab treatment and timely 
immunosuppressive therapy or other supportive care.  For complete details please to the 
Investigator Brochure v.14 that accompanies this protocol. 
11.1.1 Dose Delay Criteria 
 
Because of the potential for clinically meaningful Nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected AEs of selected categories. [See current Investigator Brochure] 
Dose delay  criteria apply  for all  drug-related  adverse  events. All  study drugs  must be 
delayed until treatment can resume. 
Dose  delay  criteria  apply  for  all  drug-related  AEs.  Nivolumab  must be  delayed  until 
treatment can resume. 
Nivolumab administration should be delayed for the following: 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
• 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
• 
Any Grade 3 skin, drug-related AE 
Any  Grade  ≥3  drug-related  laboratory  abnormality,  with  the  following  exceptions  for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 


Memorial Sloan Kettering Cancer Center 
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Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
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• 
Grade 3 lymphopenia or leukopenia does not require dose delay. 
• 
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥ 2 toxicity. 
• 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity. 
Any  AE,  laboratory  abnormality,  or  intercurrent  illness  which,  in  the  judgment  of  the 
investigator, warrants delaying the dose of study medication. 
11.1.2 Management Algorithms  for Immuno-Oncology Agents 
 
Immuno-Oncology (I-0) agents are associated with adverse events that can differ in 
severity and duration than adverse events caused by other therapeutic classes. 
Nivolumab is considered an immune-oncology agent in this protocol.  Early recognition 
and management of adverse events associated with immune-oncology agents may 
mitigate severe toxicity.  Management algorithms have been developed to assist 
investigators in assessing and managing the following groups of adverse events: 
• 
Gastrointestinal 
• 
Renal 
• 
Pulmonary 
• 
Hepatic 
• 
Endocrinopathies 
• 
Skin 
• 
Neurological 


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Approval date: 13-Mar-2018 
 
 
 
 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
 
 
 
11.1.3 Dose Modifications 
 
Dose reductions or dose escalations are not permitted. 
 
11.1.4 Criteria to Resume Treatment 
 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade <= 1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
• 
Subjects with baseline Grade 1 AST/aLT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bili may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin. 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarhea, colitis, must have resolved to baseline 
before treatment is resumed. 
• 
Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time-point per protocol.  However, if the treatment is delayed past the next 
scheduled time-point per protocol, then next scheduled time-point will be delayed until 
dosing resumes. 
Treatment may be delayed for up to a maximum of 6 weeks from the last dose; if 
treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified. 
11.1.5 Treatment of Infusion Reaction 
 
Since Nivolumab contains only human IgG protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reacitons.  However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash pruritus, 
athralgias, blood pressure shifts, bronchospasms, or other symptoms.  All Grade 3 or 5 
infusion reacitons should be reported within 24 hours to the primary investigator and 
reported as an SAE if criteria are met.  Infusion reactions should be graded according to 
NCI CTCAE v 4.0 guidelines. 
Treatment recommendations are provided  below  and may be  modified based on  local 
treatment standards and guidelines as appropriate: 
For Grade 1 symptoms:  (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional Nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the Nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further Nivolumab will be administered at that visit. Administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
The following prophylactic premedications are recommended 
for future infusions: 
diphenhydramine 
50 mg (or equivalent) 
and/or 
paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional Nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
For Grade 3 or Grade 4 symptoms:  (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or 
ventilatory support indicated). 
Immediately discontinue infusion of Nivolumab. Begin an IV infusion of normal saline, and 
treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected 
slowly for IV 
administration, and/or 
diphenhydramine 
50 mg IV 
with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic treatment may 
be given (e.g., oral antihistamine, or corticosteroids). 
11.2 Management of Toxicities Related to Radiotherapy 
 
Supportive Care During Radiotherapy 
 
o Antiemetics can be ordered at the discretion of the treating radiation oncologist. 
o Mucositis/esophagitis may be ameliorated with sucralfate or gastrointestinal 
cocktail (e.g. Tyleon #3 suspension, benadryl elixir, Maalox, viscous lidocaine). 
o Intravenous hydration is recommended in patients with inadequate oral intake. 
o Treatment-related diarrhea can be managed with loperamide. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Primary Endpoint: 
To compare overall response rate (ORR) in non irradiated lesions during the first 96 
weeks after treatment initiation as determined by the investigator using Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria between patients receiving 
Nivolumab and SBRT to those receiving Nivolumab alone.  ORR rate is defined as the 
number of patients randomized to a given arm with a best overall response (BOR) of 
complete response (CR) or partial response (PR) divided by the total number of patients 
randomized to the given arm. 
To serially evaluate tumor response to therapy, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable tumor lesion. 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
nonmeasurable. 
 
12.1.1 Measurable Lesions 
 
Of note, for purposes of this study, irradiated lesions are not considered measurable. 


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Measurable lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of the measurement to be recorded) with a minimum size of: 
 
o 10mm by CT/MRI scan 
o 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.  At 
baseline and in follow-up, only the short axis will be measured and followed. 
12.1.2 Non-measurable lesions 
 
o All other lesions including small lesions (longest diameter <10mm or pathological 
lymph nodes with >=10 to <15mm short axis), as well as truly non-measurable 
lesions. 
o Lesions considered to be truly nonmeasurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung. 
 
12.1.3 Special Considerations Regarding Lesion Measurability 
 
o Bone scan, PET scan or plain films are inadequate to measure bone lesions. 
However, these techniques can be used to confirm the presence of disappearance 
of bone lesions. 
o Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross sectional imaging techniques such as 
CT/MRI can be considered as measurable lesions if the SOFT TISSUE component 
meets the definition of measurability. 
o Blastic bone lesions are non-measurable. 
 
12.1.4 Cystic Lesions 
 
o Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions since they are, by definition simple cysts. 
o “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the aforementioned definition of measurability. 
However, non-cystic lesions are preferred. 
 
12.1.5 Lesions with Prior Local Treatment 
 
o Tumor lesions situated in the previously irradiated area can be included as target 
lesions as long as there is documented radiographic disease progression in that 
site after completion of radiotherapy. 
 
12.1.6 Baseline Documentation of “Target” and “Non-Target” Lesions 
 
12.1.6.1 Target Lesions 
 
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline. 


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Target lesions should be selected on the basis of their size, be representative of all 
involved organs, and should lend themselves to reproducible repeated measurements. 
 
A sum of 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 as noted below, 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. 
 
12.1.6.2 Non-Target Lesions 
 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should be recorded at baseline.  Measurements are 
NOT required and these lesions should be followed as “present”, “absent”, or in rare 
cases, “unequivocal progression”.  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form. 
 
12.1.7 Tumor Response Evaluation 
 
Complete Response (CR): disappearance of all target lesions. Any pathological lymph 
nodes must have reduction in short axis to <10mm. 
Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as a reference the baseline sum of diameters. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as a reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). IN addition the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5mm. Note: the appearanc e of one or more 
new lesions is also considered progression. 
Stable Disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as a reference the smallest sum diameters while on study. 
12.1.8 Evaluation of Non-Target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured 
and instead should be assessed only qualitatively at the time points specified. 
Complete Response (CR): disappearance of all non-target lesions.  All lymph nodes must 
be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: persistence of one or more non-target lesions. 
 
Progressive Disease: unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered progression) or the 
appearance of new malignant lesions.  The finding of new lesions should be unequivocal. 


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o To achieve unequivocal progression on the basis of non-target disease, there must 
be an overall level of substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. 
o A modest “increase” in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. 
o If unequivocal progression is seen, the subject should be considered to have had 
an overall PD at that point. 
 
FDG-PET Evaluation 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of qualitative assessment of FDG-PET scanning to complement CT 
scanning in assessment of progression, particularly new disease. New lesions on the  
basis of FDG-PET imaging can be identified according to the following algorithm. 
o Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If positive PET at follow-up corresponds to new site of disease, this is PD 
o IF the positive 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. 
o If the positive 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. 
 
12.1.9 Response Criteria 


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The best overall response is determined once all the data for the subjects is known.  It is 
the best response recorded from the start of the study treatment until, in our own trial, 2 
years.  The subjects best overall response will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 
 
Best response is defined as the best response at all time points.  When SD is believed to 
be the best response, it must also meet protocol specified minimum time from baseline ( 8 
weeks).  If the minimum time is not met when SD is otherwise the best time point 
response, the subjects best response depends on the subsequent assessments.  For 


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example, a subject who has SD at first assessment, PD at second and does not meet 
minimum duration of SD, will have best response of PD.  The same subject lost to follow- 
up after the first SD assessment will be considerd not evaluable. 
12.1.10 Verification Scans 
 
o Verification of Response: confirmation of response (CR or PR) is required. 
Confirmed CR or PR will be claimed only if the criteria for each are met at a 
subsequent time point (minimum 4 weeks after criteria for an objective response 
are first met). 
o Verification of Progression: progression of disease should be verified in cases 
where progression is equivocal.  If repeat scans confirm PD, then progression 
should be declared using the date of the initial scan. If repeat scans do not confirm 
PD, then the subject is considered not to have progressive disease per RECIST 
1.1. 
 
 
12.2 Secondary End Points: 
 
12.2.1 Duration of Response 
The duration of objective response is measured from the time measurement criteria are 
first met for confirmed PR/CR until the first date the progressive disease is objectively 
documented (taking as a reference for progressive disease the smallest measurements 
recorded on study).  Duration of response will be measured from the time, in months, that 
the criteria for objective response are first met until the date of a progression event.  A 
subject with objective response who does not have a progression event at 96 weeks will 
be censored. 
12.2.2 Overall Survival 
Overall survival is defined as the time from randomization to the date of death from any 
cause. For subjects that are alive, their survival time will be censored at the date of last 
contact.  Overall survival will be censored for subjects at the date of randomization if they 
were randomized but had no follow-up. 


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12.2.3 Progression Free Survival (PFS) 
PFS is defined as the time from randomization to the date of RECIST-defined progressive 
disease (PD) or death from any cause. For subjects that are alive with CR, PR, or SD, 
they will be censored at the end of the two year, study mandated tumor assessments. 
PFS will be censored for subject at the date of randomization if they were randomized but 
had no follow-up. 
 
 
12.2.5 Treatment Related Adverse Events 
These will be defined for each arm using CTCAE v 4.0 criteria. 
 
 
12.2.6 Health-Related Quality of Life 
The EORTC-QLQ-C-30 is one of the most commonly used QoL instruments in oncology 
studies and has been assessed in previous studies evaluating health related quality of life 
in patients with head and neck cancer.  It is a 30 item instrument compromising six 
functional scales (physical functioning, cognitive functioning, emotional functioning, social 
functioning, role functioning, and global quality-of-life) as well as nine symptom scales 
(fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties).  Except for overall health status and global quality of life items, 
responses for all items are 4-point categorical scales ranging from 1 (not at all) to 4 (very 
much). The overall health/quality of life responses are 7 point Likert scales. 
The questions on the EORTC-QLQ-C30 will be scaled and scored using the  
recommended EORTC Quality of Life Group procedures.  Raw scores will be transformed 
using a linear scale ranging from 0 to 100, with a higher score representing a higher level 
of functioning or a higher level of symptoms. Clinical significance will be defined as 
differences of at least 10 points (on a 0-100 scale).  For example, a mean increase of >= 
10 points on a functional scale would indicated a moderate improvement, whereas a mean 
decrease of >= 10 points would be interpreted as moderate worsening. 
 
12.3 EXPLORATORY END POINTS: 
12.3.1 Baseline PD-L1 Expression on Tumor Cells 
 
Fresh biopsies will be provided for biomarker analysis if accessible and deemed safe and 
clinically necessary by the investigator.  An archived biopsy of metastatic or loco- 
regionally recurrent disease obtained prior to therapy is acceptable if the fresh biopsy is 
not clinically indicated. If neither fresh nor archived material are available from 
recurrent/metastatic site, archived material from the primary disease at diagnosis is 
allowable with permission of PI. On-treatment biopsies are not required. 
Expression of PD-L1 expression on tumor cells will be assessed using an automated 
immunohistochemical assay developed by BMS and Dako.  PD-L1 positivity will be 
defined as at least 5% of tumor cells showing cell surface PD-L1 staining of any intensity 
in a section containing at least 100 tumor cells that could be evaluated. 
Expression of 
PD-L2 expression on tumor infiltrating lymphocytes (TILs) may also be assessed. 
Additional IHC studies may be conducted evaluating CD4, CD8, FOXP3, HLA Class I, 


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Antigen Presenting Machinery (APM), and HPV oncoproteins expression.   PD-L1 IHC will 
be conducted by BMS (see appendix for additional information) 
12.3.2 Peripheral Blood Mononuclear Cells Composition (PBMCs) 
Peripheral blood samples will be taken prior to initiation of study therapy and at designated 
time points.  Ideally,  peripheral blood samples should be used for immunophenotyping or 
characterization of the immune cell subsets in the periphery, including, but not limited to, T 
cells, B cells, NK cells, or subpopulations of the aforementioned immune cell types. 
These samples may also be used to assess immune cell function or antigen specific T cell 
proliferation. 
12.3.3 Serum Biomarkers 
Blood samples for exploratory serum biomarker analysis will be drawn at the time points 
indicated.  Blood samples will be processed to collect serum and then put in frozen 
storage.  Samples may be assessed by ELISA, seromics and/or other relevant multiplex 
based protein assay methods for immune or HNSCC-related factors that will predict for 
Nivolumab and/or Nivolumab+SBRT benefit.  Although numerous potential serum -based 
biomarkers are under investigation, we will look at soluble PD-1 and PD-L1.  However, 
other biomarkers may be of interest and future analyses may include them. 
 
12.3.4 Neo Antigen Expression (optional) 
Neo-epitope analysis using whole exome sequencing may also be conducted on baseline biopsy 
specimen and evaluated as a predictor of response to therapy. 
 
 
13.1 
CRITERIAFOR REMOVAL FROM STUDY 
 
Treatment with Nivolumab will continue until RECIST 1.1-defined progression, unacceptable 
toxicity, failure to obtain PI approval for radiation plans that exceed normal tissue dose constraints 
as outlined in the appendix, or withdrawal of consent. 
13.2 Discontinuation Criteria for Nivolumab 
 
Treatment should be permanently discontinued for the following: 
 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within re-treatment period OR 
requires systemic treatment. 
• 
Any Grade 3 non-skin, drug related adverse event lasting > 7 days with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivty reactions, and infusion reactions; 
o Grade 3 drug-related uveitis , pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
▪ 
Grade 3 drug-related thrmobocytopenia > 7 days or associated with 
bleeding requires discontinuation. 


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▪ 
Any drug related LFT abnormaltiy that meets the following criteria require 
discontinuation; 
• 
AST or ALT > 8x ULN 
• 
Total bilirubin > 5x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN. 
• 
Any grade 4 drug-related adverse event or laboratory abnormaltiy, except for the following 
events which do NOT require discontinuation: 
o Isolated grade 4 electrolyte imbalances that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset. 
o Isolated grade 4 electrolyte imbalances that are not associated with clinical 
sequelae and are corrected with supplementation within 72 hours of their onset. 
• 
Any dosing delays lasting > 6 weeks with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed.  Prior to reinitiating treatment in a subject with a dosing delay 
lasting > 6 weeks, the primary investigator must be consulted. Tumor assessments 
should continue as per protocol even if dosing is delayed. 
o Dosing delays > 6 weeks that occur for non-drug related reaosns may be allowed if 
approved by the primary investigator.  Prior to reinitiating treatment in a subject with 
a dosing delay lasting > 6 weeks, the primary investigator must be consulted. 
Tumor assessments should continue as perp protocol even if dosing is delayed. 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgement of 
the investigator, presents a substantial clinical risk to the subject with continued Nivolumab 
dosing. 
13.3 Treatment Beyond Disease Progression with Nivolumab 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease (PD).  Subjects will be 
permitted to continue on treatment with Nivolumab beyond initial RECIST 1.1 PD as long 
as they are meeting the following criteria: 
• 
Investigator-assessed clinical benefit without rapid disease progression. 
• 
Tolerance of study drug 
• 
Stable performance status 
• 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g. CNS metastases) 
• 
Subject provides written informed consent prior to receiving any additional 
nivolumab treatment, using an ICF describing any reasonably forseeable risks or 
discomforts, or other alterative treatment options. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 


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All decisions to continue treatment beyond initial progression must be discussed with the 
primary investigator and documented in the study records. Subjects will be reconsented 
with an ICF describing any reasonable foreseeable risks or discomforts. 
Subjects should discontinue study therapy upon further evidence of progression, defined 
as an additional 10% or greater increase in tumor burden volume from time of initial 
progression. 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10mm (except for pathological lymph nodes, which  must have a short 
axis of at least 15mm). Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except for pathological 
lymph nodes which must have an increase in short axis to at least 15mm). 
For statistical analyses that include investigator assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed RECIST 1.1 defined progression 
will be considered to have investigator-assessed progressive disease at the time of the 
initial progression event.  Responses beyond this 1st  progression event will not be counted 
towards the primary endpoint of overall response rate. 
Patients who have initial progression who are deemed eligible and decide to continue 
Nivolumab therapy will continue to have study mandated scans per Section 10.1 until 
further progression or 96 weeks, whichever occurs first. 
14.0 
BIOSTATISTICS 
 
11.1 Primary Objective 
 
The primary objective of this study is to compare best overall response (BOR) rate by 96 
weeks as determined by the investigator using RECIST 1.1 criteria between patients 
receiving Nivolumab and SBRT and those receiving Nivolumab alone.  BOR rate is 
defined as the number of patients randomized to a given arm with a best overall response 
of complete response (CR) or partial response (PR) of non-irradiated lesions divided by 
the total number of patients randomized to the given arm. In order to ascertain this 
endpoint, efforts will be made so that patients will be followed for 96 weeks or until 
progression of disease (and treatment cessation), whichever comes first. 
 
Based upon an estimated ORR of 15% in a PD-L1 unselected population in the Nivolumab 
alone arm (based on data from Siewert, et al; see background) and an ORR of 45% in the 
Nivolumab and SBRT arm, the enrollment of 54 patients with a two-sample proportion test 
will provide a one-sided alpha of 0.10 and a power of 0.80.  Assuming a 10% drop-out 
rate, we will enroll a total of 60 patients. Patients will be randomized to the two treatment 
arms in a 1:1 ratio.  Patients will be stratified based upon viral status (virus negative  
versus virus positive; virus status is defined by EBV (EBER testing) or HPV (p16, HPV 
ISH, HPV PCR) testing).  Assuming a constant enrollment of 3 subjects per month, it 
would take approximately 20 months to randomize 60 patients.  Calculations were 
completed using software R 3.1.1 and EAST 6. 


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To ensure eligible endpoints are well defined, a minimum of 6 months of follow up after 
treatment initiation is required.  Patients lost to follow-up prior to 6 months (24 week scan) 
will be replaced, regardless of response. Patients lost to follow-up between 6 months and 
24 months will be included in the ORR calculation. 
 
Secondary objectives: 
 
 
OS and PFS will be evaluated by the regular survival analysis tools such as Kaplan-Meier 
and competing risks methods. Comparisons will be conducted between the two arms by 
the stratified log-rank test and Gray’s test. 
 
The DOR will be calculated from the time of response to progression or last follow up and 
analyzed using the Kaplan-Meier  method among patients who showed response. 
 
 
All tr-AEs will be tabulated and summarized. The cumulative incidence of all tr-AEs and 
Grade 3+ tr-AEs, etc., will be compared between the two arms by using Gray’s test. For 
this analysis all randomized subjects who received at least one dose of study drug will be 
included. 
 
The questions on the HRQOL will be scaled and scored using the recommended EORTC 
Quality of Life Group procedures. Raw scores will be transformed using a linear scale 
ranging from 0 to 100, with a higher score representing a higher level of functioning or a 
higher level of symptoms. Wilcoxon rank sum tests will be conducted to compare the 
scores across the two arms and longitudinal plots will be made to visually examine the 
pattern of change of scores at each specified time point. If appropriate, an exploratory 
linear mixed model will also be used to incorporate correlations among various time  
points, and include additional variables such as interaction between treatment and number 
of assessments, site of the primary tumor, baseline score, and performance status. 
 
Because the toxicity of Nivolumab combined with SBRT is unclear, we will utilize an  
interim stopping rule for Arm 2 based on the first 20 randomized to this arm to protect later 
patients from unacceptably high toxicity rate. Using data from recently reported early  
phase trials of Nivolumab in NSCLC, we view 14% as an acceptable rate of acute (within 3 
months of study initiation) >= Grade 3 treatment-related adverse events; an unacceptable 
rate of acute >= Grade 3 treatment-related adverse events is 30%. If more than 5 (e.g. 6  
or more) of the first 20 patients experience an acute >= Grade 3 treatment-related adverse 
event, the trial will be stopped early. If the true toxicity rate is 30%, the above boundary 
assures a 58% probability of stopping the trial at interim analysis; if the true toxicity rate is 
40%, there is an 87% chance of stopping the trial early. If the true toxicity rate is 14%, the 
above boundary has only a 5% probability of stopping the trial early. Of note, for radiation 
dermatitis, only Grade 4 treatment-related adverse events will be included in the interim 
analysis. 
 
For the exploratory objectives, all lab measurements will be summarized and descriptive 
statistics will be provided. When correlation between lab measurements and treatment 
outcomes are of interest, Wilcoxon rank sum tests will be conducted to examine the 
difference between responders and non-responders within each arm. An exploratory 
multivariate logistic regression analysis to determine whether, once adjusted for relevant 
clinical covariates and treatment arm, tumor PD-L1 or serum immunophenotypic changes 
predict for response to Nivolumab. 


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To clarify we define population for the above analyses 
o Randomized subjects for ORR analysis: all enrolled subjects who were 
randomized and provided at least 6 months of follow-up after treatment initiation. 
This is the dataset for the primary objective and irORR. 
o All randomized subjects: all enrolled subjects who were randomized.  This is the 
dataset for baseline demographics and time-to-event endpoints (PFS, OS). 
o Treated subjects:  all randomized subjects who received at least one dose of study 
drug.  This is the dataset for safety evaluation.  For instance, if a subject receives a 
single dose of Nivolumab but withdraws from study prior to the first dose of 
radiation, that subject will be considered treated. 
o Biomarker Subjects: all randomized subjects with available biomarker data. 
o PRO subjects: all subjects with available Patient Reported Outcomes (PRO) data. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/).  The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
Patients will be randomized to the Nivolumab and SBRT arm or Nivolumab only arm. For 
patients enrolled, immediately after consent is obtained, the RSA at MSKCC will register 
participants in the Protocol Participant Registration (PPR) system. Once the participant’s 
eligibility is established the registration will be finalized and the participants will be 
randomized using the Clinical Research Database (CRDB).  Randomization will be 
accomplished by the method of random permuted block, and will be stratified by viral 
status (positive or negative). After treatment arm is determined by randomization, RSAs 
will notify the physicians at MSKCC of the treatment arm and participant ID via email 
within 24 hours of randomization. All Data will be collected and analyzed at MSKCC. 
Compiled data will be submitted to the biostatistician on study (Dr. Zhigang Zhang) for 
analysis. 
16.1 
DATA MANAGEMENT ISSUES 


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Data will be managed by a designated RSA from the Department of Radiation Oncology at 
MSKCC. All data will be managed in compliance with institutional policy and kept in 
iMedidata. 
List of variables and population characteristics 
• Patient demographic data (date of birth, height, weight) 
• Medical history 
• Concomitant medication 
• Adverse events 
• Laboratory Values 
• Tumor Assessment Data 
• Quality of Life Assessment Data 
• Tumor PD-L1 status 
• MDSC results 
 
16.2 
Quality Assurance 
 
Routine data-quality reports will be generated to assess missing data and inconsistencies.  
Accrual rates, and extent and accuracy of evaluations and follow-up, will be monitored periodically 
throughout the study period and potential problems will be brought to the attention of the study 
team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study team, 
at a minimum of once per year, more frequently if indicated. 
 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the new policies set forth by the NCI in 
the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of 
Clinical Trials” which can be found at http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet  at http://mskweb2.mskcc.org/irb/index.htm. 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research quality assurance) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees, Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., National Institutes 
of Health sponsored, in-house sponsored, industrial sponsored, National Cancer Institute 
cooperative group, etc.) will be addressed and the monitoring procedures will be established at 
the time of protocol activation. 


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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to enrollment of each patient, the risks, benefits, and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side  
effects. Alternative, non-protocol, treatment options will be discussed with the patient.  It will 
be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time.  The study is designed with careful safety monitoring for  
toxicity including physician visits and lab work.  Specific guidelines for symptom management 
are in place to protect the study participant. 
Human Subjects Involvement and Characteristics: all patients at MSKCC who meet the 
inclusion criteria will be eligible.  Both men and women and members of all ethnic groups are 
eligible for this trial. 
Consent Process: all patients who meet the inclusion criteria will be eligible. Participation is 
voluntary. All patients will be required to sign a statement of informed consent, which must 
conform to IRB guidelines.  The informed consent procedure is described in Section 18.0. 
Possible Toxicities/Side Effects: there are risks associated with treatment as described in 
Section 11.0; however, patients screened for enrollment will be deemed appropriate for 
treatment independent on this study. 
Benefits:  Image-Guided, high dose radiotherapy has the potential to augment tumor 
response to Nivolumab. 
Costs: patients will be charged for physician visits, routine laboratory tests, radiologic 
studies, and radiation therapy.  The patients will not be billed for Nivolumab. 
Alternatives: the alternative to this trial would be either standard cytotoxic chemotherapy or 
enrollment on other, open trials in HNSCC. 
Confidentiality: every effort will be made to maintain patient confidentiality.   Research and 
hospital records are confidential.  Patients’ names and any other identifying information will 
not be used in reports or publications resulting from this trial.  Other authorized agencies and 
appropriate internal personnel and external personnel (monitors from BMS), its authorized 
agents, the FDA, and other governmental agencies may review patient records as required. 
Patient Safety:  patients are monitoring by physicians and oncology nurses who are very 
familiar with clinical trials.  In the case of an adverse reaction, immediate medical attention is 
available.  In the evenings and weekends, we have 24-hour urgent care facility for 
outpatients. The PI and co-PIs will be available at all times to organize any necessary 
intervention. 
Monitoring of Data to Ensure Safety: this study will be monitoring by the institutional IRB. 
This incorporates an independent data and safety monitoring committee established by 
arrangement with the National Cancer Institute.  The analysis of safety will include all 


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Approval date: 13-Mar-2018 
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patients’ adverse events, including all toxic effects of treatment, will be tabulated individually, 
and summarized by severity and causality. 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
Suspected transmission of an infectious agent via the study drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury are not always serious 
by regulatory definition, these events must always be handled as an SAE. 
Any component of a study endpoint that is considered related to the study therapy (radiation or 
Nivolumab) should be reported as an SAE. 
 
 
SAE reporting is required as soon as the participant signs consent and is registered.  SAE reporting 
is required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol treatment 
must be reported. 
 
An SAE must be reported to the IRB/PB within 5 calendar days of the event. The IRB/PB requires a 
Clinical Research Database (CRDB) SAE report should be submitted electronically to the SAE 
Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. 
All other reports should be sent to saemskind@mskcc.org. 


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Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
 
The report should contain the following information: 
Fields populated from Medidata: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSK) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or 
intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent 
form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above.  If appropriate, the report will be forwarded to 
the FDA by the SAE staff through the IND Office. 
 
17.2.1 
 
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. 


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Approval date: 13-Mar-2018 
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All SAEs should be followed to resolution or stabilization. 
For studies conducted under an Investigator IND in the US include the following: 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided 
with a simultaneous copy of all adverse events filed with the FDA. 
SAEs   should   be   reported   on   MedWatch Form 3500A, 
which   can   be   accessed  at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness. 
• 
For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
• 
If 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 48 hours 
to BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization. All SAEs should be followed to 
resolution or stabilization. 
17.2.2 Non Serious Adverse Events 
The collection of non-serious adverse events should begin at initiation of treatment.  Non- 
serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
have become serious.  Follow-up is also required for non-serious SAEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate.  All identified nonserious AEs must be recorded and described on 
the nonserious AE page of the CRF. 


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Approval date: 13-Mar-2018 
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All non-serious adverse events should be collected continuously during the treatment period 
and for a minimum of 100 days following the last dose of Nivolumab. 
Laboratory Test Result Abnormalities 
The following laboratory test results abnormalities should be captured as non-serious or 
serious AEs. 
• 
Any laboratory test that is clinically significant or meets the definition of an SAE. 
• 
Any laboratory test result abnormality that required the subject to have Nivolumab 
discontinued or interrupted. 
• 
Any laboratory test result abnormality that required the subject o receive specific 
corrective therapy. 
17.2.3 Pregnancy 
If it is discovered that a study participant is pregnant or may have been pregnant at the time 
of study exposure, the investigator(s) must immediately notify the primary investigator and 
the MSKCC IRB. 
In most cases, the study drug/radiation will be permanently discontinued in an appropriate 
manner. 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with the IRB, the pregnant subject may continue the study drug, after a thorough 
discussion of benefits and risk with the subject. 
Protocol required procedures for study discontinuation and follow-up must be performed on 
the subject unless explicitly contraindicated by pregnancy. 
17.2.4 Overdose or Misadministration of Radiation 
An overdose or misadministration of radiation is defined as the accidental or intentional 
administration of any dose of a product or radiation considered both excessive and medically 
important.  All occurred of overdose must be reported as an SAE. 
17.2.5 Potential Drug Induced Liver Injury 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIS, 
meeting the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury must meet the following criteria: 
• 
ALT or AST > 3x ULN (or >5x ULN in patients with liver metastases) 
• 
Total Bilirubin > 2x ULN 
• 
No other immediately apparent alternative explanation. 
 
17.4  Safety Reports 
 
MSK must submit external safety reports to the MSK IRB/PB according to institutional 
guidelines. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Deeks, E.D., Nivolumab: a review of its usein patients with malignantmelanoma. Drugs, 2014. 
74(11): p. 1233-9. 
2. 
Tanguy Y. Seiwert, B.B., Jared Weiss, Iris Gluck, Joseph Paul Eder, Sara I Pai, Marisa Dolled-Filhart, 
Kenneth Emancipator, Kumudu Pathiraja, Christine Gause, Robert Iannone, Holly Brown, Jennifer 
Houp, Jonathan D. Cheng, Laura Quan Man Chow; The University of Chicago Medicine and Biological 
Sciences, Chicago, IL; Fox Chase Cancer Center, Philadelphia, PA; Lineberger Cancer Center, 
University of North Carolina at Chapel Hill, Chapel Hill, NC; Sheba Medical Center, Ramat Gan, Israel; 
Yale Cancer Center, New Haven, CT; The Johns Hopkins University Schoolof Medicine, Baltimore, 
MD; Merck & Co., Inc., Whitehouse Station, NJ; University of Washington, Seattle, WA, A phase Ib 
study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated 
head and neck (H/N) cancer. 
3. 
Durante, M., N. Reppingen, and K.D. Held, Immunologically augmented cancertreatmentusing 
modern radiotherapy. Trends Mol Med, 2013. 19(9): p. 565-82. 
4. 
Gaipl, U.S., et al., Kill and spread theword: stimulation of antitumorimmuneresponses in the context 
of radiotherapy. Immunotherapy, 2014. 6(5): p. 597-610. 
5. 
Demaria, S. and S.C. Formenti, Radiation as an immunologicaladjuvant: currentevidenceon doseand 
fractionation. Front Oncol, 2012. 2: p. 153. 
6. 
Deng, L., et al., Irradiation and anti-PD-L1 treatmentsynergistically promoteantitumorimmunity in 
mice. J Clin Invest, 2014. 124(2): p. 687-95. 
7. 
Grimaldi, A.M., et al., Abscopaleffects of radiotherapy on advanced melanoma patients who 
progressed after ipilimumab immunotherapy. Oncoimmunology, 2014. 3: p. e28780. 


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IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
8. 
Denaro, N., et al., State-of-the-art and emerging treatmentoptions in themanagementof head and 
neck cancer: news from 2013.  Oncology, 2014. 86(4): p. 212-29. 
9. 
Price, K.A. and E.E. Cohen, Current treatmentoptions formetastatichead and neck cancer. Curr Treat 
Options Oncol, 2012. 13(1): p. 35-46. 
10. 
Vermorken, J.B., et al., Cisplatin, fluorouracil, and docetaxelin unresectablehead and neck cancer. N 
Engl J Med, 2007. 357(17): p. 1695-704. 
11. 
de Mello, R.A., et al., Cetuximab plus platinum-based chemotherapy in head and neck squamous cell 
carcinoma: a retrospective study in a single comprehensive European cancerinstitution. PLoS One, 
2014. 9(2): p. e86697. 
12. 
Patel, A.N., J.M. Mehnert, and S. Kim, Treatmentof recurrentmetastatichead and neck cancer: focus 
on cetuximab. Clin Med Insights Ear Nose Throat, 2012.  5: p. 1-16. 
13. 
Gildener-Leapman, N., R.L. Ferris, and J.E. Bauman, Promising systemicimmunotherapies in head and 
neck squamous cellcarcinoma. Oral Oncol, 2013. 49(12): p. 1089-96. 
14. 
Jie, H.B., et al., Intratumoralregulatory Tcells  upregulateimmunosuppressivemolecules in head and 
neck cancerpatients. Br J Cancer, 2013.  109(10): p. 2629-35. 
15. 
Lyford-Pike, S., et al., Evidencefora role of the PD-1:PD-L1 pathway in immuneresistanceof HPV- 
associated head and neck squamous cellcarcinoma. Cancer Res, 2013.  73(6): p. 1733-41. 
16. 
Zandberg, D.P. and S.E. Strome, The role of the PD-L1:PD-1 pathway in squamous cellcarcinoma of 
the head and neck. Oral Oncol, 2014. 50(7): p. 627-32. 
17. 
Carbognin, L., et al., Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to 
the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in 
Melanoma, Lung and Genitourinary Cancers. PLoS One, 2015. 10(6): p. e0130142. 
18. 
Suzanne Louise Topalian, M.S., Julie R. Brahmer, David F. McDermott, David C. Smith, Scott N. 
Gettinger, Janis M. Taube, Charles G. Drake, Drew M. Pardoll, John D. Powderly, Richard D. Carvajal, 
Jeffrey Alan Sosman, Michael B. Atkins, Scott J. Antonia, David R. Spigel, Donald P. Lawrence, Georgia 
Kollia, Ashok Kumar Gupta, Jon M. Wigginton, F. Stephen Hodi; Sidney Kimmel Comprehensive 
Cancer Center at Johns Hopkins University, Baltimore, MD; Yale Cancer Center, New Haven, CT; Beth 
Israel Deaconess Medical Center, Boston, MA; University of Michigan Comprehensive Cancer Center, 
Ann Arbor, MI; Yale University, New Haven, CT; Johns Hopkins School of Medicine, Baltimore, MD; 
Carolina BioOncology Institute, Huntersville, NC; Memorial Sloan-Kettering Cancer Center, New York, 
NY; Vanderbilt University Medical Center, Nashville, TN; Georgetown University Lombardi 
Comprehensive Cancer Center, Washington, DC; H. Lee Moffitt Cancer Center & Research Institute, 
Tampa, FL; Sarah Cannon Research Institute; Tennessee Oncology, Nashville,TN; Massachusetts 
General Hospital Cancer Center, Boston, MA; Bristol-Myers Squibb, Princeton, NJ; Dana-Farber 
Cancer Institute, Boston, MA, Nivolumab(anti-PD-1; BMS-936558; ONO-4538) in patients with 
advanced solid tumors: Survivaland long-term safety in a phase I trial. ASCO, 2013. 
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results,  A.L.L.-B.P.A.a.a.s.o.p.i.p.p.w.a.s.c.c.o.t.h.a.n.S.P. 
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Burnette, B.C., et al., The efficacy of radiotherapy relies upon induction of typei interferon-dependent 
innateand adaptiveimmunity. Cancer Res, 2011. 71(7): p. 2488-96. 
21. 
Sharma, A., et al., Radiotherapy of human sarcoma promotes an intratumoralimmuneeffector 
signature. Clin Cancer Res, 2013. 19(17): p. 4843-53. 
22. 
Golden, E.B., et al., Radiation fosters dose-dependentand chemotherapy-induced immunogeniccell 
death. Oncoimmunology, 2014. 3: p. e28518. 
23. 
Lee, Y., et al., Therapeuticeffects of ablativeradiation on local tumorrequire CD8+ T cells: changing 
strategies forcancer treatment. Blood, 2009. 114(3): p. 589-95. 
24. 
Seung, S.K., et al., Phase 1 study of stereotactic body radiotherapy andinterleukin-2--tumorand 
immunologicalresponses. Sci Transl Med, 2012.  4(137): p. 137ra74. 
25. 
Postow, M.A., et al., Immunologiccorrelates of the abscopaleffect in a patientwith melanoma. N 
Engl J Med, 2012. 366(10): p. 925-31. 


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IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
26. 
Golden, E.B., et al., An abscopalresponseto radiation and ipilimumab in a patientwith metastatic 
non-smallcell lung cancer. Cancer Immunol Res, 2013. 1(6): p. 365-72. 
27. 
Barker, C.A., et al., Concurrentradiotherapy and ipilimumab immunotherapy forpatients with 
melanoma. Cancer Immunol Res, 2013. 1(2): p. 92-8. 
28. 
Reits, E.A., et al., Radiation modulates thepeptiderepertoire, enhances MHC class I expression, and 
induces successfulantitumorimmunotherapy. J Exp Med, 2006. 203(5): p. 1259-71. 
29. 
Dewan, M.Z., et al., Fractionated butnotsingle-doseradiotherapy induces an immune-mediated 
abscopaleffectwhen combined with anti-CTLA-4 antibody. Clin Cancer Res, 2009.  15(17): p. 5379-88. 
30. 
Witek, M., et al., Tumorradiation therapy creates therapeuticvaccineresponses to the colorectal 
cancer antigen GUCY2C. Int J Radiat Oncol Biol Phys, 2014. 88(5): p. 1188-95. 
 
 
 
 
20.0     APPENDICES 
 
Appendices will be stored in a separate file and will be submitted in electronic and/or paper 
format. If electronic format, please submit on file per appendix. 
TUMOR SAMPLE PD-L1 
This information is provided to investigators who will be submitting tumor samples to BMS 
representatives for analysis. Please do not include otherwise. 
Tumor Tissue Specimens 
Pre-treatment tumor tissue specimens in the form of a paraffin embedded block or a minimum 
of 3 unstained slides, with a single section on positively charged slides will be submitted for 
central PD-L1 immunohistochemistry (IHC) assessment. These biopsy samples should be 
excisional, incisional, punch or core needle. Fine needle aspirates or other cytology specimens 
are insufficient for downstream biomarker analyses. PD-L1 stained tissue sections will be 
assessed by a pathologist and scored as PD-L1 positive if membrane staining is observed. 
These tumor samples may also be assessed for the expression of other immune or melanoma 
related genes, RNAs and/or proteins, as well as, the presence of immune cell populations 
using a variety of methodologies inclusive of, but not limited to immunohistochemistry (IHC), 
qRT-PCR, genetic mutation detection and fluorescent in-situ hybridization (FISH). Various 
molecular markers with potential predictive value for the treatment of melanoma with 
Nivolumab, and other immunotherapies are currently under investigation and may be assessed 
in this study. These tumor tissue biomarkers include, but are not limited to PD-1, PD-L2, tumor 
infiltrating lymphocytes (TILs) or subpopulations of TILs and a Th1 immune mRNA expression 
signature. In addition, other methods of measuring tumor PD-L1 expression may also be 
assessed. Tissue from the resected solitary lesions may be assessed for residual tumor cells 
and for markers expected to accompanytumor shrinkage in this study, including, but not limited 
to TILs and subsets thereof. 
 
 
NORMAL TISSUE DOSE CONSTRAINTS 


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IRB Number: 15-253 A(11) 
Approval date: 13-Mar-2018 
 
 
 
 
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