Nivolumab in Combination With Chemoradiation for Patients With Stage II-IVB Nasopharyngeal Carcinoma, A Phase II Study With Correlative Biomarkers
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma
Sponsor: Sue Yom

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The information in this document is considered privileged and confidential, and may not be disclosed to others except 
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Nivolumab in Combination with Chemoradiation for Patients with 
Stage II-IVB Nasopharyngeal Carcinoma, A Phase II Study with 
Correlative Biomarkers
Protocol Number:  CC #162010
Study Drug:  Nivolumab
Version Number:  12.1
Version Date:  12-10-2024
IND Number:  134897
Principal Investigator (Sponsor-Investigator)
Sue S. Yom, MD, PhD, MAS
University of California San Francisco
Statistician
Li Zhang, PhD
Revision History
Version 1.0 
06-30-16
Version 2.0 
10-02-16
Version 3.0 
11-27-16
Version 4.0
03-06-17
Version 5.0
07-13-17
Version 6.0
04-02-18
Version 7.0
10-17-18
Version 8.0
01-07-19
Version 9.0
02-12-19
Version 10.0
04-23-19
Version 10.1
06-14-19
Version 10.2
08-07-19
Version 10.3
11-06-19
Version 10.4
Version 11.0
05-12-20
06-05-20
Version 12.0
08-01-24
Version 12.1
12-10-24
NCT03267498

Version date: 12-10-2024
Protocol CC# 162010 
Phase II – Nivolumab
Page 1 of 101
Protocol Signature Page
Protocol No.: CC# 162010
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC).
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations,
and state and local laws to maintain the protection of the rights and welfare of study
participants.
3.
I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the
www.clinicaltrials.gov website.
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal,
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
SUE S. YOM
Printed Name
Signature
Date
Participating Site(s)
Principal Investigator
Site
Printed Name
Signature
Date

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Abstract
Title
Nivolumab in Combination with Chemoradiation for Patients with Stage II-
IVB Nasopharyngeal Carcinoma, A Phase II Study with Correlative 
Biomarkers 
Patient 
population
Patients with stage II-IVB endemic-type nasopharyngeal carcinoma (NPC), 
who are scheduled for definitive-intent chemoradiation therapy.
Rationale for 
Study
The current platform of chemoradiation followed by adjuvant chemotherapy 
is the standard means of treating NPC around the world. However, the 
sustained use of cisplatin-based chemotherapy throughout this treatment 
plan is difficult for patients to complete and the additional chemotherapy 
delivered in the adjuvant phase may not provide optimal efficacy against the 
emergence of metastasis. Immune checkpoint inhibitors have shown 
efficacy against multiple tumor types including nasopharyngeal carcinoma 
and are efficacious in combination with platinum doublets or for post-
platinum disease relapse. There is a need to investigate novel approaches 
for the locoregionally advanced NPC population that will reduce the severe 
and life-altering toxicities of the current standard of care and improve the 
therapeutic ratio. This study has been designed to determine if nivolumab 
can be integrated into the current paradigm of combined chemoradiation 
and adjuvant chemotherapy, with improved feasibility of treatment 
completion over the current standard of care.
Primary 
Objective
To establish the feasibility of a combined chemoradiation-nivolumab 
regimen followed by adjuvant nivolumab. The primary endpoint will be the 
rate of completion of all adjuvant immunotherapy, in comparison to the rate 
of completion of a standard adjuvant cisplatin-based platform (historical 
control).
Secondary 
Objectives

To determine the clinical response as judged by the investigator;

To determine the overall response rate at 1 year from end of treatment, 
as determined by RECIST 1.1 criteria;

To determine the locoregional control rate at 1 year post-treatment;

To determine the distant metastasis rate at 1 year post-treatment;

To determine the overall survival rate at 1 year post-treatment;

To determine the rate of EBV DNA clearance at end of chemoradiation 
and at 1 year from end of treatment;

To determine the acute and late toxicity rates according to CTCAE 
v5.0, including immune-related adverse events (AEs);

To assess patients’ quality of life from baseline through 1 year from end 
of treatment;

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Exploratory 
Objectives

To determine whether PDL1-positive immunohistochemistry and novel 
quantitative assays correlate to clinical outcome;

To determine if the density of infiltrating CD3+ T cells/μm2 correlates to 
clinical outcome;

To monitor immune changes by flow cytometry in the circulating T cell 
response to EBV antigens;

To compare the change in the circulating T-cell repertoire by TCR 
sequencing and single-cell T-cell profiling;

To quantify treatment-induced changes over time in the circulating T 
cell immune response to EBV using TCR sequencing and enzyme-
linked immunospot (ELISPOT) assays
Study Design

This is a phase II multi-institution, single-arm, open label clinical trial of 
concurrent and adjuvant nivolumab in Stage II-IVB endemic-type 
nasopharyngeal carcinoma patients who plan to undergo chemoradiation 
therapy for treatment of their cancer.

A run-in phase will precede expansion, to establish basic feasibility of 
the nivolumab schedule. The run-in cohorts will include 6 patients at 
each dose schedule, with 2 planned changes to the dose schedule if 
>33% toxicity or other dose limiting toxicity (DLT) is observed. A 
minimum of 6 patients and maximum of 18 patients may be enrolled in 
the run-in phase. 

A total maximum of 40 evaluable patients will be enrolled for the primary 
endpoint.  This design yields a type I error rate of 0.05 and power of 80% 
if the true rate of completion of adjuvant therapy is 0.7.

At the starting dose schedule, patients will receive nivolumab for 1 cycle 
prior to initiation of chemoradiation (approximately 14 days). Patients will 
subsequently continue with nivolumab every 14 days until completion of 
chemoradiation. If a dose schedule shows >33% toxicity or other DLT, 
then subsequently enrolled patients will be treated at the next dose 
schedule. In dose schedule 2, patients will start nivolumab concurrent 
with start of chemoradiation. In dose schedule 3, patients will start 
nivolumab after completion of chemoradiation (adjuvant nivolumab only). 
All patients will receive the same dose of nivolumab (240mg).

DLT criteria are grade ≥3 immune-related adverse events, need to hold 
nivolumab for >28 days due to toxicity, and for patients receiving 
concurrent nivolumab with chemoradiation, inability to complete 
chemoradiation or need to hold chemoradiation for >3 days due to 
immune-related toxicity.

Adjuvant therapy with nivolumab for 6 cycles will start at 4 weeks 
following completion of chemoradiation, or when immune-related 
toxicities are at grade 1 or lower, whichever comes later. 

Patients will be followed for overall response rate, locoregional control 
and distant metastasis rates, and overall survival rate for 1 year after 
end of treatment.
Number of 
patients
A maximum of 40 evaluable patients will be enrolled in the study using a 
Simon’s two-stage design for the primary endpoint. Non-evaluable patients 
will be replaced per the replacement policy.

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Duration of 
Therapy
Patients will receive 23 weeks of an anticipated total therapy course, 
although the duration for an individual patient may be extended to as long 
as 33 weeks to allow for resolution of toxicities.
Duration of 
Follow-up
Follow-up visits will occur at 1, 3, 6, 9, and 12 months for up to 12 months 
after end of treatment. Survival follow-up information may be collected via 
telephone calls or medical records review for an additional 4 years. 
Survival and disease status will be collected during this 5-year period until 
participant death, withdrawal, or if the participant is lost to follow-up. 
Duration of 
study
The study will reach completion in 6 years from the time the study opens to 
accrual.
Study Drugs
Nivolumab will be administered intravenously, at a dose of 240 mg every 14 
days. Nivolumab may be held for toxicity but there are no dose reductions.
Safety 
Assessments
Analyses will be performed for all patients having received at least one dose 
of study drug. The study will use the CTCAE v5.0 for reporting of non-
hematologic adverse events and modified criteria for immune related 
adverse events. 
Safety assessments will consist of monitoring and reporting adverse events 
(AEs) and serious adverse events (SAEs) that are considered related to 
nivolumab, all events of death, and any study specific issue of concern. 
The study period during which all AEs and SAEs must be reported begins 
after informed consent is obtained and study treatment is initiated and ends 
12 months following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. 
Efficacy 
Assessments
The primary measure of feasibility will be the rate of completion of all 
adjuvant therapy. This will be determined based on ability to complete all 6 
cycles of adjuvant nivolumab without discontinuation for disease 
progression or toxicity. 
Secondary measures of efficacy will be clinical response as judged by the 
investigator; ORR by RECIST 1.1; locoregional control rate, distant 
metastasis rate, overall survival rate determined by standard physical 
examination and radiologic imaging; the rate of EBV DNA clearance at end-
chemoradiation and at 1 year post-treatment as determined by PCR assay; 
toxicity assessments graded by CTCAE v5.0 and modified immune related 
criteria; and quality of life by FACT-NP, FACT-Taxane, HHIE-S, and 
EuroQOL EQ-5D-3L. Exploratory assessments are self-explanatory.
Unique 
Aspects of this 
Study
This is the first study to evaluate the feasibility of nivolumab integrated with 
cisplatin in the concurrent and adjuvant treatment of nasopharyngeal 
carcinoma.

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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CHR
Committee on Human Research (UCSF IRB)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FCBP
female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBeAg
Hepatitis B “e” antigen
HBV
hepatitis B virus
HCT
Hematocrit
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
Hemoglobin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IND
investigational new drug application

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List of Abbreviations
IP
investigational product
IRB
Institutional Review Board
IV
Intravenous
LDH
lactate dehydrogenase
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PD
disease progression
PK
Pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
QOL
Quality of Life
RBC
red blood cell (count)
SD
stable disease
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
ULN
upper limit of normal
WBC
white blood cell (count)

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Table of Contents
Protocol Signature Page ............................................................................................................1
Abstract
2
List of Abbreviations...................................................................................................................6
1
Introduction .....................................................................................................................14
1.1
Background on Indication.................................................................................14
1.1.1
Nasopharyngeal Carcinoma:.........................................................................14
1.1.2
Concomitant Chemoradiation for Locoregionally Advanced Nasopharyngeal 
Carcinoma: ................................................................................................................14
1.2
Background on Nivolumab...............................................................................16
1.2.1
Overview.......................................................................................................16
1.2.2
Pharmacokinetics and Drug Metabolism (Safety) ........................................16
1.2.3
Clinical Experience with Nivolumab............................................................18
1.3
Rationale for the Proposed Study .....................................................................25
1.4
Correlative Studies............................................................................................26
1.4.1
PD-L1 immunohistochemistry......................................................................26
1.4.2
EBV DNA.....................................................................................................26
2
Objectives of the Study...................................................................................................27
2.1
Primary..............................................................................................................27
2.2
Secondary..........................................................................................................27
2.3
Exploratory Objectives, Other Assessments.....................................................27
2.4
Endpoints ..........................................................................................................27
2.4.1
Primary Endpoints ........................................................................................27
2.4.2
Secondary Endpoints ....................................................................................28
2.4.3
Exploratory Endpoints ..................................................................................28
3
Study Design...................................................................................................................28
3.1
Characteristics...................................................................................................28
3.2
Study Schema ...................................................................................................29
3.3
Feasibility assessment in the run-in phase........................................................30
3.4
Number of Subjects ..........................................................................................30
3.5
Eligibility Criteria.............................................................................................31
3.5.1
Inclusion Criteria ..........................................................................................31
3.5.2 ...........................................................................................................................33
3.5.2 Exclusion Criteria.............................................................................................33
3.6
Duration of Therapy..........................................................................................35
3.7
Duration of Follow Up......................................................................................36
3.8
Study Timeline..................................................................................................36
3.8.1
Primary Completion......................................................................................36
3.8.2
Study Completion .........................................................................................36
4
Study Drugs ....................................................................................................................36
4.1
Description, Supply and Storage of Investigational Drugs...............................36
4.1.1
Nivolumab (BMS-936558) ...........................................................................36
4.2
Drug Accountability .........................................................................................38

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4.3
Drug Ordering...................................................................................................38
4.4
Packaging and Labeling of Study Drugs ..........................................................39
5
Treatment Plan ...............................................................................................................39
5.1
Dosage and Administration ..............................................................................39
5.1.1
Other Modality(ies) or Procedures................................................................39
Dose Specifications.............................................................................................................39
5.2
Dose Modifications and Dosing Delays ...........................................................42
5.2.1
Dose Delays of Nivolumab...........................................................................42
5.2.2
Cisplatin (CDDP) Dose Modifications During Concurrent Radiation .........49
5.3
Monitoring and Toxicity Management.............................................................52
5.4
Permitted Concomitant Therapy Requiring Caution and/or Action.................52
5.5
Prohibited Concomitant Therapy......................................................................52
5.5.1
Other Anticancer or Investigational Therapies.............................................53
5.5.2
Hormonal Contraception Allowed/Excluded................................................53
6
Study Procedures and Observations ..............................................................................53
6.1
Schedule of Procedures and Observations........................................................53
6.1.1
Pretreatment Period.......................................................................................53
6.1.2
Treatment Period...........................................................................................55
6.1.3
End-of-Treatment Study Procedures.............................................................56
6.1.4
Post-treatment/Follow-Up Visits ..................................................................56
6.1.5
Long Term/Survival Follow-up Procedures .................................................57
6.1.6
Discontinuation of Therapy ..........................................................................57
6.2
Prohibited Medications.....................................................................................61
Permitted Therapy .....................................................................................................61
7
Reporting and Documentation of Results .......................................................................61
7.1
Evaluation of Efficacy (or Activity).................................................................61
7.1.1
Antitumor Effect – Solid Tumors .................................................................61
7.1.2
Definitions.....................................................................................................61
7.2
Evaluation of Safety..........................................................................................64
7.3
Definitions of Adverse Events..........................................................................64
7.3.1
Adverse Event...............................................................................................64
7.3.2
Adverse reaction ...........................................................................................65
7.4
Recording of an Adverse Event........................................................................67
Laboratory Test Abnormalities ...........................................................................................68
Other Safety Considerations ...............................................................................................69
7.5
Follow-up of Adverse Events ...........................................................................69
7.6
Adverse Events Monitoring..............................................................................69
7.7
Expedited Reporting .........................................................................................70
8
Statistical Considerations and Evaluation of Results......................................................72
8.1
Study Endpoints................................................................................................72
8.1.1
Primary Endpoint:.........................................................................................72
8.1.2
Secondary Endpoints ....................................................................................72
8.1.3
Correlative Studies........................................................................................73
8.2
Determination of Sample Size and Accrual Rate .............................................73

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8.2.1
Sample Size and Power Estimate..................................................................73
8.2.2
Run-in phase .................................................................................................73
8.2.3
Expansion phase............................................................................................74
8.2.4
Statistical plan...............................................................................................74
8.2.5
Replacement Policy ......................................................................................75
8.2.6
Accrual estimates..........................................................................................75
8.3
Interim Analyses and Stopping Rules...............................................................75
8.4
Analysis Plans...................................................................................................75
8.4.1
Analysis Population ......................................................................................75
8.4.2
Primary Analysis (or Analysis of Primary Endpoints) .................................75
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints) .........................75
8.4.4
Other Analyses/Assessments ........................................................................76
8.5
Evaluation of Safety..........................................................................................76
8.6
Study Results ....................................................................................................77
9
Study Management.........................................................................................................77
9.1
Pre-study Documentation .................................................................................77
9.2
Institutional Review Board Approval...............................................................77
9.3
Informed Consent .............................................................................................77
9.4
Changes in the Protocol....................................................................................78
9.5
Handling and Documentation of Clinical Supplies ..........................................78
9.6
Case Report Forms (CRFs)...............................................................................78
9.7
Oversight and Monitoring Plan.........................................................................79
9.8
Multicenter communication..............................................................................79
9.9
Coordinating Center Documentation of Distribution .......................................80
9.10
Regulatory Documentation...............................................................................80
10
Protection of Human Subjects ........................................................................................82
10.1
Protection from Unnecessary Harm..................................................................82
10.2
Protection of Privacy ........................................................................................82
References
83
Appendices
86
Appendix 1
Performance Status Criteria............................................................................86
Appendix 2
Multicenter Institutional Studies ......................................................................87
Appendix 3
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an Investigator 
held Investigational New Drug (IND)...............................................................92
Appendix 4
Specimen and Blood Collection ......................................................................96
Appendix 5 Management Algorithms .......................................................................................98
List of Tables
Table 5.1
Regimen Description.......................................................................................37
Table 7.1
Response Criteria ...........................................................................................61

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1
Introduction
1.1
Background on Indication
1.1.1
Nasopharyngeal Carcinoma:
Nasopharyngeal carcinoma (NPC) is the predominant cancer type arising from the 
mucosal tissues of the nasopharynx. It has an incidence of 0.5-2 per 100,000 in Europe and the 
U.S., but it is an endemic disease in Southern China where the annual age-standardized 
incidence rates are as high as 20-30 cases per 100,000. NPC is also a common disease 
throughout the rest of Southeast Asia, the Mediterranean and the Artic. Among NPC patients in 
areas dominated by the endemic type, over 95% are classified as the undifferentiated type (type 
2b) according to World Health Organization criteria, while in North America, 25% are classified 
as keratinizing (type 1) and 12% are classified as nonkeratizing (type 2a). The endemic-type NPC 
(type 2a and 2b) are near-universally associated with Epstein-Barr Virus (EBV), a strong etiologic 
factor that interacts with genetic predisposition and dietary intake of chemically preserved foods, 
while the keratizing cancers are associated with the traditional risk factors for head and neck 
cancer such as alcohol and tobacco consumption1.
NPC is staged according to the AJCC/UICC staging system. Presentation with stage I 
disease is relatively uncommon, at approximately 7% of new incidence, whereas 66% of patients 
present with stage II or III disease and the rest present with stage IV disease. The 5-year survival 
for stage I and II cancer approaches 85-90% but for non-metastatic stage III-IV disease it is 
around 60%.
1.1.2
Concomitant Chemoradiation for Locoregionally Advanced 
Nasopharyngeal Carcinoma:
The current standard of care for stage I NPC is radiation monotherapy, but for newly 
diagnosed stage II-IVB NPC patients, treatment consists of a definitive upfront combination of 
approximately 7 weeks of fractionated radiation therapy (RT) with concurrent cisplatin 
chemotherapy that is often followed by 3 cycles of adjuvant cisplatin-5FU. This framework was 
established in the landmark Intergroup 0099 study, for which accrual terminated early due to a 
statistically significant survival advantage in the chemoradiotherapy arm as compared to 
radiotherapy alone2. 
Since that time, at least 8 randomized studies have confirmed the survival benefit of 
adding concurrent platinum-based chemotherapy to RT in patients with non-metastatic stage II to 
IVB NPC. Two meta-analyses have reported an 18% reduction in the risk of death and an absolute 
survival benefit of 4% to 6% at 5 years with the use of chemotherapy in addition to radiation. The 
largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 
to 0.72), which corresponds to an absolute survival benefit of 20% after 3 years, from 
approximately 65% to 85%3,4.
However, despite the classic status of the Intergroup 0099 study regimen and its 
widespread reproduction and clinical use across the U.S. and Asia, there are numerous issues 
with this current standard of care, including a relatively low efficacy of this regimen of systemic 
chemotherapy in preventing distant metastases, difficulties with tolerability of the overall platinum 
burden particularly as prescribed in the concurrent plus adjuvant regimens, and a lack of 
recognized and efficacious alternatives to cisplatin for patients who cannot tolerate full courses of 
therapy. 

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In particular, the feasibility of adjuvant CDDP and 5-FU is problematic as only 50-60% of 
the patients enrolled in past trials were able to complete the prescribed regimen. For instance, in 
the Intergroup study, 63% of patients completed all 3 cycles of concurrent cisplatin (100 mg/m2 
given every 3 weeks) and only 55% of patients completed all 3 cycles of adjuvant chemotherapy 
afterwards2 . This is considered unfortunate as the adjuvant phase is intended to provide systemic 
therapy for a patient population at high risk of distant metastasis.
Justification for omission of adjuvant CDDP/5FU:
The very pressing question of whether there is any oncologic benefit to be accrued from 
the use of adjuvant chemotherapy in locoregionally advanced NPC was studied in a recent 
randomized trial from China5. This phase III study compared RT with weekly CDDP followed either 
by 3 cycles of CDDP/5-FU or no adjuvant treatment. In 508 patients, the study found no 
statistically significant improvement in either progression-free or overall survival from the addition 
of adjuvant cytotoxic chemotherapy. Of note, in this study, 82% of patients assigned to the arm 
receiving weekly cisplatin plus adjuvant cisplatin-5FU started adjuvant chemotherapy, but only 
63% were able to complete all 3 adjuvant cycles (52% therefore started and completed all 
adjuvant therapy)5. During adjuvant chemotherapy, 42% of patients experienced grade 3-4 toxic 
effects; 49% had dose reductions and 69% experienced delays in treatment. This is notable given 
that there was no apparent increase in rates of completion or better tolerance compared to results 
from the earlier era. 
This Chinese randomized study specifically tested the exact additional contribution of the 
adjuvant phase as opposed to the Intergroup study which tested the addition of concurrent-
adjuvant chemotherapy but did not examine whether the concurrent or the adjuvant phase 
produced the observed benefits. Therefore, many consider the Chinese study to be more relevant 
in speaking to the issue of whether adjuvant chemotherapy should be included in the standard of 
care. At this point, given the high toxicity and lack of established additional benefit of adjuvant 
chemotherapy, the U.S.-based National Comprehensive Cancer Network guidelines no longer 
consider the adjuvant phase to be supported at the highest level of evidence and have 
downgraded the adjuvant phase of chemotherapy to a Category 2B recommendation. The 
category 2B designation indicates that the evidence supporting adjuvant-phase chemotherapy is 
of a low grade based on historical practice and that there is not uniform consensus on the NCCN 
panel that it is required. In keeping with this, many major centers in the U.S. and Asia no longer 
consider adjuvant therapy to be necessary to the standard of care and no longer administer it. In 
fact, several major standard-defining nasopharynx clinical trials in Asia did not administer adjuvant 
chemotherapy and produced major survival benefits comparable to those that did. Lastly, from a 
practical standpoint, up to half of patients cannot complete adjuvant chemotherapy anyway. Thus 
omission of adjuvant chemotherapy is entirely within the contemporary standard of care and 
experimental testing of improvements to the adjuvant phase of therapy is justifiable and 
desperately needed.
Overall justification for study concept:
Within this context, this phase II study is designed to establish the feasibility of nivolumab 
integrated into the chemoradiation backbone and establish the superior tolerability and feasibility 
of treatment completion of this strategy as an adjuvant regimen as compared to stand of care 
adjuvant chemotherapy. Our study is intended to establish the role of nivolumab in the 
locoregionally advanced disease setting and furthermore, to provide a scientific rationale for future 
study based on the extent of immunomodulation achieved by nivolumab initiated as a priming 

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dose, given concurrently with chemoradiation and continued into the adjuvant phase. The point 
is that if adjuvant CDDP/5FU is being increasingly abandoned due to toxicity, adjuvant nivolumab 
may offer greater benefit without the excessive toxicities of traditional adjuvant cytotoxic therapy.
The study will include an initial run-in over three cohorts with planned alterations in 
administration of concurrent or adjuvant nivolumab if unacceptable toxicity is observed. After 
completion of the run-in phase, an expansion cohort will be enrolled which is designed to test 
formally for the feasibility of completion of adjuvant therapy as compared to the standard of care 
adjuvant chemotherapy.
1.2
Background on Nivolumab 
1.2.1
Overview
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-
1) cluster of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab is a soluble 
protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical 
light chains. The physical and chemical properties of nivolumab are provided in the Table below.
Physical and Chemical Properties
BMS Number 
BMS-936558-01
Other Names 
Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1
Molecular Weight
146,221 daltons (143,619.17 daltons, protein portion)
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may be 
present
Solution pH 
5.5 to 6.5
PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes6. 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in 
the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. Nivolumab has been shown to bind specifically to the human 
PD-1 receptor and not to related members of the CD28 family7,8.
Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in 
enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro9-11. Nivolumab binds 
with high affinity to activated human T-cells expressing cell surface PD-1 and to cynomolgus 
monkey PD-1. In a mixed lymphocyte reaction (MLR), nivolumab promoted a reproducible 
concentration-dependent enhancement of IFN-α release12.
Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. OPDIVO (nivolumab) is 
approved for use in multiple countries including the United States.
1.2.2
Pharmacokinetics and Drug Metabolism (Safety)
1.2.2.1 Safety studies in cynomolgus monkeys 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab 

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was well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up 
to 50 mg/kg, administered twice weekly for 27 doses. Five weekly IV doses of nivolumab were 
administered to cynomolgus monkeys at dose levels of 1, 10, and 50 mg/kg. The apparent 
elimination half-life (T-HALF) estimates were long (124 to 148 hours after 1 mg/kg doses, 223 to 
267 hours after 10 or 50 mg/kg doses), and serum clearance was low13-15.
Systemic exposure to nivolumab increased in an approximately dose-proportional 
manner. The low volume of distribution in cynomolgus monkeys (0.046 L/kg to 0.071 L/kg) 
indicates that there is little extravascular distribution of nivolumab.
Nivolumab at all doses was well tolerated. There were no clinical signs of toxicity or 
effects on body weight, food consumption, blood pressure, heart rate, respiration rate, 
ophthalmic and electrocardiographic parameters, or clinical or anatomic pathology related to the 
administration of nivolumab. Nivolumab was immunogenic in this study; anti-nivolumab 
antibodies were detected in 6 of 30 animals and, in general, correlated with reduced nivolumab 
exposures and PD-1 receptor occupancy. Despite the presence of anti-nivolumab antibodies, 
the majority of the animals tested at the end of the 4-week recovery phase (9 of 12) 
demonstrated PD-1 receptor occupancy and circulating levels of nivolumab. Thus, the presence 
of antibodies did not significantly impact the objective of the study to evaluate the potential 
toxicity of nivolumab. The results of this study showed that nivolumab was well tolerated when 
administered by weekly IV injections for 5 weeks at doses up to 50 mg/kg (5× the clinical dose 
of 10 mg/kg), with no adverse effects on any of the evaluated parameters. 
In a 3-month toxicity study, twice weekly IV doses of nivolumab were administered to 6 
animals per sex at doses of 0, 10, and 50 mg/kg and were well tolerated; no clinical signs of 
toxicity or drug-related body weight, cardiovascular, neurologic, respiratory, urinalysis, 
hematologic, organ weights, or macroscopic or histologic pathology findings were observed. 
Serum chemistry changes were limited to a reversible 28% decrease in T3 at Week 13 in 
females treated with 50 mg/kg. T4 and TSH levels were not affected, and in males treated with 
50 mg/kg, no changes in T3, T4, or TSH levels were observed. Although anti-nivolumab 
antibodies were only detected in 1 of 24 animals, it is possible that high nivolumab 
concentrations interfered with the assay. The results of this study showed that nivolumab was 
well tolerated when administered by IV injections twice weekly for 3 months at doses up to 50 
mg/kg (5x the clinical dose of 10 mg/kg), with no adverse effects on any of the evaluated 
parameters. In addition, an enhanced pre- and postnatal development (ePPND) study in 
pregnant cynomolgus monkeys with nivolumab was conducted16.
Administration of nivolumab at up to 50 mg/kg 2QW was well tolerated by pregnant 
monkeys; however, nivolumab was determined to be a selective developmental toxicant when 
administered from the period of organogenesis to parturition at 10 mg/kg (area under the 
concentration-time curve [AUC] from time zero to 168 hours [AUC(0-168 h)] 117,000 ugh/mL). 
Specifically, increased developmental mortality (including late gestational fetal losses and 
extreme prematurity with associated neonatal mortality) was noted in the absence of overt 
maternal toxicity. There were no nivolumab-related changes in surviving infants tested 
throughout the 6-month postnatal period. Although the cause of these pregnancy failures was 
undetermined, nivolumab-related effects on pregnancy maintenance are consistent with the 
established role of PD-L1 in maintaining fetomaternal tolerance in mice17.
No mass balance or metabolism studies with nivolumab have been conducted in 
animals. The expected in vivo degradation of monoclonal antibodies is to small peptides and 

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amino acids via biochemical pathways that are independent of drug metabolism enzymes. 
Nivolumab is not expected to have any effect on cytochrome P450 or other drug metabolizing 
enzymes in terms of inhibition or induction, and is, therefore, not expected to induce these types 
of PK-based drug interactions.
1.2.2.2 Safety studies in humans
Single-dose PK of nivolumab was studied in 39 subjects with cancer18.The single-dose 
PK of nivolumab was linear and dose-proportional in the range of 0.3 mg/kg to 10 mg/kg7.
The mean terminal T-HALF of nivolumab ranged between 17 and 25 days across the 
dose range of 0.3 mg/kg to 10 mg/kg. Geometric mean total clearance varied from 0.13 mL/h/kg 
to 0.19 mL/h/kg, while mean volume of distribution varied between 83 mL/kg and 113 mL/kg 
across doses. The clearance and half-life of nivolumab are consistent with that of IgG4.
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 
0.1 to 10 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 
weeks. Based on a population pharmacokinetic (PPK) analysis using data from subjects with 
various tumor types, including melanoma and NSCLC, the geometric mean (% CV%) clearance 
(CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) is 8.0 L 
(30.4%), and geometric mean elimination half-life (t1/2) is 26.7 days (101%). Steady-state 
concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 
weeks, and systemic accumulation was approximately 3-fold. The exposure to nivolumab 
increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 
weeks. The clearance of nivolumab increased with increasing body weight. The PPK analysis 
suggested that the following factors had no clinically important effect on the clearance of 
nivolumab: age (23 to 87 years), gender, race, baseline LDH, PD-L1, tumour type, baseline 
tumor size, and hepatic impairment. Although ECOG status, baseline glomerular filtration rate 
(GFR), albumin, and body weight had an effect on nivolumab CL, the effect was not clinically 
meaningful.
1.2.3
Clinical Experience with Nivolumab 
1.2.3.1 Clinical Efficacy of Nivolumab
In the U.S., nivolumab has been approved for the treatment of patients with unresectable 
or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor. It has also been approved for use in patients with advanced 
(metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after 
platinum-based chemotherapy. 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy 
and in combination with ipilimumab in several tumor types, including NSCLC, melanoma, renal 
cell carcinoma, and some lymphomas. In confirmatory trials, nivolumab as monotherapy 
demonstrated a statistically significant improvement in OS as compared with the current 
standard of care in subjects with advanced or metastatic NSCLC and in subjects with 
unresectable or metastatic melanoma. 
Nivolumab has demonstrated clinical activity in subjects with a variety of malignancies in 
the following indications and studies with available data:

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Non small cell lung cancer:

CA209057: completed Phase 3, randomized, open-label study of nivolumab vs. 
docetaxel in subjects with advanced NSQ NSCLC previously treated with platinum-
based doublet chemotherapies

CA209017: completed Phase 3, randomized, open-label study of nivolumab vs. 
docetaxel in subjects with advanced SQ NSCLC previously treated with platinum-based 
doublet chemotherapies

CA209012: ongoing Phase 1 study with nivolumab monotherapy or in combination with 
ipilimumab, platinum-based chemotherapy or erlotinib in subjects with treatment-
naiveStage IIIB/IV NSCLC

ONO-4538-05: completed Phase 2, open-label study of nivolumab in Japanese subjects 
with Stage IIIB/IV or recurrent SQ NSCLC

ONO-4538-06: completed Phase 2, open label study of nivolumab in Japanese subjects 
with Stage IIIB/IV or recurrent NSQ NSCLC
Melanoma:

CA209069: completed Phase 2, randomized, double-blind study of nivolumab in 
combination with ipilimumab vs. ipilimumab monotherapy in subjects with previously 
untreated, unresectable or metastatic melanoma

CA209066: completed Phase 3, randomized, double-blind study of nivolumab vs. 
dacarbazine in subjects with untreated, unresectable or metastatic melanoma who are 
BRAF-WT

CA209067: ongoing Phase 3, randomized, double-blind study of nivolumab 
monotherapy or nivolumab combined with ipilimumab vs. ipilimumab monotherapy in 
subjects with previously untreated, unresectable or metastatic melanoma

ONO-4538-02: completed Phase 2, open-label study of nivolumab in Japanese subjects 
with unresectable Stage III/IV or recurrent malignant melanoma
Renal cell carcinoma:

MDX1106-03/CA20903: completed Phase 1 multidose escalation study with nivolumab 
monotherapy

CA209010: completed Phase 2 dose-ranging monotherapy study in subjects with 
advanced or metastatic clear-cell RCC who received prior anti-angiogenic therapy

CA209016: ongoing Phase 1 dose-escalation study of nivolumab in combination with 
VEGFR-TKIs or ipilimumab in subjects with metastatic RCC
Combined Malignant Tumors/Esophageal Cancer:

ONO-4538-01: completed Phase 1, dose-escalation study of nivolumab monotherapy in 
subjects with advanced or recurrent malignant tumors

ONO-4538-07: ongoing Phase 2 study of nivolumab monotherapy in subjects with 
esophageal cancer
Rationale for nivolumab in nasopharyngeal carcinoma

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Programmed cell death ligand-1 (PD-L1) is highly expressed by cancer cells and tumor-
infiltrating macrophages in virus-associated malignancies such as NPC19. There is emerging 
evidence that activation of the PD-1/PD-L1 pathway contributes to immune escape in NPC 
models20,21. PD-L1 is expressed in up to 90% of NPC tumors19,20. 
Nivolumab is being employed for recurrent/metastatic NPC (NCT02339558). Recently, 
results were reported from an ongoing multi-cohort, non-randomized Phase 1b trial (KEYNOTE-
028) for patients with advanced unresectable and refractory NPC whose tumors expressed PD-
L1 (≥1% of cells in tumor nests or PD-L1+ bands in stroma). Early findings from 27 heavily pre-
treated patients with advanced NPC demonstrated an ORR of 22.2 percent (n=6/27) (per 
RECIST v1.1), including six partial responses (95% CI, 8.6-42.3). Additionally, 55.6 percent of 
patients had stable disease (n=15/27) (95% CI, 35.3-74.5), the disease control rate (DCR) was 
77.8 percent (n=21/27) (95% CI, 57.7-91.4), and tumor shrinkage was achieved in 67 percent of 
patients. The 6-month progression-free survival (PFS) rate was 49.7 percent and the 12-month 
PFS rate was 28.9 percent. The median follow-up duration for evaluable patients was 12.9 
months (range, 2.2-15.0) and the median response duration was 10.8 months (range, 4.8-10.8).
CheckMate-141 was a phase 3, open label, randomized study of nivolumab versus 
investigator’s choice of therapy (2:1 randomization) in previously treated patients with 
squamous cell carcinoma of the head and neck who had tumor progression on or within 6 
months of platinum therapy in the primary, recurrent, or metastatic setting. The trial randomized 
361 patients and was stopped early when an assessment concluded that the study had met the 
primary endpoint of superior overall survival in the nivolumab arm. The median overall survival 
was 7.5 months in the nivolumab-treated patients versus 5.1 months for patients on 
chemotherapy, representing a 30% reduction in the survival hazard, and 36% of the nivolumab-
treated patients were alive at 1 year compared to 16.6% of the patients receiving standard 
treatment. The incidence of adverse events (all grades) was 58.9% with nivolumab and 77.5% 
with investigator's-choice regimens. Grade 3/4 toxicity occurred in 13.1% versus 35.1% of the 
nivolumab and control groups. CheckMate-141 was the first study in head and neck cancer to 
demonstrate an improvement in survival with an immune checkpoint inhibitor as compared to 
standard chemotherapy. While the trial did not specifically investigate NPC, it lends further 
support to the rationale of potentially improved outcomes with nivolumab, at a lower rate of high-
grade toxicity.
1.2.3.2 Clinical safety of nivolumab in humans
The overall safety experience with nivolumab, as a monotherapy or in combination with 
other therapeutics, is based on experience in approximately 8,600 subjects treated to date. For 
monotherapy, all available data suggest that nivolumab has a consistent AE profile across 
tumor types, with no maximum tolerated dose (MTD) reached at any monotherapy dose tested 
up to 10 mg/kg. The only exception is pulmonary inflammation AEs, which may be numerically 
greater in subjects with non-small cell lung cancer, possibly because in some cases, it can be 
difficult to distinguish between nivolumab-related and unrelated causes of pulmonary symptoms 
and radiographic changes. The most common adverse reaction (≥20%) in patients with 
melanoma is rash, and the most common adverse reactions (≥20%) in patients with advanced 
squamous non-small cell lung cancer are fatigue, dyspnea, musculoskeletal pain, decreased 
appetite, cough, nausea, and constipation. The most frequently reported treatment-related AE 
overall is fatigue, which is almost always of low grade.
There is no pattern in the incidence, severity, or causality of AEs to nivolumab dose 

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level. In Phase 3 controlled studies, the safety profile of nivolumab monotherapy is acceptable 
in the context of the observed clinical efficacy, and manageable using established safety 
guidelines. Clinically relevant AEs typical of stimulation of the immune system were infrequent 
and manageable by delaying or stopping nivolumab treatment and timely immunosuppressive 
therapy or other supportive care.
Across all studies conducted to date, the most common and impactful drug-related AEs 
have included pulmonary toxicity, renal toxicity (including acute renal failure), endocrine 
abnormalities, GI toxicity, dermatologic toxicity (including rash), hepatotoxicity, and 
hypersensitivity/infusion reaction. For nivolumab monotherapy and combination therapy, the 
majority of these AEs have been managed successfully with supportive care and, in more 
severe cases, a combination of dose delay, permanent discontinuation, and/or use of 
corticosteroids or hormone replacement therapy (endocrinopathies) according to standardized 
management guidelines. 
In several ongoing clinical trials, the safety of nivolumab in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies is being explored. Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues to evolve. The most advanced immunotherapy combination 
under development is nivolumab + ipilimumab in subjects with non-small cell lung cancer, 
melanoma, and renal cell carcinoma. The combination of both agents results in a safety profile 
with similar types of AEs as either agent alone, but in some cases, with a greater frequency.
1.2.3.3 Adverse events associated with nivolumab
Adverse drug reactions (ADRs) that are considered to be causally related to nivolumab are 
classified by system organ class and frequency. The frequency of ADRs is defined using the 
following convention: very common (1/10); common (1/100 to < 1/10); uncommon (1/1,000 
to < 1/100); rare (1/10,000 to < 1/1,000); and very rare (< 1/10,000).
As of 04-July-2016, the following ADRs were reported in clinical studies where nivolumab was 
given as monotherapy. The reported overall frequency includes reported serious and non-
serious ADRs.
System Organ 
Class
Preferred Term
Overall 
Frequencya
Serious
Life 
Threatening
Fatal
Cardiac
Tachycardia
Uncommon
Arrhythmia
Uncommon
X
Ear and Labyrinth 
Disorders
Vertigo
Uncommon
Endocrine
Hypothyroidism
Common
X
Hyperthyroidism
Common
X
Hyperglycemia
Uncommon
X
X
Adrenal insufficiency
Uncommon
X
X
Thyroiditis
Uncommon
X
Hypophysitis 
Uncommon
X
Diabetes mellitus
Uncommon
X
Hypopituitarism
Uncommon
X
Diabetic ketoacidosis
Rare
X
X
Eye
Dry eye
Uncommon
Vision blurred
Uncommon

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Uveitis (including iridocyclitis)
Uncommon
X
Gastrointestinal
Diarrhea
Common
X
Nausea (Autoimmune)
Common
X
Vomiting
Common
X
Constipation
Common
Abdominal pain
Common
X
Stomatitis (including mucosal 
inflammation/ulceration, mouth 
ulceration)
Common
X
Dry mouth
Common
Colitis
Common
X
X
Pancreatitis
Uncommon
X
Gastritis
Uncommon
X
General
Fatigue (including asthenia)
Very 
common
X
Pyrexia
Common
X
Edema
Common
X
Chills
Common
X
Hepatobiliary
Hepatitis (Autoimmune)
Uncommon
X
X
Immune System
Infusion related reaction
Common
X
X
Hypersensitivity
Uncommon
X
X
Anaphylactic reaction
Rare
X
X
Sarcoidosis
Rare
X
Infections and 
Infestations
Upper respiratory tract 
infection
Uncommon
Bronchitis
Uncommon
Investigations
Alanine aminotransferase 
increased
Common
X
Aspartate aminotransferase 
increased
Common
X
Lipase increased
Common
X
Blood alkaline phosphatase 
increased
Common
X
Amylase increased
Common
X
Blood creatinine increased
Common
X
Blood thyroid stimulating 
hormone increased
Common
Blood bilirubin increased
Uncommon
X
Metabolism and 
nutrition
Decreased appetite
Common
X
Hyponatremia
Common
X
Musculoskeletal 
and connective 
tissue
Musculoskeletal pain
Common
X
Arthralgia (including arthritis, 
polyarthritis, and osteoarthritis)
Common
X
Myositis
Rare
X
Polymyalgia rheumatica
Rare
X
Rhabdomyolysis
Rare
X
Nervous system
Headache
Common
X

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Neuropathy
Common
X
Dizziness (including vertigo, 
vertigo positional)
Uncommon
X
Cranial nerve disorder
Uncommon
X
Myasthenia syndrome
Rare
X
Guillain-Barre syndrome
Rare
X
Demyelination syndrome
Rare
X
Encephalitis 
Rare
X
Renal and urinary
Renal failure (including acute 
kidney injury)
Uncommon
X
Nephritis
Uncommon
X
Respiratory, 
thoracic, and 
mediastinal
Pneumonitis (including 
interstitial lung disease)
Common
X
X
X
Dyspnea
Common
X
X
X
Cough
Common
X
Respiratory failure
Uncommon
X
X
X
Lung infiltration
Rare
X
Skin and 
Subcutaneous
Rash
Very 
common
X
Pruritis
Common
X
Dry skin
Common
Vitiligo
Common
Erythema
Uncommon
Alopecia
Uncommon
Urticaria
Uncommon
X
Erythema multiforme
Rare
X
Rosacea
Rare
Stevens Johnson syndrome
Rare
X
Toxic epidermal necrolysis
Rare
X
X
Vascular
Hypotension
Uncommon
X
Hypertension
Uncommon
Vasculitis
Rare
Laboratory abnormalities observed in monotherapy studies are as follows, graded by CTC 
version 4.0.
Number (%) of subjects with worsening laboratory results from baseline
Nivolumab 3 mg/kg, unresectable 
or metastatic melanoma
Nivolumab 3 mg/kg, squamous cell 
carcinoma of the lung
Test
N
Grade 1-4
Grade 3-4
N
Grade 1-4
Grade 3-4
Decreased 
hemoglobin
458
183 (40)
21 (4.6)
244
74 (30.3)
6 (2.5)
Decreased platelet 
count
464     53 (11.4) 
1(0.2)
244 
30(12.3)
1 (0.4)
Decreased absolute 
lymphocytes
456  
188 (41.2)
32 (7.0)
243
113 (46.5)
32 (13.2)
Decreased absolute 
neutrophil count
457 
43 (9.4)
4 (0.9)
244
17 (7.0)
4 (1.6)
Increased alkaline 
phosphatase
450 
103 (22.9)
11 (2.4)
240
47 (19.6)
0

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Increased AST
452 
125 (27.7)
15 (3.3)
242
50 (20.7)
1 (0.4)
Increased ALT
455 
98 (21.5)
11 (2.4)
242
36 (14.9)
0
Increased total 
bilirubin
452 
52 (11.5)
7 (1.5)
242
10 (4.1)
2 (0.8)
Increased creatinine
457 
68(14.9)
4 (0.9)
244
47(19.3)
0
Additional adverse drug reactions in subjects treated with nivolumab combined with 
ipilimumab were as follows.
At least one with the outcome
System Organ 
Class
Preferred Term
Overall 
Frequency
Serious
Life 
Threatening
Fatal
Eye
Diplopia
Uncommon
X
Dry eye
Uncommon
X
Vision blurred
Uncommon
X
Gastrointestinal
Appendix disorder 
(enlarged appendix)
Uncommon
X
Colitis ulcerative
Uncommon
X
Enteritis
Uncommon
X
Enterocolitis
Uncommon
X
X
Gastritis
Uncommon
X
Ileus
Uncommon
X
Impaired gastric emptying
Uncommon
X
General
Chills
Uncommon
X
Multi-organ failure
Uncommon
X
X
Drug-induced liver injury
Uncommon
X
Hepatitis acute
Uncommon
X
Hyperbilirubinemia
Uncommon
X
Autoimmune disorder
Uncommon
X
Blood alkaline phosphatase 
increased
Uncommon
X
Hepatic enzyme increased
Uncommon
X
Transaminases increased
Uncommon
X
Blood creatinine increased
Uncommon
X
Dehydration
Uncommon
X
Meningitis (noninfective)
Uncommon
X
Myasthenia Gravis
Uncommon
X
X
Miller Fisher Syndrome
Uncommon
X
Optic neuritis
Uncommon
X
Nephiritis allergic
Uncommon
X
Acute respiratory distress 
syndrome
Uncommon
X
X
X
Respiratory distress
Uncommon
X
X
Respiratory failure
Uncommon
X
X
X
As of 04-July-2016, there were no additional ADRs that have been reported in clinical studies in 
which the nivolumab was given as combination therapy with other agents and no additional 
ADRs were identified from ongoing blinded clinical studies with nivolumab. There have been no 
additional ADRs identified from postmarketing experience.

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1.2.3.4 General management strategy for nivolumab related ADRs
The approach to suspected nivolumab-related AEs is similar across any involved organ 
system. Standardized safety algorithms have been developed (see Appendix 7).  Subjects 
should have a thorough diagnostic work-up to evaluate potential drug- and non-drug-related 
diagnoses. For suspected nivolumab-related AEs, based on the severity of the event, 
management with immunosuppressants may be necessary. In general, dose delays and 
observation are adequate for low-grade AEs. For moderate- and high-grade AEs, 
immunosuppression with corticosteroids should be utilized. Once the AE has begun to improve, 
corticosteroids can be tapered over approximately 3 weeks to 6 weeks (depending on the 
severity of the AE). The management of AEs considered related to any combination treatment is 
similar to the management of AEs caused by either agent alone and utilizes the same safety 
management algorithms.
It is rare for a patient receiving immunosuppression for nivolumab-related AEs to 
develop an opportunistic infection. Subjects with inflammatory events of any organ category 
expected to require more than 4 weeks of corticosteroid or other immunosuppressive agents to 
manage the AE should be considered for antimicrobial/antifungal prophylaxis, per institutional 
guidelines, to prevent opportunistic infections such as P. jiroveci (formerly P carinii) and fungal 
infections. Early consultation with an infectious disease specialist should be considered. 
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. In addition, a concomitant 
opportunistic infection should be considered in the differential diagnosis if a patient develops 
recurrent AEs in the setting of ongoing or prior immunosuppressive use. Nivolumab should not 
be used in subjects with active autoimmune disease given the mechanism of action of the 
antibody.
Specific management algorithms are provided in Appendix 7.
1.3
Rationale for the Proposed Study
We hypothesize that standard concurrent chemoradiation in combination with priming, 
concurrent, and adjuvant nivolumab will improve the feasibility of treatment completion by allowing 
completion of a regimen that is highly effective but more tolerable than the current standard of 
care.  
This study will begin with a run-in phase to establish the basic feasibility of the nivolumab 
schedule and determine the MTD (maximally tolerated dose) schedule. This will be followed by 
an expansion phase which will more rigorously test the feasibility of completion of all therapy as 
compared to the standard of care.
Furthermore, the design of this trial will allow us to perform immunologic analyses on tumor and 
peripheral blood specimens pre-treatment and after exposure to nivolumab, chemoradiation-
nivolumab, and adjuvant nivolumab. This will allow us to investigate possible future patient 
specific selection criteria for this regimen and correlate mechanisms of incomplete response to 
immunologic predictors, which may allow for design of more advanced rational therapies for 
patients at high risk of distant metastasis.

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1.4
Correlative Studies
1.4.1
PD-L1 immunohistochemistry 
In a study of 119 patients with histological diagnosis of NPC from a cancer registry in 
Thailand, PD-1 and PD-L1 expression were characterized using immunohistochemistry staining 
on formalin-fixed, paraffin-embedded tumor samples. PD-L1 expression was defined by using a 
cut-off of ≥1% (≥1-9%=1+, 10-49%=2+, ≥50%=3+). PD-L1 was found to be positive in 72% 
(13% IHC 3+). PD1+ was observed in 11% of patients. Most patients in this study had EBER+ 
tumors (96%) indicating EBV-related etiology. 
In another study from China, co-expression of PD-1 and PD-L1 was found to correlate to 
poor outcome in NPC treated with standard chemoradiation. Formalin-fixed, paraffin-embedded 
tissue biopsies from 139 patients treated with conventional chemoradiotherapy were studied. By 
immunohistochemistry, expressions of PD-1 on tumor-infiltrating lymphocyte and PD-L1 on 
tumor tissue were detected. The staining results were evaluated with H-score. 52 of these 139 
tumors (37.4%) were PD-1+. PD-L1 expression was detected in 132 patients (95.0%) on tumor 
tissue. High expression of PD-L1 (median H-score >35) in tumor tissue significantly correlated 
with a poor prognosis of disease-free survival (P = 0.009). Co-expression of PD-1 and PD-L1 in 
NPC at diagnosis correlated with the poorest prognosis of disease-free survival (P = 0.038)22. 
The DAKO PD-L1 IHC 28-8 pharmDxTM test was recently FDA-approved as a 
complementary diagnostic test to help physicians determine which patients may benefit most 
with nivolumab. By using immunohistochemistry staining, expression of PD-L1 on tumor tissue 
will be detected. The staining results will be evaluated with H-score. The correlation between 
PD-L1 expression and clinical response will be analyzed. We hypothesize that upregulated PD-
L1 expression that persists after two weeks of treatment with nivolumab will be predictive of 
poor clinical response, but patients who show lower PD-L1 expression at the time of rebiopsy 
will show an improved clinical response.
1.4.2
EBV DNA
Pre-treatment EBV DNA in plasma has been proven to correlate with cancer stage, 
clinical outcome, and prognosis in patients with endemic NPC23-25. However, post-radiation 
plasma EBV DNA has an even better correlation with prognosis and has been used to monitor 
recurrence after definitive therapy26-29. Rising post-treatment plasma EBV DNA has been shown 
to predate clinical recurrence by 3 to 7 months30-32. Undetectable levels of plasma EBV DNA are 
observed in patients who remained in remission.  
In a large (n=170) NPC study in which most patients were treated uniformly with 
definitive RT (with only 15 patients also receiving weekly CDDP at 40mg/m2 during RT), the 
levels of post-treatment plasma EBV DNA strongly predicted for progression-free survival (PFS) 
(p<0.001) and OS (p<0.001), and this post-treatment EBV DNA dominated the effect of pre-
treatment EBV DNA. The 1-year PFS was 93% among patients with post-treatment EBV DNA ≤ 
500 copies/mL, and 48% for those with > 500 copies/mL33.
A quantitative plasma EBV DNA assay was developed as an international harmonization 
study to facilitate EBV biomarker trials. Post-harmonization, the intraclass correlations for each 
site compared to the index site were 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), 

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respectively34. The centers in this study will use an assay harmonized among the participating 
sites.
2
Objectives of the Study
2.1
Primary

To establish the feasibility of treatment completion of a combined chemoradiation-
nivolumab regimen followed by adjuvant nivolumab.
2.2
Secondary

To determine the clinical response as judged by the investigator;

To determine the overall response rate at 1 year from completion of therapy, as 
determined by RECIST 1.1 criteria;

To determine the locoregional control rate at 1 year post-treatment;

To determine the distant metastasis rate at 1 year post-treatment;

;

To determine the rate of EBV DNA clearance at end of chemoradiation and at 1 year 
post-treatment;

To determine the acute and late toxicity rates according to CTCAE v5.0, including 
immune-related adverse events (AEs);

To assess patients’ quality of life from baseline through 1 year post-treatment
2.3
 Exploratory Objectives, Other Assessments

To determine the overall survival rate at 5 year post-treatment

To determine whether PDL1-positive immunohistochemistry and novel quantitative 
assays correlate to clinical outcome;

To determine if the density of infiltrating CD3+ T cells/μm2 correlates to clinical outcome;

To monitor immune changes by flow cytometry in the circulating T cell response to EBV 
antigens;

To compare the change in the circulating T-cell repertoire by TCR sequencing and 
single-cell T-cell profiling;

To quantify treatment-induced changes over time in the circulating T cell immune 
response to EBV using TCR sequencing and enzyme-linked immunospot (ELISPOT) 
assays.
2.4
Endpoints
2.4.1
Primary Endpoints

The primary endpoint will be the rate of completion of adjuvant immunotherapy, in 
comparison to the rate of completion of a standard adjuvant cisplatin-based platform 
(historical control). This will be determined based on the ability to complete all 
prescribed concurrent and/or adjuvant nivolumab without discontinuation for disease 
progression or toxicity. 

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2.4.2
Secondary Endpoints

ORR determined by investigator’s assessment and RECIST 1.1 criteria;

Locoregional control rate;

Distant metastasis rate;

Rate of EBV DNA clearance from plasma by standardized PCR assay;

Treatment-emergent AEs and laboratory abnormalities as determined by National 
Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0 and modified 
immune related criteria;

Quality of life as assessed by patient reported outcomes (FACT-NP, FACT-Taxane, 
HHIE-S, and EuroQOL EQ-5D).
2.4.3
Exploratory Endpoints

Overall survival rate;

PDL1-positive immunohistochemistry and novel quantitative assays;

Density of infiltrating CD3+ T cells/μm2;

Changes by flow cytometry in the circulating T cell response to EBV antigens;

Change in the circulating T-cell repertoire by TCR sequencing and single-cell T-cell 
profiling;

Changes over time in the circulating T cell immune response to EBV using TCR 
sequencing and enzyme-linked immunospot (ELISPOT) assays;
3
Study Design
3.1
Characteristics
This is a Phase 2, single arm, open-label, multicenter study evaluating the feasibility of a 
treatment regimen comprised of nivolumab administered approximately every 2 weeks before 
and during chemoradiation and as an adjuvant therapy for 3 months to patients with stage II-IVB 
NPC who are planning to undergo chemoradiation treatment of their cancer.  
A run-in phase will precede expansion, to establish basic feasibility of the nivolumab schedule. 
The run-in cohorts will include 6 patients at each dose schedule, with 2 planned changes in 
dose schedule if >33% toxicity or other DLT is observed. A minimum of 6 patients and 
maximum of 18 patients may be enrolled in the three run-in cohorts. The MTD schedule will be 
selected when 4/6 patients at a dose schedule complete therapy without grade 3-4 immune 
related toxicity. All patients will receive the same dose of nivolumab (240mg).
At the starting dose schedule, patients will receive nivolumab for 1 cycle prior to initiation of 
chemoradiation (approximately 14 days). Patients will subsequently continue with nivolumab 
every 14 days until completion of chemoradiation. In dose schedule 2, patients will start 
nivolumab concurrent with start of chemoradiation. In dose schedule 3, patients will start 
nivolumab after completion of chemoradiation (adjuvant nivolumab only).
DLT criteria are grade ≥3 immune-related adverse events, need to hold nivolumab for >28 days 
due to toxicity, and for patients receiving concurrent nivolumab with chemoradiation, inability to 
complete chemoradiation or need to hold chemoradiation for >3 days due to immune-related 

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toxicity.
The expansion phase will continue after the run-in phase has been used to establish the MTD 
schedule for nivolumab. The expansion phase will be powered to test the feasibility of 
completion of the program as compared to the current standard of care.
3.2
Study Schema
On-treatment schema (Dose Schedule 1):
Adjuvant Phase
Cycle #
1
2
3
4
5
6
7
8
9
10
11
12
Week #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cisplatin
 
 
C
C
C
C
C
C
C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiation
 
 
X
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab
N
 
N
 
N
 
N
 
N
 
 
 
N
 
N
 
N
 
N
 
N
 
N
Nivolumab schedule (starting dose schedule): Priming and concurrent nivolumab will be given in 
conjunction with chemoradiation. Patients will receive 1 cycle of priming nivolumab on C1D1, 
and 14 days later, start weekly cisplatin 40 mg/m2, IV, concurrent with 33-35 fractions (6.5-7 
weeks) of RT, with concurrent cycles 2-5 of nivolumab every 14 days. No nivolumab will be 
given on C6D1, to allow for recovery from toxicities. At C7D1, patients will initiate adjuvant 
nivolumab, every 14 days for cycles 7-12. Immune-related toxicities should be at grade 1 or 
lower prior to starting a patient on the adjuvant phase of therapy; if not, initiation of the adjuvant 
phase should be delayed until resolution of toxicities.
On-treatment schema (Dose Schedule 2):
Adjuvant Phase
Cycle #
1
2
3
4
5
6
7
8
9
10
11
Week #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cisplatin
C 
 C
C
C
C
C
C
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiation
X 
X 
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab
N
 
N
 
N
 
N
 
 
 
N
 
N
 
N
 
N
 
N
 
N
Nivolumab schedule (Dose Schedule 2): Priming and concurrent nivolumab will be given in 
conjunction with chemoradiation. Patients will receive 1 cycle of nivolumab on C1D1 (no 
priming), and start weekly cisplatin 40 mg/m2, IV, concurrent with 33-35 fractions (6.5-7 weeks) 
of RT, with concurrent cycles 2-5 of nivolumab every 14 days. No nivolumab will be given on 
C5D1, to allow for recovery from toxicities. At C6D1, patients will initiate adjuvant nivolumab, 
every 14 days for cycles 6-11. Immune-related toxicities should be at grade 1 or lower prior to 
starting a patient on the adjuvant phase of therapy; if not, initiation of the adjuvant phase should 
be delayed until resolution of toxicities.
On-treatment schema (Dose Schedule 3):

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Adjuvant Phase
Cycle #
1
2
3
4
5
6
7
8
9
10
11
Week #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cisplatin
C 
 C
C
C
C
C
C
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiation
X 
X 
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab
 
 
 
N
 
N
 
N
 
N
 
N
 
N
Nivolumab schedule (Dose Schedule 3): Nivolumab will be only given after chemoradiation. On 
C1D1, patients will start weekly cisplatin 40 mg/m2, IV, concurrent with 33-35 fractions (6.5-7 
weeks) of RT every 14 days. At C6D1, patients will initiate adjuvant nivolumab, every 14 days 
for cycles 6-11. Immune-related toxicities should be at grade 1 or lower prior to starting a patient 
on the adjuvant phase of therapy; if not, initiation of the adjuvant phase should be delayed until 
resolution of toxicities.
3.3
Feasibility assessment in the run-in phase
A run-in phase will be conducted initially to determine feasibility. The main schema will be used 
as illustrated, but dosing of nivolumab will be subject to dose reduction if high grade immune 
related adverse events are observed. 
Six patients will be enrolled for the initial run-in phase, starting with nivolumab dosing of 240 mg. 
Enrollment will cease until all 6 patients have completed concurrent chemoradiation and 
nivolumab. If 3/6 patients have experienced grade 3-4 immune related toxicity or other DLT 
during concurrent chemoradiation and nivolumab therapy, then the dose schedule will be 
changed to the next dose schedule and the run-in will restart at that schedule. In dose schedule 
2, patients will start nivolumab concurrently with chemoradiation and there will be no priming 
dose prior to chemoradiation. Using these same procedures, there may be one further change 
to dose schedule 3. In dose schedule 3, patients will not have priming or concurrent nivolumab 
and will only start nivolumab in the adjuvant phase after chemoradiation is concluded. No dose 
reductions of nivolumab will be allowed. No dose escalation will be allowed. 
The run-in will cease when 4/6 patients or more have completed their specified concurrent 
nivolumab therapy at the same nivolumab dose schedule without experiencing grade 3-4 toxicity 
or other DLT, or alternatively, if 3/6 patients have experienced grade 3-4 toxicity or other DLT 
during the adjuvant phase at dose schedule 3 (in which case the entire study will terminate). 
Therefore, a minimum of 6 patients and a maximum of 18 patients will be enrolled in the run-in 
phase. 
DLT criteria are grade ≥3 immune-related adverse events, need to hold nivolumab for >28 days 
due to toxicity, and for patients receiving concurrent nivolumab with chemoradiation, inability to 
complete chemoradiation or need to hold chemoradiation for >3 days due to immune-related 
toxicity.
3.4
Number of Subjects
A maximum of 40 evaluable patients will be enrolled in the study using a Simon’s two-stage 
design for the primary endpoint. Patients who are enrolled at the maximally tolerated dose of 

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nivolumab during the run-in phase will be included in the determination of the primary endpoint. 
Non-evaluable patients will be replaced per the replacement policy (see section 8.2.5). For the 
primary endpoint, this design yields a type I error rate of 0.05 and power of 80% if the true rate 
of completion of adjuvant therapy is 0.7. 
3.5
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients and all eligibility 
criteria must be met prior to enrollment on the study unless otherwise specified.
3.5.1
Inclusion Criteria
1.
Males and females ≥18 years of age.
2.
Histologically or cytologically confirmed nasopharyngeal carcinoma, stage II-IV by AJCC 
7th edition, endemic-type (defined as WHO type 2a and 2b nonkeratizing or 
undifferentiated subtypes, excluding WHO type I keratizing subtype) performed on a 
biopsy that occurred within 90 days of registration. 
3.
PET-CT (preferred) or a CT of chest, abdomen, and pelvis within 60 days of registration 
showing radiographic stage II to IVB nasopharyngeal cancer. 
4.
No distant metastasis as verified by one of the study investigators.
5.
Documentation that the patient is a candidate for chemoradiation of their 
nasopharyngeal cancer by one of the study investigators.
6.
Ability to tolerate radiation therapy (e.g. lie flat and hold position for treatment).
7.
Measurable disease as defined by RECIST v1.1.
8.
ECOG performance status of 0 to 1.
9.
Lack of contraindications to systemic immunotherapy (see list of exclusions below).
10. Resolution of all acute toxic effects of any prior chemotherapy, radiotherapy or surgical 
procedures to NCI CTCAE Version 5.0 grade 1.
11. Adequate hepatic, hematologic, and renal indices permitting administration of cisplatin 
and nivolumab (within 14 days of registration):
Hepatic Function:
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  3 × upper limit 
of normal (ULN);

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Total bilirubin  1.5 × ULN (except subjects with Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL)
Adequate bone marrow function:
WBC ≥ 2000/μL
Neutrophils ≥ 1500/μL
Platelet ≥ 100 x103/μL
Hemoglobin > 9.0 g/dL
Adequate renal function:
Serum creatinine
 1.5 × upper limit of normal (ULN)
OR
Creatinine clearance
> 40 mL/min (or > 50 mL/min for Singapore sites only) (if using 
the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85
                           72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00 
                            72 x serum creatinine in mg/dL
12. Women of childbearing potential must have a negative serum pregnancy test within 24 
hours prior to the first dose of study treatment and agree to use appropriate highly 
effective methods of contraception, during the study and for 5 months following 
completion of study treatment;
A “Woman of childbearing potential” is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 
in the absence of other biological or physiological causes. In addition, women 
under the age of 62 must have a documented serum follicle stimulating hormone 
(FSH) level less than 40 mIU/mL. 
Female Subjects: 
Women of child bearing potential are expected to use one of the highly effective 
methods of contraception listed below. 
Male Subjects:
Male subjects must inform their female partners who are women of child bearing 
potential of the contraceptive requirements and are expected to adhere to using 
contraception with their partner. Female partners of male subjects, who are 
women of child bearing potential, are expected to use one of the highly effective 

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methods of contraception listed below. In addition, male subjects are expected to 
use a condom as noted in the list below.
Progestogen only hormonal contraception associated with inhibition of 
ovulation
Hormonal methods of contraception including oral contraceptive pills 
(combination of estrogen and progesterone), vaginal ring, injectables, 
implants and intrauterine devices (IUDs)
Non-hormonal IUDs such as ParaGard®
Bilateral tubal ligation
Vasectomized Partner
Intrauterine hormone-releasing system (IUS)
Complete abstinence
Highly Effective
Condom
Other Methods
Vaginal sponge
Progestin only pills
Cervical cap with spermicide
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus interruptus)
Spermicide only
Lactation amenorrhea method (LAM)
Unacceptable 
Methods
A male and a female condom must not be used together
13. Men with a female partner of childbearing potential must agree to use highly effective 
methods of contraception or any contraceptive method with a failure rate of less than 1% 
per year during the study and for 7 months following completion of study treatment.
14. Ability to sign informed consent.
3.5.2 Exclusion Criteria
Any of the following criteria will exclude patients from study participation:
1. Active second malignancy, i.e. patient known to have potentially fatal hematologic 
malignancy or another solid primary tumor present for which he/she may be (but not 
necessarily) currently receiving treatment. Patients with a prior or concurrent malignancy 
whose natural history or treatment does not have the potential to interfere with the safety 
or efficacy assessment of the investigational regimen are allowed to enroll in this trial. 
For example, patients with early-stage skin cancers, prostate cancer under surveillance 
with non-rising PSA, or meningioma or thyroid papillary cancers which are under 
surveillance are eligible. For determinations of a specific clinical condition, please 
consult with the Principal Investigator. 
2. Active, untreated central nervous system (CNS) metastases;
3. Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD 
Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2), anti-CTLA-4 antibody, or any other antibody 
or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or 
cancer vaccine;

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4. Prior systemic cytotoxic therapy, antineoplastic biologic therapy, or major surgery within 
28 days of first dose of study medication; 
5. Severe hypersensitivity reaction to treatment during prior administration of a monoclonal 
antibody (mAb) or history of allergy to any study drug component;
6. Has received a live-virus vaccination within 30 days of planned treatment start;
7. 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 > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease.
8. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of 
ILD or pneumonitis requiring oral or IV glucocorticoids;
9. Active, known, or suspected autoimmune disease or any autoimmune condition that has 
required systemic treatment in the past 2 years (replacement therapies for hormone 
deficiencies are allowed);
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.
10.Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, 
or abdominal carcinomatosis (known risks factors for bowel perforation);
11.Signs or symptoms of infection within 2 weeks prior to first day of study treatment.
12.Patients with active tuberculosis (clinical evaluation in line with local practice), or a 
known history of active tuberculosis that in the opinion of the treating investigator has a 
high risk of reactivation.
13.Received therapeutic oral or IV antibiotics within 2 weeks prior to first day of study 
treatment:
Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible.
14.Known positive test for human immunodeficiency virus (HIV);
15.Known active hepatitis B or hepatitis C virus (HBV or HCV):
Patients with past or resolved HBV infection (defined by a negative hepatitis B 
surface antigen [HBsAg] test and a positive anti-hepatitis B core antigen [anti-HBc] 

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antibody test) are eligible. HBV DNA must be obtained in these patients prior to first 
day of study treatment.
Patients who have been recently discovered to have HBV with positive HBsAg test 
and positive anti-HBc antibody test but who have been started on antiretroviral 
treatment with nondetectable HBV DNA are eligible. HBV DNA must be obtained in 
these patients prior to first day of study treatment.
16.Patients with known active hepatitis C virus ribonucleic acid (HCV antibody) indicating 
acute or chronic infection:
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
17.Prior radiation therapy of any type within 7 days of first dose of study medication;
18.Prior radiation therapy to head and neck region that would overlap with intended 
radiation treatment for nasopharyngeal carcinoma; 
19.Medical contraindication to radiation treatment (e.g. active systemic sclerosis, other 
uncontrolled autoimmune condition)
20.Treatment with prohibited medications (including concurrent anticancer therapy including 
chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterol 
acetate] ≤ 14 days prior to treatment.
21.Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study;
22.Active, uncontrolled psychiatric disorders or substance (drug/alcohol) abuse that 
interfere with patient’s safety, ability to provide informed consent, or ability to comply 
with the protocol. 
23.Persons who are incarcerated or otherwise under compulsory detention by an authority 
are not eligible.
3.6
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment with nivolumab may 
continue from the specified initiation timepoint and for 3 months after chemoradiation or until:

The patient or legally authorized representative withdraws consent.

Progression of disease by RECIST 1.1 criteria.

Any adverse event that in the opinion of the investigator would pose an unacceptable 
safety risk to the patient.

Closure of the study

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3.7
 Duration of Follow Up
Patients will be followed for safety assessments for 100 days after completion of treatment or 
removal from study, or until death, whichever occurs first.  All SAEs must be collected that occur 
within 100 days of discontinuation of dosing.  Patients removed from study for unacceptable 
treatment related adverse event(s) will be followed until resolution or stabilization of all 
treatment related adverse events to Grade 2 or lower.  Patients will be followed for adverse 
events for up to 1 year. Survival and disease status information may also be collected from 
review of the electronic medical records, patient visits, or telephone calls. Survival and disease 
status will be collected until participant death, withdrawal, or if the participant is lost to follow-up.
3.8
 Study Timeline
3.8.1
Primary Completion
It is expected that the study will reach primary completion 20 months from the time the study 
opens to accrual. 
3.8.2
Study Completion
It is expected that the study will reach full completion 6 years from the time the study opens to 
accrual.  
4
Study Drugs
At study sites, all study medication will be stored as described in the pharmacy manual and 
inventoried in accordance with applicable state and federal regulations.
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1
Nivolumab (BMS-936558)
Classification:
Nivolumab is a fully human IgG4 anti-PD1 monoclonal antibody. 
Mechanism of Action:
In vitro, nivolumab binds to PD-1 on activated human T cells with high affinity (half maximal 
effective concentration [EC50]: 0.64 nM by FACS analysis and 2.6 nM by Scatchard), and 
inhibits the binding of PD-1 to its ligands, programmed death-ligand-1 (PD-L1) and programmed 
death-ligand-2 (PD-L2) (half maximal inhibitory concentration [IC50] of ~1 nM)1. Nivolumab 
binds specifically to PD-1 and not to related members of the CD28 family such as CD28, 
inducible co-stimulator (ICOS), cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and B 
and T lymphocyte attenuator (BTLA). Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and IFN-α release in the mixed lymphocyte 
reaction (MLR). Using a cytomegalovirus (CMV)-re-stimulation assay with human peripheral 
blood mononuclear cell (PBMC), the effect of nivolumab on antigen specific recall response 
indicates that nivolumab augmented IFN-α secretion from CMV specific memory T-cells in a 
dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine 
analog of nivolumab enhances the anti-tumor immune response and results in tumor rejections 
and tumor growth delays in MC38 and SA1/N immunocompetent mouse tumor models.

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Storage Conditions & Handling:

Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials 
are provided in a carton.

Store at 2-8°C (36-46°F), protect from light, freezing, and shaking.

If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.   

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 site following procedures for the disposal of 
anticancer drugs. 
Use Time/Stability: 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be 
completed within 24 hours of preparation. If not used immediately, the infusion solution may be 
stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and 
used within 4 for up to 24 hours, and a maximum of 4 hours of the total 24 hours can be at room 
temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour period under room 
temperature and room light conditions for undiluted and diluted solutions of BMS-936558-01 
injection in the IV bag should be inclusive of the includes the product administration period.
Preparation and Administration:
1.
Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution may 
have a pale-yellow color), or if there is foreign particulate matter other than a few translucent-
to-white, amorphous particles.
Note: Mix by gently inverting several times.  Do not shake.
2.
Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense 
into an IV. bag.  If multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, 
stopper coring, repeated friction of plunger against syringe barrel wall. Do not enter into each 
vial more than once.  Do not administer study drug as an IV push or bolus injection
3.
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an appropriate 
pre-filled bag of diluent.
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2]

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Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab.
4.
Attach the IV bag containing the nivolumab solution to the infusion set and filter.
5.
At the end of the infusion period, flush the line with a sufficient quantity of approved diluents.
4.2
Drug Accountability
The Investigational Pharmacist will manage drug accountability records.
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. For further information, please either discuss 
with the protocol manager or refer to Destruction policies and procedures 
4.3
Drug Ordering
Participating sites will obtain nivolumab directly from Bristol-Myers-Squibb as study supply.
Initial Orders 

Following submission and approval of the required regulatory documents, a supply of 
nivolumab may be ordered from by completing a Drug Request Form provided by BMS for 
this specific trial. The first request may take place upon screening of the first patient 

The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug from 
BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient specific. All 
drug product will be shipped by courier in a temperature-controlled container. It is possible 
that sites may have more than one nivolumab clinical study ongoing at the same time. It is 
imperative that only drug product designated for this protocol number be used for this study.

Pharmacy supplies that are not provided by BMS:  Empty IV bags/containers, approved 
diluents, In-line filters and infusion tubing
Re-Supply

Drug re-supply request form should be submitted electronically business days before the 
expected delivery date.  Deliveries will be made Tuesday through Friday.

When assessing need for resupply, institutions should keep in mind the number of vials used 
per treatment dose, and that shipments may take 14 business days from receipt of request. 
Drug is not patient-specific. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand.
Drug Excursions

Drug excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form

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4.4
Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per institutional standards, adhering to applicable local and 
federal laws.
5
Treatment Plan
5.1
Dosage and Administration
Treatment will be administered on an outpatient basis.
Table 5.1
Regimen Description
Study 
Drug
Dose
Route
Schedule 
Cycle 
Length
Radiation
2.12 Gy / 
fraction
External
Daily, Monday-
Friday
33 fractions
Cisplatin
40 mg/m2
Intravenous, over 30-60 
minutes
Every 7 days
7 days
Nivolumab
240 mg
Intravenous, over 60 
minutes
Every 14 days
14 days
5.1.1
Other Modality(ies) or Procedures
5.1.1.1 Radiation therapy
Radiation therapy of the patients’ nasopharyngeal cancer will be carried out in accordance 
with institutional standard practice and standard-of-care guidelines. 
Associated imaging and plans (planning CT and associated RTst and RTDOSE files) should be 
transmitted in anonymized DICOM format for central archiving. These data must be anonymized 
and labeled clearly by patient study number prior to transmittal. The data may be transmitted 
electronically or batch-mailed on a CD-ROM to the attention of the Principal Investigator at the 
UCSF Department of Radiation Oncology.
Dose Specifications
Treatment will be delivered once daily, 5 fractions per week, over approximately 6 weeks 
and 3 days. All targets will be treated simultaneously. To treat gross disease, PTV6996 (CTV6996 + 
margin) will receive 69.96 Gy in 33 fractions at 2.12 Gy per fraction. The PTV5940 (CTV5940 + 
margin) to the high-risk subclinical region will receive 59.4 Gy. The CTV5940 typically includes the 
primary site CTV as well as the neck CTV where there are gross nodes present; typically this CTV 
would include a 5 mm expansion around any GTV in addition to the high risk areas of the neck, 
but the expansion from the GTV may be reduced or omitted in cases where a critical structure 
would exceed tolerance due to the CTV expansion (e.g. the brainstem or optic chiasm or nerve). 
If the treating physician would like to treat all sites such as primary, upper neck, and lower neck 
with a single IMRT plan, the low neck which is considered low risk may receive 54.12 Gy at 1.64 
Gy per fraction. This is known as PTV5412 (CTV5412 + margin).  However, if there are gross nodes 
in the low neck, the surrounding subclinical region must receive 59.4 Gy in this case, as it is still 
considered high risk due to the presence of gross nodes in the same region.  

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The uninvolved low neck or supraclavicular field also may be treated independent of the 
IMRT plan with conventional AP or AP/PA fields, with a half-beam block superior to the isocentric 
junction with the IMRT plan, and will receive 28 fractions of 1.8 Gy/fraction, for a total of 50.4 Gy. 
If all involved adenopathy is confined only to level 2 of the neck and no lower, the low neck dose 
may be as low as 45 Gy in 25 fractions of 1.8 Gy/fraction. If using a single AP field, the prescription 
depth is dependent on the thickness of the low anterior neck, which is typically at a depth of 3 cm. 
For AP/PA fields, the prescription point will be at midplane for an AP field or midline for AP/PA 
fields. The investigator should place a midline cord block. However, if there are grossly involved 
nodes in the low neck, these nodes should receive the same dose as the PTV69.96, except for 
small volume lymph nodes which can be prescribed a total dose of 62.7 Gy (optional PTV62.70 to 
be used at investigator’s discretion). Should the treating physician choose to use a low anterior 
neck field in the presence of gross nodal disease, electrons or photons can be used to boost 
these nodes. 
Description of margin: The PTV volumes consist of a 3 mm expansion from the CTV 
volumes. However, in cases where a critical structure would exceed tolerance due to the PTV 
expansion (e.g. the brainstem or optic chiasm or nerve), the PTV expansion can be reduced or 
omitted for safety, at the treating investigator’s discretion.
Technical Specifications
Intensity modulated radiation therapy (IMRT) and image-guidance (IGRT) are 
mandatory for this study. Megavoltage equipment capable of delivering static-gantry intensity 
modulation beams with a multileaf collimator or dynamic intensity modulation (using a multileaf 
collimator or tomotherapy) is required. Other techniques are acceptable as long as dose 
specifications and constraints are satisfied. This includes tomotherapy and Volumetric Modulated 
Arc Therapy (VMAT) techniques.
IGRT specifications
Daily image guidance of IMRT may be achieved using any one or more of the following 
techniques:

Orthogonal kilovoltage (KV) images, e.g. ExacTrac

Linear-accelerator mounted kV and MV helical conebeam CT images

Linear-accelerator mounted MV CT images (e.g. Tomotherapy)

Other Mechanism, after discussion with the PI
Required Critical Normal Tissue Constraints
Per protocol
Acceptable
Unacceptable
Maximum dose to 0.03 cc of BrainStem
 54 Gy
 54-60 Gy 
>60 Gy
Maximum dose to 0.03 cc of Spinal Cord
 ≤45 Gy
 45-50 Gy
>50 Gy
Maximum dose to 0.03 cc of Optic Nerves and Chiasm
 ≤54 Gy
 54-56 Gy
>56 Gy

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Maximum dose to  0.03 cc of Mandible and TM joint
 ≤70 Gy
 70-75 Gy
>75 Gy
Maximum dose to 0.03 cc of one Temporal Lobe
≤70 Gy
 70-72 Gy
>72 Gy
Mean dose to one of Parotid glands
≤26 Gy
 26.1-33 Gy
>33 Gy
Recommended dose constraints for other normal tissues
Oral cavity (excluding PTV’s)
Mean dose less than 40 Gy
Each cochlea
Maximum dose less than 55 Gy 
Eyes       
Max dose less than 55 Gy
Lens       
Max dose less than 15 Gy
Glottic Larynx
Mean dose less than 40 Gy
Esophagus, Postcricoid pharynx
Mean dose less than 50 Gy
Brachial plexus
Mean dose less than 66 Gy
5.1.1.2 Cisplatin chemotherapy
Weekly cisplatin chemotherapy will be delivered in accordance with institutional standard 
practice and standard-of-care guidelines.
Cisplatin:  40 mg/m2/day, weekly during radiation  
No concurrent cisplatin will be administered after the final week of radiation, but the final dose of 
cisplatin may be administered following the last dose of radiation if it is administered within the 
same calendar week. Cisplatin should be ideally be administered on Mondays or Tuesdays 
to maximize overlap of daily radiation with cisplatin exposure. Administration on Wednesday 
or Thursday concurrent with that day’s radiation dose is acceptable. Investigators should strive to 
administer cisplatin on the same day each week but variance of 1 day is acceptable for vacations, 
holidays, etc.  If radiation treatments are held for toxicity, cisplatin dosing should also be held. 
Guidelines for Administration of Cisplatin Concurrent with Radiation 
Many institutions will have standard guidelines for the administration of cisplatin at the doses used 
in this study. For purposes of this protocol, individual investigators may use these local 
guidelines for cisplatin administration. One possible approach is outlined below. This may 
need to be modified based on local guidelines and patient related factors (e.g. the substitution of 
normal saline in diabetic patients). Similarly, the anti-emetic regimen for this combination is to be 
determined by the local investigator.

Low-dose Cisplatin  anti-emetic administration guidelines:  5-HT3 antagonists (e.g. 
ondansetron 16 mg  PO prior to cisplatin  and 8 mg PO up to  3 times daily on days 2 and 
3 following cisplatin weekly. Use of other anti-nausea meds such as fosaprepitant or 
aprepitant 
(these 
are 
strongly 
encouraged), 
lorazepam, 
metoclopramide, 
or 
prochlorperazine is left to the discretion of the investigator. 

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
Use of dexamethasone or other corticosteroids are highly discouraged but may be used 
at investigator’s discretion for unusual conditions such as highly refractory nausea 
unresponsive to above-listed interventions, immune-treatment-related toxicity requiring 
steroids for management, or airway compromise or other emergent conditions.

Low-dose Cisplatin pre-hydration guidelines: Pre-hydration with 1 liter D5 ½ NS and 40 
meq KCL/ liter x 1 liter prior to cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin.

Cisplatin administration: Cisplatin, 40 mg/m2 over 30-60 minutes IV in 250 cc NS. See 
above discussion on scheduling and number of doses concurrent with radiation.

Cisplatin post-hydration guidelines: Following the end of the cisplatin administration, an 
additional  liter of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and  25 g mannitol is infused 
over 2 hours. On the second and third day following cisplatin, patient should be 
encouraged to take at least 2 liters of fluid per day orally.  Patients unable to orally self-
hydrate should be considered for additional IV hydration on these days with NS.
5.2
Dose Modifications and Dosing Delays
5.2.1
Dose Delays of Nivolumab
No dose escalation or dose reduction of nivolumab from the patient’s starting dose is allowed. 
Dose delays are allowed for an individual patient at the investigator’s discretion to allow for 
resolution of toxicities as described below.  
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
Specific management algorithms for immune-related toxicities are given in Appendix
5 and should be referenced in case of any immune-related AE. 
If dosing with study drug is delayed for > 28 consecutive days due to toxicity, protocol therapy 
should be discontinued unless otherwise agreed between the investigators and Principal 
Investigator. 
For patients expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following recommendations: 

Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 

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infections such as Pneumocystis jiroveci and fungal infections. 

Early consultation with an infectious disease specialist should be considered. Depending 
on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 

In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the 
differential diagnosis. 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation.  
The following dose delay rules will be used with respect to potential toxicity.  Toxicity will be 
assessed according to the NCI Common Terminology Criteria for Adverse Events Version 4.0 
(CTCAE v5.0).
Nivolumab administration should be delayed for CTCAE v5.0 toxicities as indicated in the tables 
below that in the opinion of the treating physician are related to the study drug. 
Dosing Delays for General and Immune-Related Adverse Events
Algorithms in tables which follow and Appendix 5 should be consulted for specific immune-
related AEs and followed preferentially rather than this general guideline.
Grade of Event
Management/Next Dose for Nivolumab
≤ Grade 1
No change in dose
Grade 2 
Hold until ≤ Grade 1
Resume at same dose schedule when toxicity ≤ Grade 1
Grade 3 
Hold* until ≤ Grade 2
Resume at same dose schedule when toxicity ≤ Grade 2
Grade 4 
Off protocol therapy
*Patients requiring a delay of > 28 days should go off protocol therapy
Please note nivolumab therapy will not be delayed for the following: 

Grade 2 weight loss; 

Grade 2 or 3 nausea that in the opinion of the investigator is related to cisplatin; 

Grade 3 radiation dermatitis; 

Any Grade 2-3 mucositis, dysphasia, or pharyngolaryngeal pain that in the opinion of the 
treating physician is related to radiation therapy for head and neck cancer; 

Grade 2 hypokalemia or hypomagnesemia that in the opinion of the investigator is 
related to cisplatin; 

Grade 2 or greater hearing impairment that in the opinion of the treating physician is 
related to cisplatin; 

Grade 3 or 4 isolated lymphopenia; 

Grade 3 isolated anemia if, in the opinion of the treating physician, the anemia is not 
related to the study drug (e.g. related to chronic disease, iron deficiency, radiotherapy). 
Skin Rash and Oral Lesions 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose* 

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Grade 2 
No change in dose; see guidelines for management in Appendix 5. 
Grade 3 
Hold* until ≤ Grade 1; see guidelines for management in Appendix 
5. Resume at same level at investigator discretion 
Grade 4 
Off protocol therapy 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, TEN, and autoimmune bullous disease including oral lesions of bullous 
pemphigus/pemphagoid. Pruritus may occur with or without skin rash and should be treated 
symptomatically if there is no associated liver or GI toxicity. Note skin rash typically occurs early 
and may be followed by additional events particularly during steroids tapering. 
Liver Function 
AST/ALT/T. Bili * 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change. 
Grade 2 
Hold until UNL or baseline. Resume at same dose schedule; see 
guidelines for management in Appendix 5. 
Grade 3 
Off protocol therapy; see guidelines for management in Appendix 5. 
Grade 4 
Off protocol therapy see guidelines for management in Appendix 5. 
Continued treatment of active immune-mediated hepatitis may exacerbate ongoing 
inflammation. Holding drug to evaluate LFT changes and early treatment are recommended. 
LFT changes may occur during steroid tapers from other events and may occur together with 
other GI events including cholecystitis/pancreatitis. 
Renal Function 
Serum Creatinine 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue treatment. 
Grade 2 
Hold until UNL or baseline. Resume at same dose 
schedule; see guidelines for management in 
Appendix 5. 
Grade 3 
Hold until UNL or baseline. Resume at same dose 
schedule; see guidelines for management in 
Appendix 5. 
Grade 4 
Off protocol therapy 
For Grade 2 or greater, consider renal biopsy.
Diarrhea/ Colitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose; see guidelines for management in Appendix 5. 
Grade 2 
Hold until Grade 0 or baseline; see guidelines for management in Appendix 5. 
Grade 3 
Off protocol therapy; see guidelines for management in Appendix 5. 
Grade 4 
Off protocol therapy; see guidelines for management in Appendix 5. 
See GI AE Algorithm for management of symptomatic colitis (in IB). 
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution. 
Patients with persistent symptoms greater than 14 days who require steroids should be taken 
off study treatment. 
Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care. 
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious 
and foodborne illness, ischemic bowel, diverticulitis, and IBD. 
Pancreatitis 
Amylase/Lipase 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose until grade 0. 

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Grade 2 
Hold until Grade 0. Resume at same dose 
schedule if asymptomatic. 
Grade 3 
Hold* until Grade 0. Resume at same 
dose schedule if asymptomatic. Patients 
who develop symptomatic pancreatitis or 
DM should be taken off treatment.* 
*Grade 4 
Off protocol therapy 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and 
DKA. Lipase elevation may occur during the period of steroid withdrawal and with other 
immune-mediated events or associated with colitis, hepatitis, and patients who have 
asymptomatic lipase elevation typically have self-limited course and may be retreated. 
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse 
Event Management Algorithm (in Appendix 5). 
*Excluding asymptomatic amylase and lipase increases 
Pneumonitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and 
resolution to ≤ Grade 0 or baseline 
including baseline pO2. Resume no 
change in dose after pulmonary and/or ID 
consultation. 
Grade 2 
Hold dose pending evaluation. Resume no 
change in dose after pulmonary and/or ID 
consultation if lymphocytic pneumonitis is 
excluded. Off study if grade 2 symptoms 
do not improve or worsen after 2 weeks of 
steroids and dose delay; see guidelines 
for management in Appendix 5. 
Grade 3 
Off protocol therapy; see guidelines for 
management in Appendix 5. 
Grade 4 
Off protocol therapy; see guidelines for 
management in Appendix 5. 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified including influenza. Most 
patients with respiratory failure or hypoxia will be treated with steroids. Bronchoscopy may be 
required and analysis of lavage fluid for lymphocytic predominance may be helpful. Patients with 
new lung nodules should be evaluated for sarcoid like granuloma. Please consider 
recommending seasonal influenza killed vaccine for all patients. 
Other GI N-V 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose. 
Grade 2 
Hold pending evaluation for gastritis 
duodenitis and other immune adverse 
events or other causes. Resume at same 
dose schedule after resolution to ≤ Grade 
1. 
Grade 3 
Hold pending evaluation until ≤ Grade 1. 
Resume at same dose schedule. If 
symptoms do not resolve within 7 days 

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with symptomatic treatment patients 
should go off protocol therapy. 
Grade 4 
Off protocol therapy. 
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other immune 
related events. 
Fatigue 
Management/Next Dose for 
Nivolumab 
≤ Grade 1 
No change in dose.
Grade 2 
No change in dose. 
Grade 3 
Hold until ≤ Grade 2. Resume at 
same dose schedule.
Fatigue is the most common adverse event associated with immune checkpoint therapy. Grade 
2 or greater fatigue should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation. 
Neurologic events 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose. 
Grade 2 
Hold dose pending evaluation and 
observation. Hold until ≤ Grade 1; see 
guidelines for management in Appendix 5. 
Resume at same dose schedule for 
peripheral isolated n. VII (Bell’s palsy); see 
guidelines for management in Appendix 5. 
Grade 3 
Off protocol therapy; see guidelines for 
management in Appendix 5. 
Grade 4 
Off protocol therapy; see guidelines for 
management in Appendix 5. 
*Patients with any CNS events including aseptic meningitis, encephalitis, or myopathy, 
peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), GB 
syndrome, myasthenia gravis should be off study. 
Endocrine Hypophysitis Adrenal 
Insufficiency 
Management/Next Dose for Nivolumab 
Discontinue protocol therapy for grade 4 hypophysitis and grade 3 or greater adrenal 
insufficiency. Note that protocol-specific actions and management are not strictly by 
CTCAE grade; see guidelines for management in Appendix 5 for recommendations on I-O 
therapy and management of adverse events. 
Fever 
Management/Next Dose for 
Nivolumab 
≤ Grade 1 
Hold until ≤ Grade 1. Resume at 
same dose schedule. 
Grade 2 
Hold until ≤ Grade 1. Resume at 
same dose schedule. 
Grade 3 
Hold until ≤ Grade 1. Resume at 
same dose schedule. 
Grade 4 
Off treatment 

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Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever 
See detailed section below with instructions for management of infusion reactions. 
ALL OTHER EVENTS 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 OR baseline.** When 
resolved or following steroids, resume at 
same dose schedule. 
Grade 3 
Any grade 2 or 3 drug-related uveitis or 
eye pain or blurred vision that does not 
respond to topical therapy and does not 
improve to Grade 1 severity within the re-
treatment period OR requires systemic 
treatment requires treatment 
discontinuation. 
Any other immune-related grade 3 toxicity 
not covered in the tables above would 
require that the patient go off protocol 
therapy with the following exceptions: 

Any grade 3 or 4 drug-related 
laboratory abnormality or 
electrolyte abnormality, not 
associated with underlying organ 
pathology, that does not require 
treatment except for electrolyte 
replacement OR hormone/steroid 
replacement does not require 
treatment discontinuation. 
Grade 4 
Off protocol therapy (except for drug-
related laboratory abnormality or 
electrolyte abnormality, not associated 
with underlying organ pathology, that does 
not require treatment except for electrolyte 
replacement OR hormone/steroid 
replacement does not require treatment 
discontinuation). 
** Immunologically mediated 
Criteria to Resume Nivolumab
Patients may resume treatment with nivolumab when the drug-related AE(s) resolve to the 
grade specified in the tables above and as detailed in Appendix 5.
If the criteria to resume treatment are met, the patient should restart treatment at the next 
scheduled time point (two-week interval) per the protocol.
Discontinuation Criteria 

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Treatment with nivolumab should be permanently discontinued as specified in the tables above 
and guidelines for management in Appendix 5. Additional criteria for discontinuation include:

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment; 

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
adverse event, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation; 

Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation; 

Any Grade 4 drug-related adverse event or laboratory abnormality, with the exception of 
those noted below: 
o
Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset; 
o
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
o
Any grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality 
not associated with underlying organ pathology that does not require treatment 
except for electrolyte replacement OR hormone/steroid replacement does not 
require treatment discontinuation. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the patient with continued 
nivolumab dosing; 

A delay in nivolumab treatment of 28 days. 
Treatment of Nivolumab-Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to CTCAE v5.0 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 patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations. 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but 

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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 patient with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen 325 to 1000 mg; remain at bedside and monitor patient 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 patient 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 patient 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 acetaminophen 325 to 1000 mg should be administered at least 30 minutes 
before additional nivolumab administrations. If necessary, corticosteroids (recommended dose: 
up to 25 mg of IV hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, 
renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated): Immediately discontinue infusion of nivolumab. Begin an IV infusion of 
normal saline, and treat the patient 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. Patient 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 patient until recovery from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritis within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
5.2.2
Cisplatin (CDDP) Dose Modifications During Concurrent Radiation
Patients will be examined and graded for subjective/objective evidence of developing toxicity 
weekly according to CTCAE v5.0 while receiving concurrent cisplatin with radiotherapy. 
Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction that, in the 
judgment of the clinician, warrants a break. For chemotherapy attributable AEs requiring a break 
in treatment, resumption of concurrent CDDP may begin when AEs have recovered to the levels 
specified below. If an AE does not resolve to the levels specified in the sections below prior to 
the calendar week of the last radiation treatment, treatment off protocol can continue according 
to the judgment of the treating physician.
There will be no dose re-escalation for concurrent cisplatin. If a patient requires >2 dose 
reductions then the patient should discontinue protocol therapy. For Grade 4 toxicity, protocol 
therapy is discontinued. If dosing with study drug is interrupted for > 28 consecutive days due to 
toxicity, protocol therapy should be discontinued unless otherwise agreed between the 

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investigators before reintroduction of study drug.
Chemotherapy dosage modifications are based upon lab values obtained within the 24 hours 
prior to cisplatin and interim non-hematologic toxicities during the week prior to a particular 
cisplatin dose.
The dose modifications for cisplatin (below) are intended to be permanent (i.e., if the patient’s 
dose is reduced to dose level -1, it remains at the reduced dose level) unless adverse events 
(AEs) are ongoing requiring further reduction.
Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent Radiation
Starting Dose
Dose Level -1
Dose Level -2
40 mg/m2
30 mg/m2
23 mg/m2
Chemotherapy must not be administered until the ANC is ≥ 1,000 and platelets are ≥ 75,000. If 
not, delay 7 days. Cisplatin should be held every week until the above ANC and platelet 
parameters are met. Dose reductions when cisplatin is resumed after delay for low ANC or 
platelets will be as follows, based upon counts at time cisplatin was held.
ANC
Platelets
Reduction
≥ 1000 mm3 
and
≥ 75,000
None
< 1000 mm3
or
< 75,000
One dose level
Note: Hematologic growth factors for neutropenia or anemia are not allowed during 
concurrent cisplatin and radiation treatment.
Cisplatin Dose Modifications for Non-Hematologic Adverse Events during Concurrent Radiation
Neutropenic Fever: If on the day of scheduled treatment with cisplatin the absolute neutrophil 
count (ANC) is < 1200, hold treatment until ANC ≥ 1200, then treat at 100% dose. Neutropenic 
fever will require permanent 25% dose reduction. Febrile neutropenia is fever of unknown origin 
without clinically or microbiologically documented infection; ANC < 1.0 x 10e9L, fever > 38.5°C.
Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet count is < 
75,000, hold treatment until platelets are > 75,000, then treat at 100% dose. Thrombocytopenia 
that results in bleeding will require a 25% dose reduction.
Renal Adverse Events: Cisplatin should be administered on the scheduled day of treatment 
using the following guidelines: 

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Note: If creatinine is > 1.2 mg/dl, clearance must be done in order to make dose adjustment. If 
the calculated nomogram is 50 mL/min or above, a 24-hour urine collection is not needed, but if 
the nomogram calculation is less than 50 mL/min, a 24-hour urine collection is mandated. 
Once the creatinine has met the above parameters, cisplatin may be restarted with the 
modifications below, based on the creatinine at the time the cisplatin was held: In general, 
cisplatin should be held for weekly intervals (rather than restarting cisplatin later in the same 
week that a dose limiting AE is seen).
Cisplatin dose modifications for creatinine during concurrent radiation
Creatinine (mg/dL)
Creatinine 
clearance, 
measured or 
calculated ml/min
Cisplatin dose 
reduction
≤ 1.2
or
> 50
100% 
> 1.2
and
40-50
50%
< 40
Discontinue drug
Neurologic (neuropathy) adverse events: If any signs of grade 3 or greater neurotoxicity occur, 
discontinue cisplatin. 
Grade (CTCAE v5.0)
Dose Reduction
0-1
None
2
One dose level
3-4
Discontinue drug
Ototoxicity: For new clinical hearing loss not requiring a hearing aid or for tinnitus that interferes 
with activities of daily living, treat at 50% dose reduction. For hearing loss requiring a hearing 
aid, discontinue cisplatin. Continue radiation. If the physician is unsure about the severity of the 
hearing loss, an audiogram is encouraged. 
All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent 
Radiation: For all other non-hematologic adverse events in which toxicity is ≥ grade 2 (CTCAE 
v5.0), investigators are advised to evaluate and manage correctable issues promptly to prevent 
worsening of toxicity. For these events in which toxicity is ≥ grade 3, investigators should hold 
cisplatin, with weekly re-evaluation until AE grade falls to 0-1, then restart cisplatin at one lower 
dose level. 

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Note: Grade 3 mucositis is commonly experienced by head and neck cancer patients; the 
investigator generally would not hold the cisplatin dosing in this case, unless there is unusual 
concern for progression to grade 4 mucositis. Grade 4 mucositis will require a cisplatin dose 
reduction.
If a weight change of ≥ 10% occurs, the cisplatin dose should be adjusted.
5.3
Monitoring and Toxicity Management
Each patient receiving nivolumab will be evaluable for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of 
adverse events reported to the investigator by patients.
Each patient will be assessed periodically for the development of any toxicity. Toxicity will be 
assessed according to the NCI CTCAE v5.0.  Dose adjustments will be made according to the 
system showing the greatest degree of toxicity. 
Management of any grade 3 or higher toxicity should be discussed with the PI of the study.   
5.4
Permitted Concomitant Therapy Requiring Caution and/or Action 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 30 days before the first dose of study treatment through 30 days after the date of the 
last dose of study treatment are to be recorded in the case report forms.

Antiemetics and antidiarrheal medications are allowed in accordance to standard clinical 
practice if clinically indicated; 

Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are generally not to be used in 
this protocol. Note that hematologic growth factors are not allowed during concurrent cisplatin 
and radiation treatment. If hematologic growth factors must be used outside of the radiation 
phase of treatment, they should be used per clinical guidelines (eg, American Society of 
Clinical Oncology [ASCO] or [European Society for Medical Oncology] ESMO guidelines);

Transfusions, hormone replacement, and short term higher doses of corticosteroids should 
be utilized as indicated by standard clinical practice
5.5
Prohibited Concomitant Therapy
The following medications are prohibited during the treatment and follow-up phases (before 
recurrence) of the study (unless utilized to treat a drug-related adverse event):

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.4)

Any concurrent anti-neoplastic therapy (including, but not limited to chemotherapy, 
hormonal therapy, immunotherapy, or radiation therapy), other than those allowed in the 
protocol. 

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5.5.1
Other Anticancer or Investigational Therapies
No other anti-cancer therapies (including non-platinum chemotherapy, radiation, hormonal 
treatment [except Corticosteroids, bisphosphonates, or denosumab], antibody or other 
immunotherapy or other experimental drugs) of any kind will be permitted while the patient is 
participating in the study.
Patients experiencing unacceptable toxicity due to cisplatin may be switched to carboplatin by 
the treating physician after consulting with the Study Chair. Carboplatin should be administered 
weekly at AUC 2, further modifications to the regimen should be discussed with the study chair.
5.5.2
Hormonal Contraception Allowed/Excluded
The use of oral contraceptives is allowed during the study.
6
Study Procedures and Observations
6.1
Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments.  Screening assessments must be performed within 30 
days prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 3 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation.
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.
6.1.1
Pretreatment Period
During the Pre-Treatment Period, subjects are consented and qualified (screened) for the study. 
Informed consent must be obtained before initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for this study. Evaluations performed as 
part of routine care before informed consent can be considered as screening evaluations if done 
within the defined screening period, and if permitted by the site’s institutional review board 
(IRB)/ethics committee (EC) policies. 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening and on Study Day 1 before study treatment administration. The following 
assessments will be conducted before subjects receiving their first dose of nivolumab on this 
protocol:
6.1.1.1 Screening Assessments 
Patients will undergo screening assessments within 30 days before receiving the first dose of 
nivolumab, unless otherwise noted.  Study procedure-related AEs that occur after signing of the 

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Informed Consent Form (ICF) and before administration of nivolumab will also be collected. 
The Screening procedures and assessments must be completed within 30 days prior to the 
Cycle 1 Day 1 Visit, unless otherwise noted. 

Physical examination

Weight

Vital signs

Complete medical history

Baseline conditions assessment

Disease Assessment 

ECOG Performance status 

History of prior treatments and any residual toxicity relating to prior treatment

Concomitant medications and procedures

Biopsy or archived tissue procurement
o
Archived tissue: If no intervening treatment received, adequate tissue available, 
and performed within 90 days of day 1 (cycle 1 day 1) of study treatment; 
otherwise, fresh biopsy required. See Appendix 4.

Complete blood count (CBC) with differential and platelet count (within 14 days of Cycle 1 
Day 1)

Serum chemistry assessment (within 14 days of Cycle 1 Day 1), including:
o
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, total protein, albumin, calcium, phosphorus, magnesium, 
blood urea nitrogen (BUN), creatinine, glucose (fasting), potassium, sodium, 
chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, total cholesterol, 
triglycerides).

Serum or urine pregnancy test within 7 days prior to the start of study drug in pre-
menopausal females.

TSH evaluation (within 14 days of Cycle 1 Day 1)

Urinalysis (within 14 days of Cycle 1 Day 1)

MRI of nasopharynx, face, and neck within 60 days prior to start of study drug. 

Whole body PET-CT of top of head to mid-thigh (preferred) or CT of chest, abdomen, and 
pelvis within 60 days prior to the start of study drug.

Research blood draw: collection of peripheral blood for EBV DNA and correlative biomarker 
studies.

All blood draws may be done within 7 days prior to start of therapy unless otherwise 
specified.  

Contraceptive counseling

Serum pregnancy test (by local laboratory) ≤ 1 days prior to the first day of dosing for 
women of childbearing potential. If the serum pregnancy test results are not available on 
C1D1, a urine pregnancy test can be performed on C1D1 to confirm that the patient is not 
pregnant prior to dosing.

Baseline quality of life assessments
For each subject, the Pre-Treatment Period ends upon receipt of the first dose of study treatment 
or final determination that the subject is ineligible for the study.
The following assessments are not required but highly recommended:

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
Audiogram;

Speech and swallowing consultation with formal assessment by modified barium swallow;

Dental evaluation and counseling in preparation for radiation therapy;

Nutritional evaluation
6.1.2
Treatment Period
During the Treatment Period subjects will receive nivolumab until the period of adjuvant therapy 
is complete, disease progression, the occurrence of unacceptable drug-related toxicity or for other 
reason(s) such as subject withdrawal. Subjects should be instructed to immediately inform the 
principal investigator (PI) of any AEs. Patients will be monitored for AEs from the time the first 
dose of nivolumab is administered through 30 days after the last dose.
Nivolumab will be administered to patients every 2 weeks through the intravenous route. Each 
14-day period of treatment represents 1 cycle, with dosing initiated on C1D1. No dose 
escalation beyond the starting dose is allowed. 
Patients will undergo serial assessments for anti-tumor efficacy and drug safety.  Tumor samples 
will be collected at baseline and after the first cycle of nivolumab at the investigator’s discretion. 
Serial blood sampling will be conducted for longitudinal immunologic assessment (see Appendix 
4). Radiologic scans will be acquired by the investigative site and evaluated locally for patient 
treatment decisions. Patients will be followed with monthly clinical and laboratory assessments 
while on protocol-mandated treatment, as well as routine physical examinations every 3 months 
and scans at the end of treatment and 12 months to assess for disease status for a 1 year period 
following completion of all treatment.
6.1.2.1 Study Procedures 
Table 6.1 summarizes the procedures and assessments to be performed for all patients. Before 
enrolling a patient, all eligibility criteria must be satisfied.

Physical examination

Weight

ECOG performance status

Vital signs (blood pressure, pulse, and temperature)

Disease Assessment

Concomitant medications and procedures

Serum chemistry 

Complete blood count (CBC) with differential and platelet count

Research tissue procurement: collection of biopsy tissue from accessible sites (see 
schedule)

Research blood draw: collection of peripheral blood for EBV DNA and correlative 
biomarker studies (see schedule)

AE monitoring

TSH evaluation

Quality of life assessments (see schedule)

Administration of intravenous (IV) nivolumab
o
72-hour window of scheduled nivolumab administration allowed

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Study visits will be required on the first day of each cycle.
6.1.3
End-of-Treatment Study Procedures
After having received the last dose of nivolumab on this study, all patients will remain in the
study to be followed for safety until the EOT Visit. The EOT Visit should occur 28 (± 7) days
after the last dose of nivolumab. Patients with ongoing SAEs will be followed until either 
resolution or stabilization of the event(s) has been determined. Please see Table 6.1 for details 
of assessments.

Physical examination

Weight

ECOG performance status

Vital signs (blood pressure, pulse, and temperature)

Disease Assessment

Concomitant medications and procedures

Serum chemistry 

Fasting glucose 

Complete blood count (CBC) with differential and platelet count

MRI of nasopharynx, face, and neck. 

Whole body PET-CT (top of head to mid-thigh).

Blood sampling for EBV DNA and exploratory research (see schedule)

AE monitoring

Quality of life assessments (see schedule)

TSH evaluation

Measurable Disease 
6.1.4
Post-treatment/Follow-Up Visits
After completion of all treatment, patients will be followed at 1, 3, 6, and 12 months +/- 1 week 
for up to 1 year or until disease progression.  Please see Table 6.1 for details of assessment.

Physical examination

Weight

ECOG performance status

Vital signs (blood pressure, pulse, and temperature)

Concomitant medications and procedures

Serum chemistry 

Fasting glucose

Complete blood count (CBC) with differential and platelet count

MRI of nasopharynx, face, and neck, if applicable (see schedule)

Whole body PET-CT (top of head to mid-thigh), if applicable (see schedule)

Blood sampling for EBV DNA and exploratory research, if applicable (see schedule)

AE monitoring

Quality of life assessments, if applicable (see schedule)

TSH evaluation

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6.1.5
Long Term/Survival Follow-up Procedures
Survival follow-up information may be collected via telephone calls or medical records review for 
an additional 4 years. Survival and disease status will be collected during this period until 
participant death, withdrawal, or if the participant is lost to follow-up. .
6.1.6
Discontinuation of Therapy
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s non-compliance or simply significant uncertainty on the 
part of the Investigator that continued participation is prudent.  There may also be administrative 
reasons to terminate participation, such as concern about a patient’s compliance with the 
prescribed treatment regimen. 

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Table 6.1
Schedule of Study Procedures and Assessments
Table 6.1 Schedule of Procedures and Assessments
Test/study
Screening
Cycle 1 to 
Cycle 5a
Cycle 6f and 
future cycles
End of 
Treatments
Follow-up 
visitst
Survival 
Follow-upv
Day -30 to -1
Day 1 (+/- 3)
Day 1 (+/- 3)
28 days (+/- 7) 
after last dose
12 month 
Follow-up
48 Month 
Follow-up
Informed consent
X
Baseline conditionsb       
X
Quality of life 
assessmentsc
X
X
X
X
AE assessmentd
X
X
X
X
Xv
Concomitant 
medications and 
procedures
X
X
X
X
X
Treatment/Drug Administrationf
Nivolumab 
X
X
Radiation therapy
X
Cisplatin
X
Clinical proceduresg
Physical examh
X
X
X
X
X
Vital signs
X
X
X
X
X
Medical history
X
X
Disease assessmenti
X
X
X
X
ECOG 
X
X
X
X
X
Measurable diseasej
X
X
X
X
Biopsy or archived 
tissue procurementk
X
X
Laboratory proceduresl
CBC w/ Diffm
X
X u
X
X
X
Blood chemistryn
X
X u
X
X
X
Fasting Glucosen
X
X u
X
X
X
TSH evaluationn
X
X u
X
X
X
Urinalysisn
X
Pregnancy test 
(Serum or urine 
HCG)o
X
Tissue for 
exploratory researchp
X
X

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Table 6.1
Schedule of Study Procedures and Assessments
Table 6.1 Schedule of Procedures and Assessments
Test/study
Screening
Cycle 1 to 
Cycle 5a
Cycle 6f and 
future cycles
End of 
Treatments
Follow-up 
visitst
Survival 
Follow-upv
Day -30 to -1
Day 1 (+/- 3)
Day 1 (+/- 3)
28 days (+/- 7) 
after last dose
12 month 
Follow-up
48 Month 
Follow-up
Blood for exploratory 
researchq
X
X
X
X
X
Imaging proceduresr
Whole body PET-CTr
X
X 
X
MRIr 
nasopharynx/face/ne
ck
X
X
X
a Each 14-day period of treatment will represent 1 cycle and begins from C1D1.
b Baseline conditions assessment 
c As part of efficacy assessments, quality of life by FACT-NP, FACT-Taxane, HHIE-S, and EuroQOL EQ-5D will be administered at 
baseline, at cycle 6, at end of treatment and at all followup visits. Survey’s not available in the patient’s language may be 
administered by the study staff in an interview format with a translator, however failure to obtain any individual quality of life survey 
not available in the patient’s language will not be considered a protocol deviation.
d Toxicity will be assessed by CTCAE v5.0
f There is a 72 hour window of scheduled nivolumab administration. In Dose Schedule 1: Nivolumab will be administered on C1D1 
for priming and then q14 days beginning C2D1, concurrent with chemoradiation, until C5D1. Nivolumab will not be administered on 
C6D1 to allow for any resolution of toxicities. Beginning C7D1, adjuvant nivolumab q14 days will be administered until C12D1. In 
Dose Schedule 2: Nivolumab will be administered on C1D1 concurrent with chemoradiation (no priming), and then q14 days until 
C4D1. Nivolumab will not be administered on C5D1 to allow for any resolution of toxicities. Beginning C6D1, adjuvant nivolumab 
q14 days will be administered until C11D1. In Dose Schedule 3: Nivolumab will not be administered until after completion of 
chemoradiation. Beginning C6D1, adjuvant nivolumab q14 days will be administered until C11D1. Immune-related toxicities should 
be at grade 1 or lower prior to starting a patient on the adjuvant phase of therapy; if not, initiation of the adjuvant phase should be 
delayed until resolution of toxicities.
h Physical Exam includes weight measurements
i Disease-specific criteria (for CRF purposes, e.g.: GU assessment, BR disease Eval, AML-MDS Summary, etc.)
j Measurable disease will be assessed using RECIST 1.1 criteria
k For the baseline tissue collection, if a biopsy was performed within 90 days prior to C1D1, and no intervening treatment was given, 
a repeat biopsy is not required if adequate tumor tissue can be provided. Repeat biopsy will be at the discretion of the investigator, 
and timing will depend on Dose Schedule. In Dose Schedule 1: Tumor tissue post-nivolumab during cycle 1 AND after first week of 
radiation therapy. In Dose Schedule 2 and 3: Tumor tissue after first week of radiation therapy only. See appendix 4 for further 
details. 
l All blood draws may be completed within 7 days prior to start of therapy unless otherwise specified; screening labs must be 
completed within 14 days of Cycle 1 Day 1.
m Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential
n Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, total protein, albumin, 
calcium, phosphorus, magnesium, blood urea nitrogen (BUN), creatinine, glucose fasting), potassium, sodium, chloride, bicarbonate, 
uric acid, LDH, fasting lipid panel (LDL, total cholesterol, triglycerides), thyroid stimulating hormone (TSH).
o Pre-menopausal females: serum or urine pregnancy test within 7 days prior to start of study drug.  Serum pregnancy test by local 
laboratory < 1day prior to C1D1 for women of childbearing potential.  If the serum pregnancy test results are not available on C1D1, 
a urine pregnancy test can be performed on C1D1 to confirm that the patient is not pregnant prior to dosing.
p See Appendix 4 for details on tissue specimen collection and processing. 
q Collection of peripheral blood for correlative biomarkers and peripheral immune changes must be collected with every cycle of 
nivolumab. Blood will also be collected in post-treatment followup to 1 year.
r Imaging with MRI nasopharynx/face/neck and whole body PET-CT will be performed at screening and at end of treatment and at 1 
year followup, with further imaging to be performed as clinically indicated. 

If a whole body PET-CT (top of head to mid-thigh) scan (preferred) or a CT of the chest, abdomen, and pelvis was 
performed within 60 days prior to C1D1, then a repeat scan is not required provided the images are adequate for 
analysis. PET-CT is required after protocol treatment completion.

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
MRI scan of nasopharynx/face/neck required within 60 days prior to C1D1 and after protocol treatment completion.
sAll patients to be followed for safety until the EOT visit. This visit should occur 28 (+/-7) days after the last dose of nivolumab.  
  Patients with ongoing SAEs will be followed until either resolution or stabilization of the event(s) have been determined.
t After completion of all treatment, patient will be followed at 1, 3, 6, 9 and 12 months +/- 1 week for up to 1 year. 
u Fasting lipid panel and TSH blood tests will not be performed on day 8.  Only CBC with differential and blood chemistry tests 
including non-fasting glucose are required on day 8 of Cycles 2, 3, and 4.  
v Survival follow-up information may be collected via telephone calls, and/or review of the medical record, every 3 months for an 
additional 4 years. Survival and disease status will be collected until participant death, withdrawal, or if the participant is lost to 
follow-up.

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6.2
Prohibited Medications
Permitted Therapy 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
Intravitreal injections of vascular endothelial growth (VEGF) inhibitors are permitted if used 
according to the approved ocular indication, such as macular degeneration.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy (or Activity)
7.1.1
Antitumor Effect – Solid Tumors
A secondary measure of response to neoadjuvant therapy in this study will be determined by 
RECIST 1.1 criteria according to the new international criteria proposed by the Response 
Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3):205-216, 2000].  Changes 
in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST v1.1 criteria (or International Workshop on Chronic Lymphocytic Leukemia [IWCLL]).  
RECIST 1.1 will also be used to determine whether the patient has progressive disease in the 
adjuvant portion and follow-up portion of the study in accordance with standard of care 
practices.
7.1.2
Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
Evaluable for objective response
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.)
7.1.2.1 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung).

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All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI.    Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up.
Non-measurable disease (Tumor Markers)
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by e.g. PSA, CA-125, CA19-9, CEA)
7.1.2.2 Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment.
PET-CT
PET-CTs for a given patient should be performed at the same institution and on the same 
scanner if possible.  Patient should fast for at least 6 hours before undergoing scanning and 
measured serum glucose must be < 200 mg/dL.  Patients can be on oral hypoglycemic but not 
insulin.  PET should be obtained 50-70 minutes after tracer injection.  The same amount of 
radioactivity +/- 20% should be injected for a given patient pre- and post- nivolumab treatment. 
Conventional CT
CTs should be performed with cuts of 10 mm or less in slice thickness contiguously.  
Cytology, Histology

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Any effusion that appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between response or stable 
disease or progressive disease.  
7.1.2.3 Response Criteria
Objective Response
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD.  There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis).
Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions.
Evaluation of Best Overall Response (BOR)
The best overall response is the best response recorded from the first day of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.

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Table 7.2
Response Criteria
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this 
Category Also Requires
CR
CR
No
CR
> 4 weeks confirmation
CR
Non-CR/
Non-PD
No
PR
PR
Non-PD
No
PR
> 4 weeks confirmation
SD
Non-PD
No
SD
documented at least once > 4 
weeks from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
* In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression
Duration of Response
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of stable disease
Stable disease is measured from the first day of treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
Metabolic Response
Summarized in Table 7.1 and in reference36.
7.2
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v5.0 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events.
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the 
role of Study Chair.  The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites.
7.3
Definitions of Adverse Events
7.3.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 

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an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.3.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure  as occurring with the same class 
of drugs, or as anticipated from the pharmacological properties of the drug, even though they 
have not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
7.3.2.3 Serious

An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes: 

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
Results in death

Is life-threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe)

Requires inpatient hospitalization or causes prolongation of existing 
hospitalization

Results in a persistent or significant disability/incapacity or substantial disruption 
of the ability to conduct normal life function

Is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 

Potential drug induced liver injury (DILI) is also considered an important medical 
event. 

Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE. 

Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs.
Note: The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-
threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases

Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason).
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs.

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Potential drug induced liver injury is defined as:
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase)
AND
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
7.3.2.4 Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.4
Recording of an Adverse Event
Grade 1-5 adverse events will be entered into OnCore®, whether or not the event is believed to 
be associated with use of the study drug.  Data about these events and their severity will be 
recorded using the NCI CTCAE v5.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:

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Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 
3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
Grade 
4:
Life-threatening consequences; urgent intervention indicated
Grade 
5:
Death related to AE
NONSERIOUS ADVERSE EVENT

Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US 
trial] as part of an annual reporting requirement. 

Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the 
subjects. 
A nonserious adverse event is an AE not classified as serious. 
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. All nonserious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
during the treatment period and for a minimum of 100 days following the last dose of study 
treatment. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
Laboratory Test Abnormalities
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such.
The following laboratory abnormalities should be documented and reported appropriately:

any laboratory test result that is clinically significant or meets the definition of an SAE

any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted

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
any laboratory abnormality that required the subject to receive specific corrective therapy. 
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). 
The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS]
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE.
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
x-rays, and any other potential safety assessments, whether or not these procedures are required 
by the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and 
reported accordingly.
7.5
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
7.6
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board 
(IRB) and, when the study is conducted under an Investigational New Drug Application (IND), to 
the Food and Drug Administration (FDA) if it meets the FDA reporting criteria.

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All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s).
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks.
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 
Multicenter Institutional Studies.
7.7
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to UCSF Institutional Review Board
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
Suspected adverse reaction (as defined in 7.3)
Unexpected (as defined in 7.3)
Serious (as defined in 7.3)
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.

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The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
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
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
Reporting to Pharmaceutical Companies providing Study Drug
All 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:  
SAE Facsimile Number:  

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.

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
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 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 stabilizationIf only limited information 
is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include 
the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization.
The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS 
and any applicable health authority during the conduct of the study including periodic 
reconciliation. 
8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
8.1.1
Primary Endpoint:
The primary objective of this study is to establish the feasibility of completing a combined 
chemoradiation-nivolumab regimen followed by adjuvant nivolumab. Feasibility of completing 
adjuvant phase therapy is a key relevant clinical question in ongoing NPC research, as the 
efficacy of the current standard of care of platinum-based concurrent and adjuvant phase 
chemotherapy is in question but its toxic effects are severe, resulting in frequent early 
discontinuation of adjuvant therapy. Adjuvant nivolumab is likely to be much more tolerable and 
feasible and if feasibility of the program is established, this will open the possibility of testing its 
efficacy in various subsets of patients.
Feasibility of treatment completion: The primary endpoint of the study will be the rate of 
completion of all adjuvant immunotherapy, in comparison to the rate of completion of a standard 
adjuvant cisplatin-based platform. The rate of completion of all adjuvant therapy by patients 
treated at the MTD schedule will be determined and compared to a historical control rate of 
52%. 
8.1.2
Secondary Endpoints
Efficacy:  ORR as assessed by the study investigator by RECIST 1.1 criteria.  The ORR is defined 
as the best overall response (BOR) recorded from the first day of treatment until time of 
assessment.
Safety and tolerability:  Evaluate the number and frequency of Adverse Events (AEs) as 
determined by National   Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0 by 
investigator assessment.

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
To determine the clinical response as judged by the investigator;

To determine the overall response rate from the first day of treatment to 1 year post-
treatment, as determined by RECIST 1.1 criteria;

To determine the locoregional control rate at 1 year post-treatment;

To determine the distant metastasis rate at 1 year post-treatment;

;

To determine the rate of EBV DNA clearance at end of chemoradiation and at 1 year 
post-treatment;
To determine the acute and late toxicity rates according to CTCAE v5.0, including 
immune-related adverse events (AEs);

To assess patients’ quality of life from baseline through 1 year post-treatment;
8.1.3
Correlative Studies
Exploratory studies

To determine the overall survival rate at 5 year post-treatment
When adequate tissue is available, To determine whether PDL1-positive immunohistochemistry 
and novel quantitative assays correlate to clinical outcome;

To determine if the density of infiltrating CD3+ T cells/μm2 correlates to clinical outcome;

To monitor immune changes by flow cytometry in the circulating T cell response to EBV 
antigens;

To compare the change in the circulating T-cell repertoire by TCR sequencing and 
single-cell T-cell profiling;

To quantify treatment-induced changes over time in the circulating T cell immune 
response to EBV using TCR sequencing and enzyme-linked immunospot (ELISPOT) 
assays.
8.2
Determination of Sample Size and Accrual Rate
8.2.1
Sample Size and Power Estimate
We expect the true completion rate of this combined chemoradiation-nivolumab regimen 
followed by adjuvant nivolumab to be 70%, versus the null hypothesis of 50% (the rate of 
completion of a standard adjuvant cisplatin-based platform is 52%). 
Simon's two-stage design will be used to test this endpoint. In the first stage, 22 patients will be 
accrued. If 11 or fewer completions, the study will be stopped. Otherwise, 18 additional patients 
will be accrued for a total of 40 participants.. The null hypothesis will be rejected if 26 or more 
completions are observed in 40 patients. This design yields a type I error rate of 0.05 and power 
of 80% when the true completion rate is 0.7. 
8.2.2
Run-in phase
Six patients will be enrolled for the initial run-in phase, with nivolumab dosing of 240 mg. 
Enrollment will cease until all 6 patients have completed concurrent chemoradiation and 
nivolumab. If 3 or more of the first 6 patients experience grade 3-4 immune related toxicity or 
other DLT during concurrent chemoradiation and nivolumab therapy, then the run-in will restart 
at dose schedule 2 with 6 additional patients. In dose schedule 2, patients will start nivolumab 

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concurrent with chemoradiation and will not start nivolumab prior to chemoradiation. If 3 or more 
of the first 6 patients experience grade 3-4 immune related toxicity or other DLT during 
concurrent chemoradiation and nivolumab at dose schedule 2, then the dose schedule will be 
changed to dose schedule 3 and the run-in will restart at dose schedule 3 with 6 additional 
patients. In dose schedule 3, patients will start nivolumab in the adjuvant phase only and will not 
receive nivolumab before or during chemoradiation, and the toxicity of nivolumab will be 
assessed during the adjuvant phase. No dose escalation or reduction will be allowed in the run-
in phase. Dose modifications of nivolumab are not permitted from the standard dose of 240 mg 
every 14 days.
The run-in will cease when 4 or more patients have completed chemoradiation and nivolumab 
therapy at the same nivolumab dose schedule without experiencing grade 3-4 toxicity or other 
DLT (this will be considered the maximally tolerated dose), or alternatively, if 3/6 patients have 
experienced grade 3-4 toxicity at dose schedule 3 during administration of adjuvant nivolumab 
(in which case the entire study will terminate). Therefore, a minimum of 6 patients and a 
maximum of 18 patients will be enrolled in the run-in phase. 
DLT criteria are grade ≥3 immune-related adverse events, need to hold nivolumab for >28 days 
due to toxicity, and for patients receiving concurrent nivolumab with chemoradiation, inability to 
complete chemoradiation or need to hold chemoradiation for >3 days due to immune-related 
toxicity.
8.2.3
Expansion phase
Sample size for the expansion cohort will be a minimum of 9 patients and a maximum of 22 
patients (Simon’s two-stage design, see statistical plan).
The 6 patients treated at the final dose from the run-in cohort will be included in statistical 
comparisons. This would yield a minimum total sample size of 15 patients, and a maximum 
sample size of 28 patients treated at the MTD schedule across the run-in and expansion 
phases, assuming 6 patients treated at the MTD schedule in the run-in and 22 patients treated 
at MTD schedule in the expansion cohort.)
The rate of completion of all adjuvant therapy by patients treated at the MTD schedule will be 
determined and compared to a historical control rate of 52%.
8.2.4
Statistical plan
Simon's two-stage design37 will be used to test the primary endpoint for the phase II study. The 
null hypothesis that the completion rate is 0.5 will be tested against a one-sided alternative 0.7. 
In the first stage, 15 patients will be accrued (including 6 patients at MTD schedule from the run-
in phase). If there are 7 or fewer completions in these 15 patients, the study will be stopped. 
Otherwise, 13 additional patients will be accrued for a total of 28 patients accrued in the 
expansion phase. The null hypothesis will be rejected if 18 or more completions are observed in 
28 patients. This design yields a type I error rate of 0.09 and power of 80% when the true 
completion rate is 0.7. 
We propose that the final decision about the direction of future strategy and additional 
expansion studies should be made based on careful analysis of subpopulations with particular 
attention to feasibility, toxicity, and observed immodulatory responses.

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8.2.5
Replacement Policy
A maximum of 40 evaluable patients will be enrolled in the study using a Simon’s two-stage 
design for the primary endpoint. An evaluable patient will be defined as one who receives any 
amount of study drug. If a patient drops out of the study before receiving nivolumab, a 
replacement patient will be allowed. 
8.2.6
Accrual estimates
A maximum of 40 evaluable patients will be enrolled in the study using a Simon’s two-stage 
design  for the primary endpoint. At UCSF, approximately 20 NPC patients are treated with 
definitive radiation therapy yearly and we plan to partner with other high accruing centers. Thus 
we expect to be able to complete accrual to this study within a reasonable time frame. 
It is anticipated that accrual will be completed in approximately 18 months, with each patient 
treated for approximately 6 months and then followed for 12 months after completing protocol 
therapy. The total study duration is expected to be about 3 years. If a longer duration of clinical 
follow-up is desired (such as 2 or 3 years), the timeline would lengthen by an additional year but 
that follow-up is at the discretion of the treating investigators and not mandated by the study.
8.3
Interim Analyses and Stopping Rules
There is no interim analysis planned. There is a safety run-in which will be evaluated prior to 
continuing into the expansion phase. Safety of the study will be continuously assessed by the PI 
and the data safety monitoring committee (DSMC). The study may be stopped early if there is 
deemed to be an unacceptable safety risk by either the PI or the DSMC.
8.4
Analysis Plans
8.4.1
Analysis Population
Primary endpoint will determined in patients who receive the study drug for a minimum of 1 
cycle (or 14 days) at the MTD schedule.
8.4.2
Primary Analysis (or Analysis of Primary Endpoints)
Rate of completion of all adjuvant immunotherapy is defined as completion of all post-
chemoradiation cycles of nivolumab, per protocol.
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints)
Objective Response Rate (ORR): The ORR is based on the best overall response (BOR) 
recorded from the first day of treatment until time of assessment. The frequency and 
percentages of patients with a best overall response rate of complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) will be determined.  
Locoregional Control (LRC) Rate: Duration of LRC will be calculated as 1+ the number of 
days from  the first day of treatment to time of documented locoregional clinical or radiographic 
relapse, progression or death due to any cause. For patients who continue treatment post-
progression, the date of clinical or radiographic relapse or progression will be used for analysis. 
The Kaplan-Meier analysis will be used to calculate the mean LRC rate with 95% confidence 
interval.

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Distant Metastasis (DM) Rate: Time to DM will be calculated as 1+ the number of days from  
the first day of treatment to documented clinical or radiographic progression at a distant 
metastatic site, or death due to any cause. Pathologic confirmation is not required to document 
the date of distant progression. For patients who continue treatment post-progression, the date 
of clinical or radiographic progression will be used for analysis. The Kaplan-Meier analysis will 
be used to calculate the mean DM rate with 95% confidence interval.
8.4.4
Other Analyses/Assessments
Correlative and exploratory analyses will be performed as described in 8.1.3.
8.5
Evaluation of Safety
Safety analyses will be performed for all patients having received at least one dose of study 
drug.  The study will use the NCI CTCAE v5.0.
The safety population will consist of all subjects who receive any amount of study treatment. 
Safety will be assessed by evaluation of AEs. All safety analyses will be performed using the 
safety population. Adverse event terms recorded on the CRFs will be mapped to preferred terms 
using the Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and 
relationship to study treatment will be assessed by the investigator. Severity grade will be defined 
by the National Cancer Institute (NCI) CTCAE v5.0. Listings of AEs will be provided.
Separate tables will present the following by dose group and study phase:
• All treatment-emergent AEs
• Treatment-emergent AEs by CTCAE grade
• Grade 3 or greater treatment-emergent AEs
• Treatment-related, treatment-emergent AEs
• Dose-limiting toxicity AEs
• Serious treatment-emergent AEs
• Treatment-emergent AEs with an outcome of death
• Treatment-emergent AEs leading to discontinuation of nivolumab.
• Treatment-emergent AEs resulting in interruption or reduction or delay of nivolumab.
8.6
Study Results
Study results will be submitted to drug manufacturer (BMS), as well as presented at national or 
international oncology conferences, and published in peer-reviewed scientific journals.

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9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with Good Clinical 
Practice (GCP), as defined by the International Conference on Harmonisation (ICH), WHO and 
local directives including all applicable regulatory requirements.
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval before initiation of the study. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF Institutional Review Board.  Prior to obtaining IRB approval, the protocol 
must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee 
and by the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments 
must be approved by the IRB prior to implementation.  
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
Informed consent will be obtained by personnel who are qualified by education, training, and 
experience to perform their respective tasks and that the study will not use the services of study 
personnel for whom sanctions have been invoked or where there has been scientific misconduct 
or fraud. Signed, dated Informed Consent will be obtained from each of the participants. 
Investigators will ensure that subjects--or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives--are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. The approved informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki. The informed consent will include 

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relevant safety information regarding dose/schedule of investigational products and any other 
drugs/procedures. BMS and health authorities will have direct access to study records. The 
informed consent will disclose BMS support of the study (e.g., study drug, funding).
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites.
9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.

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The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 2 Data and Safety Monitoring Plan for a Multicenter Institutional Study (For Run-In 
Phase) and Data and Safety Monitoring Plan for Multicenter Institutional Study (Phase 2 or 3 
Institutional Study) – For Dose Expansion Phase for additional information.
9.8
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed 
to discuss risk assessment.  
The following issues will be discussed as appropriate: 

Enrollment information

Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information)

Protocol violations

Other issues affecting the conduct of the study
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 

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physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.
9.9
Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
9.10
Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF IRB. Prior to implementing this protocol at the participating sites, approval for the 
UCSF IRB approved protocol must be obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 

Curriculum vitae and medical license for each investigator and consenting professional 

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
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.

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10
Protection of Human Subjects
10.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
10.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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

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Appendix 2 Multicenter Institutional Studies
Data and Safety Monitoring Plan for a Multicenter Institutional Study (For Run-In Phase)
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 

Review of patient data in each cohort. 

Review of serious adverse events.

Approval of dose escalation by DSMC Chair or Vice Chair.

Real time monitoring (depending on study accrual).

Minimum of a yearly regulatory audit.
2.
Monitoring and Reporting Guidelines
The data is monitored by a DSMC monitor once a month as patients are enrolled and includes 
all visits through the first post-Dose Limiting Toxicity (DLT) period.  At the time of dose 
escalation, a written report will be submitted to the DSMC Chair outlining the cohort dose, all 
adverse events and serious adverse event reports, and any Dose Limiting Toxicity as described 
in the protocol.  The report will be reviewed by the DSMC Chair or qualified alternate and written 
authorization to proceed or a request for more information will be issued within two business 
days of the request.  The report is then reviewed at the subsequent DSMC meeting.  In the 
event that the committee does not concur with the DSMC Chair’s decision, further study accrual 
is held while further investigation takes place.  
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and patient safety and discuss each patient’s treatment at weekly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  For 
each dose level, the discussion will include the number of patients, significant toxicities in 
accordance with the protocol, doses adjustments, and observed responses.
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:

Enrollment information.

Cohort updates (i.e., DLTs).

Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol violations.

Other issues affecting the conduct of the study.

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Dose Level Considerations
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each patient scheduled to be 
enrolled at a site.  Dose level assignments for any patient scheduled to begin treatment must be 
confirmed by the UCSF Coordinating Center via e-mail.
If a Dose Limiting Toxicity (DLT) arises in a patient treated at a participating site, all sites must 
be notified immediately by the UCSF Coordinating Center.  The Study Chair has 1 business day 
(after first becoming aware of the event at either the UCSF Coordinating Center or the 
participating site) in which to report the information to all participating sites.  If the DLT occurs at 
a participating site, the local investigator must report it to the UCSF Coordinating Center within 
one business day, after which the UCSF Coordinating Center will notify the other participating 
sites.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites as per the 
study-specific guidelines.The data (i.e., redacted copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the monitoring 
visits in order for the DSMC to monitor the participating site’s compliance with the protocol and 
FDA guidelines.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All clinically significant adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of study drug, will be 
entered into OnCore®, UCSF’s Clinical Trial Management System.  
Adverse Events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse Events are further given an assignment of attribution or 
relationship to treatment or medical procedure.  Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure.

Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.

Unlikely – The adverse event is doubtfully related to the investigational agent(s) 
or medical procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or medical procedure.

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All adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Coordinating Center’s Site Committee.  All clinically significant adverse events 
must be reported to the UCSF Coordinating Center by the participating sites within 1 
business days of becoming aware of the event.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the 
adverse event to the administration of the study drug(s) from the UCSF Coordinating 
Center and the participating sites.
3.2
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according 
to the following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with the UCSF IRB Regulations 
and Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a 
Med Watch form.
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be 
reported to the UCSF Coordinating Center within 10 business days of becoming aware 
of the event or during the next scheduled conference all, whichever is sooner.  The 
SAEs are reviewed and monitored by the Data and Safety Monitoring Committee on an 
ongoing basis and discussed at DSMC meetings, which take place every six weeks.  
The date the SAE was sent to all required reporting agencies will be documented in 
OnCore®.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or 
definitely related either to the investigational drug or any research related procedure, the 

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Study Chair at the UCSF Coordinating Center or the assigned designee must be notified 
within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of this notification.  The 
reporting procedure is by communication via e-mail, with a copy of the e-mail to the 
DSMC Manager.
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Study Chair at the 
UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased 
rate is identified. The report will indicate if the incidence of adverse events observed in the 
study is above the range stated in the Investigator’s Brochure or package insert.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail 
and the IRB must be notified via 10 business days via an iRIS Reporting Form.
Data and Safety Monitoring Committee Contacts:
Thierry Jahan, MD (DSMC Chair)
UCSF HDFCCC
San Francisco, CA 94158
DSMC Monitors 
UCSF HDFCCC
San Francisco, CA 
94143

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Data and Safety Monitoring Plan for Multicenter Institutional Study
(Phase 2 or 3 Institutional Study) – For Dose Expansion Phase 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 

Review of subject data

Review of suspected adverse reactions considered “serious”

Monthly monitoring (depending on study accrual)

Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three).
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes.
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate:

Enrollment information 

Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information)

Protocol violations

Other issues affecting the conduct of the study
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site’s compliance with the protocol, patient safety, and to verify data entry.
Adverse Event Review and Monitoring

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Adverse Event Monitoring
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites.
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail.
Increase in Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in 
the Investigator Brochure or package insert.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC 
must receive a formal letter within 10 business days and the IRB must be notified.
Data and Safety Monitoring Committee Contacts:
DSMC Chair: Thierry Jahan, MD
DSMC Monitors 
Phone: 
Email:
Address: 
UCSF
San Francisco, CA 94115
UCSF Helen Diller Family 
Comprehensive Cancer Center
San Francisco, CA 94115
*  DSMP approved by NCI 09/February2012
Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND)
Purpose

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This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) 
in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iRIS:

UCSF IRB approvals for initial submission of application, all modifications, and 
continuing annual renewals

Current and prior approved protocol versions with signed protocol signature page(s)

UCSF IRB approval letters and Informed Consent Form(s) (ICF)

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event Reporting

Protocol Violations and Single Patient Exception (SPE) Reports to the UCSF IRB with 
supporting fax documentation
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial) or Investigator Brochure

Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)

Patient handouts

Screening/enrollment log

Data and Safety Monitoring Committee (DSMC) monitoring reports

OnCore® Case Report Form (CRF) completion manual

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Documents Filed in Regulatory Binder:

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e., Collaborative Institute Training Initiative 
(CITI), etc.)

Site Initiation Visit (SIV) minutes and correspondence with participating site(s).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center

Serious Adverse Event (SAE) reports to IRB and sponsor.

BMS pregnancy reporting forms, if applicable

MedWatch reporting to FDA and sponsor

Delegation of Authority Form

Drug Destruction Standard Operating Procedure (SOP)

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
2.  Additional Essential Documents for Multicenter Trials for the Coordinating Center 
(filed in Regulatory Binder or OnCore)

Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for 
the Participating Site(s)

For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational 
New Drug Application

Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). 

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s)

Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting 
fax documentation for Participating Site(s)

Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s)

Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s)

For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, 
lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating 
Site(s)

Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan 
(if an outside CRO is used for the study)

Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the 
Participating Site(s)
27 April 2012

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3. Required Regulatory Documents for Sub-sites Participating in a UCSF Investigator 
Initiated Multicenter Trial (Checklist)
Directions: 
1)  Fax the documents listed below to the UCSF Coordinating center 
or 
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found
1572
  PI and Sub investigators:
CV and Medical license 
Financial disclosure form
NIH or CITI human subject protection training certification
  Laboratories  
CLIA and CAP
CV of Lab Director and Lab Licenses
Laboratory reference ranges
Local Institutional Review Board 
  IRB Approval letter
  Reviewed/Approved documents

Protocol version date:  
___________

Informed consent version date:  ___________

Investigator Brochure version date:  ___________

HIPAA 
  Current IRB Roster
Other 
  Delegation of Authority Log 

Include NIH or CITI human subject protection training certificates or GCP training 
certification
  Pharmacy

Drug destruction SOP and Policy
  Protocol signature page 
  Executed sub contract
27.apr.2012

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Appendix 4 Specimen and Blood Collection
A. For tissue analysis:
Immunohistochemistry (IHC) analyses will be performed on the following diagnostic biopsy 
tissue specimens. 
1.
Baseline biopsy tissue (nasopharyngeal tumor tissue, core biopsy) is required to be 
submitted. Fresh nasopharyngeal tumor tissue obtained from a biopsy within 90 days 
prior to C1D1 is preferred but archival blocks of tissue are acceptable.
Acquisition of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens 
in paraffin blocks (blocks preferred) or at least 15 slides, with an associated pathology 
report, is required. 
Criteria for fresh tissue collection: 1) exophytic mass or tumor, or 2) amenable to cup 
forceps or ultrasound guided core biopsy. At least three cores should be obtained. A fine 
needle aspirate is not acceptable. 
If tumor may not be able to obtained from the primary site safely at all initial and 
subsequent tissue collection timepoints, then tissue from another anatomic area (e.g. 
core biopsies of neck) should be substituted. Every effort should be made to biopsy at 
baseline and subsequently from the same tissue site, e.g. always from the primary 
nasopharyngeal tumor or always from the neck.
2.
1 – 2 further tumor samples should be collected (if deemed appropriate by the 
investigator) as follows:
a)
Dose Schedule 1: (1) After the first cycle of nivolumab AND (2) after the first 
week of radiation therapy. 
b)
Dose Schedule 2 and 3: (1) After the first week of radiation therapy. 
See above for specifications of criteria for tissue collection. These samples should be collected 
from the same site that was biopsied at baseline.
See Laboratory Manual for processing and submission of paraffin-embedded tissue.
Formalin Fixed Paraffin Embedded (FFPE) tissue is stored at room temperature. These tissue 
samples may be batch-shipped to the UCSF Cancer Immunotherapy Lab for analysis.
B: For blood analyses:  
All patients will have 4 (four) 10mL green top tubes and a purple top EDTA of blood specimens 
collected at baseline, at cycle 7 day 1 prior to initiation of adjuvant-phase nivolumab (whether 
nivolumab is actually given or not), and at 1 year followup.  The purple top tube of blood will be 
reserved for EBV DNA testing in addition to immunologic correlative analyses. 
Other than these three time points, 4 (four) 10mL green top tubes of blood specimens will be 
collected on day 1 and before administration of each nivolumab cycle. In addition,  4 (four) 

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10mL green top tubes of blood specimens will be collected at time of treatment discontinuation, 
and 4 (four) 10mL green top tubes of blood specimens will be collected at each regular post-
treatment follow-up (at 1, 3, 6, 9 months post-treatment).
# of green + purple top tubes
Baseline or before treatment on C1D1
4 (40mL total) + 1 (10mL total)
Day 1 of each cycle (before administration of study therapies)
4 (40mL total)
Day 1 of cycle 7 
4 (40mL total) + 1 (10 mL total)
Treatment discontinuation 
4 (40mL total)
Follow-up at 1, 3, 6, 9 months post-treatment
4 (40mL total)
Follow-up at 12 months post-treatment 
4 (40mL total) + 1 (10 mL total)
See Laboratory Manual for processing and submission of blood samples. 
Blood samples should be stored at room temperature no longer than 24 hours. 
Peripheral blood mononuclear cells (PBMCs) and plasma should be isolated within 24 hours of 
blood collection and stored at -80°C. These samples may be batch-shipped to the UCSF 
Cancer Immunotherapy Lab for analysis.
C. Specimens saved for future research:
Excess blood and tissue samples remaining after all study procedures have been 
performed will be banked for future research. Samples will be stored indefinitely, and will 
be located at the Cancer Immunotherapy Lab at UCSF:
Cancer Immunotherapy Lab (CIL)
University of California, San Francisco
San Francisco, CA 94143
The patient consent form will include a specimen banking consent section. Study participants 
will be able to withdraw consent for specimen banking at any time by sending written 
correspondence to the principal investigator.

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Appendix 5 Management Algorithms 
As detailed in Investigator Brochure v15.0 for nivolumab (BMS-936558/MDX1106), appendix 3 Management Algorithms. 

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