Multicenter Phase II Study of Nivolumab in Previously Treated Patients With Recurrent and Metastatic Nasopharyngeal Carcinoma
Phase: PHASE2
Conditions: Nasopharyngeal Nonkeratinizing Carcinoma, Recurrent Nasopharynx Carcinoma, Stage III Nasopharyngeal Carcinoma AJCC v7, Stage IV Nasopharyngeal Carcinoma AJCC v7, Stage IVA Nasopharyngeal Carcinoma AJCC v7, Stage IVB Nasopharyngeal Carcinoma AJCC v7, Stage IVC Nasopharyngeal Carcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)

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NCI 9742 / MC1471: Multicenter Phase II Study of Nivolumab in Previously Treated 
Patients with Recurrent and Metastatic Nasopharyngeal Carcinoma 
 
 
Amendment 4  
 
 
# 
Section 
Revision 
1. 
Throughout 
protocol 
The title page and headers of the document have been updated to the new 
NCI version date.   
2. 
6.2 
Addition of more specific guidelines for cardiac toxicities including the 
stipulations listed below : 
 
o Add on study evaluation of cardiac function including EKG and 
ECHO cardiogram for any patients with a history of CHF or at risk 
because of underlying cardiovascular disease or exposure to 
cardiotoxic drugs as clinically indicated.  
o For patients with evidence of CHF, MI, cardiomyopathy, or myositis 
cardiac evaluation including lab tests and cardiology consultations as 
clinically indicated including EKG, CPK, troponin, ECHO 
cardiogram.  
o Drug modification table for cardiomyopathy myocarditis should be 
included in the appropriate section  
▪ Drug will be held for grade 2 cardiac dysfunction pending 
evaluation 
▪ Drug will be permanently discontinued for grade  3 or 4 cardiac 
dysfunction and grade 2 events that do not recover to baseline or 
that reoccur 
▪ Treatment with steroids as clinically indicated  
▪ Add the table as follows in the treatment  modification and AE 
management section 
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) + 
Ipilimumab Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for 
signs and symptoms of CHF, ischemia, arrhythmia or myositis.  
Obtain history EKG, CK (for concomitant myositis), CK-MB.  
Repeat troponin, CK and EKG 2-3 days.  If troponin and labs 
normalize may resume therapy.   If labs worsen or symptoms 
develop then treat as below.  Hold pending evaluation  
Grade >2 
with 
suspected 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out 
MI and other causes of cardiac disease.  Cardiac Monitoring.  
Cardiac Echo.  Consider cardiac MRI and cardiac biopsy.  

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myocarditis 
Initiate high dose methylprednisolone.  If no improvement 
within 24 hours, add either infliximab, ATG or tacrolimus. 
Consult algorithm for more details.  Resume therapy if there is 
a return to baseline and myocarditis is excluded or considered 
unlikely. 
Grade >2 
with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to 
nearest Cardiac Transplant Unit).  Treat as above.  Consider 
high dose methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has 
not been established.  Since this toxicity has caused patient deaths, an 
aggressive approach is recommended.   
 
 
3. 
7.1 
The CAEPR and corresponding Condensed Risk List for Nivolumab is 
updated to version 2.2 dated November 15, 2016 from version 2.1 dated 
December 11, 2015.  The revisions are as follow: 
 
• Added New Risk:  
• Less Likely: Skin and subcutaneous tissue disorders - Other 
(Sweet's Syndrome) 
• Rare but Serious: Immune system disorders - Other (GVHD in 
the setting of allotransplant); Myositis; Nervous system 
disorders - Other (encephalitis)  
• Also Reported on BMS-936558 Trials But With Insufficient 
Evidence for Attribution: Immune system disorders - Other 
(autoimmune thrombotic microangiopathy) 
 
• Increase in Risk Attribution: 
• Changed to Less Likely from Rare But Serious: Infusion 
related reaction 
• Changed to Rare but Serious from Also Reported on BMS-
936558 Trials But With Insufficient Evidence for Attribution: 
Pericarditis 
 
• Deleted Risk:  
• Also Reported on BMS-936558 Trials But With Insufficient 
Evidence for Attribution: Alkaline phosphatase increased; 
Arthritis; CPK increased; Encephalitis infection; Endocrine 
disorders - Other (autoimmune thyroiditis); Endocrine 
disorders - Other (hypopituitarism); Enterocolitis; 

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Hepatobiliary disorders - Other (autoimmune hepatitis); 
Investigations - Other (CRP increased); Investigations - Other 
(eosinophil count increased); Investigations - Other (thyroxine 
free increased); Investigations - Other (tri-iodothyronine free 
decreased); Nervous system disorders -  Other (autoimmune 
neuropathy); Renal and urinary disorders - Other (nephritis); 
Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (interstitial lung disease); Respiratory, 
thoracic and mediastinal disorders - Other (lung infiltration); 
Stroke; Wheezing; White blood cell decreased 
 
• Provided Further Clarification:  
• The following footnote #7 was added: “Complications 
including hyperacute graft-versus-host disease (GVHD), some 
fatal, have occurred in patients receiving allo stem cell 
transplant (SCT) after receiving BMS-936558 (Nivolumab, 
MDX-1106).  These complications may occur despite 
intervening therapy between receiving BMS-936558 
(Nivolumab, MDX-1106) and allo-SCT.” 
 
 

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TITLE:   
Multicenter Phase II Study of Nivolumab in Previously Treated Patients with 
Recurrent and Metastatic Nasopharyngeal Carcinoma 
 
 
Corresponding Organization: P2C-MN026 / Mayo Clinic Cancer Center P2C 
 
Principal Investigator: 
Brigette B.Y. Ma 
Department of Clinical Oncology  
Prince of Wales Hospital 
Shatin, NT, Hong Kong SAR 
Telephone: (852) 26321042 
Telefax: (852) 26487097 
Email: brigette@clo.cuhk.edu.hk 
 
 
Participating “Rostered” Organizations  
P2C-IL057 / University of Chicago Comprehensive Cancer Center P2C 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistican: 
Nathan R. Foster 
 
Mayo Clinic Cancer Center 
 
Telephone: (507) 284-5051 
Email: foster.nathan@mayo.edu 
 
NCI-Supplied Agent:  Nivolumab (BMS-936558, MDX-1106, and ONO-4538) (NSC #748726) 
 
IND #:  126146 
IND Sponsor:  DCTD, NCI 
 

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Protocol Type: / Version / Version Date: 
Original / Version 1 / December 8, 2014  
Resubmission / Version 2 / March 17, 2015 
Resubmission / Version 3/ April 10, 2015 
Resubmission / Version 4/ June 2, 2015  
 
Resubmission / Version 5 / November 19, 2015 
Resubmission / Version 6 / Amendment 1 / December 22, 2015 
Resubmission / Version 7 / Amendment 2 / March 14, 2016 
Resubmission / Version 8 / Amendment 3 / March 18, 2016 
Resubmission / Version 9 / Amendment 4 / January 6, 2017 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length= 4 weeks 
Treatment 
 Nivolumab 3mg/kg IV every 2 weeks until 
disease progression1 
Event Monitoring 
PD* at any time 
Unacceptable adverse events 
         
Event  
 
       
Patient refusal 
 
 
Monitoring 
 
 
 
 
*unless otherwise specified 
Registration 

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TABLE OF CONTENTS 
TITLE: .............................................................................................................................................1 
SCHEMA .........................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
1.  
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
1.3 
Correlative Objectives .............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Nasopharyngeal Carcinoma and Programmed Cell Death Protein 1 
Signaling ..................................................................................................................7 
2.2 
Nivolumab..............................................................................................................10 
2.3 
Rationale ................................................................................................................13 
2.4 
Correlative Studies .................................................................................................13 
3. 
PATIENT SELECTION ....................................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................18 
4. 
REGISTRATION PROCEDURES (Rostered Protocol Model)........................................18 
4.1 
Investigator and Research Associate Registration with CTEP ..............................18 
4.2 
Site Registration .....................................................................................................19 
4.3 
Patient Registration ................................................................................................21 
4.4 
Screening and General Guidelines .........................................................................22 
5. 
TREATMENT PLAN ........................................................................................................22 
5.1 
Agent Administration.............................................................................................22 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................23 
5.3 
Duration of Therapy and Criteria for Study Discontinuation ................................23 
5.4 
Duration of Follow Up ...........................................................................................24 
5.5 
Criteria to Resume Treatment ................................................................................25 
5.6 
Treatment of Nivolumab-Related Infusion Reactions ...........................................26 
5.7 
Treatment Beyond Progression ..............................................................................28 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................29 
6.1 
Guideline for Nivolumab Related Adverse Events in General ..............................29 
6.2 
Guideline for Specific Nivolumab Related Adverse Events..................................30 
6.3 
Guideline for Steroid Use ......................................................................................35 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................35 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................36 

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7.2 
Adverse Event Characteristics ...............................................................................40 
7.3 
Expedited Adverse Event Reporting ......................................................................40 
7.4 
Routine Adverse Event Reporting .........................................................................42 
7.5 
Secondary Malignancy...........................................................................................43 
7.6 
Second Malignancy ................................................................................................43 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................43 
8.1 
CTEP IND Agent(s) ...............................................................................................43 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................45 
9.1 
Integral Correlative Laboratory Studies .................................................................45 
9.2 
Exploratory/Ancillary Correlative Studies ............................................................47 
10. 
STUDY CALENDAR .......................................................................................................51 
11. 
MEASUREMENT OF EFFECT........................................................................................54 
11.1 
Schedule of Evaluations .........................................................................................54 
11.2 
Definitions of Measurable and Non-Measurable Disease .....................................54 
11.3 
Guidelines for Evaluation of Measurable Disease .................................................55 
11.4 
Measurement of Effect ...........................................................................................57 
11.5 
Antitumor Effect – Immune Response Criteria .....................................................60 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................61 
12.1 
Data Reporting .......................................................................................................61 
12.2 
Collaborative Agreements Language .....................................................................63 
13. 
STATISTICAL CONSIDERATIONS...............................................................................65 
13.1 
Study Design/Endpoints.........................................................................................65 
13.2 
Sample Size/Accrual Rate ......................................................................................67 
13.3 
Stratification Factors and Subset Analyses for Primary Endpoint.........................67 
13.4 
Analysis of Secondary Endpoints ..........................................................................67 
13.5 
Adverse Event Stopping Rule ................................................................................68 
13.6 
Inclusion of Women and Minorities ......................................................................69 
14. 
STUDY STATUS UPDATES AND STUDY CLOSURE ................................................71 
14.1 
Definitions of Study Status Changes .....................................................................71 
14.2 
Responsibility for Filing Protocol Status Update Forms .......................................73 
REFERENCES ..............................................................................................................................73 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................77 
APPENDIX B: BIOASSAY TEMPLATES ..................................................................................78 
APPENDIX C: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, 
AND SKIN ADVERSE EVENTS .....................................................................................91 

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APPENDIX D: CARD FOR STUDY PARTICIPANTS ..............................................................99 
 
 

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1.  OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Objective tumor response to nivolumab in patients with previously treated recurrent 
and/or metastatic nasopharyngeal carcinoma (NPC) based on RECIST criteria version 
1.1. 
 
1.2 
Secondary Objectives 
 
1.2.1 Tumor response to nivolumab based on immune-related response criteria (IRC). 
 
1.2.2 Duration of response.  
 
1.2.3 Progression-free survival and overall survival. 
 
1.2.4 Safety and tolerability. 
 
1.3 
Correlative Objectives 
 
1.3.1 To investigate the effect of nivolumab on tumor burden by analyzing the clearance of 
plasma Epstein-Barr virus (EBV) DNA during the first 4-6 weeks of treatment.   
 
1.3.2 To investigate the association between treatment outcome and immunological markers:  
a) (Mandatory) Intratumoral expression of PD-1 and PD-L1 in archived NPC tissues 
b) (Mandatory) Serum absolute lymphocyte count at baseline and post-treatment 
c) Plasma cytokine levels at baseline and serially during the first 8 weeks of treatment. 
d) (Optional) Expression of PD-1 in CD8+ T cells in tumor infiltrating lymphocytes 
(TIL) at baseline. 
 
1.3.3 To investigate functional MRI sequences as an early predictor of response to nivolumab. 
(Optional only at CUHK) 
 
2. BACKGROUND 
 
2.1 
Nasopharyngeal Carcinoma and Programmed Cell Death Protein 1 Signaling 
 
Non-keratinizing nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia where 
the incidence reaches its peak in regions such as Hong Kong, Guangzhou province of China and 
Singapore.  It is the 7th most common cancer in Hong Kong and in 2008, over 84,000 incident 
cases were diagnosed worldwide.  Despite the high rate of cure of AJCC stage I-II NPC, overall 
50,000 people died of NPC in 2002 alone worldwide.  This is because 20% of patients who 
present with metastatic disease have a median overall survival (OS) of only 12 to 15 months 

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despite chemotherapy.  For the 50% of patients who present with locoregionally advanced (stage 
III-IVB) disease, 30% will develop distant metastases following modern chemoradiotherapy.  
Immunotherapy for EBV associated NPC – our experience: EBV is ubiquitous in 
undifferentiated NPC in endemic regions, and EBV latent infection plays a vital role in NPC 
tumorigenesis.  Expression of the oncogenic EBV latent proteins has been shown to modulate the 
tumor inflammatory microenvironment and abolish host immune response [1].  In order to 
overcome the immune-escape mechanisms of the EBV-associated NPC, strategies such as 
adoptive EBV-specific cytotoxic T-cell therapy and active immunization with EBV vaccines 
have been evaluated in patients with recurrent NPC [2-4].  Significant tumor regressions have 
been reported in a few patients.  However, the labor-intensive and costly nature of these 
technologies has limited the broader application of these therapies in the clinics.  Based on the 
collaborative effort by some of our investigators from the Chinese University of Hong Kong 
(CUHK) with the University of Birmingham, a new, recombinant modified vaccinia Ankara-
based vaccine that encodes EBV-specific tumor antigens has been developed and evaluated in a 
phase 1 study in NPC patients in Hong Kong [5].  Our work underscores our capability in and 
commitment to research in immunotherapy for NPC.  
Targeting programmed cell death protein 1 (PD-1) signaling in cancer: In a healthy host, 
PD-1 signaling in T cells regulates immune responses to minimize damage to bystander tissue 
and prevents the development of autoimmunity by promoting tolerance to self-antigens [6].  PD-
1 is a trans-membranous protein receptor member that is highly expressed on activated T cells.  
It has 2 known ligands, PD-ligand 1 (B7-H1 or CD274, which is expressed on tumor, antigen-
presenting cells APCs and dendritic cells) and PD-L2 (B7-DC or CD273).  PD-L1 is 
overexpressed in many cancers and has been linked to poor prognosis [6].  Membranous PD-L1 
is thought to be more relevant prognostically than cytosolic PD-L1.  Inhibition of PD-1 signaling 
can induce tumor regression in vivo, increase effector T-cell function and cytokine production 
theoretically by reactivating PD-1 expressing TILs.  
PD-1 signaling pathway in NPC: To provide a proof-of-concept for the current study, our Prof 
K.W. Lo and his team from the Chinese University of Hong Kong (unpublished confidential 
data) has generated some preliminary data on PD-1 signaling in NPC:  
Figure 1, a and b: Expression of PD-L1 and PD-L2 in NPC models. PD-L1 is up-regulated in 
EBV-positive NPC cell lines, and expressed in over 70% of the 20 NPC samples analyzed.   
Figure 2 & 3 a and b: A significant number of PD-1+ cells in tumor infiltrating lymphocytes 
and also circulating CD8+ T cells can be found in NPC patients.  By IHC staining, we also 
detected PD-1-expressing infiltrating lymphocytes in NPC primary tumors. PD-L2 is also 
overexpressed in some NPC tumors (data not shown) but its significance is uncertain. 

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2.2 
Nivolumab 
 
2.2.1 Mechanism of Action 
 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for human programmed death-1 
(PD-1, cluster of differentiation 279 [CD279]) cell surface membrane receptor [7].  PD-1 is a 
negative regulatory molecule that is expressed transiently following T-cell activation and on 
chronically stimulated T cells characterized by an “exhausted” phenotype.  Nivolumab binds to 
cynomolgus monkey PD-1 but not mouse, rat, or rabbit molecules.  Clinical activity of 
nivolumab has been observed in patients with melanoma, non-small cell lung cancer (NSCLC), 
and renal cell carcinoma (RCC).   The combination of nivolumab and ipilimumab (anti-cytotoxic 
T lymphocyte associated antigen-4 [anti-CTLA-4]) in a phase 1/2 trial showed markedly 
enhanced clinical activity with an acceptable safety profile in melanoma patients [8].   
 
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer.  An emerging picture 
suggests that endogenous immune responses can mediate effective tumor regression and/or 
improved survival even in patients with large volume tumors resistant to other forms of therapy.  
Some of the unique features of this type of therapy, based largely on experience in advanced 
melanoma, include:  improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be delayed or occur after 
radiographic disease progression; combinations of immune modulators with enhanced or novel 
activities (in the example of ipilimumab and nivolumab); and toxicity that is almost exclusively 
immune or inflammatory in nature.  It is not yet clear what factors determine responses and 
which components of the immune system are needed for this to occur.  It seems likely that both 
memory helper and effector cells would be needed to sustain long-term responses. Increasing 
emphasis has been placed on understanding the relationships of the tumor, cellular infiltrate, and 
immunologic milieu surrounding each tumor. 
 
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell co-
stimulatory receptors that include Ig super family member CD28, CTLA-4, inducible co-
stimulator (ICOS), and B and T lymphocyte attenuator (BTLA) [7].  PD-1 is transiently but 
highly expressed on activated T cells functioning to limit immune effectors at the site of 
activation.  Chronic stimulation may prevent the re-methylation of the PD-1 gene leading to 
continuous expression and characterizes a state of “exhausted” T cells that lose function and 
proliferative capacity while enhancing a suppressive tumor microenvironment.  PD-1 may act 
together with other T-cell modulating molecules, including CTLA-4, TIM-3, lymphocyte-
activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-1), cytokines, 
and transforming growth factor beta (TGF-beta).   
 
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also known as B7-H1 
or CD274, expressed on tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) and 
PD-L2 (also known as B7-DC or CD273, expressed on endothelial cells).  The interaction of PD-
1 with PD-L1 and PD-L2 results in negative regulatory stimuli that down-modulate the activated 

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T-cell immune response through SHP-1 phosphatase. 
 
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) and 
cardiomyopathy (BALB/c).  In transplantable tumor models that expressed PD-1 and LAG-3 on 
tumor-infiltrating CD4+ and CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured 
most mice of established tumors that were largely resistant to single antibody treatment [9].  
Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual 
knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, 
leading to eventual lethality. 
 
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses based 
on OS in many tumors, including melanoma[10], renal [11-13], esophageal [14], gastric [15], 
ovarian [16], pancreatic [17], lung [18], and other cancers [7]. 
 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus (HCV) 
and human immunodeficiency virus (HIV).  In these cases, high expression levels of PD-1 were 
found in viral-specific CD8+ T cells that also display a non-responsive or exhausted phenotype.  
Non-responsive PD-1-high T cells were observed in simian immunodeficiency virus (SIV) 
infection in rhesus macaques.  Treatment of SIV-infected macaques with an anti-PD-1 mAb (3 
mg/kg x4) resulted in decreased viral loads and increased survival along with expanded T cells 
with increased T-cell functionality.   
 
2.2.2 Nonclinical Development of Nivolumab 
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab alone 
was well tolerated [7].  Combination studies have highlighted the potential for toxicity when 
combined with ipilimumab, MDX-1408, and BMS-986016.  Nivolumab bound specifically to 
PD-1 (and not to related members of the CD28 family such as CD28, ICOS, CTLA-4, and 
BTLA) with a Kd = 3.06 nM.  A surrogate rat anti-mouse PD-1 antibody (4H2) was derived and 
expressed as chimeric IgG1 murine antibody.  Antitumor activity was seen for several tumor 
models, including colon carcinoma and fibrosarcoma. 
 
2.2.3 Clinical Development of Nivolumab 
 
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic chemotherapy, 
other immunotherapy (such as ipilimumab), anti-angiogenesis therapy, and targeted therapies in 
completed and ongoing BMS-sponsored clinical trials in NSCLC, melanoma, RCC, 
hepatocellular carcinoma (HCC), gastrointestinal (GI) malignancies including microsatellite 
instability (MSI) in colorectal cancer, and triple-negative breast cancer (TNBC) with an 
expanding group of indications [7].  In addition, two investigator-sponsored trials (ISTs) of 
nivolumab in combination with a peptide vaccine in melanoma are being conducted in the 
adjuvant setting and advanced disease.  
 
Seven nivolumab studies were conducted in Japan, including six studies in advanced solid 
tumors and recurrent or unresectable stage III/IV melanoma sponsored by Ono Pharmaceuticals 
Co. Ltd., and one IST in recurrent or advanced platinum-refractory ovarian cancer.   

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2.2.4 Pharmacokinetics 
 
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, with dose-
proportional increases in maximum serum concentration (Cmax) and area under the concentration-
time curve from time zero to infinity (AUC0-∞), with low to moderate inter-subject variability 
observed at each dose level [7].  Clearance of nivolumab is independent of dose in the dose range 
(0.1 to 10 mg/kg) and tumor types studied.  Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body weights.  The mean 
terminal elimination half-life of BMS-936558 is 17 to 25 days consistent with the half-life of 
endogenous IgG4.   
 
2.2.5 Efficacy 
 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 mg/kg dose was 
chosen for expanded cohorts.  Among 236 patients, objective responses (ORs) (complete or 
partial responses [CR or PR]) were seen in NSCLC, melanoma, and RCC.  ORs were observed at 
all doses [19].  Median OS was 16.8 months across doses and 20.3 months at the 3 mg/kg dose.  
Median OS across all dose cohorts was 9.2 months and 9.6 months for squamous and non-
squamous NSCLC, respectively [20].  In the RCC cohort, median duration of response was 12.9 
months for both doses with 5 of the 10 responses lasting ≥ 1 year [21].   
 
In an advanced melanoma phase 1 study, nivolumab and ipilimumab were administered IV every 
3 weeks for 4 doses followed by nivolumab alone every 3 weeks for 4 doses (concurrent 
regimen) [8].  The combined treatment was subsequently administered every 12 weeks for up to 
8 doses.  In a sequenced regimen, patients previously treated with ipilimumab received 
nivolumab every 2 weeks for up to 48 doses.  In the concurrent regimen (53 patients), 53% of 
patients had an OR at doses 1 mg/kg nivolumab and 3 mg/kg ipilimumab, with tumor reduction 
of 80% or more (modified World Health Organization [mWHO] criteria).  In the sequenced-
regimen (33 patients), the objective response rate (ORR) was 20%. 
 
In a phase 1 study of nivolumab plus platinum-based doublet chemotherapy (PT-doublet) in 
chemotherapy-naïve NSCLC patients, 43 patients were treated with nivolumab + PT-doublet 
[22].  No dose-limiting toxicities (DLTs) were reported and total/confirmed ORRs were 43/33%, 
40/33%, and 31/31% in nivolumab/gemcitabine/cisplatin, nivolumab/pemetrexed/cisplatin, and 
nivolumab/carboplatin/paclitaxel arms, respectively. 
 
2.2.6 Toxicology 
 
A maximum tolerated dose (MTD) of nivolumab was not defined [23].  Serious adverse events 
(SAEs) occurred in 32 of 296 patients (11%) similar to the immune-related inflammatory events 
seen with ipilimumab:  pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis (with 
noted pulmonary toxicity resulting in 3 deaths. Renal failure, symptomatic pancreatic and DM, 
neurologic events, and vasculitis have also been reported.).   In combination with ipilimumab in 
the concurrent-regimen group [8], grade 3 or 4 treatment-related events were noted in 53% of 
patients.  Skin rash represents the majority of these events.   

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2.2.7 Pharmacodynamics/Biomarkers 
 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with ipilimumab 
with the use of IHC staining and pharmacodynamics changes in the peripheral-blood absolute 
lymphocyte count [8].  With PD-L1 positivity defined as expression in at least 5% of tumor cells, 
biopsy specimens from 21 of 56 patients (38%) were PD-L1–positive.  Among patients treated 
with the concurrent regimen of nivolumab and ipilimumab, ORs were observed in patients with 
either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor samples (9 of 
22).  In the sequenced regimen cohorts, a higher number of overall responses was seen among 
patients with PD-L1–positive tumor samples (4 of 8 patients) than among patients with PD-L1–
negative tumor samples (1 of 13) suggesting the possibility that these tumors have higher 
response rates to the combination.  The relationship between PDL-1 expression and responses 
may not be present in patients treated with the combination.  Tissue expression of PDL-2, 
interferon-γ (IFN- γ), IDO, and T cell CD8+ are of current interest.  Until more reliable data 
based on standardized procedures for tissue collection and assays are available, PD-L1 status 
cannot be used to select patients for treatment at this time. 
 
2.3 
Rationale 
Hypothesis for current study:  
 
a) Based on our preliminary preclinical data as generated from NPC cell lines and patient’s 
tissues (see above), we hypothesize that NPC inhibits the activity and proliferation of 
tumor-specific CD8+ T cells via PD-L1/PD-1 inhibitory receptor pathways, thereby 
contributing to the evasion of host’s immune-surveillance in EBV-positive NPC.  
 
b) Inhibition of PD-1 signaling may thus reactivate PD-1 expressing tumor-infiltrating 
lymphocytes and induce tumor regression. 
 
2.4 
Correlative Studies 
Rationale for using plasma EBV DNA as a surrogate marker of tumor burden in NPC 
 
Investigators at the CUHK pioneered the use of quantitative real-time-PCR to quantitate the level 
of plasma EBV DNA [24, 25].  It is a powerful prognostic marker which closely reflects tumor 
burden in NPC [26, 27].  Our investigators have also reported the kinetics of plasma EBV DNA 
during radiotherapy and surgery for NPC.  An initial surge followed by a rapid drop in plasma 
EBV DNA level can be observed, with an estimated half-life of around 3.8 days (range 2.2-4.4 
days) [25, 28].  Wang et al. found that the plasma EBV DNA clearance during the 1st 4 weeks of 
chemotherapy was prognostic, such that patients with a half-life of < 8 days were more likely to 
respond than those with longer half-life values [29].  Our experience with plasma EBV DNA 
half-life in a phase II study of a AKT inhibitor, MK-2206, suggested that patients with a drop in 
plasma EBV DNA levels were more likely to remain on treatment for 6 months or more, 
compared with those who did not experience with a drop in level [30].  
In a recently published study which compared the detection capability of this marker across 
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was found to have one of the highest detection sensitivity (93%) [31].  This study also serves to 
harmonize the plasma EBV DNA assay in preparation for an international NRG study (NRG-
HN001, NCT02135042).  This study aims to individualize adjuvant chemotherapy using plasma 
EBV DNA in locoregionally advanced NPC, and involves investigators from the NRG, Chinese 
University of Hong Kong and Taiwan.  
Rationale for measuring PD-L1 expression in tumor and immune cells  
Topalian et al. found that high level of tumoral expression of PD-L1 was associated with higher 
response duration in nivolumab-treated patients [23].  But this was not observed in a nivolumab-
ipilimumab study in melanoma [8].  Our preliminary work has shown that 15/20 NPC tumors 
(75%) expressed PD-L1, thus we plan to validate this marker in this study.  The dynamic nature 
of tumoral PD-L1 expression may be dependent upon changes in the tumor microenvironment, 
and is closely correlated with the degree of immune infiltrate in tumors [32].  More recently in a 
phase 1b study of another PD-1 inhibitor, MK-3475 in recurrent head and neck squamous 
carcinoma, patients with tumors that overexpressed PD-L1 above an arbitrary cut-off point 
(Roche/Genentech assay used, defined as PD-L1 expression in > 1% of both tumor and adjacent 
immune cells) had higher tumor response rate (45.5%) than those who did not (11.4%) [33].  
Based on these data, therefore, PD-L1 expression in the TILs in tumors will also be measured in 
this study.  A recently published study has shown that the EBV oncogenic protein, latent 
membrane protein-1 (LMP-1) could up-regulate PD-L1 through STAT3, AP-1 and NF-κB 
pathways in NPC cell lines.  IFN-γ could also up-regulate PD-L1 independent of but synergetic 
with LMP1 in vitro [42].  
Rationale for measuring absolute lymphocyte count 
 
A study on ipilimumab has shown that an absolute lymphocyte count (ALC) of > 1,000/mL and 
an increase in ALC around 2 months after treatment may predict clinical benefit [12].  But this 
was not observed in a nivolumab-ipilimumab study [8]. Further validation in this study is 
warranted. 
 
Rationale for the functional MRI study  
Discussed in section 9.2.2.1. 
 
 
 

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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Age ≥ 18 years old 
 
3.1.2 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.3 Histologically or cytologically confirmed non-keratinizing nasopharyngeal carcinoma 
(NPC) that has recurred at locoregional and/or distant sites.  Note: Patients with local 
recurrence at the bony skull-base as the only site of index disease are excluded since such 
lesions are difficult to measure radiologically.  Patients with locoregional recurrence 
without distant metastases must have undergone radical radiotherapy previously. 
 
3.1.4 Measurable disease according to the RECIST criteria (version 1.1), as defined in section 
11 for the evaluation of measurable disease. 
 
3.1.5 Received one or more lines of chemotherapy, which must include prior treatment with a 
platinum agent and must not be amenable to potentially curative radiotherapy or surgery.  
 
3.1.6 Archived or fresh tumor sample available.  Willingness to donate blood and tissue for 
mandatory correlative research studies. (see Section 9). 
 
3.1.7 ECOG performance status of 0, 1 or 2 (see Appendix A). 
 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
 
• 
Absolute neutrophil count 
> 1.5 x 109/L 
• 
Platelets 
≥ 100 x 109/L 
• 
Hemoglobin 
≥ 8.0 g/dL 
 
• 
Serum alanine aminotransferase 
(ALT; serum glutamate-pyruvate 
transferase, [SGPT]),  or Serum 
aspartate aminotransferase (AST) 
where available at the center) 
        
< 2.5 x upper limit of normal (ULN), 
OR < 5 x ULN in the presence of liver 
metastases.   
• 
Serum total bilirubin                
< 2 x ULN (except patients with 
Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL) 
 
• 
Serum creatinine  
< 1.5 x ULN 
 
 

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3.2 
Exclusion Criteria 
 
3.2.1 Any of the following: 
• Chemotherapy ≤ 4 weeks prior to registration  
• Radiotherapy ≤ 4 weeks prior to registration  
• Nitrosoureas or Mitomycin C ≤ 6 weeks prior to registration 
• Those who have not recovered from adverse events (to grade ≤ 1 in severity) due to 
agents administered more than 4 weeks earlier.  Prior palliative radiotherapy to bone 
metastases ≤ 2 weeks prior to registration (i.e., prior palliative radiotherapy to bone 
metastases is allowed if it is performed > 2 weeks prior to registration.) 
 
3.2.2 Prior investigational agents ≤ 4 weeks prior to registration. 
 
3.2.3 Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways. 
 
3.2.4 Known brain metastases or leptomeningeal metastases.  Note:  symptomatic, and/or if they 
require immunosuppressive doses of corticosteroids (e.g., >10 mg/day prednisone or 
equivalents) for at least 2 weeks prior to study drug administration.  Patients with treated 
brain metastases, who are deemed clinically stable and without radiological progression on 
PET, MRI or CT scan performed ≤ 8 weeks of study entry, are not excluded. Note:  Primary 
nasopharyngeal cancers that directly invade the skull base and extend into the infratemporal 
fossa (e) are not regarded as brain metastases and are not excluded.   
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nivolumab. 
 
3.2.6 History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.8 Any of the following: 
• Pregnant women  
• Nursing women 
• Men or women of childbearing potential who are unwilling to employ adequate 
contraception 
 
Note: Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with nivolumab, breastfeeding should be discontinued 
if the mother is treated with nivolumab.  Women of childbearing potential and men must use 
two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to 

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study entry and for the duration of study participation.  They must adhere to contraception for 
a period of 31 weeks after the last dose of nivolumab.” 
 
3.2.9 For patients with unknown HIV status at the time of enrollment, HIV serology must be tested 
during screening.  Patients who are tested positive for HIV could be included if there is an 
adequate CD4 count (>350/µl) on a stable regimen of HAART with no detectable or minimal 
viral burden, and no active infections.    
 
3.2.10 For patients with unknown hepatitis B virus surface antigen (HbsAg) status, they must be 
tested during study screening.  Patients who are tested positive test for HbsAg are excluded if 
they have inadequately controlled hepatitis B and/or Child-Pugh Class B or C cirrhosis.  
However, patients with adequately controlled hepatitis are not excluded from the study if 
they satisfy all of the following criteria: (i) must be receiving a nucleoside analog anti-viral 
drug for 3 or more months, and (ii) have a serum HBV DNA level of less than 100 IU/ml via 
polymerase chain reaction quantification assays prior to enrollment.  
3.2.11 For patients with unknown hepatitis C virus ribonucleic acid (HCV antibody) status, they 
must be tested during study screening.  Patients who are tested positive for HCV antibody are 
excluded from the study if they have inadequately controlled hepatitis C and/or Child-Pugh 
Class B or C cirrhosis.  Patients with adequately controlled hepatitis are not excluded from 
the study as defined by having undetectable level of serum HCV antibody level prior to 
enrollment.  Patients who are currently on interferon or other anti-HCV therapy may be at 
risk of developing anemia and neutropenia from such therapy, therefore will be excluded 
from study.  
 
3.2.12 Active autoimmune disease or history of autoimmune disease that might recur, which may 
affect vital organ function or require immune suppressive treatment including systemic 
corticosteroids.  Note:  These include but are not limited to patients with a history of immune 
related neurologic disease,  multiple sclerosis, autoimmune (demyelinating)  neuropathy, 
Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, 
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, 
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), 
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the 
risk of recurrence or exacerbation of disease.  Patients with vitiligo, endocrine deficiencies 
including thyroiditis managed with replacement hormones including physiologic 
corticosteroids are eligible.  Patients with rheumatoid arthritis and other arthropathies, 
Sjögren’s syndrome and psoriasis controlled with topical medication and patients with 
positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be 
evaluated for the presence of target organ involvement and potential need for systemic 
treatment but should otherwise be eligible. 
 
3.2.13 Patients 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 (precipitating event). 
 

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3.2.14 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.  Patients 
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 (e.g., contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted. 
 
3.2.15 Evidence of active or acute (i.e. current, or recent within 4 weeks prior to registration) 
diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which 
are known risk factors for bowel perforation.  Patients with abdominal carcinomatosis, a 
history of non-recent intra-abdominal abscess, or a history of non-recent GI obstruction 
should be evaluated for the potential need for additional treatment before coming on study. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES (ROSTERED PROTOCOL MODEL) 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to 
renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.nih.gov. 
 

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4.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all 
physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all 
staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual 
re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account is needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, and is critical to the conduct of this study, including 
document access, patient enrollment, and clinical data submission. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please contact 
the CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov. 
 
4.1.3 For Questions and Support 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk: pmbregpend@ctep.nci.nih.gov. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please contact 
the CTEP Registration Help Desk: ctepreghelp@ctep.nci.nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit all required regulatory documents 
(including any protocol specific documents) to the CTSU Regulatory Office before they can 
be approved to enroll patients. 
 
The CTSU Regulatory Office tracks receipt of these documents in the CTSU Regulatory 
Support System (RSS), reviews for compliance, and transmits site approval data to CTEP. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are 
not required to submit separate IRB approval documentation to the CTSU Regulatory Office 
for initial, continuing, or amendment review.  However, sites must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate their 

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intention to open the study locally.  The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office for compliance in the RSS.  The Signatory site may be 
contacted by the CTSU Regulatory Office or asked to complete information verifying the 
participating institutions on the study.  Other site registration requirements (i.e., laboratory 
certifications, protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per protocol 
instructions. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the #9742 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based on 
person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol organization 
in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and password 
• Click on the Protocols tab in the upper left of your screen  
• Click on the ETCTN link to expand, then select [Phase 2 Consortia], followed by 
[P2C-MN026], and protocol #9742 
• Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.  (Note: For sites under the CIRB initiative, IRB 
data will automatically load to RSS.) 
 
4.2.2 Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory 
Office, where they will be entered and tracked in the CTSU RSS. 
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone:  1-866-651-2878 
Fax:  215-569-0206 
 
E-mail:  CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
4.2.3 Checking Site Registration Status 
 
Sites can check the status of their registration packets by querying the Site Registration sub 
tab of the members’ section of the CTSU Web site.  (Note: Sites will not receive formal 
notification of regulatory approval from the CTSU Regulatory Office.) 
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Regulatory tab at the top of your screen. 

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• Click on the Site Registration sub tab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: If possible, please allow three working days for site registration approval before 
attempting to enroll your first patient. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange and 
with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is available 
and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to Theradex 
as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the CTSU web site as a tool to verify 
eligibility. 
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 

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website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://theradex.com/CTMS/Downloads.aspx. This link to 
the Theradex website is also on the CTSU website OPEN tab. For questions about the use of 
IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7802 or Theradex main 
number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
Screening and General Guidelines 
 
Following registration, patients should begin protocol treatment ≤ 21 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does 
not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible. After the consent form is signed, refer to section 10 ‘Study Calendar’ for screening 
procedures.  Standard contrast CT will be done for assessing non-local recurrences. MRI will 
be used for assessing local recurrence.  If dual PET and contrast CT is used to assess non-
local recurrences at baseline, all subsequent radiological assessments must include a PET-
CT. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the patient's malignancy. 
 
5.1.1 Nivolumab 
 
Nivolumab is given every 2 weeks on day 1 and day 15 (± 1 days), in a 4-week cycle, at a 
dose of 3mg/kg intravenously.  
 
Patients may be dosed no less than 13 days from the previous dose of drug. 
 
The dosing calculations should be based on the actual body weight.  If the patient’s weight 
on the day of dosing differs by >10% from the weight used to calculate the original dose, the 
dose must be recalculated.  All doses should be rounded to the nearest milligram.  Dose 
rounding based on institutional guidelines is not preferred.  There will be no dose 
modifications allowed.   
Nivolumab is to be administered as a 60-minute IV infusion (± 10 minutes), using a 
volumetric pump with a 0.2/1.2 micron in-line filter at the protocol-specified dose.  The drug 
can be diluted with 0.9% normal saline for delivery but the total drug concentration of the 

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solution cannot be below 0.35 mg/mL.  It is not to be administered as an IV push or bolus 
injection.  At the end of the infusion, flush the line with a sufficient quantity of normal saline.  
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
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 [7]. 
 
Nivolumab is a full human monoclonal antibody and infusion reactions, including high-grade 
hypersensitivity reactions, following administration of nivolumab are uncommon [7]. Pre-
medications are not routinely given.  
 
Growth factors (e.g. granulocyte colony stimulating factor, erythropoietin) are not allowed 
during the study.  
 
Supportive measures such as anti-emetics (e.g., metoclopramide, tropisetron, granisetron) 
and other pre-medications which have been mentioned in this protocol will be allowed. 
 
5.3 
Duration of Therapy and Criteria for Study Discontinuation 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 
• 
Disease progression (unless the investigator judges that the patient is eligible for 
continuing beyond progression as stated in section 5.7), 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
• 
Unacceptable adverse event(s) which include the following (see also section 6 and 
specific algorithms in Appendix C): 
 
a) Any grade 4 events except as noted in item ‘h’ below. 
 
b) Grade 3 drug-related autoimmune or inflammatory events including uveitis, 
pneumonitis, diarrhea, colitis, neurologic adverse events, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation except 
as noted in item ‘h’ below: 
 
c) 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 

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re-treatment period OR requires systemic treatment. 
 
d) Patients requiring > two dose delays for the same type of event (of grade 2 
severity or above) should go off protocol therapy, unless the study doctor 
thinks that it is in the patient’s best interest to remain in the study. The study 
doctor should also consult the Principal Investigator before continuing study 
treatment.   
 
e) Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the investigator, presents a substantial clinical risk to the 
subject with continued study drug dosing  
 
f) Tumor assessments should continue as per protocol even if dosing is 
interrupted.  Any patients who require additional immune suppressive 
treatment beyond steroids should go off study treatment 
 
g) Any dosing interruption lasting > 6 weeks, with the following exceptions:   
Patients being tapered after high dose corticosteroids over one month followed 
by a two-week observation period will be allowed an additional two weeks to 
restart treatment ( a maximum  eight week interruption).  Dosing interruptions 
> 6 weeks that occur for non-drug-related reasons may be allowed if approved 
by the Investigator.  Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the Principal Investigator must be consulted. 
 
h) The following exceptions do NOT require permanent study discontinuation:  
- 
Any other grade 3 non-skin, drug-related AE (other than grade 3 immune 
mediated event) lasting < 7 days including fatigue. 
 
- 
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 replacements does not require 
treatment discontinuation.  
 
- 
Grade 3 or 4 amylase or lipase abnormalities that are not associated with 
diabetes mellitus (DM), associated liver or gall bladder inflammation 
clinical manifestations of pancreatitis and which decrease to 0 Grade 0 
may resume study treatment when resolved.   
 
5.4 
Duration of Follow Up 
 
Patients will be followed for a maximum of 3 years from study entry or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  The frequency and procedure 
of follow-up is determined at the discretion of the doctor, or according to institutional 
practice.   

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5.5 
Criteria to Resume Treatment 
 
5.5.1 General Criteria for Restarting Nivolumab: 
 
Some patients may continue to benefit from treatment, maintaining or improving responses 
after progression including those treated with steroids. 
 
Restarting applies only to grade 2 events and some grade 3 events (skin rash and thyroiditis). 
The section should emphasize stopping treatment and starting steroids earlier to obtain 
resolution with the possibility for restarting rather than waiting for higher grade events. 
 
For non-autoimmune or non-inflammatory events patients may resume treatment with study 
drug when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following 
exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue 
• Evaluation to exclude any additional immune mediated events endocrine, GI, and 
liver / pancreas function as clinically indicated must be made prior to restarting.  
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, 
must have resolved to baseline before treatment is resumed. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than 
the next scheduled time point per protocol.  However, if the treatment is delayed past the next 
scheduled time point per protocol the treatment should resume at the earliest convenient 
point that is within the six week delay period.  
 
If treatment is delayed for > 6 weeks, (> 8 weeks for patients on a steroid taper), the patient 
must be permanently discontinued from study therapy, except as specified in Section 5.3 
(Duration of Therapy). 
 
It should be emphasized that if adverse event occurs which requires treatment with steroids, 
it is preferable to withhold nivolumab and start steroids earlier to obtain resolution with the 
possibility for restarting nivolumab, rather than just waiting for higher grade events. 
 
5.5.2 Restarting Nivolumab in Patients Treated with Corticosteroids 
 
Grade 2 events must resolve to < Grade 1 before considering retreatment.  
 
All patients treated with steroids for grade 2 events should have nivolumab withheld until 
resolution to < Grade 1 for at least 2 weeks following complete removal from steroid 
treatment except for maintenance replacement doses for adrenal insufficiency (preferably no 
greater than 10mg prednisone equivalent daily).   
 
All patients treated with steroids for grade ≥ 3 events should have nivolumab discontinued.  

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Patients with grade 3 thyroiditis and skin rash may continue therapy, as for grade 2 events 
with resolution and stable replacement treatment. 
 
Patients with hepatitis, pancreatitis, pneumonitis, and colitis are at risk for exacerbation with 
retreatment if there is residual inflammation and should resolve to Grade 0 or baseline before 
retreatment.  Baseline can mean the initial grade i.e. grade <1 where permitted on study. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses only of 
corticosteroids. Please note that grading and for hypophysitis with symptoms of headache, 
visual or neurologic changes or radiologic evidence of pituitary enlargement and other CNS 
events such as aseptic meningitis or encephalitis should be considered grade 3 events.  
 
New immune related events or exacerbation of existing events during steroid treatment or 
taper suggest the presence of ongoing immune activation and should require permanent 
discontinuation of nivolumab.  
 
A patient who is treated with steroids, evaluated, and found to not have an autoimmune or 
inflammatory event requiring steroid treatment, may be restarted if asymptomatic off steroids 
for 2 weeks and other restarting criteria are met.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, ACTH, TSH and T4 must be drawn if clinically feasible  
to document baseline function and distinguish the pituitary from peripheral organ 
dysfunction and later from steroid (or thyroid)  treatment associated  ACTH ( or TSH)  
suppression.  Steroids should be started prior to obtaining results based on clinical 
indications.  
 
5.6 
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, urticaria, 
angioedema, 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 NCI CTCAE version 4.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as medically appropriate: 
 
5.6.1 For Grade 1 Symptoms 
(Mild reaction; infusion interruption not indicated; intervention not indicated) 
 
Remain at bedside and monitor subject until recovery from symptoms.  Infusion rate may be 
slowed.  If the infusion is interrupted, then restart the infusion at 50% of the original infusion 

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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.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
at least 30 minutes before additional nivolumab administrations, slowing infusion rate as 
above. 
 
5.6.2 For Grade 2 Symptoms   
(Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; close observation for recurrence and 
treatment medications may need to be continued for 24-48 hours).   
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor 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 (acetaminophen) (or paracetamol) 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. 
 
5.6.3 For Grade 3 or Grade 4 Symptoms 
(Severe reaction), Grade 3 symptoms: prolonged [i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, 
pulmonary infiltrates]).Grade 4 symptoms: (life threatening; pressor or ventilator support 
indicated).  
 
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of normal saline, and 
treat the subject as follows.  Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed.  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 (e.g., appearance of a 

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localized or generalized pruritis within 1 week after treatment), symptomatic treatment may 
be given (e.g., oral antihistamine, or corticosteroids). 
 
• Please note that late occurring events including isolated fever and fatigue may represent 
the presentation of systemic inflammation.  Please evaluate accordingly.  
 
 
5.7 
Treatment Beyond Progression 
 
A minority of subjects treated with immunotherapy may derive clinical benefit either delayed 
responses, stable disease, or increased overall survival despite initial evidence of progressive 
disease (PD) with nivolumab or combination treatment.   
 
Patients may be permitted to continue treatment beyond initial RECIST 1.1-defined PD 
occurring during the initial induction period (up to 12 weeks), as long as they meet all of the 
following criteria (see section 5.7.1 below).  Patients are allowed to continue treatment for 
one additional cycle (4 weeks) and then be reassessed.    
 
5.7.1 Criteria for Continuing Treatment Beyond Progression 
  
1) No more than 4 new lesions (excluding new brain metastases), with the total sum of 
the longest diameter (SHORT diameter for LN) cannot exceed  40% of the initial sum 
including new lesions   
2) Patients must be clinically stable with no change in performance status due to disease 
progression 
3) No indication for immediate alternative treatment (such as radiotherapy).  
4) Patient [assessed by the investigator] is showing clinical benefit and tolerates study 
drug.  The assessment of clinical benefit should take into account whether the subject 
is clinically stable or deteriorating and likely or unlikely to receive further benefit 
from continued treatment.  
5) The time of progression is noted from the first assessment that exceeds standard 
criteria 
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a short 
axis of at least 15 mm).  Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except for pathological 
lymph nodes, which must have an increase in short axis to at least 15 mm).  
 
All decisions to continue treatment beyond initial progression must be documented in the 
study record and are a part of an agreement with DCTD, NCI.   
 
For statistical analyses: Subjects who continue treatment beyond first progression (as 
determined by the initial investigator-assessed, RECIST 1.1-defined progression) will be 
considered to have investigator-assessed ‘progressive disease’ at the time of the initial 

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progression event. However, if they subsequently experience a CR or PR they may be 
designated as a ‘delayed response’ for the purposes of determining ORR and thus, in the final 
analysis, be counted as a responder for the two-stage design. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
No dose modifications are allowed in this protocol.  Nivolumab can be ‘continued’, ‘delayed’, 
‘withheld’ or ‘permanently discontinued’.  
 
See Appendix C to the protocol for toxicity management algorithms which include specific 
treatment guidelines.  These algorithms should be followed unless there are specific clinical 
circumstances which the treating physician indicates variations or alternative treatment is 
needed.  
 
6.1 
Guideline for Nivolumab Related Adverse Events in General 
 
ALL NON-
IMMUNOLOGIC 
EVENTS* 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 OR baseline Resume at same dose level. 
Grade 3 
Hold* until ≤ Grade 1 continue at investigator discretion 
Grade 4 
Off protocol therapy 
* Not agent related,  OR agent-related but non-immunologically mediated 
Recommended management:  As clinically indicated 
 
ALL 
IMMUNOLOGIC 
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 level. 
Grade 3 
 Off protocol therapy (exceptions noted in 5.3)  
Grade 4 
Off protocol therapy 
Recommended management:  As clinically indicated  
 
 
 

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6.2 
Guideline for Specific Nivolumab Related Adverse Events 
 
Skin Rash and Oral 
Lesions 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose * 
Grade 2 
Hold* until ≤ 1 Grade resolved.  Consider steroid treatment if > 7 days. 
Resume at same dose level.  
Grade 3 
Hold* until ≤ Grade 1.  Consider steroid treatment.  
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/pemphigoid.  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.   
Recommended management:  AE management guidelines 
 
Liver Function: 
ALT, AST, total 
bilirubin  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue nivolumab and monitor liver enzymes as per protocol.  
Grade 2 
Hold until ULN or baseline.  Resume at same dose level. Consider 
steroid treatment  > 7 days 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
Continuation of nivolumab during active immune-mediated hepatitis may exacerbate the 
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. 
Recommended management:  see Hepatic AE  management algorithm (Appendix C) 
 
 
 

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Diarrhea/ Colitis  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold until Grade 0 or baseline.  No change in dose 
Grade 2 
Hold until Grade 0 or baseline.  Consider steroid treatment if lasting > 7 
days, if condition does not improve within a reasonable time frame, the 
patient should be withdrawn from study if this is in the best interest of 
the patient as judged by the investigator.   
Grade 3 
Off protocol therapy. 
Grade 4 
Off protocol therapy 
See GI AE Algorithm for management of symptomatic colitis.  
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution.  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 
inflammatory bowel disease.  
Recommended management:  see GI AE management Algorithm (Appendix C) 
 
Pancreatitis 
Amylase/Lipase*  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose until grade 0 
Grade 2 
Hold until Grade 0.  Resume at same dose level if asymptomatic 
Grade 3** 
Hold until Grade 0.  Resume at same dose level if asymptomatic. 
Patients who develop symptomatic pancreatitis or diabetes mellitus 
should be taken off treatment 
Grade 4** 
Patients who develop symptomatic pancreatitis or diabetes mellitus 
should be taken off treatment 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes 
mellitus and diabetic ketoacidosis.  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 (Appendix C). * In sites where lipase analysis is not 
readily available, monitoring with amylase level will suffice. **Grade 3 or 4 amylase or lipase 
abnormalities that are not associated with diabetes mellitus (DM), associated liver or gall 
bladder inflammation clinical manifestations of pancreatitis and which decrease to Grade 0 may 
resume study treatment when resolved.   
 
 

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Pneumonitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and resolution to ≤ Grade 0 or baseline.  
Resume no change in dose. Consultation with pulmonary and/or 
infectious disease (ID) specialist is recommended.    
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 steroids are required.  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
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. 
Recommended management:  See Pulmonary Adverse Event Management Algorithm 
(Appendix C) 
 
 
Other GI, Nausea-
Vomiting  
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose.  
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level after resolution to ≤ 
Grade 1.  If recurs after resuming nivolumab, evaluate for gastritis 
duodenitis and other immune adverse events or other causes 
Grade 3 
Hold pending evaluation until ≤ Grade 1.  Evaluate for gastritis 
duodenitis and other immune adverse events or other causes.  Resume at 
same dose level.  If symptoms do not resolve within 7 days with 
symptomatic treatment  patients should go off protocol therapy 
Grade 4 
Off protocol therapy 
Patients with grade 3 (or recurrent grade 2) nausea-vomiting 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 level 
Grade 4 
Off protocol therapy 
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  
 
 

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Neurologic events  
 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and observation. Resume with no change 
in dose.* 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1.*   
Off protocol therapy if treatment with steroids is required. Resume at 
same dose level for peripheral isolated n. VII (Bell’s palsy).  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
*Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), Guillain Barre syndrome, myasthenia gravis should be off study.   
Recommended management:  See Neurologic Adverse Event Management Algorithm 
(Appendix C) 
 
 
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Asymptomatic TSH elevation *   
Hold pending evaluation, consider endocrine consultation.  
Grade 2 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids patients must be stable off steroids for two weeks. 
Resume at same dose level.  
Grade 3 
Off study treatment. 
Grade 4 
Off protocol therapy 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered grade 3 events.  
Isolated thyroid or testosterone deficiency may be treated as grade 2 if there are no other 
associated deficiencies and adrenal function is monitored.  Please evaluate pituitary function 
before beginning steroid therapy or replacement therapy of any kind.  
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be 
evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
Recommended management: See Endocrine Management Algorithm (Appendix C) 
 
 

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Fever  
Management/Next Dose for Nivolumab 
≤ Grade 1 
 Hold dose pending evaluation and observation. Resume with no change 
in dose if patient is clinically stable*. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 4 
Off treatment 
*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 section 5.6 for management of infusion reactions   
 
 
 
Cardiac *   
Management/Next Dose for  
BMS-936558 (Nivolumab) + Ipilimumab Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain history EKG, 
CK (for concomitant myositis), CK-MB.  Repeat troponin, CK and EKG 2-
3 days.  If troponin and labs normalize may resume therapy.   If labs 
worsen or symptoms develop then treat as below.  Hold pending evaluation  
Grade >2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Consult algorithm for more details.  
Resume therapy if there is a return to baseline and myocarditis is excluded 
or considered unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac 
Transplant Unit).  Treat as above.  Consider high dose methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
 
 
 
 
 
 

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6.3 
Guideline for Steroid Use 
 
If treatment is delayed > 6 weeks, > 8 weeks for patients on high dose steroids with 
recommended 4 weeks taper and 2 week observation, the patient must be permanently 
discontinued from study therapy, except as specified in Section 5.5 (Criteria to Resume 
Treatment.) 
 
Patients requiring a delay of > 6 weeks, > 8 weeks for patients on high dose steroids with 
required 4 weeks minimal taper and 2 weeks observation, should go off protocol therapy.  
Patients requiring > two dose delays for the same event should go off protocol therapy. 
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, ACTH, TSH and T4 must be obtained to document 
baseline.  
 
Patients may be dose-delayed for evaluation and restarted depending on results.  
 
Any patient started on corticosteroids initially who is determined to not require steroids 
treatment for an autoimmune adverse event may resume therapy after a 2 week 
observation period without further symptoms at the discretion of the PI or investigator. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
 

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7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR)  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for BMS-936558 (Nivolumab, MDX-1106, NSC 748726) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients.  Below is the CAEPR for 
BMS-936558 (Nivolumab, MDX-1106). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
                                                                                                         Version 2.2, November 15, 20161 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 4.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency 
 
  
 
Endocrine disorders - Other 
(hypophysitis) 
 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
  
EYE DISORDERS 
  
 
 
Eye disorders - Other (diplopia)   
 
 
Eye disorders - Other (Graves 
ophthalmopathy) 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 

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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 4.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Colitis 
 
  
 
 
Colonic perforation 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Gastritis 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis3 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Infusion related reaction4 
 
  
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Autoimmune disorder5 
  
 
 
Cytokine release syndrome6 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)7 
  
 
 
Immune system disorders - 
Other (sarcoid granuloma)5  
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
(Gr 2) 
  
Neutrophil count decreased  
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis) 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (rhabdomyolysis) 
  

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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 4.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Myositis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy 
  
 
 
Facial nerve disorder5 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis) 
  
 
 
Nervous system disorders - 
Other (Guillain-Barre 
syndrome)5  
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis) 
  
 
 
Nervous system disorders - 
Other (myasthenia gravis)5  
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy   
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion 
 
  
 
Pneumonitis 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Skin hypopigmentation 
 
  
 
Skin and subcutaneous 
disorders - Other (Sweet’s 
Syndrome) 
 
  
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Pancreatitis may result in increased serum amylase and/or more frequently lipase. 

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4Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
 
 
 
 
5BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the inhibition of 
“immune checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably 
due to T-cell activation and proliferation.  This may result in autoimmune disorders that can include (but 
are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune 
aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune 
thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia 
systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic encephalitis, 
hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders 
(e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome. 
 
6Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
 
7Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving BMS-936558 (Nivolumab, MDX-1106).  
These complications may occur despite intervening therapy between receiving BMS-936558 (Nivolumab, 
MDX-1106) and allo-SCT. 
 
Adverse events reported on BMS-936558 (Nivolumab, MDX-1106) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that BMS-936558 
(Nivolumab, MDX-1106) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal 
disorders - Other (mouth sores); Mucositis oral; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune 
thrombotic microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory 
infection 
INVESTIGATIONS - GGT increased; Investigations - Other (blood LDH increased); Investigations - Other 
(protein total decreased); Investigations - Other (WBC count increased); Lymphocyte count increased; 
Weight loss  
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder 
- Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (histiocytic necrotizing lymphadenitis) 

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NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Periorbital edema; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea); Toxic epidermal necrolysis 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: BMS-936558 (Nivolumab, MDX-1106) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 
 
 
 
7.2 
Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 

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7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  
The reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization, the local treating physician, and the Reporter and Submitter.  
CTEP-AERS provides a copy feature for other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting to 
the CTSU documentation of AEs that they deem reportable for posting on the CTSU protocol 
web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (including cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 

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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
None. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 

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Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of patients enrolled in the studies as well as those who will 
enroll in future studies using similar agents.  AEs are reported in a routine manner at 
scheduled times during the trial using Medidata Rave.   
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are 
available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is 
required. 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational administered in 
this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Nivolumab (NSC 748726) 
 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 
440 amino acids and 2 identical light chains. 
 
Other Names:  BMS-936558, MDX1106 

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Classification:  Anti-PD-1MAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:  Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor.  PD-1 is a negative regulatory 
receptor expressed by activated T and B lymphocytes.  Binding of PD-1 to its ligands, 
programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation.  Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2.  
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. 
 
Description:  Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; 
light (few) particulates may be present.  The drug product is a sterile, nonpyrogenic, single-
use, isotonic aqueous solution formulated in sodium citrate, sodium chloride, mannitol, 
diethylenetriamine pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
 
How Supplied:  Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with a 
0.7 mL overfill.  It is supplied in 10 mL type I flint glass vials, with butyl rubber stoppers and 
aluminum seals. 
 
Preparation:  Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose, USP to concentrations no less than 
0.35 mg/mL. 
 
Storage:  Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected 
from light, freezing, and shaking.  
 
Stability:  Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed 
within 24 hours of preparation.  If not used immediately, the infusion solution may be stored 
up to 24 hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 4 hours of the total 
24 hours can be at room temperature (20°-25°C, 68°-77°F) and room light.  The maximum 4-
hour period under room temperature and room light conditions includes the product 
administration period. 
 
CAUTION:  The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent.  Therefore, it is advised that the product be discarded 8 hours after initial 
entry.  
 
Route of Administration:  Intravenous infusion.  Do not administer as an IV push or bolus 
injection.  NOTE REF TO DOSING SCHEDULE 
 

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Method of Administration:  Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding polyethersulfone membrane in-line filter. 
 
Potential Drug Interactions:  No incompatibilities between Nivolumab injection and 
polyvinyl chloride (PVC), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) IV components, 
or glass bottles have been observed. 
 
Availability: Nivolumab is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Nivolumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Integral Correlative Laboratory Studies  
  

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9.1.1 Immunohistochemistry (IHC) in NPC tissues: PD-L1, PD-L2, PD-1 and PD-1 expression 
9.1.1.1 
Hypothesis, rationale and preliminary data:  
See sections 2.1 and 2.4.  For information on sample processing and analysis, see 
Appendix B ’Immunohistochemical (IHC) Marker Template for Integral Markers’.  In 
essence, for this clinical trial, archival tumor will be tested using the BMS provided 
DAKO kits in addition to testing done at Dr. Lo’s laboratory.  Slides will also be sent to a 
BMS reference laboratory.  Positive tumor expression will be defined as the presence of  
≥ 1% of NPC tumor cells AND ≥ 1% Tumor infiltrative lymphocytes (TIL) which are 
positively stained [33]. 
9.1.1.2 
Collection of Specimen(s):  
Mandatory collection of archived, paraffin-embedded NPC tissue (derived from primary 
or metastatic tumors) will apply to all enrolled subjects. 
9.1.1.3 
Handling of Specimens(s):  
For archived samples: Samples can be sent as tumor blocks, or as 8-10 unstained slides, 
4μm thick tissue sections.  The sections should be labelled with the subject’s initials, 
study code and protocol number (NCI# 9742).  Each sample should be accompanied by a 
laboratory form containing the following information: site where subject was enrolled 
(e.g., Prince of Wales Hospital, Hong Kong), anatomical origin of the specimen (e.g. 
NPC primary tumor, or liver metastasis). 
9.1.1.4 
Shipping of Specimen(s):  
 
For archived specimens: samples can be sent in room temperature.  Specimens should be 
sent preferably on a working weekday (Monday to Wednesday) so that the samples will 
not arrive on a non-working day.  Shipment can be done in batches to   
 
Professor Kwok-Wai Lo 
Nasopharyngeal Carcinoma Laboratory, 
Rm 321, 3/F Sir YK Pao Centre for Cancer, 
Prince of Wales Hospital, 
The Chinese University of Hong Kong, Shatin, N.T., 
Hong Kong SAR 
Telephone (852) 26322178 or (852) 26321130 
Telefax: (852) 26376274 
Email: kwlo@cuhk.edu.hk 
9.1.1.5 
Site Performing Correlative Study 
Analysis of the archived sections will be performed in the research laboratory of Prof. 
Kwok Wai Lo. Ph.D. at Chinese University of Hong Kong. 
 
 
9.1.2 
Mandatory Baseline Serum Lymphocyte Count 
The baseline absolute lymphocyte count result will be collected during routine blood 
sampling for differential white cell count. This value will be correlated with response.  
 

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9.2 
Exploratory/Ancillary Correlative Studies 
 
9.2.1 Plasma EBV DNA Clearance 
9.2.1.1 
Hypothesis: We hypothesize that plasma EBV DNA half-life during the first 6 weeks of 
treatment may be associated with subsequent RECIST-response to nivolumab.  
9.2.1.2 
Collection of Specimen(s):  
This test is mandatory for all enrolled subjects. 3-5ml of EDTA blood sample (x 1 tube) 
will be taken at baseline (within 7 days of starting the first dose of study drug), and then 
at weekly interval: week 1 (day 7 +/- 2 days), week 3 (day 21 +/-2 days), week 4 (day 28 
+/- 2 days), week 5 (day 35 +/- 2 days) and week 6 (day 42, +/- 2 days). Week 2 sampling 
is omitted given the possibility of a surge in level.  Consecutive samples can only be 
taken with no more than 5 to 9 days apart.  
9.2.1.3 
Handling of Specimens 
 
After blood sampling, the EDTA blood samples should be centrifuged as soon as possible 
(within 30 minutes to 1 hour) at 1600 x g for 10 minutes at 4degrees Celsius temperature.  
The plasma will be transferred to a fresh tube (1.5 ml) and then centrifuged at 16000 x g 
for 10 minutes at 4 degree Celsius. The centrifuged plasma will be transferred to a fresh 
tube without disturbing the pellet at the bottom of the tube, and then stored at –70 to -80 
degree until analysis.  Analysis will be performed using the real-time quantitative PCR 
technique as previously described [25, 28].  Each sample will be labeled by the patient’s 
study code, study protocol number and date of sample collection.  Each blood tube should 
be accompanied by a laboratory form containing the following information: date of blood 
collection, patient’s study code, type of sample (e.g. ‘baseline’, ‘week 1’, ‘week 2’, 
‘week3’, ‘week 4’). 
 
9.2.1.4 
Shipping of Specimens  
 
Samples should be shipped at -70 to -80 degree Celsius temperature (or shipped frozen on 
dry ice) in batches, preferably on a working weekday (Monday to Wednesday) so that the 
samples will not arrive on a non-working day.  Samples can be shipped in batched to the 
following address:  
 
Professor Brigette Ma (c/o Dr Charles Chan) 
Tumor Marker Laboratory  
4th floor Sir Y.K. Pao Cancer Center 
Prince of Wales Hospital 
Shatin, New Territories, Hong Kong SAR 
Email: brigette@clo.cuhk.edu.hk 
Telefax: (852) 26487097 
Telephone: (852) 26322118 
 

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9.2.1.5 
Site Performing Correlative Study  
 
Plasma EBV DBA analysis using real-time quantitative PCR assays will be performed at 
the Prince of Wales Hospital, Hong Kong, through collaboration with the Department of 
Chemical Pathology, Chinese University of Hong Kong. This is one of the reference 
laboratories for determining this biomarker in a NRG study (31).  
 
 
9.2.2 Functional Magnetic Resonance Imaging (For Prince of Wales Hospital only) 
9.2.2.1 
Hypothesis and rationale 
 
Anatomical imaging (CT and MRI) and functional imaging (FDG- PET) are the current 
standards for monitoring cancer treatment response.  However, research into functional 
MRI techniques has also shown potential value for predicting and monitoring treatment 
response (41).  Dynamic contrast enhanced MRI (DCE-MRI) (which uses the same 
standard contrast agent that is used for conventional anatomic imaging) and T2* mapping 
assess the vascularity of tumours, while diffusion weighted imaging (DWI) provides 
ADC parameters that can reflect cell density, cell swelling and membranes.  Using the 
ADC values obtained at low b values by an intatravoxel incoherent motion (IVIM) DWI 
technique the vascularity can be assessed also without the need for intravenous contrast.   
An early (around 2-3 weeks) intratreatment increase in ADC values (as cells shrink and 
die) has been shown to predict a favourable treatment response to chemoradiation in head 
and neck tumours (44, 45), but there are conflicting results for other regions of the body 
where it is known that results are influenced by tumour types and treatment modalities.  It 
has also been reported that head and neck tumours which, after an initial ADC rise early 
intratreatment, later in the course of treatment show a fall in ADC (presumed to represent 
repopulation by tumour cells so increasing cell density) are also associated with an 
unfavourable outcome (45).   
The effect of Nivolumab treatment on functional imaging parameters in NPC is unknown 
but the use of PD-1 inhibitor maybe associated with an increased level of tumor 
infiltration by T-cells and inflammatory cells.  We hypothesize that this early 
inflammatory response will increase vascularity and cell density and decrease the 
extracellular space and so will be reflected as an early increase in vascular parameters on 
DCE and T* and decease in ADC, before a reversal in these parameters later in the 
course of treatment.  
The first step is to document these changes in functional imaging parameters over the 
course of treatment and correlate with changes in tumour volume.  Subsequently, if the 
sample size is sufficient, we plan to correlate the functional imaging parameters with 
treatment outcome based on objective response (RECIST) and survival.  
 
9.2.2.2 
Data collection and analysis  
 
MRI will be performed on a 3T MRI scanner (Achieva, Philips Healthcare, Best, The 

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Netherlands) using a 16 channel head and neck SENSE coil.  Anatomical and functional 
data will be obtained to document changes in the target lesions during and after 
treatment.  Target lesions will include: Primary or nodal metastases in the head and neck, 
distant metastatic sites.  MRI scanning will be performed at the Department of Diagnostic 
Radiology and Interventional Radiology at the Prince of Wales Hospital (PWH), Hong 
Kong.  Only subjects enrolled from the PWH will be invited to participate in this optional 
correlative study. 
 
MRI Sequences  
a) Conventional axial The MRI examination (1.5 or 3T) will cover the skull base 
down to the lower neck below the suprasternal notch using section thickness = 
4mm with no intersection gap.  Conventional MRI consists of following images; 
axial T1W, axial T2W with fat suppression; sagittal T1W; contrast-enhanced 
axial T1W post contrast with and without fat suppression; coronal T1W post 
contrast. The T1W and T2W images will be obtained before the functional images 
and the T1+C will be performed after the DCE-MRI).  Tumour volume will be 
calculated (summation of areas X slice thickness).   
b) Functional sequences  
• Diffusion weighted imaging (DWI). Single-shot echo-planar imaging 
technique with b-values from 0-1000 s/mm2. Assessment of the apparent 
diffusion coefficient (ADC), diffusion coefficient (D), pseudo-diffusion 
(perfusion) coefficient (D*), and fraction of pseudo-diffusion (f). Whole 
body Diffusion weighted MRI (DWIBS) will be performed.  T2* Mapping: 
T2* mapping is derived from data acquired using a multiecho T2* sequence 
based on a multishot fast-field echo technique. T2* mapping will be 
obtained by exponentially fitting the six images pixel by pixel with different 
TEs for each slice to obtain the T2* measurements.  
 
• Dynamic contrast enhanced MRI (DCE-MRI), a pre-contrast T1 map is 
derived using two different flip angles [2º, 15º]. The dynamic sequence is 
obtained using a short 3D T1-weighted spoiled gradient echo sequence. 
Contrast injection is commenced 6 seconds after the start of the dynamic 
MRI acquisitions, given in the form of an intravenous bolus injection of a 
standard MRI contrast agent (gadopenetate dimeglumine (Dotarem, 
Guerbet, France) at a concentration of 0.1 mmol/kg of body weight. In 
addition, immediately after the DCE-MRI scan, post-contrast enhanced 
anatomical T1-weighted images will be obtained. Assessment of the Ktrans, 
Kep and Ve of tumors pre-treatment. 
 
 
9.2.2.3 
Imaging timepoints (see also section 10, Study Calendar):  
• 
Routine MRI scan points as part of response assessments (mandatory): 
Anatomical based MRI examination (T2W, T1W, T1W post contrast) for 
conventional assessment of treatment response based on size, plus addition of 

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functional MRI (DCE, DWI/DWIBS, T2* mapping) performed within the same 
week as the scheduled mandatory contrast MRI and/or CT scans, at the following 
time-points: baseline, after cycle 4 (on week 8) and after cycle 8 (on week 16). 
 
• 
Additional MRI scans points (optional).  
(a) Early intra-treatment Week 3 (after the 2nd dose of nivolumab), 
Anatomical and functional MRI will be repeated 
(b) Intra-treatment Week 6- short MRI protocol without IV contrast (T1W, 
T2W, DWI and  T2*)  
 
Table Summarizing the Time Points for MRI Scans 
 
Baseline 
Week 3 
Week 6 
Week 8 
Week 16 
Routine 
(Mandatory) 
Yes 
(Contrast, 
anatomical 
MRI) 
No 
No 
Yes 
(Contrast, 
anatomical 
MRI) 
Yes 
(Contrast, 
anatomical 
MRI) 
MRI sub-
study 
(Optional) 
Yes 
(Functional 
MRI) 
Yes 
(Functional 
MRI) 
Yes 
(Plain 
MRI) 
Yes 
(Functional 
MRI) 
Yes 
(Functional 
MRI) 
 
 
 
9.2.3 Monitoring of Inflammatory Cytokines during Nivolumab Therapy 
 
9.2.3.1 
Hypothesis: Nivolumab may affect the level of inflammatory cytokines (e.g. IFN-γ, 
TNF-α, IL-6) and immune cell levels in nasopharyngeal carcinoma.  
9.2.3.2        Sample collection:  This blood sampling is mandatory for all patients enrolled into 
this study. 5 ml of EDTA blood will be collected at baseline, and just prior to 
nivolumab dosing on week 3 (± 2 days), week 5 (± 2 days) and week 7 (± 2 days). 
The blood sampling schedules should coincide with the plasma EBV DNA blood 
samples (section 9.2.1) or routine bloods (see section 10), where applicable.  
9.2.3.3       Sample processing: same as section 9.2.1.3.  
 
9.2.3.4       Shipment: same as section 9.2.1.4    
 

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10.   STUDY CALENDAR 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11, 
etc 
Wk 
16 
Off 
Studyc 
Nivolumab 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X--------------------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
Wk 13 
onwards: 
every 4 
weeks  
 
X 
Vital signs 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC w/diff, plts 
X* 
X * 
 
X d 
 
X d 
 
X d 
 
X d 
 
X d 
 
X 
Serum chemistry 
X a* 
X * 
 
X d 
 
X d,e 
 
X d 
 
X d,e 
 
X d 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X-------------------------------------------------------------------------------------------------------X 
X 
Tumor 
measurements/Radiologic 
Evaluation i 
X 
Tumor assessments will be done at week 8 after the first dose of nivolumab, and then at week 
16 and week 24, and then every 12 weeks thereafter.  Starting at week 16, imaging may be 
performed within ± 7 days of the scheduled visit.  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease. Patients who have not 
progressed at study discontinuation are encouraged to undergo radiological assessment every 8 
to 12 weeks until progression, at the discretion of the study doctor.  
X 

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Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11, 
etc 
Wk 
16 
Off 
Studyc 
B-HCG 
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived tumor retrieval or 
fresh tissue collected by 
biopsy (Mandatory) R 
X f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma EBV DNA blood 
sampling (Mandatory) h,R 
X* 
X* 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Plasma cytokine level h, R 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
MRI study (Optional for 
Hong Kong site only) R 
X g 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
HIV, hepatitis B and C 
serology j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline blood tests  are to be conducted within 1 week prior to start of protocol therapy except for the HIV, hepatitis B and C serology which may 
be done within 4 weeks prior to starting study treatment.  Scans and x-rays must be done < 4 weeks prior to the start of therapy.  In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.  
All visits may be held within ± 2 days of scheduled visit. 
 
A: Administration schedule of nivolumab 
 
a: Baseline chemistry: Albumin, alkaline phosphatase, total bilirubin, urea, calcium, creatinine, fasting glucose, LDH, phosphorus, potassium, 
total protein, SGPT [ALT] (or AST if available at the center), sodium, TSH (with reflexive Free T4 and Free T3), amylase. (* The tests done 
at ‘pre-study’ period can be used as ‘week 1’ bloods as long as they are done within 7 days of the 1st dose.  Baseline serum absolute 
lymphocyte count will be collected.)  
 
b: A serum or urine pregnancy testing is required within 24 hrs of study enrollment. 
  
c: Off-study evaluation should be performed within 30 days of coming off study.   Should reinforce criteria for follow up for 100 days for AE 
assessment. 

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d:    Laboratory tests to be done within 72 hrs prior to re-dosing: CBC w/ differential, LFTs, serum urea and creatinine, Ca, Mg, Na, K, LDH, 
random glucose, amylase. 
 
e:     Laboratory tests to be done every 4 weeks:  TSH (with reflexive Free T4 and Free T3) 
 
f:     Retrieval of archived tumor block/ unstained slides is mandatory.  Each site should retrieve the specimen within 4 weeks of study registration.   
If a patient does not have archived tissue available, a fresh tissue sample must be obtained by biopsy at this time. 
 
g:    MRI study (section 9.2.3): This optional study applies only to the Hong Kong site and will be performed at baseline, weeks 3, 6, 8 and 16. For 
the patient’s convenience, the contrast-enhanced sessions of the MRI scans that are required at baseline, week 8 and 16, should be scheduled 
on the same day (if possible) as the mandatory radiological assessments (e.g. CT or MRI). For the other time points that happen to fall on 
nivolumab administration days (i.e. week 3 and 6), the MRI scan should be scheduled after nivolumab has been given and not on the same 
day. An interval of at least 5 days should be allowed between consecutive scans.   
 
h:     Plasma EBV DNA sampling time intervals – see section 9.2.1.2.  Plasma cytokine level: see section 9.2.3. 
 
i:     Standard contrast CT will be done for assessing non-local recurrences. MRI will be used for assessing local recurrence. If dual PET and 
contrast CT is used to assess non-local recurrences at baseline, all subsequent radiological assessments must include a PET-CT.  Starting at 
Week 16, imaging may be performed within ± 7 days   
 
j:     HIV and hepatitis B and C serology: See section 3.2.9-3.2.11. If the HIV and/or hepatitis B and C status is unknown at the time of study 
registration, these tests must be performed during screening and may be performed within 4 weeks prior to starting study treatment.   
 
R: Research, not standard of care (SOC)

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11. MEASUREMENT OF EFFECT 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. [42] 
 
11.1 
Schedule of Evaluations 
 
For the purposes of this study, patients should be re-evaluated for objective tumor response at 
week 8 after the first dose of nivolumab, and then at week 16 and week 24, and then every 12 
weeks thereafter.  In addition to a baseline scan, confirmatory scans should also be obtained 
within 8 weeks (not less than 4) following initial documentation of objective response. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.2.1 
Measurable Disease 
 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as  2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) or imaging.  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).   
 
Note:  Tumor lesions in a previously irradiated area are not considered measurable disease.   
 
 
11.2.2 
Non-Measurable Disease 
 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥1.0 to <1.5 cm).  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 

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selection as target lesions.  In addition, lymph nodes that have a short axis <1.0 cm 
are considered non-pathological (i.e., normal) and should not be recorded or 
followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.3.1 
Measurement Methods   
 
• All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients 
having only lesions measuring at least 1 cm to less than 2 cm must use CT imaging 
for both pre- and post-treatment tumor assessments.   
• Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect of 
a treatment.  
 
11.3.2 
Acceptable Modalities for Measurable Disease 
 
• 
Conventional CT and MRI:  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. 
 
• As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  The lesions should be measured on the same pulse sequence.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
• PET-CT:  If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over 
time.   
 
• Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT scans are 
preferable. 
 
• Physical Examination:  For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 

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documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
 
• FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  A 
‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with an 
update greater than twice that of the surrounding tissue on the attenuation corrected 
image; otherwise, an FDG-PET scanned lesion is considered ‘negative.’  New 
lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT at the same evaluation, additional follow-up CT scans 
(i.e., additional follow-up scans at least 4 weeks later) are needed to 
determine if there is truly progression occurring at that site.  In this 
situation, the date of PD will be the date of the initial abnormal PDG-
PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing site 
of disease on CT that is not progressing on the basis of the anatomic 
images, it is not classified as PD. 
 
11.3.3 Measurement at Follow-up Evaluation  
 
A subsequent scan must be obtained at least 4 weeks (within 8 weeks but not less than 4 
weeks apart) following initial documentation of an objective status of either complete 
response (CR) or partial response (PR).  
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g., residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain.) 
 
 

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11.4 
Measurement of Effect 
 
11.4.1 Target Lesions and Target Lymph Nodes 
 
• Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline.  These lesions can be non-nodal or nodal (as 
defined in 11.21), where no more than 2 lesions are from the same organ and no more 
than 2 malignant nodal lesions are selected.  
 
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those specified 
in the protocol to discover new lesions.   
 
• Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.   
 
• Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD).  The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease.   
 
• Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm.  If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned.  If it is the opinion of the radiologist that 
the target lesion or target lymph node has likely disappeared, the measurement should 
be recorded as 0 cm. 
 
• The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
11.4.2 
Non-Target Lesions and Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions or non-
target lymph nodes and should also be recorded at baseline.  These lesions and lymph nodes 
should be followed in accord with 11.433. 

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11.4.3 Response Criteria 
 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray/physical examination must be measured on re-evaluation at evaluation times specified in 
Section 11.1.  Specifically, a change in objective status to either a PR or CR cannot be done 
without re-measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response.  In selected 
circumstances, certain non-target organs may be evaluated less frequently.  For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 cm. 
 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes at 
current evaluation) taking as reference the BSD (see Section 11.41). 
• 
Progression (PD): At least one of the following must be true: 
a.  At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up. 
b.  At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.41).  In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from the 
MSD. 
c. See Section 11.32 for details in regards to the requirements for PD via FDG-
PET imaging. 
 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
 
Evaluation of Non-Target Lesions and Non-target Lymph Nodes 
 
• 
Complete Response (CR): All of the following must be true: 
 
a.  Disappearance of all non-target lesions. 
b.  Each non-target lymph node must have a reduction in short axis to < 1.0 cm. 
 

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• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-target lymph 
nodes. 
 
• 
Progression (PD): At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up. 
b. Unequivocal progression of existing non-target lesions and non-target lymph 
nodes.  (Note:  Unequivocal progression should not normally trump target 
lesion and target lymph node status.  It must be representative of overall 
disease status change.) 
c. See Section 11.32 for details in regards to the requirements for PD via FDG-
PET imaging. 
 
11.44 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the patient’s status 
on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, and new 
disease as defined in the following table:  
 
 
Target Lesions and 
Target Lymph Nodes 
Non-Target Lesions 
and 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall 
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
 

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11.45 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic 
deterioration.  A patient is classified as having PD due to “symptomatic deterioration” if any 
of the following occur that are not either related to study treatment or other medical 
conditions: 
 
• 
Weight loss >10% of body weight. 
• 
Worsening of tumor-related symptoms. 
• 
Decline in performance status of >1 level on ECOG scale. 
 
11.5 
Antitumor Effect – Immune Response Criteria 
 
Wolchok et al [34] described the Immune Response Criteria (IRC) which was used to 
evaluate response to nivolumab and ipilimumab in melanoma. The IRC is derived from the 
WHO criteria and is characterized by the following features: 
 
• Objective response is based on the total measurable tumor burden: For the irRC, only 
index and measurable new lesions are taken into account. 
 
• At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 
visceral lesions and five cutaneous index lesions) is calculated. At each subsequent 
tumor assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 
5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) 
are added together to provide the total tumor burden:  
 
• Complete response: Disappearance of all lesions in two consecutive observations not 
less than 4 weeks apart. 
• Partial response: ≥ 50% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart (within 8 weeks and not less than 4 weeks apart).  
• Stable disease: 50% decrease in tumor burden compared with baseline cannot be 
established nor 25% increase compared with nadir. 
• Progressive disease: At least 25% increase in tumor burden compared with nadir (at 
any single time point) in two consecutive observations at least 4 weeks apart. 
• At each tumor assessment, the response in index and new, measurable lesions is 
defined based on the change in tumor burden (after ruling out PD). Decreases in 
tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all 
index lesions at screening). 
 
 

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Measurable lesions 
Non-measurable Lesions 
Overall 
Response 
Index and new, measurable 
lesions (tumor burden),* % 
Non-index lesions 
New, non-measurable 
lesions 
 
100 
Absent 
Absent 
CR† 
100 
Stable 
Any 
PR† 
100 
Unequivocal 
progression 
Any 
PR† 
>50 
Absent/ Stable 
Any 
PR† 
>50 
Unequivocal 
progression 
Any 
PR† 
<50 to <25 
Absent/ Stable 
Any 
SD 
<50 to <25 
Unequivocal 
progression 
Any 
SD 
> 25 ? 
Any 
Any 
PD 
*Decreases assessed relative to baseline, including measurable lesions only (> 5 × 5 mm). 
†Assuming response (CR) and progression (PD) are confirmed by a second, consecutive assessment at 
least 8 weeks apart in this protocol. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the 
site user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the 
Corresponding Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To 
accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial 

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site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com. 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will 
be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/CTMS.  On-site audits will be conducted on an 18-36 month basis 
as part of routine cancer center site visits for U.S. and Canadian sites.  CTRG sites will be 
audited under the previously established procedures for Mayo P2C CTRG participation.  
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated 
their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
12.1.2 Responsibility for Data Submission 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators 
at the ETCTN Sites understand the procedures for data submission for each ETCTN protocol 
and that protocol specified data are submitted accurately and in a timely manner to the 
CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than 
once every 2 weeks.  The timeliness of data submissions and timeliness in resolving data 
queries will be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a 
quarterly basis.  For the purpose of Institutional Performance Monitoring, data will be 
considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis 
as data is received.  Queries will be issued by CTMS directly within Rave.  The queries will 
appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP.  
Onsite audits will be conducted by the CTMS to ensure compliance with regulatory 
requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring 
the integrity of data generated from NCI-sponsored clinical trials, as described in the ETCTN 
Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include the recommended phase 
2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will utilize 

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a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-
and-semantics/metadata-and-models).  Customized eCRFs will be included when appropriate 
to meet unique study requirements.  The PI is encouraged to review the eCRFs, working 
closely with CTMS to ensure prospectively that all required items are appropriately captured 
in the eCRFs prior to study activation.  CTMS will prepare the eCRFs with built-in edit 
checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out 
by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a 
monthly basis.  The trial’s lead institution is responsible for timely submission to CTMS via 
Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
See Section 12.1.1 for details on CDUS reporting.  As the data management center for this 
trial, Theradex is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   
12.2 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement.  A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 

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a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other 

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media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 
Background/Overview   
In a study of nivolumab alone, the response rates were 18% in lung cancer, 28% in 
melanoma and 27% in renal-cell cancer (RCC). Over 60% of responders have durable 
responses lasting > 1 year [23], the PFS at 24 weeks was 41% for melanoma, 26% for lung 
cancer and 56% for RCC.  In the phase 1 study, the median duration of therapy was 12 weeks 
(range, 2 to 111), and the objective response rates were: 17% in melanoma, 11% in RCC, 
10% in lung cancer and 5% in ovarian cancer.  Responses > 1 year were reported in 50% of 
patients [35].  In general, there is a paucity of data on PFS at 24 weeks, SD rate and other 
survival data from studies involving multiply-treated NPC patients. Data from phase II 2nd 
line studies of cytotoxic agents such as a gemcitabine and capecitabine, reported the SD rate 
to be around 30-49%, median TTP of 3.6-5 months, and *PFS at 6 months of around 30-40% 
(*estimated from the published curves) [36-38]. The overall response rate (ORR) for 
cytotoxic agents in patients who failed only 1 prior line of chemotherapy is estimated to be 
around 20%, but the response is usually not durable [36-38]. The problem of using such data 
for this proposal is that nearly all patients from these studies had just 1 prior line of therapy, 
while the current proposal (and also published studies on nivolumab) enrolled patients who 
were more heavily pre-treated.  
 
Therefore, we have decided to use the data from two of our prior phase II studies of targeted 
agents, namely, pazopanib and cetuximab (the latter in combination with carboplatin) for 
calculating the sample size in this proposal because the cohort in these studies are similar to 
the current proposal.  In the pazopanib study, patients had a median of 3 lines of therapy, and 
clinical benefit rate (CBR, PR + SD + CR) at 12 weeks was used to calculate the sample size. 
A CBR of 35% was estimated to be clinically meaningful, and the actual rate reported was > 
50% [39]. The ORR was 6.1%, median TTP was 4.4 months (95% CI: 3.9–5.8 months) and 
the PFS-6 month was around 30-35% (read from the curve).  In the cetuximab study [40], 
70% of patients had 1 prior line of chemotherapy only.  Although the ORR was 11.7% and 
the CBR rate was 60% (which is higher than the pazopanib study), the median TTP was quite 
short at 2.7 months, and the PFS-6 months was around 20-30% (read off the curve) [40]. 
Therefore, the average PFS at 24 weeks (6 months) is around 25-30% a benchmark for 
heavily-pretreated NPC patients, with a ORR between 6% to 20%. 
 

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These prior studies have shown that the response rate is generally around 5% in this disease 
setting [39-40].  If Nivolumab can increase the response rate to 20% or more, that would be 
exciting and worth further study.  This protocol will assess the confirmed response rate as the 
primary endpoint.  In addition this study will assess multiple secondary endpoints, including 
adverse events, tumor response to nivolumab based on immune-related response criteria 
(IRC), duration of response, progression-free survival (PFS), overall survival (OS), and 
laboratory correlates. 
 
13.1.2 
Primary Endpoint 
The primary endpoint of this trial is the confirmed response rate using RECIST 1.1 criteria.  
All patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be considered evaluable for the primary endpoint.  A confirmed tumor 
response is defined to be a CR or PR noted as the objective status on 2 consecutive 
evaluations at least 4 weeks apart (within 8 weeks and not less than 4 weeks apart).   
• 
For late responders to nivolumab (see section 5.7.1): Subjects who continue treatment 
beyond first progression (as determined by the initial investigator-assessed, RECIST 
1.1-defined progression) will be considered to have investigator-assessed ‘progressive 
disease’ at the time of the initial progression event. However, if they subsequently 
experience a CR or PR,  they may be designated as a ‘delayed responder’ for the 
purposes of determining ORR and thus, in the final analysis, be counted as a 
‘responder’ for the study. 
 
13.1.3 
Statistical Design Overview 
A patient that has a confirmed response is considered a treatment “success”.  The following 
one-stage design with an interim analysis requires a maximum of 35 evaluable patients, and 
simultaneously discriminates between tumor response rates of 5% vs. 20%.   
 
13.1.4 
Final Analysis Decision Rule 
Enroll 35 evaluable patients.  If at least 4 patients have a confirmed tumor response (at least 
11%) among the 35 evaluable patients, this agent would be considered worthy of further 
testing in this disease.  If 3 or fewer patients have a confirmed tumor response, this agent will 
be considered negative and no further study would be warranted.  
 
Interim Analysis Decision Rule:  Enter 20 evaluable patients.  If 2 or more of these 20 
evaluable patients have a confirmed tumor response, the study will continue to full accrual.  
Otherwise, if fewer than 2 confirmed responses are observed, the study will be stopped early 
and the treatment will be considered ineffective in this patient population.  Accrual will 
continue through the interim analysis phase, unless undue toxicity is observed.   
 
13.1.5 
Power and Significance Level 
This design has 90% power to detect a true confirmed response rate of 20%, with a 
significance level of 0.09 if the true confirmed response rate is 5%. The likelihood of 
stopping at stage 1 of enrollment is 64.5% and 7% if the true confirmed response rate is 5% 
and 20%, respectively.  
 

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13.1.6 
Over Accrual 
 If more than the target number of patients are accrued, the additional patients will not be 
used to evaluate the stopping rule or used in any decision making process.   
 
13.1.7 
Other Considerations 
Toxicity, quality/duration of response, and patterns of treatment failure observed in this 
study, as well as scientific discoveries or changes in standard care will be taken into account 
in any decision to terminate the study. 
 
13.2 
Sample Size/Accrual Rate 
 
13.2.1  Sample Size 
 A total of 35 evaluable patients will be accrued per study design, unless the study is 
permanently closed at interim analysis or undue toxicity is observed.  We anticipate accruing 
an additional 5 patients in order to account for ineligibility, cancellation, major treatment 
violation, or other reasons.  Therefore, maximum accrual is 40 patients for this trial. 
 
13.2.2 
Accrual Time and Study Duration 
 We expect to accrue about 2 patients per month to this trial.  Therefore, the accrual period 
for this Phase II study is expected to be about 20 months.  The final analysis can begin 
approximately 26 months after the trial begins, i.e. as soon as the last patient has been 
observed for at least 6 months.   
 
13.3 
Stratification Factors and Subset Analyses for Primary Endpoint 
Since the study is not randomized, there are no stratification factors for randomization 
purposes.  In an exploratory analyses, response rates will also be summarized in the 
following subsets:  PD-L1, PD-L2, PD-1 and PD-1 IHC expression levels (positive vs. 
negative expression), number of lines of prior chemotherapy for metastatic or recurrent NPC 
(1 or > 1 line), and prior exposure to EBV vaccines. 
 
13.4 
Analysis of Secondary Endpoints 
This study will assess multiple secondary endpoints, including adverse events, tumor 
response to nivolumab based on immune-related response criteria (IRC), duration of 
response, progression-free survival (PFS), overall survival (OS), and laboratory correlates.  
The analysis population for these endpoints will be the same as that for the primary endpoint 
– i.e., all patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment. 
 
13.4.1 
Adverse Events 
 All patients that have initiated treatment will be considered evaluable for assessing adverse 
events. The maximum grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine adverse event patterns.  Only the severe 
or worse adverse events will be assessed, regardless of relationship to the study treatment.  In 
addition, the following adverse events will be captured and followed over time: pneumonitis, 
endocrinopathy, infusion-related reactions, diarrhea, skin events [23]. 

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13.4.2 
Immune-Related Response 
Tumor response to nivolumab based on immune-related response criteria (IRC) will also be 
assessed.  Responses will be summarized descriptively using frequencies and percentages.  
See section 11 for details on IRC response.   
 
13.4.3 
Duration of Response   
Defined for all evaluable patients who have achieved an objective response as the date at 
which the patient’s objective status is first noted to be either a CR or PR to the date 
progression is documented for both response criteria (RECIST 1.1 and IRC).   
 
13.4.4 
Progression-Free Survival (PFS) 
Defined as the time from registration to the first of either death due to any cause or 
progression.  The distribution of PFS will be estimated using the method of Kaplan-Meier 
[46].  
 
13.4.5 
Overall Survival 
Defined as the time from registration to death due to any cause.  The distribution of survival 
time will be estimated using the method of Kaplan-Meier [46Special attention will be paid to 
any registered patient who dies early (i.e., within 60 days) of initiating their treatment.  
Circumstances surrounding such early deaths will be classified as being either due to 
malignant disease, toxicity, other causes, or of unknown reasons. 
 
13.4.6 
Laboratory Correlative Studies 
All analyses with respect to the translational component of this study are intended to be 
hypothesis-generating and descriptive in manner. For this study, we will investigate the effect 
of nivolumab on tumor burden by analyzing the clearance of plasma Epstein-Barr virus 
(EBV) DNA during the first 4-6 weeks of treatment.  In addition, we will investigate the 
association between treatment outcome and the following immunological markers: 
Intratumoral expression of PD-1 and PD-L1 in archived NPC tissues, serum absolute 
lymphocyte count at baseline and post-treatment, expression of PD-1 in CD8+ T cells in 
tumor infiltrating lymphocytes (TIL) at baseline.  Plasma EBV DNA half-life during the first 
6 weeks of treatment will be correlated with RECIST-response to nivolumab. 
The Chi-Square (or Fisher’s Exact test) will be used to assess the association of categorical 
clinical data with categorical biomarker data.  Time-to-event clinical data (PFS, OS) will be 
correlated with biomarker data using Kaplan-Meier methodology and Cox regression models.  
Logistic regression models will also be used to predict binary clinical data with baseline 
biomarker data.  Finally, graphical methods and descriptive statistics will be used to 
summarize the data as well.  Two-sided p-values < 0.05 will be considered statistically 
significant. For the functional MRI parameters, graphical methods and descriptive statistics 
will be used to assess the changes in these parameters over time.  In addition, we will 
determine the associations between the MRI parameters and clinical endpoints like response 
and survival.   
 
13.5 
Adverse Event Stopping Rule 
 

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13.5.1 
Monitoring 
 The principal investigator and the study statistician will review the study periodically (every 
4-6 months, or more frequently if clinically indicated) to identify accrual, toxicity, and any 
endpoint problems that might be developing. 
 
13.5.2 
Adverse Event Stopping Rule 
Based on prior studies using nivolumab at the dose and schedule to be used in this study, we 
expect approximately 10% of patients to experience grade 4+ adverse events (at least 
possibly related to study medication).  In this study, we will suspend accrual to allow for a 
full review of the data, if any of the following occur: 
(1)  If at any time, 4 of the initial 20 patients (or 20% of all patients when 
accrual is greater than 20) have experienced any grade 4 adverse event (at 
least possibly related to the study medication).  
(2) If at any time, 2 of the initial 20 patients (or 10% of all patients when 
accrual is greater than 20) have experienced any grade 5 adverse event (at 
least possibly related to the study medication).  Of course, we will also closely 
monitor each grade 5 event on a case-by-case basis, and may immediately 
suspend accrual after one grade 5 event if we feel it is best for patient safety.    
 
After consideration by the study team [ie, Study Chair(s), Statistician, P2C Operations 
Office, etc] and consultation with representatives at the Cancer Therapy Evaluation Program 
(CTEP) and the NCI Central IRB (CIRB) , a decision will be made as to whether and how 
the study will proceed. 
 
13.6 
Inclusion of Women and Minorities 
 
Non-keratinizing NPC has a unique epidemiological predilection for southern China, 
Southeast Asia, the Arctic, and the Middle East/North Africa. Furthermore, there is a male 
predominance. 
 
 

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Racial Categories 
(U.S.A sites) 
Ethnic Categories 
Total 
Not Hispanic  
or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
0 
0 
0 
0 
0 
More Than One Race 
0 
0 
0 
0 
0 
Total 
0 
2 
0 
0 
2 
Racial Categories 
(Outside U.S.A) 
Ethnic Categories 
Total 
Not Hispanic  
or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
9 
28 
0 
0 
37 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
0 
0 
0 
0 
0 
More Than One Race 
0 
1 
0 
0 
1 
Total 
9 
29 
0 
0 
38 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino – all other ethnicities not listed above 
 

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14. STUDY STATUS UPDATES AND STUDY CLOSURE 
 
14.1 Definitions of Study Status Changes 
 
14.1.1 
Temporarily Closed to Accrual 
 
The study status is Temporarily Closed to Accrual when no patient slots are currently 
available, but there is the possibility that the trial will re-open for accrual (patient slots 
become available).  Sites are not permitted to accrue additional patients until CTEP is 
notified of Re-Activation. 
 
Study status will need to be changed to Temporarily Closed to Accrual when any of the 
following criteria are met: 
 
• Sites are notified by CTEP (via Request for Rapid Amendment [RRA]) of changes in 
the risk/benefit ratio that necessitate changes to the patient Informed Consent 
document.  Requested changes will be specified in the RRA and must be reviewed by 
the study’s IRB. 
• CTEP and the lead investigator agree that unacceptable toxicities necessitate a 
discussion to change the dosing/regimen. 
• A protocol-defined benchmark has been achieved (such as an interim analysis before 
proceeding to the next stage). 
• Investigators encounter any of the stopping criteria described in Section 5.3. 
 
14.1.2 
Closed to Accrual 
 
The study status is Permanently Closed to Accrual when no more patient enrollment slots are 
available and at least one patient is still actively receiving the study treatment.  Sites are no 
longer permitted to enroll additional patients. 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands have been recorded 
as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 

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Patient slots are no longer available when the following criteria are met: 
 
• The pre-specified number of evaluable patients has been successfully enrolled, 
treated, and evaluated. 
• The study treatment has failed to meet the pre-specified efficacy goal at the stage 1 
interim analysis. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment. 
• Investigators encounter any of the stopping criteria described in Section 5.3. 
 
14.1.3 
Closed to Accrual and Treatment 
 
The study status is Closed to Accrual and Treatment when no more patient enrollment slots 
are available and no patients are currently receiving the study treatment.  Patients may still be 
enrolled on the protocol only for the purposes of follow-up. 
 
Patient accrual and treatment will be permanently halted when any of the following criteria 
are met: 
 
• Enrollment was previously closed (study status of “Closed to Accrual”), and no 
patients are receiving the study treatment. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment.  In this case, CTEP and the investigators must collaborate to alter the 
regimen or to halt the study treatment altogether as soon as it can be safely done for 
patients currently receiving treatment.  
 
CTEP and Theradex must be notified when patients are no longer receiving treatment [i.e., 
when the last patient(s) to be receiving treatment is/are no longer receiving the study regimen 
for any reason]. 
 
14.1.4 
Closed to Follow-Up 
 
The study is considered Closed to Follow-Up when all protocol-defined follow-up 
procedures have been completed for all patients who have not been removed from the study 
for other reasons.  That is, there are no outstanding follow-up procedures to be performed as 
mandated by the protocol. 
 
CTEP does not need to be notified of a status change to “Closed to Follow Up.” 
 
14.1.5 
Complete 
 
Study is considered Complete if it has been at least thirty (30) days since the last patient 
follow-up evaluation.   
 

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A citation to a final study report (manuscript, meeting abstract, etc.) is required with the 
submission of the Protocol Status Update Form to CTEP PIO.   
 
14.2 
Responsibility for Filing Protocol Status Update Forms 
 
CTEP must be notified of all study status changes in Section 14.1 (except for Closed to 
Follow-Up) by the Corresponding Organization via Protocol Status Update Form, available 
from the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/default.htm#amendments.    
 
Theradex must be notified as soon as all patients are off treatment (i.e., when study status 
changes to Closed to Accrual and Treatment).  Theradex will produce a report within 90 days 
of this notification. 
 
 
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936558; ONO-4538) in ASCO. J Clin Oncol.  31:ACRA9006.2013. 
20. Brahmer JR, L. Horn, S.J. Antonia, et al. Survival and long-term follow-up of the phase I trial of 
nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated 
advanced non-small cell lung cancer (NSCLC) in ASCO. J Clin Oncol.  31:A8030. 2013. 
21. Drake CG, D.F. McDermott, M. Sznol, et al. . Survival, safety, and response duration results of 
nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously 
treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up. in ASCO J Clin 
Oncol.  31:A4514. 2013. 
22. Rizvi NA, SJ Antonia, Chow L, et al. A phase I study of nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive 
non-small cell lung cancer (NSCLC) patients (pts). in ASCO. J Clin Oncol.  31:A8072. 2013. 
23. Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N 
Engl J Med, 2012. 366(26): p. 2443-54. 
24. Lo, Y.M., Chan AT, Chan LY, et al. Molecular prognostication of nasopharyngeal carcinoma by 
quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res, 2000. 60(24): p. 6878-
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25. Lo, Y.M., Leung SF, Chan LY, et al. Kinetics of plasma Epstein-Barr virus DNA during 
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26. Chan, A.T., Lo YM, Zee B, et al. Plasma Epstein-Barr Virus DNA and residual disease after 
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27. Ma BB, Kam M, Lo YM, et al. Relationship between pretreatment level of plasma Epstein-Barr 
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28. To, E.W., et al., Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of 
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metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res, 2010. 16(3): p. 1016. 
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Clinic Phase II Consortium (Protocol: MC1079). Mol Cancer Ther November 2013 12; B273, 
2013. Abstract B273:. 
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October 21, 2014 
43. Eisenhauer EA, Therasse P, Bogaert J, et al. New response evaluation criteria in solid tumors:  
revised RECIST guideline (version 1. 1).  Eur J Cancer 45(2):  228-247, 2009.) 
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45. Vandecaveye V, Dirix P, De Keyzer F, et al. Predictive value of diffusion-weighted magnetic 
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Radiol. 2010 Jul; 20(7):1703-14 
46. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 
1958; 53: 457-481. 
 
 

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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on 
all pre-disease performance without restriction. 
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). 
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. 
3 
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 
 

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APPENDIX B: BIOASSAY TEMPLATES 
 

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APPENDIX C: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 
SKIN ADVERSE EVENTS 

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APPENDIX D: CARD FOR STUDY PARTICIPANTS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using nivolumab.  
This clinical trial is sponsored by the National Cancer Institute.  This form is addressed to the 
patient, but includes important information for others who care for this patient.  
 
Although nivolumab is not expected to interact with drugs that are processed by your liver, it is 
still very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements.  
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.   
 
These are the things that you and they need to know:  
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is: _________________   
and he or she can be contacted at __________________________. 
 
 
 
 

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INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using nivolumab.  This clinical trial 
is sponsored by the NCI.  Although nivolumab is not expected to 
interact with drugs that are processed by your liver, you should: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.