A Phase II Evaluation of Nivolumab, a Fully Human Antibody Against PD-1, in the Treatment of Persistent or Recurrent Cervical Cancer
Phase: PHASE2
Conditions: Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Recurrent Cervical Carcinoma, Stage IV Cervical Cancer AJCC v6 and v7, Stage IVA Cervical Cancer AJCC v6 and v7, Stage IVB Cervical Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

 
 
i 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #3 to: NRG-GY002 
 
NCI Protocol #: NRG-GY002 
Local Protocol #: NRG-GY002 
 
NCI Version Date: 01/31/2017 
Protocol Date:  
 
This amendment is being submitted in response to an RRA from Dr. Howard Streicher 
(streicherh@ctep.nci.nih.gov): 
 
# 
Section 
Page(s) 
Change 
1 
Title Page 
1, 2 
• NCI Version Date is now 01/31/2017. 
• Includes Amendments #1-3.  
• Amendment Date has been added to the Document History 
table. 
 
4.2 
17 
The *note now reads:  “*As clinically indicated during treatment for 
symptoms or physical signs of congestive heart failure or 
cardiomyopathy.” 
2 
6.312 and 
6.3.13 
26, 27 
• Drug modification table for Cardiac Toxicities has been added 
as Section 6.3.12. 
• All Other Events is now Section 6.3.13. 
3 
7.31 
29-36 
Updated BMS-936558 CAEPR, Version 2.2, November 15, 2016, has been 
inserted: 
• 
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 

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NCI Version Date 01/31/2017 
ii 
# 
Section 
Page(s) 
Change 
• 
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; 
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.” 
 
 
IC 
 
Additional changes have been made to the IC document. 

Protocol NRG-GY002 
NCI Version Date: 01/31/2017 
 
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NRG ONCOLOGY  
 
NRG-GY002 
(ClinicalTrials.gov NCT #02257528) 
 
A Phase II Evaluation of Nivolumab, a Fully Human Antibody against PD-1, in the Treatment of 
Persistent or Recurrent Cervical Cancer 
NCI Version Date 01/31/2017 
Includes Amendments #1-3 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). 
 
Lead Organization: NRG / NRG Oncology 
This study is limited to NRG Oncology participation 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center, 1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
 
Study Team 
Study Chair 
Study Co-Chair 
Alessandro D. Santin, M.D./Gynecologic Oncology 
Michael Frumovitz, M.D., M.P.H. 
Yale University School of Medicine 
MD Anderson Cancer Center 
Department of Obstetrics and Gynecology 
Dept of Gynecologic Oncology and 
LSOG Bld. Room 305, 333 Cedar Street, PO Box 208063 
Reproductive Medicine 
New Haven, CT 06520-8063 
Unit 1362, CPB 6.3562 
203-737-4450/FAX: 203-737-4339 
1515 Holcombe Blvd 
Alessandro.santin@yale.edu  
Houston, TX 77030 
 
713-792-9599/FAX: 713-792-7586 
 
mfrumovitz@mdanderson.org 
Translational Science Co-Chair 
 
Samir Khleif, MD 
Translational Scientist  
Georgia Health Sciences Center 
Heather A Lankes, PhD, MPH 
Cancer Research Center 
NRG SDMC-Buffalo Office 
1120 15th St, CN 2133 
Roswell Park Cancer Institute 
Augusta, GA 30912 
Elm & Carlton Streets 
706-721-0570 
Buffalo NY 14263 
khleif@gru.edu 
716-845-8508/FAX: 716-845-8393 
 
lankesh@nrgoncology.org 

Protocol NRG-GY002 
NCI Version Date: 01/31/2017 
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Correlative Scientists 
Warner Huh, MD 
Michael Birrer, MD, PhD 
University of Alabama at Birmingham 
Massachusetts General Hospital 
Department of OB/GYN 
Yawkey 9072 
618 20th St S, 538 OHB 
55 Fruit St 
Birmingham, AL 35233 
Boston, MA 02114 
205-934-4986 
317-724-4800 
whuh@uab.edu 
mbirrer@partners.org 
 
 
Data Manager and/or Data Operations Center  
Statistician 
Sandra Dascomb, MS, MT (ASCP) 
Wei Deng, Ph.D. 
NRG SDMC-Buffalo Office 
NRG SDMC-Buffalo Office 
Roswell Park Cancer Institute 
Roswell Park Cancer Institute 
Elm and Carlton Streets 
Elm and Carlton Streets 
Buffalo, NY 14263-0001  
Buffalo, NY 14263-0001 
716-845-5702/FAX: 716-845-8393 
716-845-5702/FAX: 716-845-8393 
sdascomb@gogstats.org 
wdeng@gogstats.org 
 
 
Protocol Coordinator 
Research Nurse 
Meg Colahan, M.A. 
Lisa D. Baker, RN, BSN, OCN 
NRG Oncology 
Yale University School of Medicine 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
Gyn Oncology 
Philadelphia, PA 19103 
333 Cedar Street, FMB340 
215-854-0770/FAX: 215-854-0716 
New Haven, CT 06520 
mcolahan@gog.org 
203-785-6398/FAX: 203-785-7480 
 
Lisa.baker@yale.edu 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Nivolumab 
CTEP 
748726 
125336 
DCTD, NCI 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 3 
01/31/2017 
 
Closure 
04/01/2016 
06/09/2016 
Re-Activation and 
Amendment 2 
04/01/2016 
04/25/2016 
Amendment 1 
03/07/2016 
03/21/2016 
Temporary Closure 
04/24/2015 
08/24/2015 
Activation 
04/24/2015 
05/18/2015 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be used only in conjunction with 
institution-specific IRB approval for study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of this protocol. 

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TABLE OF CONTENTS 
SCHEMA .................................................................................................................................... - 5 - 
1. 
OBJECTIVES ................................................................................................................. - 6 - 
1.1 
Primary Objectives.............................................................................................. - 6 - 
1.2 
Secondary Objective ........................................................................................... - 6 - 
1.3 
Translational Science Objectives ........................................................................ - 6 - 
2. 
BACKGROUND ............................................................................................................ - 6 - 
2.1 
Nivolumab........................................................................................................... - 7 - 
2.2 
Inclusion of Women and Minorities ................................................................. - 12 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ............ - 12 - 
3.1 
Eligibility Criteria ............................................................................................. - 12 - 
3.2 
Ineligibility Criteria .......................................................................................... - 13 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 16 - 
4.1 
PRE-TREATMENT ASSESSMENTS ............................................................. - 16 - 
4.2 
ASSESSMENTS DURING TREATMENT ..................................................... - 17 - 
4.3 
ASSESSMENTS IN FOLLOW UP .................................................................. - 18 - 
5.  
TREATMENT PLAN/Regimen description................................................................. - 18 - 
5.1 
 NIVOLUMAB Therapy ................................................................................... - 18 - 
5.2 
 General Concomitant Medication and Supportive Care Guidelines ................ - 19 - 
5.3 
Duration of Therapy .......................................................................................... - 19 - 
6.  
TREATMENT MODIFICATIONS/managEment........................................................ - 19 - 
6.1 
Criteria to Resume Treatment ........................................................................... - 19 - 
6.2 
Treatment of Nivolumab-Related Infusion Reactions ...................................... - 20 - 
6.3 
Treatment Delay and Discontinuation and Toxicity Management ................... - 22 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 28 - 
7.1   
Protocol Agents ................................................................................................. - 28 - 
7.2  
Adverse Events and Serious Adverse Events ................................................... - 28 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP 
Study Agents ..................................................................................................... - 29 - 
7.4 
Expedited Reporting of Adverse Events ........................................................... - 33 - 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ......... - 36 - 
8.1 
Registration Procedures .................................................................................... - 36 - 
8.2 
Patient Enrollment ............................................................................................ - 38 - 
8.3 
Oncology Patient Enrollment Network (OPEN)............................................... - 38 - 
8.4 
Agent Ordering and Agent Accountability ....................................................... - 39 - 
9. 
DRUG INFORMATION .............................................................................................. - 39 - 
9.1 
Nivolumab (BMS-936558, MDX1106), NSC #748726 ................................... - 39 - 

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10. 
Pathology ...................................................................................................................... - 40 - 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL studies ......................................... - 41 - 
11.1 
Reimbursement ................................................................................................. - 41 - 
11.2 
Translational Science ........................................................................................ - 41 - 
11.3 
Specimen Requirements.................................................................................... - 41 - 
11.4 
Quality of Life................................................................................................... - 43 - 
12. 
DATA AND RECORDS .............................................................................................. - 43 - 
12.1 
Data Management/Collection ........................................................................... - 43 - 
12.2 
NRG Data Management Forms ........................................................................ - 44 - 
12.3 
Summary of Data Submission .......................................................................... - 47 - 
12.4 
Global Reporting/Monitoring ........................................................................... - 47 - 
13. 
STATISTICAL CONSIDERATIONS.......................................................................... - 47 - 
13.1 
Study Design ..................................................................................................... - 47 - 
13.2 
Study Endpoints ................................................................................................ - 48 - 
13.3 
Primary Objectives Study Design ..................................................................... - 48 - 
13.4 
Study Monitoring of Primary Objectives .......................................................... - 50 - 
13.5 
Accrual Considerations ..................................................................................... - 51 - 
13.6 
Dose Level Guidelines ...................................................................................... - 52 - 
13.7 
Secondary or Exploratory Elements (including correlative science aims) ....... - 52 - 
13.8 
 Exploratory Hypothesis and Endpoints ........................................................... - 53 - 
13.9 
Gender/Ethnicity/Race Distribution.................................................................. - 54 - 
14. 
EVALUATION CRITERIA ......................................................................................... - 54 - 
14.1 
Response Assessment:  RECIST 1.1 ................................................................ - 54 - 
15. 
REFERENCES ............................................................................................................. - 60 - 
APPENDIX I - COLLABORATIVE AGREEMENT .............................................................. - 64 - 
APPENDIX II - PERFORMANCE STATUS CRITERIA ....................................................... - 66 - 
APPENDIX III 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 
SKIN ADVERSE EVENTS ......................................................................................... - 67 - 
APPENDIX IV - TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES ................... - 74 - 
 
 

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Patients must have persistent, recurrent or metastatic squamous 
cell carcinoma, adenosquamous carcinoma or adenocarcinoma 
of the cervix with documented disease progression (disease not 
amendable to curative therapy). 
Patients must have had one prior systemic chemotherapeutic 
regimen for management of persistent, recurrent or metastatic 
disease 
Nivolumab 3 mg/kg IV every 2 weeks (+/- 2 days) for 4 
doses followed by an additional 42 doses 3mg/kg IV q 2 
weeks for a maximum of 46 doses over 92 weeks until 
disease progression or adverse effects prohibit therapy, 
whichever comes first.  
One Cycle = 2 doses (Day 1 Dose and Day 15 Dose) 
(03/21/2016) 
 
NRG-GY002 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
1.1.1  
To assess the antitumor activity (proportion of objective response by RECIST 1.1 
criteria) of nivolumab with objective tumor response in patients with persistent, 
recurrent or metastatic carcinoma of the cervix 
1.1.2  
To determine the nature and degree of toxicity of nivolumab as assessed by CTCAE in 
patients with persistent, recurrent or metastatic carcinoma of the cervix 
 
1.2 
Secondary Objective 
To estimate the duration of progression-free survival (PFS) and overall survival (OS). 
 
1.3 
Translational Science Objectives 
1.3.1 
To systematically evaluate PD-1 and B7-H1 (i.e., PD-1 Ligand) expression in tumor 
infiltrating lymphocytes (TILs) and cervical cancer cells and explore their correlations 
with objective response, PFS, and OS in nivolumab-treated patients with PD-1 and B7-
H1 scoring results.  
1.3.2 
To explore the composition of immune infiltrates in tumor specimens/biopsies from 
primary and/or metastatic/recurrent sites with selected markers including (but not 
limited) to CD4+,CD8+, FoxP3, CD25, LAG-3, TIM-3, and ICOS and their correlations 
to objective response, PFS and OS in nivolumab-treated patients. 
1.3.3 
To evaluate HPV status and to explore the changes of pre- and post-immune therapy 
responses to HPV16/18/31/35/45 E7 antigens in patients peripheral blood lymphocytes 
(PBL) and serum using proliferative and IFN-gamma ELISPOT (cellular immunity) and 
serological (ELISA) assays. 
1.3.4 
To explore the levels of circulating tumor cells (CTCs) pre-treatment and at 8 and 12 
weeks and their association with patient outcome. 
 
2. 
BACKGROUND 
The usual treatment for recurrent or metastatic cervical cancer is a combination of 
paclitaxel and cisplatin or paclitaxel, cisplatin and bevacizumab.(Monk et al, 2009; 
Tewari et al, 2014)  This treatment, although not curative, results in median survival 
times of approximately one to 1.5 years.  Once patients progress after this initial therapy 
for recurrent or metastatic disease, options are limited (there are no FDA approved or 
NCCN level 1 or 2A therapies available). 
Human Papillomavirus (HPV) DNA is detected in more than 99% of cervical cancer 
specimens and a large portion of these tumors are associated with HPV types 16 and 18. 
E6 and E7 play a major role in the transformation of HPV-infected cervical 
keratinocytes and these viral antigens are consistently expressed in HPV-associated 
neoplasms and may represent ideal targets for cervical cancer immunotherapy.(Santin et 
al, 1999; Santin et al, 2006; Santin et al, 2008) However, despite the great potential of 
immunotherapeutic approaches to treat chemotherapy/radiation resistant cervical cancer, 
tumor immunity is hindered by the expression of a series of cell surface molecules 
known as immune checkpoints in the suppressive tumor microenvironment.(Mellman et 
al, 2011)  

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Compelling evidence indicates that B7 molecules (i.e., B7-1/CD80, B7-2/CD86, B7-
H1/PDL1, B7-H2/L-ICOS, B7-DC, B7-H3 and B7-H4) and their ligands (i.e., CTLA-4, 
CD28, PD-1, ICOS) not only provide crucial positive signals to stimulate and support T-
cell activation, but can also offer negative signals that control and suppress potentially 
protective T-cell responses against spontaneously arising and virally-induced human 
tumors.(Mellman et al, 2011) Expression of these molecules on the surface of cervical 
tumor cells, tumor associated macrophages (TAM) and/or dendritic cells (DC), may 
attenuate or abrogate the ability of the immune system to successfully eliminate strongly 
antigenic (i.e., virus-infected) tumors such as cervical cancer.(Mellman et al, 2011) 
Because these negative signals in multiple human solid tumors have been shown to be 
largely provided by programmed death-1 (PD-1), blockade of PD-1/PD-L1 co-inhibitory 
pathways by novel monoclonal antibodies may represent an innovative, potentially 
highly effective therapeutic approach to reverse immune suppression while inducing 
tumor-specific immunity in cervical cancer patients. Consistent with this hypothesis, 
exciting results have recently been reported in the clinical setting against multiple 
human cancers by the use of a fully-human antibody that targets the inhibitory receptor 
PD1 expressed on activated T-cells.(Topalian et al, 2012) In this study, objective 
response rates (ORs) across dose cohorts, as measured by standard RECIST criteria, 
ranged from 6% to 32% in non–small-cell lung cancer, 19% to 41% in metastatic 
melanoma and 24% to 31% in renal-cell cancer. Most of the responses were durable in 
these patients and the toxicity profile of nivolumab was found to be safer than that of 
ipilimumab (i.e., a monoclonal antibody targeting CTLA4, another crucial inhibitory 
molecule expressed on activated T cells, recently approved by the FDA for treatment of 
advanced melanoma patients).(6, 7) Importantly, an additional study targeting the 
blockade of PD-L1 (i.e., B7H1 or PD1-ligand) also induced durable tumor regression 
(objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 
to 41% at 24 weeks) in patients with advanced cancers, including non–small-cell lung 
cancer, melanoma, and renal-cell cancer. (Brahmer et al, 2012)  
PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, has been recently 
reported to be associated with high risk-HPV positivity and to be increased in parallel 
with increasing cervical intraepithelial neoplasia (CIN) grade.(Yang et al, 2013) 
Furthermore, increased expression of PD-1 and its ligand PD-L1 correlates with 
impaired cell-mediated immunity in high-risk HPV-related CIN.(Yang et al, 2013) 
Finally, in cervical cancer, PD-1 is expressed by a vast number of infiltrating CD8 T 
cells, suggesting that blocking of PD-1 could have therapeutic potential in cervical 
cancer patients with recurrent and/or metastatic disease unresponsive to 
treatment.(Karim et al, 2009)  
 
Taken together, these studies strongly validate the importance of the PD-1-PD-L1 
pathway for the treatment of patients harboring multiple human solid tumors, including 
virally-infected tumors such as cervical cancer. 
2.1 
Nivolumab 
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 

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(Investigator Brochure, 2013).  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 
(Wolchok et al., 2013).   
 
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) 
(Investigator Brochure, 2013).  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 23-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 T-cell immune response through SHP-1 
phosphastase.   
 
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) 

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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 (Woo et al., 2012).  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 (Taube et al., 2012), renal 
(Thompson et al., 2004; Thompson et al., 2005; Thompson et al., 2006), esophageal 
(Ohigashi, et al. 2005), gastric (Wu et al., 2006), ovarian (Dong et al., 2003), pancreatic 
(Nomi, et al., 2007), lung (Zitvogel, et al., 2006), and other cancers (Investigator 
Brochure, 2013). 
 
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.   
2.1.1 
Nonclinical Development of Nivolumab 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab 
alone was well tolerated (Investigator Brochure, 2013).  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. 
2.1.2 
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 (Investigator 
Brochure, 2013).  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 

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ovarian cancer.   
2.1.2.1 
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 (Investigator Brochure, 2013).  
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.   
2.1.2.2 
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 (Sznol et al., 2013).  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 
(Brahmer et al., 2013).  In the RCC cohort, median duration of response was 12.9 
months for both doses with 5 of the 10 responses lasting ≥1 year (Drake et al., 2013).   
 
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) (Wolchok et al., 2013).  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 (Rizvi et al., 2013).  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. 
2.1.2.3 
Toxicology 
A maximum tolerated dose (MTD) of nivolumab was not defined (Topalian et al., 2012).  
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 (Wolchok et al., 2013), grade 3 or 4 treatment-related events were noted 
in 53% of patients.  Skin rash represents the majority of these event.  

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2.1.2.4 
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 (Wolchok et al., 2013).  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.  
 
2.1.2.5 
Translational Science Background 
A variety of factors may potentially predict clinical response to nivolumab in cervical 
cancer patients. Accordingly, an exploratory objective of this study is to investigate in 
tumor specimens obtained at screening, and in peripheral blood taken both at screening 
(prior to the first dose of study drug) and during the study, biomarkers and their 
association with nivolumab treatment and treatment outcome (as outlined in section 11 
and Appendix IV).  
 
Briefly, PD-L1 expression has been reported in a number of human tumors, and 
associated with poor prognoses based on OS.  However, limited information is available 
regarding PD-1 and PD-L1 expression on cervical HPV-infected tumor cells and T cells 
infiltrating cervical cancers (TIL). Accordingly, this study will systematically evaluate 
PD-1 and B7-H1 (i.e., PD-1 Ligand) expression in tumor infiltrating lymphocytes (TILs) 
and cervical cancer cells using standardized immunohistochemistry (IHC) techniques 
(Velcheti et al., 2014) and explore their correlations with objective response, PFS, and 
OS in nivolumab-treated patients with PD-1 and B7-H1 scoring results.  We will explore 
the composition of immune infiltrates in tumor specimens/biopsies from primary and/or 
metastatic/recurrent sites with selected markers including (but not limited) to 
CD4+,CD8+, FoxP3, CD25, LAG-3, TIM-3, and ICOS and their correlations to 
objective response, PFS and OS in nivolumab-treated patients (Velcheti et al., 2014).  
We are also planning to evaluate HPV status and to explore the changes of pre- and 
post-immune therapy responses to HPV16/18/31/35/45 E7 antigens in patients 
peripheral blood lymphocytes (PBL) and serum using proliferative and IFN-gamma 
ELISPOT (cellular immunity) assays and a new streptavidin-biotin capture ELISA 
method to investigate anti-HPV E7 antibody prevalence in serum (Ravaggi et al., 2006). 
These explorative assays have previously been validated in studies using reagents 
obtained from both healthy women as well as cervical cancer patients vaccinated within 
Phase I clinical studies with HPV type 16 and 18 E7 antigen-loaded autologous dendritic 

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cells (DC) as a therapeutic cellular vaccine (Santin et al., 1999, Ravaggi et al., 2006, 
Santin et al., 2006, Santin et al., 2008). Finally, the levels of circulating tumor cells 
(CTCs) pre-treatment and at 8 and 12 weeks and their association with patient outcome 
we will be explored using multi-marker µ-nuclear magnetic resonance, as recently 
described (Ghazani et al, 2014). 
 
2.2 
Inclusion of Women and Minorities 
NRG Oncology and NRG participating institutions will not exclude potential subjects 
from participating in this or any study solely on the basis of ethnic origin of 
socioeconomic status.  Every attempt will be made to enter all eligible patients into this 
protocol and therefore address the study objectives in a patient population representative 
of the entire cervical cancer population treated by participating institutions. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Statistical and 
Data Management Center-Buffalo Office (716-845-5702).  
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.1.1 
Patients must have persistent, recurrent or metastatic squamous cell carcinoma, 
adenosquamous carcinoma or adenocarcinoma of the cervix with documented disease 
progression (disease not amendable to curative therapy).  NOTE:  the following cervical 
tumors are not eligible:  minimal deviation/adenoma malignum, gastric type 
adenocarcinoma, clear cell carcinoma and mesonephric carcinoma.  Histologic 
confirmation of the original primary tumor is required via the pathology report. 
(04/25/2016) 
3.1.2 
All patents must have measurable disease as defined by RECIST 1.1.  Measurable 
disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded).  Each lesion must be ≥ 10 mm when 
measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when 
measured by chest x-ray.  Lymph nodes must be ≥ 15 mm in short axis when measured 
by CT or MRI. 
3.1.3 
Patients must have at least one “target” lesion” to be used to assess response on this 
protocol as defined by RECIST 1.1.  Tumors within a previously irradiated field will be 
designated as “non-target” lesions unless progression is documented or a biopsy is 
obtained to confirm persistence at least 90 days following completion of radiation 
therapy. 
3.1.4 
Appropriate for study entry based on the following diagnostic workup: 
• 
History/physical examination within 28 days prior to registration; 
• 
Imaging of target lesion(s) within 28 days prior to registration; 
• 
Further protocol-specific assessments: 
o Recovery from adverse effects of recent surgery, radiotherapy or chemotherapy 
o Any other prior therapy directed at the malignant tumor including chemotherapy, 
biologic/targeted agents and immunologic agents must be discontinued at least three 
weeks prior to registration. 

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o Investigation agents must be discontinued for at least 30 days prior to registration. 
o Any prior radiation therapy must be completed at least 4 weeks prior to registration. 
o At least 4 weeks must have elapsed since any major surgery prior to registration. 
 
3.1.5 
Prior Therapy 
Patients must have had one prior systemic chemotherapeutic regimen for management of 
persistent, recurrent or metastatic carcinoma of the cervix (e.g.; paclitaxel/cisplatin, 
paclitaxel/cisplatin/bevacizumab).  Chemotherapy administered concurrent with primary 
radiation (e.g.; weekly cisplatin) is not counted as a systemic chemotherapy regimen.  
Adjuvant chemotherapy given following the completion of radiation therapy (or 
concurrent chemotherapy and radiation therapy) is not counted as a systemic 
chemotherapy regimen (e.g.; paclitaxel and carboplatin for up to 4 cycles).  NOTE: 
Patients who have received more than one prior regimen are NOT eligible. 
3.1.6 
Age ≥ 18; because no dosing or adverse event data are currently available on the use of 
nivolumab in patients <18 years of age, children are excluded from this study, but will 
be eligible for future pediatric trials. 
3.1.7 
The trial is open to females only. 
 
3.1.8 
Performance Status of 0 or 1. 
3.1.9 
Adequate hematologic function within 14 days prior to registration defined as follows: 
• 
ANC ≥ 1,500/ul 
• 
Platelets ≥ 100,000/ul 
3.1.10 
Adequate renal function within 14 days prior to registration defined as follows: 
• 
Creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or CrCl ≥ 40mL/min 
using Cockcroft-Gault formula 
3.1.11 
Adequate hepatic function within 14 days prior to registration defined as follows: 
• 
Bilirubin ≤ 1.5 x ULN 
• 
ALT and AST ≤ 3 x ULN 
3.1.12 
Normal thyroid function testing (TSH) within 14 days prior to registration   
3.1.13 
The patient or a legally authorized representative must provide study-specific informed 
consent and authorization permitting release of personal health information prior to 
study entry. 
 
3.2 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this 
study. 
3.2.1 
Patients who have had prior therapy with nivolumab or 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 check point pathways. 
3.2.2 
History of severe hypersensitivity reaction to any monoclonal antibody. 
3.2.3 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 
a minimum of 3 years.  
3.2.4 
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure and unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
3.2.5 
Patients who are pregnant or nursing.  The effects of nivolumab on the developing 

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human fetus are unknown.  For this reason, women of child-bearing potential (WOCBP) 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  WOCBP 
should use an adequate method to avoid pregnancy for 23 weeks after the last dose of 
investigational drug.  WOCBP must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IV/L or equivalent units of HCG) within 24 hours prior to the 
start of nivolumab.  Women must not be breastfeeding. 
 
 
Women who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile or have undergone definitive radiation) do not require contraception. 
 
 
Women of childbearing potential (WOCBP) is defined as any female who has 
experience menarche and who has not undergone surgical sterilization (hysterectomy of 
bilateral oophorectomy) or who is not postmenopausal.  Menopause is defined clinically 
as 12 month amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes.  In addition, women under the age of 55 must have a documented 
serum follicle stimulating hormone (FSH) level greater than 40mIU/mL. 
 
 
WOCBP receiving nivolumab will be instructed to adhere to contraception for a period 
of 23 weeks after the last dose of investigational product.  This duration has been 
calculated using the upper limit of the half-life of nivolumab (25 days) and are based on 
the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days. 
 
Should a woman become pregnant or suspect she is pregnant while she is participating 
in this study, she should inform the treating physician immediately. 
3.2.6 
Patients with known brain metastases or leptomeningeal metastases are excluded unless 
the following conditions are met: 
o 
Metastases have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete (must be 
confirmed within 28 days prior to the first dose of nivolumab administration)  
o 
There must also be no requirement for immunosuppressive doses of systemic 
corticosteroids (>10 mg/day prednisone equivalents) for at least 2 weeks prior to 
study drug administration. 
3.2.7 
Patients should be excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome 
(AIDS). 
 
 
Cervical cancer patients on combination antiretroviral therapy and those with other 
acquired/inherited immunodeficiencies are excluded from this protocol secondary to the 
possibility the immune condition and medications may affect tumor response to 
nivolumab as well as the higher risk of active opportunistic infections. 
 
Patients should be excluded if they have a positive test for hepatitis B virus surface 
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating 
acute or chronic infection. 
 
 
Autoimmune hepatotoxicity is a side effect of immune checkpoint inhibitors as a class. 

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Hepatitis B and C subjects with active/chronic disease may have an increased risk for 
development of nivolumab-induced liver-autoimmunity and for this reason are excluded 
from this protocol. 
 
3.2.8 
Patients with 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, should be excluded.  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 (IRB), 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.  Patient with vitiligo, endocrine deficiencies 
including thyroiditis managed with replacement hormones including physiologic 
corticosteroids are eligible.  Patients with rheumatoid arthritis and other arthropathies, 
Sjogren’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. 
 
NOTE:  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). 
3.2.9 
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration.  Inhaled 
or topical steroids and adrenal replacement doses <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. 
3.2.10 
Patients who have had evidence of active or acute diverticulitis, intra-abdominal 
abscess, abdominal/pelvic fistula, gastrointestinal perforation, GI obstruction and/or who 
require parenteral hydration and/or nutrition. 
 
 

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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PRE-TREATMENT ASSESSMENTS (03/21/2016) (04/25/2016) 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(Cycle 1, Day 1) 
 
History and Physical 
≤ 28 days 
≤ 28 days 
Vital Signs (heart rate, 
temperature, blood pressure) 
≤ 28 days 
≤ 28 days 
Height 
Any prior documentation 
on adult medical record 
of treating site 
 
Weight 
≤ 28 days 
≤ 28 days 
Performance Status 
≤ 28 days 
≤ 28 days 
Toxicity Assessment 
≤ 14 days 
≤ 14 days 
Concurrent Medications 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
≤ 14 days 
≤ 14 days 
Chemistries (including Sodium, 
Potassium, Chloride, bicarbonate, 
Calcium, Glucose, BUN, 
Creatinine (and/or Creatinine 
Clearance), Total Bilirubin, Total 
Protein, ALT, AST, Alkaline 
Phosphatase, Albumin) 
≤ 14 days 
≤ 14 days 
TSH 
≤ 14 days 
≤ 14 days 
Testing for hepatitis C (HCV) and 
hepatitis B (HBV) 
≤ 14 days 
≤ 14 days 
Pregnancy Test (for patients of 
child bearing potential) 
≤ 14 days 
≤ 24 hours 
Chest imaging (X-ray or CT scan 
of the chest) 
≤ 28 days 
≤ 28 days 
Radiographic Tumor Measurement 
(CT or MRI of the abdomen and 
pelvis) 
≤ 28 days 
≤ 28 days 
ECG 
≤ 28 days 
 
 
 
 

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4.2 
ASSESSMENTS DURING TREATMENT (03/21/2016) (04/25/2016) 
Assessments 
Prior to Each 
Nivolumab Dose 
(Cycle 1, Day 15 
Dose and Forward) 
Prior to Day 1 of 
each Cycle (Cycle 
2 and Forward) 
Every 8 weeks x 6 
months and then 
every 12 weeks (+/- 
7 days) 
History and Physical 
X 
 
 
Vital Signs (heart rate, 
temperature, blood pressure) 
X 
 
 
Weight 
X 
 
 
Performance Status 
X 
 
 
Toxicity Assessment 
X 
 
 
Concurrent Medications 
X 
 
 
CBC/Differential/Platelets 
X (within 72 hours) 
 
 
 Chemistries (including Sodium, 
Potassium, Chloride, bicarbonate, 
Calcium, Glucose, 
BUN/Creatinine, Total Bilirubin, 
Total Protein, ALT, AST, 
Alkaline Phosphatase, Albumin) 
X (within 72 hours) 
 
 
Amylase/Lipase 
 
X (within 72 hours) 
 
TSH 
 
X (within 72 hours) 
 
 Chest imaging if initially 
abnormal or required to monitor 
tumor response 
 
 
X (see Excel tool) 
Radiographic tumor measurement 
 
 
X (see Excel tool) 
ECG* 
 
 
 
*As clinically indicated during treatment for symptoms or physical signs of congestive heart failure or 
cardiomyopathy. (  ) 
 
 

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4.3 
ASSESSMENTS IN FOLLOW UP (03/21/2016) 
Assessments 
From end of treatment: q3 mos. x 2 yrs.; 
q6 mos. x 3 years until disease progression 
or until patient initiates a subsequent cancer 
therapy.  Follow-up forms (Q forms) are 
collected for the 5 year follow-up period or 
until study termination. 
Vital Status 
X 
Toxicity Assessment 
X (Report all adverse events that occur 
within 100 days of last protocol treatment on 
Follow-Up Adverse Event Reporting Form.  
For reporting delayed toxicity, see section 7. 
Chest imaging if initially 
abnormal or required to 
monitor tumor response 
Every three months until disease progression 
or until patient initiates a subsequent cancer 
therapy 
Radiography tumor 
measurement 
Every three months until disease progression 
or until patient initiates a subsequent cancer 
therapy 
 
Patients will be followed for 100 days from last dose of nivolumab.  Patients who 
discontinue treatment for unacceptable adverse events(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.  
TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
 
NIVOLUMAB Therapy  
 
 
Nivolumab 3 mg/kg IV every 2 weeks (+/- 2 days) for 4 doses followed by an 
additional 42 doses 3mg/kg IV q 2 weeks for a total of 46 doses over 92 weeks 
unless adverse effects prohibit therapy.  Patients may be dosed no less than 12 days 
from the previous dose of drug.  
 
During maintenance, a patient will be permitted to have an infusion delayed up to 7 days 
(without this being considered to be a protocol violation) for major life events (e.g., 
serious illness in a family member, major holiday, vacation which is unable to be re-
scheduled). Documentation to justify this decision should be provided. 
 
 
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 (or most recent) dose, the dose must be recalculated.  All doses should be 
rounded to the nearest milligram or as per institutional guidelines.  There will be no dose 
modifications allowed. (03/21/2016) 
 
 
 
Nivolumab is to be administered over approximately 60-minutes as an IV infusion, 
using a volumetric pump with a 0.2-1.2 micron 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 solution cannot be below 0.35 mg/mL.  It is not to be administered as an IV push 

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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 
5.2.1  
Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol. 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified or until one of the following criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) , which include the following (see also section 6 and 
specific algorithms in Appendix III ): (04/25/2016) 
o 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. 
o Tumor assessments should continue as per protocol even if 
dosing is interrupted.  
• 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. 
 
6.  
TREATMENT MODIFICATIONS/MANAGEMENT (04/25/2016) 
No dose reductions or escalations for nivolumab are permitted or specified. In the 
case of adverse effects, please see guidelines below and Appendix III for treatment 
delay/discontinuation and for management.  
NOTE:  Management algorithms for endocrinopathy, gastrointestinal, hepatic, 
neurological, pulmonary, renal and skin adverse events are detailed in Appendix 
III. 
 
6.1 
Criteria to Resume Treatment (04/25/2016) 
Some patients may continue to benefit from treatment, maintaining or improving 
responses, including those treated with steroids. 
 
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: 
• Evaluation to exclude any additional immune mediated events endocrine, GI, and 

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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.  
 
For patients treated with high dose steroids:  Must resolve to baseline within 6 weeks of 
treatment. 
 
Must be off steroids for at least 2 weeks with no recurrence or new events.  New 
immune related events or exacerbation of existing events during steroid treatment or 
taper suggest the presence of ongoing immune activation and require permanent 
discontinuation of nivolumab.  
 
Must have had no recurrence of symptoms or new symptoms during steroid taper. 
 
6.2 
Treatment of Nivolumab-Related Infusion Reactions (04/25/2016) 
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, pruritus, 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: 
 
Remain at bedside and monitor subject until recovery from symptoms.   
 
For Grade 1 symptoms:  (Mild reaction; infusion interruption not indicated; 
intervention not indicated) 
 
Infusion rate may be slowed.  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.   
 
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. 

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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, re-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. 
 
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 ventilatory support indicated).  
 
Nivolumab will be permanently discontinued. 
 
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.  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 localized or generalized pruritus 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 

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the presentation of systemic inflammation.  Please evaluate accordingly.  
 
6.3 
Treatment Delay and Discontinuation and Toxicity Management (04/25/2016) 
 
 
Please refer to the Nivolumab Investigator Brochure or Appendix III to the protocol 
for toxicity management algorithms which include specific treatment guidelines.  
These algorithms should be followed unless there are specific clinical circumstances 
for which the treating physician decides an alternative treatment approach is 
clinically appropriate.  Consultation with the study PI is recommended.  
 
 
 
In several places there are differences from the algorithms regarding protocol directed 
drug modifications and these are identified with (#).  In these cases please follow the 
protocol specific guidelines in this section.  
  
 
Generally we strongly encourage early evaluation while withholding drug, and 
appropriate treatment as indicated in the management tables and event specific 
guidelines. 
 
 
6.3.1 
Skin Rash and Oral Lesions (see Appendix III:  Skin Adverse Event Management 
Algorithm) (04/25/2016) 
 
Skin Rash 
and Oral 
Lesions 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue therapy per protocol* 
Grade 2 
Hold* until ≤ Grade 1 (#) 
Grade 3 
Hold* until ≤ Grade 1.  Resume 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:  See Appendix III 
 
 
 

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6.3.2 
Liver Function/AST/ALT and Bilirubin (see Appendix III:  Hepatic Adverse Event 
Management Algorithm) (04/25/2016) 
 
Liver Function 
AST/ALT/Bilirubin 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold until ≤ UNL or baseline (#)  
Grade 2 
Hold until ≤ UNL or baseline 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.  Holding drug to evaluate LFT changes and early treatment are recommended.   
LFT changes may occur during steroid tapers from other events and may occur together with 
other GI events including cholecystitis/pancreatitis. 
Recommended management:  see Appendix III 
 
 
6.3.3 Diarrhea/Colitis (see Appendix III:  GI Adverse Event Management Algorithm) 
(04/25/2016) 
 
Diarrhea/ 
Colitis  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold until baseline (#) 
Grade 2 
Hold until baseline  
Grade 3 
Off protocol therapy 
Grade 4 
Off protocol therapy 
See GI AE Management Algorithm (Appendix III) for management of symptomatic colitis.  
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution.  
Patients who require steroids should be taken off study treatment.  
Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-limited 
infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.  
Recommended management:  see Appendix III 
 
6.3.4 
Pancreatitis-Amylase/Lipase (04/25/2016) 
 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold until baseline.  Resume if asymptomatic 
Grade 2 
Hold until baseline.  Resume if asymptomatic 
Grade 3 
Hold until baseline.  Resume if asymptomatic. Patients who 
develop symptomatic pancreatitis or DM should be taken off 
protocol therapy. 
Grade 4 
Hold until baseline.  Resume if asymptomatic. Patients who 
develop symptomatic pancreatitis or DM should be taken off 
protocol therapy. 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as 

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Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab 
DM and DKA.  Lipase elevation may occur during the period of steroid withdrawal 
and with other immune mediated events or associated with colitis, hepatitis, and 
patients who have asymptomatic lipase elevation typically have self-limited course 
and may be retreated.  
For treatment management of symptomatic pancreatitis please follow the Hepatic 
Adverse Event Management Algorithm (Appendix III). 
 
6.3.5 
Pneumonitis (see Appendix III:  Pulmonary Adverse Event Management 
 
Algorithm) (04/25/2016) 
 
Pneumonitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and resolution to baseline including 
baseline pO2.  Resume after pulmonary and/or ID consultation 
excludes lymphocytic pneumonitis. (#) 
Grade 2 
Hold dose pending evaluation. Resume after pulmonary and/or ID 
consultation excludes lymphocytic pneumonitis.  Off protocol 
therapy if steroids are required. (#)  
Grade 3 
Hold dose pending evaluation. Resume after pulmonary and/or ID 
consultation excludes lymphocytic pneumonitis.  Off protocol 
therapy if steroids are required. (#)  
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 Appendix III 
 
6.3.6 
Other GI/Nausea and Vomiting (04/25/2016) 
 
Other GI N-V  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue therapy per protocol 
Grade 2 
Hold pending evaluation for gastritis, duodenitis and other 
immune adverse events or other causes.  Resume after resolution 
to ≤ Grade 1.   
Grade 3 
Hold pending evaluation and until ≤ Grade 1.  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 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events.   
 
 
 

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6.3.7 
Fatigue (04/25/2016) 
 
Fatigue  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue therapy per protocol 
Grade 2 
Continue therapy per protocol 
Grade 3 
Hold until ≤ Grade 2 
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, hepatic, and/or muscle (CPK) 
inflammation  
 
6.3.8 
Neurologic Events (see Appendix III:  Neurological Adverse Event Management 
 
Algorithm) (04/25/2016) 
 
Neurologic events  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold pending evaluation and observation. (#) Resume when 
resolved to baseline. 
Grade 2 
Hold pending evaluation and observation. (#) Hold until ≤ Grade 
1.  Off protocol therapy if treatment with steroids is required. 
Resume 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, myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, and myasthenia gravis should be off 
study.   
Recommended management:  See Appendix III 
 
6.3.9 
Endocrine Hypophysitis/Adrenal Insufficiency (see Appendix III:  Endocrinopathy 
 
Management Guidelines) (04/25/2016) 
 
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Asymptomatic TSH elevation *  Hold pending evaluation, 
consider endocrine consult (#)  
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.  
Grade 3 
Off protocol therapy 
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 

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Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
Management/Next Dose for Nivolumab 
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 Appendix III 
 
6.3.10 
Fever (04/25/2016) 
 
Fever  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Evaluate and continue therapy per protocol 
Grade 2 
Evaluate.  Hold until ≤ Grade 1 
Grade 3 
Evaluate.  Hold until ≤ Grade 1 
Grade 4 
Off protocol therapy 
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 6.2 “Treatment of Nivolumab-Related Infusion Reactions”  
 
6.3.11 
Renal Adverse Event Management Algorithm) see Appendix III:  Renal 
Management Guidelines) (4/25/2016) 
 
Renal Adverse 
Events 
Management/Protocol Therapy Modifications 
Grade 1 
Continue therapy per protocol and monitor creatinine weekly 
Grade 2 
Hold until ≤ Grade 1 
Grade 3 
Hold until ≤ Grade 1 
Grade 4 
Off protocol therapy 
Recommended management:  See Renal Adverse Event Management Algorithm in 
Appendix III 
 
6.3.12 
Cardiac Adverse Event Management (  ) 
 
 
 
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 

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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. 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.   
 
 
6.3.13 
All Other Events (04/25/2016) 
 
ALL OTHER 
EVENTS 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Continue therapy per protocol 
Grade 2 
Hold until ≤ Grade 1 OR baseline (exceptions as noted below) 
Grade 3 
Off protocol therapy (exceptions as noted below) 
Grade 4 
Off protocol therapy 
Recommended management:  As clinically indicated  
 
• Any grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment should go off protocol treatment. 
 
• 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 should go off protocol treatment.  
 
• Any grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality that can 
be managed with electrolyte replacement, hormone replacement, insulin, or that does not 
require treatment does not require discontinuation.  
 

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6.3.13 
Treatment Delays 
 
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 6.1 (Criteria to Resume 
Treatment.) 
  
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 REPORTING REQUIREMENTS 
7.1   
Protocol Agents 
 
Investigational Agents 
The investigational agents administered in NRG-GY002 are: 
Nivolumab:  IND #125336; IND Sponsor:  DCTD, NCI 
For Nivolumab, determination of whether an adverse event meets expedited reporting 
criteria, see the reporting table in section 7.4.3 of the protocol. 
7.2  
Adverse Events and Serious Adverse Events 
7.2.1 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for CTEP-AERS (CTEP Adverse Event Reporting System) 
CAERs reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
7.2.2 
Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of 
unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 

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Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP Study 
Agents 
7.3.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
 
BMS-936558 (Nivolumab, MDX-1106, NSC 748726) (03/21/2016) (  ) 
 
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) 
  
 
 
Myositis 
  
NERVOUS SYSTEM DISORDERS 
  

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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%) 
 
 
 
 
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. 
 
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 

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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) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 

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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. 
 
 
7.4 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Regulatory Affairs by phone at 215-854-0770.  An electronic report 
must be submitted immediately upon re-establishment of the Internet connection. 
 
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 (incl 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.  
 
7.4.1 
Expedited Reporting Methods 
• CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS 24-hour notification must be followed by a complete report within 3 
days. Supporting source documentation is requested by NRG as needed to complete 

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adverse event review.  When submitting supporting source documentation, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each 
page, and fax supporting documentation to the NRG Regulatory Affairs by phone at 
215-854-0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. 
Sites must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
7.4.2 
Expedited Reporting Requirements for Adverse Events  
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a CTEP IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
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 CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 

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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; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 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 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For 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. 
 
7.4.3 
Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.4.4 
Secondary Malignancy  
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 during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported 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.  
 
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 reporting via CDUS unless otherwise specified. 
  

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8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
8.1 
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>. 
8.1.1 
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 will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
 
To obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam. 
 
 
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>. 
8.1.2 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
8.1.2.1 
IRB Approval:   

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Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering 
credentials at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
 
Sites participating on the NCI CIRB initiative and that are approved by the CIRB for the 
study are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review.  This information will be 
provided to the CTSU Regulatory Office from the CIRB at the time of the CIRB 
approval.  The Signatory Institution must inform the CTSU which CIRB-approved 
institutions alighed with the Signatory Institution are participating in a given study so 
that the study approval can be applied to those institutions. 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. 
8.1.2.2 
Requirements for NRG-GY002 Site Registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating 
via the NCI CIRB)  
8.1.2.3 
Submitting Regulatory Documents:  
 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent 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) 
8.1.2.4 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go  
 

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8.2 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
8.3 
Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. All site 
staff (NRG and CTSU Sites) will use OPEN to enroll patients to this study. It is 
integrated with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the Rave database. OPEN can be accessed 
at https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN 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 group or CTSU web site 
as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
Access requirements for OPEN: 
• 
See Section 8.1.1 for information on obtaining a CTEP-IAM account.  
• 
To perform registrations, the site user must have been assigned the 'Registrar' 
role on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the NRG, 
you must have an equivalent 'Registrar' role on the NRG roster.  Role 
assignments are handled through the Groups in which you are a member.  
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU 
roster. Site and/or Data Administrators can manage CTSU roster roles via the 
new Site Roles maintenance feature under RSS on the CTSU members' web site. 
This will allow them to assign staff the "Registrar" role. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the OPEN tab located on the CTSU 
members' web site 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.  
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: [email to come] or call the NRG 
Registration Desk at [phone number to come], Monday through Friday, 8:30 a.m. to 
5:00 p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will 
need the registering individual’s e-mail address and/or return fax number. This 

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information is required to assure that mechanisms usually triggered by the OPEN web 
registration system (e.g. drug shipment and confirmation of registration) will occur.  
8.4 
Agent Ordering and Agent Accountability 
 
8.4.1 
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. 
 
8.4.2 
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. 
DRUG INFORMATION  
 
9.1 
Nivolumab (BMS-936558, MDX1106), NSC #748726 
9.1.1 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains 
with 440 amino acids and 2 identical light chains. 
9.1.2 
Classification: 
Anti-PD-1MAb 
9.1.3 
M.W.:  126,211 daltons 
9.1.4 
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. 

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9.1.5 
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. 
9.1.6 
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. 
9.1.7 
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. All vials must come from the same batch. 
9.1.8 
Storage: Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected 
from light, freezing and shaking.  
9.1.9 
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.  
9.1.10 
Route of Administration: Intravenous infusion.  Do not administer as an IV push or bolus 
injection. 
9.1.11 
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding polyethersulfone membrane in-line filter.  
9.1.12 
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. 
9.1.13 
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 Appendix I). 
9.1.14  
See Section 7.3.1 for the Nivolumab CAEPR. 
 
10. 
PATHOLOGY   
 
No pathology is required for central pathology review, but pathology reports are 
required. 
 

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11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
11.1 
Reimbursement 
 
See the Reimbursement and Case Credit Schedule found on the CTSU web site 
(www.ctsu.org). 
11.2 
Translational Science 
Note: Testing of banked specimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
11.3 
Specimen Requirements 
 
 
If the patient gives permission to participate in this optional study component, then 
participating sites are required to submit the patient’s specimens as outlined below. 
 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to all treatment (Preferred 
FFPE) 
NRG Oncology 
Biospecimen Bank-
Columbus within 8 weeks 
of registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to all treatment (Optional 
if FP01, FRP01, FRM01, 
FPP01, or FPM01 is submitted) 
FFPE Recurrent Primary Tumor (FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to study treatment 
(Optional if FP01, FM01, 
FRM01, FPP01, or FPM01 is 
submitted) 
FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to study treatment 
(Optional if FP01, FM01, 
FRP01, FPP01, or FPM01 is 
submitted) 
FFPE Persistent Primary Tumor (FPP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to study treatment 
(Optional if FP01, FM01, 
FRP01,  FRM01, or FPM01 is 
submitted) 
FFPE Persistent Metastatic Tumor 
(FPM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (charged, 5µm) 
Prior to study treatment 
(Optional if FP01, FM01, 
FRP01, FRM01, or FPP01 is 
submitted) 
Pre-treatment Serum (SB01) 
prepared from 7-10mL of blood drawn into 
plain red top tube(s) 
Prior to study treatment 
NRG Oncology 
Biospecimen Bank-
Columbus within 14 weeks 
of registration1 
Pre-treatment Immune Whole Blood (WB01) 
30mL drawn into green top (sodium 
heparin) tube(s) 
Yale University School of 
Medicine the day the 
specimen is collected2 
Pre-treatment CTC Whole Blood (WB02) 
10mL drawn into purple top (EDTA) 
tube(s) 
Massachusetts General 
Hospital the day the 
specimen is collected3 
8 Week Serum (SB02) (03/21/2016) 
prepared from 7-10mL of blood drawn into 
plain red top tube(s) 
8 weeks after starting study 
treatment (03/21/2016) 
NRG Oncology 
Biospecimen Bank-
Columbus within 14 weeks 
of registration1 
8 Week Immune Whole Blood (WB03) 
(03/21/2016) 
30mL drawn into green top (sodium 
heparin) tube(s) 
Yale University School of 
Medicine the day the 
specimen is collected2 

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8 Week CTC Whole Blood (WB04) 
(03/21/2016) 
10mL drawn into purple top (EDTA) 
tube(s) 
Massachusetts General 
Hospital the day the 
specimen is collected3 
12 Week Serum (SB03) (03/21/2016) 
prepared from 7-10mL of blood drawn into 
plain red top tube(s) 
12 weeks after starting study 
treatment (03/21/2016) 
NRG Oncology 
Biospecimen Bank-
Columbus within 14 weeks 
of registration1 
12 Week Immune Whole Blood (WB05) 
(03/21/2016) 
30mL drawn into green top (sodium 
heparin) tube(s) 
Yale University School of 
Medicine the day the 
specimen is collected2 
12 Week CTC Whole Blood (WB06) 
(03/21/2016) 
10mL drawn into purple top (EDTA) 
tube(s) 
Massachusetts General 
Hospital the day the 
specimen is collected3 
* A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG Oncology 
Biospecimen Bank-Columbus 
1 NRG Oncology Biospecimen Bank-Columbus / Protocol NRG GY002, Nationwide Children’s Hospital, 700 Children’s 
Drive, WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org 
2 Dr. Alessandro Santin, c/o Lisa Patriub, Yale University School of Medicine, 330 Cedar St, LSOG 305, New Haven, CT 
06520, Phone: 203-737-4450, Email: lisa.patriub@yale.edu 
3 Dr. Michael Birrer, c/o Giulia Fulci, Massachusetts General Hospital, Jackson 9, 55 Fruit St, Boston, MA 02114, Phone: 
617-726-6081, Email: gfulci@partners.org, wei.wei@mgh.harvard.edu. Please email prior to shipping. 
 
11.3.1 
Specimen Procedures 
 
A detailed description of specimen procedures can be found in Appendix IV. 
11.3.2 
Laboratory Testing 
 
Details regarding the distribution of translational science specimens to investigators can 
be found in Appendix IV. 
11.3.2.1 
PD-L1/B7-H1 and PD-1 Immunohistochemistry 
 
 
Upon trial completion, the NRG Oncology Biospecimen Bank-Columbus will batch ship 
unstained sections of formalin-fixed, paraffin-embedded (FFPE) tumor to TBD for 
immunohistochemical analysis of PD-L1/B7-H1 and PD-1 IHC. 
11.3.2.2 
Tumor Infiltrating Lymphocytes 
Upon trial completion, the NRG Oncology Biospecimen Bank-Columbus will batch ship 
unstained sections of FFPE tumor to Dr. Warner Huh (address below) for 
immunohistochemical analysis of tumor infiltrating lymphocytes (TILs). 
 
Dr. Warner Huh 
University of Alabama at Birmingham 
176F RM 10250619 
19th Street South 
Birmingham, AL 35249 
Phone: 205-934-4986 
Email: whuh@uab.edu 
11.3.2.3 
HPV Typing 
Upon trial completion, the NRG Oncology Biospecimen Bank-Columbus will batch ship 
unstained sections of FFPE tumor to Dr. Alessandro Santin (address below) for HPV 
typing. 

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Dr. Alessandro Santin 
c/o Lisa Patriub 
Yale University School of Medicine 
330 Cedar St, LSOG 305 
New Haven, CT 06520 
Phone: 203-737-4450 
Email: lisa.patriub@yale.edu 
11.3.2.4 
ELISPOT 
Immune whole blood will be shipped directly from sites to Dr. Santin (address above) 
for analysis of HPV16/18/31/35/45 E7 antigens in peripheral blood lymphocytes (PBLs) 
by proliferative and IFN-gamma ELISPOT. 
11.3.2.5 
ELISA 
Upon trial completion, the NRG Oncology Biospecimen Bank-Columbus will batch ship 
frozen serum from each time point to Dr. Santin (address above) for analysis of 
HPV16/18/31/35/45 E7 antigens in serum by ELISA. 
11.3.2.6 
CTC 
CTC whole blood will be shipped directly from sites to Dr. Michael Birrer (address 
below) for analysis of circulating tumor cells (CTCs). Please email prior to shipping. 
 
Dr. Michael Birrer 
c/o Giulia Fulci 
Massachusetts General Hospital 
Jackson 9 
55 Fruit St 
Boston, MA 02114 
Phone: 617-726-6081 
Email: gfulci@partners.org, wei.wei@mgh.harvard.edu 
11.3.3 
Banking Specimens for Future Research 
 
Details regarding the banking and use of specimens for future research can be found in 
Appendix IV. 
11.4 
Quality of Life 
 
Not applicable. 
 
12. 
DATA AND RECORDS 
12.1 
Data Management/Collection 
 
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 Regulatory Support System (RSS). To access Rave via 
iMedidata, the site user must have an active CTEP-IAM account (check at https://eapps-
ctep.nci.nih.give/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-Only, 
Site Investigator) on either the LPO or participating organization roster at the enrolling 
site. 
 
Each person responsible for data entry must be on the NRG roster in order to receive 
access to Medidata Rave®.  

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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 
(iMedidata-Notification@mdsol.com) to activate their account. 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. Once an account is activated, eLearning modules 
will be available for Rave RDC instructions.  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 listed in the upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave account at the time of 
initial 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 website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2 
NRG Data Management Forms 
The following forms must be completed for all patients registered and submitted to the 
NRG Oncology Statistics and Data Management Center (SDMC) in Buffalo, NY, 
according to the schedule below. Electronic case report forms must be submitted 
through the Medidata Rave Electronic Data Entry System (www.imedidata.com). All 
amendments to forms must also be submitted through Medidata Rave. The pathology 
reports can be sent to the NRG Oncology SDMC in Buffalo, NY, via postal mail or 
uploaded in Medidata Rave. The upload option is an alternative method for submitting 
paper reports.  
Form 
Comments 
Baseline Folder  
(Forms due within 2 weeks of registration) 
Baseline/History Forms: 
- 
Visit Information – Baseline Form 
- 
Registration Form 
- 
Pre-Treatment Summary Form 
- 
Vitals Form 
- 
Concomitant Medications Form 
- 
ECG Information 
- 
Body Diagram Form 
 
Pre-Study History 
- 
History Information Form 
- 
Primary Surgery Form 
- 
Chemotherapy Information Form 
- 
Prior Radiation Therapy Form 
The appropriate forms will load in the Baseline Folder 
based on the answers reported on the corresponding 
Baseline Visit Information form. 
 

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Baseline Adverse Events Reporting 
- 
Baseline Adverse Event- Terms 
- 
Baseline Adverse Event AE Grades        
 
Solid Tumor Evaluation Forms: 
- 
Target Lesions Form 
- 
Non-Target Lesions Form 
 
- 
Specimen Consent 
Visit Folder 
(Forms due within 2 weeks of the completion of each cycle) 
Cycle Information and Treatment Forms: 
- 
Visit Information Form 
- 
Cycle Patient Information Form 
- 
Cycle Drug Information Form  
- 
Labs and Chemistries Form 
- 
Vitals Form 
- 
Concomitant Medications Form 
- 
ECG Information 
 
Toxicity Forms: 
- 
Section 1 Form 
- 
NADIRS Form 
- 
Adverse Event Form 
- 
Adverse Event Grades 
 
Solid Tumor Evaluation Forms: 
- 
 Target Lesions Form 
- 
Non-Target Form 
- 
 New Target Lesions Form 
- 
 Status and Response Form 
The appropriate forms will load in the Visit Folder based 
on the answers reported on the corresponding Visit 
Information forms. 
 
Labs and Chemistries Forms will be collected prior to 
each dose of study drug 
Pathology Folder 
(Reports and slides due within 6 weeks of registration) 
 
Primary disease: 
Pathology Report 
 
Recurrent or Persistent Disease: 
Pathology Report 
 
 
Submit one copy of the pathology report to SDC via postal 
mail or upload the pathology report online via RAVE. 
 
 
 
Form 
Comments 

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Translational Research Folder 
 TR Forms: (03/21/2016) 
- FFPE Primary Tumor (FP01) 
- FFPE Metastatic Tumor (FM01) 
optional 
- FFPE Recurrent Primary Tumor 
(FRP01) optional 
- FFPE Recurrent Metastatic Tumor 
(FRM01) optional 
- FFPE Persistent Primary Tumor 
(FPP01) optional 
- FFPE Persistent Metastatic Tumor 
(FPM01) optional 
- Pre-treatment Serum (SB01) 
- 8 Week Serum (SB02) 
- 12 Week Serum (SB03) 
- Pre-treatment Immune Whole Blood 
(WB01) 
- Pre-treatment CTC Whole Blood 
(WB02) 
- 8 Week Immune Whole Blood (WB03) 
- 8 Week CTC Whole Blood (WB04) 
- 12 Week Immune Whole Blood 
(WB05) 
- 12 Week CTC Whole Blood (WB06) 
An electronically-completed copy of Form TR must 
accompany each specimen shipped to the NRG Oncology 
Biospecimen Bank-Columbus (or alternate laboratory). 
Handwritten forms will not be accepted. 
 
FP01, FM01, FRP01, FRM01, FPP01, and FPM01 are 
due 8 weeks from registration. 
 
SB01-SB03 are due 14 weeks from registration. 
 
WB01 and WB02 are due 1 week from registration. 
 
WB03 and WB04 are due 9 weeks from registration. 
 
WB05 and WB06 are due 13 weeks from registration. 
Treatment Completion Folder 
(Forms due within 2 weeks of treatment completion) 
Treatment Completion Form 
 
 
Form 
Comments 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 
 
Visit Information Follow-Up Form 
 
Follow-Up Form 
 
Follow-Up Period Adverse Event: 
- 
 Follow-Up Adverse Event- Part 1 
- 
Follow-Up Adverse Event- Terms 
- 
Follow-Up Adverse Event- AE Grades 
- 
 
Solid Tumor Evaluation: 
Follow-up visits should be scheduled quarterly for 2 
years, semi-annually for 3 more years 
The appropriate forms will load in the Follow-up Visit 
Folder based on the answers reported on the 
corresponding Follow-up Visit Information forms. 
 
 
Report all adverse events that occur within 100 days of 
last protocol treatment on Follow-Up Adverse Event 
Reporting form. 

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- 
 Target Lesions Form 
- 
Non-Target Form 
- 
 New Target Lesions Form 
- 
 Status and Response Form 
 
12.3 
Summary of Data Submission 
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. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.   
 
For reporting of secondary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, time frames, add if loading of the pathology report 
is required. 
12.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
13. 
STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
 
This is a single-arm, open-label phase II study using an optimal flexible two-stage 
design (Chen and Ng, 1998) to evaluate the efficacy of the study regimen through 
objective tumor response.  There are no treatment comparisons involved and no known 
historical controls available. The study design will be primarily based on prior GOG 
experience in this disease entity.  
 
 
The targeted accrual for the first stage of the study will be 12 eligible and evaluable 
patients but permitted to range from 8 to 15 for administrative reasons. The cumulative 
targeted accrual for the second stage will be 22 eligible and evaluable patients but 
permitted to range from 18 to 25 for administrative reasons. 
 
If the true probability of tumor response is 5%, then the study has a 65% average 
probability of early termination and an expected probability of 10% of incorrectly 
declaring the study regimen interesting. If the true probability of tumor response is 25%, 
then the study has an expected 90% chance of correctly classifying the study regimen as 
being interesting. 
13.1.1 
Stratification 
             
There are no stratification factors applied in this single-arm phase II study. 
13.1.2 
Randomization 
             
This is a single-arm phase II study and hence, no randomization is involved. 
13.1.3 
Total Accrual 
 
The planned total accrual of eligible and evaluable patients onto this study is 25. 

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13.1.4  
Justification of Design:  
             
This study will employ the optimal flexible two-stage design since it not only minimizes 
the average expected number of patient exposure to inactive regimen, but also allows the 
actual study accrual to slightly deviate from the targeted study accrual in a multi-center 
trial while maintaining the levels of the average type I and II errors. 
13.2 
Study Endpoints  
 
13.2.1 
Primary Endpoints 
1) Frequency of objective tumor response as assessed by RECIST 1.1 criteria (Section 
14).   
            
2) Frequency and severity of adverse events as assessed by CTCAE v4. 
13.2.2  
Secondary Endpoints 
            
1) Duration of progression-free survival (PFS) and overall survival (OS). 
13.2.3  
Translational Science Endpoints 
            
1) Measures of PD-1 and PD-L1 expressions in tumor infiltrating lymphocytes and 
cervical cancer cells  and objective tumor response, PFS and OS. 
           
 2) Measures of immune infiltration related biomarkers in tumor specimens with 
objective tumor response, PFS and OS. 
3) Measures of HPV genotype/positivity and pre and post-treatment immune response to 
HPV 16/18/31/35/45 E7 antigen in peripheral blood lymphocytes and serum. 
4) Pre and Post-treatment CTC counts and objective tumor response, PFS and OS. 
13.3 
Primary Objectives Study Design 
13.3.1 
Primary Hypothesis and Endpoints 
             
Primary Hypothesis: 
 
 
The intent of this study is to evaluate the efficacy of the study regimen measured by 
objective tumor response. Tumor response is dichotomized as response (i.e., complete or 
partial response) vs. non-response (i.e., stable disease, progressive disease, or 
indeterminate disease) and is assumed to have a Bernoulli distribution with a probability 
equal to π. Given a sample size, the number of tumor responses is binomially distributed 
with a given sample size and probability equal to π. Statistically, the evaluation of the 
study regimen efficacy measured by tumor response will be formulated through 
hypothesis testing via tumor response.  
 
Since there is no known historical control available, a series of single-agent GOG-0127 
studies were selected based on their similarity on this disease entity. The purpose of 
these studies was to evaluate several cytotoxic salvage regimens.  These studies also 
implemented two-stage stopping guidelines. The conclusions from these studies are that 
the agents studied had at most modest activity. The estimated probability of responding  
is summarized in Figure 14.1. The average proportion of patients responding in these 
studies is 7% with a standard error of 0.014. 
 
Figure 14.1 indicated that a probability of a true tumor response of 5% or less was 
uninteresting. Clinically a probability of a true tumor response of at least 25% is 
considered significant and important to detect. Therefore, the primary hypotheses for 
this study can be formulated as follow:            
H0: π ≤ 0.05, 
                                                                   H1: π ≥ 0.25, 

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where π is the probability of true tumor response, H0 is the null hypothesis and H1 is the 
alternative hypothesis. The optimal flexible two-stage design with early stopping 
guidelines will be implemented to evaluate the primary hypotheses with average type I 
and type II errors at 0.1 level, respectively.  
 
Figure 14.1 
 
 
We will target an accrual of 12 eligible and evaluable patients in the first stage of the 
study, but permit the accrual to range from 8 to 15 for administration reasons. If there 
are more than 0 out of 8-13 or 1 out of 14-15 patients responding (complete or partial 
response) and medical judgment indicates, accrual to the second stage of the trial will be 
initiated. Otherwise, the study will be stopped and the treatment will be classified as 
clinically uninteresting. If the study advances to the second stage, then a cumulative 
accrual of 22 eligible and evaluable patients will be targeted, but permitted to range 
from 18 to 25 for administration reasons. If more than 1 out 18, or 2 out 19-25 patients 
respond and medical judgment indicates, then the study regimen will be considered 
worthy for further investigation. 
 
Under the assumed accrual ranges of 8 to 15 (stage 1) and 18 to 25 (cumulatively after 
stage 2), if the true probability of tumor response is 5%, then the study has a 65% 
probability of early termination and a probability of 10% of incorrectly declaring the 
study regimen interesting; if the true probability of tumor response is 25%, then the 
study has a 90% chance of correctly classifying the study regimen as being interesting. 
 

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The following table summarizes the accrual and decision guideline. 
Stage of 
Accrual 
Targeted Cumulative 
Accrual 
Limits of Actual 
Accrual 
Max Number of Responses to 
Reject Study Regimen 
1 
12 
8-15 
0/(8-13), 1/14-15 
2 
22 
18-25 
1/(18), 2/(19-25) 
 
Primary Endpoints: See Section 13.2.1. 
13.3.2 
Definitions of Primary Endpoints and How These Will Be Analyzed 
           
1) 
Frequency of objective tumor response as assessed by RECIST 1.1 
 
criteria. 
            
 
See Section 13.3.1. 
 
2) 
Frequency and severity of adverse events as assessed by CTCAE v4 and 
corresponding frequency table will be provided as descriptive statistics. 
 
 
All eligible patients who receive any study therapy will be evaluated for both treatment 
efficacy and toxicity. Only those patients who are deemed "ineligible" or who receive no 
therapy will be eliminated from the efficacy analysis. All patients (eligible and 
ineligible) who receive any study therapy will be evaluated for safety and toxicity.  
While on occasion, circumstances may prevent the determination of treatment efficacy, 
such patients will be included in the analysis and labeled as "indeterminate." This 
category will be listed and be reflected in the calculation of the proportion responding. 
13.3.3 
Sample Size and Power Calculations:  
 
The sample size and power calculations will be based on the optimal flexible two-stage 
method by Chen and Ng. This method assumes that the number of patients responding to 
the study regimen has binomial distribution and the accrual combination for stage 1 and 
2 is uniformly distributed.   
 
The minimum and maximum accruals for this study are 8 and 25 eligible and evaluable 
patients, respectively. 
 
Under the assumed accrual ranges of 8 to 15 (stage 1) and 18 to 25 (cumulatively after 
stage 2), the study has an average 90% power to detect a 20% increase of the probability 
of tumor response from 5% at a significant level of 10%. 
 
            
Details see Section 13.3.1 
13.4 
Study Monitoring of Primary Objectives 
         
There will be one formal futility interim analysis for treatment efficacy in the study. 
 
If the study has an accrual of 12 eligible and evaluable patients in the first stage since 
the study is activated, which is permitted to range from 8 to 15, the accrual of the study 
will be temporarily suspended until the data of primary endpoint is matured to make a 
decision on whether to go forward to second stage accrual according to the guidelines. 
That is, if there are 0 out of 8-13 or at most 1 out of 14-15 patients responding (complete 
or partial response) and medical judgment indicates, the study will be stopped and the 

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treatment will be classified as clinically uninteresting. Otherwise, accrual to the second 
stage of the trial will be initiated.        
 
Data sheets from studies on this protocol will be reviewed before each semi-annual 
meeting and will also be reviewed by the Study Chairperson in conjunction with the 
NRG Statistical and Data Center. In some instances, because of unexpectedly severe 
toxicity, the NRG Statistical and Data Center may elect, after consultation with the 
Study Chairperson and the Medical Oncology Committee, to recommend early closure 
of a study. 
 
The frequency and severity of all toxicities are tabulated from submitted case report 
forms and summarized for review by the study chairperson, Developmental 
Therapeutics Committee, and NRG Safety Review Committee (SRC) in conjunction 
with each semi-annual NRG meeting. For studies sponsored by the Cancer Therapy 
Evaluation Program (CTEP) of the National Cancer Institute (NCI), standardized 
toxicity reports are also submitted to the drug and disease monitors at the Investigational 
Drug Branch (IDB) and Clinical Investigation Branch (CIB). As this is a two-stage 
multi-institutional phase II protocol, the initial overall review of toxicity is usually 
performed after completion of the first stage of accrual, at which point accrual is 
generally suspended pending formal analysis of response. 
 
All serious and/or unexpected events are communicated to the Study Chair, sponsor, and 
regulatory agencies as mandated in the protocol. These reports are reviewed by the 
Study Chair (or designated co-chair) within two working days for consideration of 
investigator notification, amendment, or immediate study suspension. All participating 
institutions will then receive notification of the toxicities and reason for study 
suspension. Under these circumstances, accrual cannot be re-activated until the study is 
reviewed by the NRG SRC. However, patients currently receiving treatment may 
continue to receive treatment in accordance with protocol guidelines at the discretion of 
their physicians, unless directed otherwise. 
13.5 
Accrual Considerations 
13.5.1 
Accrual Rate 
The projected accrual rate for this study is approximately 1.1 patients per month based 
on historial GOG-0127 studies shown in Table 1. 
 
 
 
Table 1.  Estimated accrual rate (per month) in historical GOG-0127 studies 
Protocol 
Stage 
Start Date 
End Date 
Number 
Months 
Accrual Rate 
0127Q 
1 
10/2/2000 
6/3/2002 
32 
20.0082 
1.59934 
0127R 
1 
6/3/2002 
12/1/2003 
27 
17.9384 
1.50515 
0127S 
1 
6/2/2002 
12/6/2004 
23 
30.1602 
0.7626 
0127T 
1 
7/6/2004 
4/3/2006 
25 
20.8953 
1.19644 
0127U 
1 
1/3/2005 
10/29/2007 
25 
33.807 
0.73949 
0127V 
1 
11/6/2006 
3/19/2008 
24 
16.3943 
1.46393 
0127V 
2 
9/8/2009 
2/1/2011 
11 
16.7885 
0.65521 
0127W 
1 
2/7/2011 
1/17/2013 
27 
23.3265 
1.15748 

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13.5.2    
Accrual Goal 
The projected minimum and maximum accruals for the study are 8 and 25 eligible and 
evaluable patients, respectively. The targeted accrual is 12 eligible and evaluable 
patients in the first stage of the study, and cumulatively 22 eligible and evaluable 
patients will be targeted in the second stage if the study advances.  
13.5.3 
Study Duration 
1) Patients will receive therapy for a maximum of 46 doses (92 weeks), until disease 
progression or intolerable toxicity intervenes, whichever comes first. 
            The patient can refuse the study treatment at any time. 
           2) All patients will be treated (with completion of all required case report forms)with a 
maximum of 46 doses of study drug until disease progression, initiation of a subsequent 
cancer treatment or study withdrawal. 
Patients will then be followed every three months for the first two years and then every 
six months for the next three years. Patients will be monitored for delayed toxicity and 
survival for this 5 year period with Follow-up Forms submitted to the NRG SDMC-
Buffalo Office, unless consent is withdrawn. Follow-up Forms will no longer be 
required if the study is terminated prior to the completion of the 5-year follow-up period.  
        
3) A patient is considered off study therapy when the patient has progressed or died, a 
non-protocol drug or therapy (directed at the disease) is initiated, or all study therapy is 
discontinued. Report all treatment received on Cycle Drug Information Forms and 
adverse events on Adverse Events Forms until the patient qualifies as being off study 
therapy.  
13.5.4 
Estimated Duration for Completion of Primary Endpoint: provision of timeframe, e.g. 24 
months from activation 
        
The projected accrual rate is 1.1 patients per month based on the GOG-0127 historical 
studies.  Thus, the accrual duration will take approximate 11 months for the first stage 
and 9 months for the second stage, separately. Additionally, the evaluation of patients 
with complete/partial response takes at least 12 weeks, and it can take even longer to 
evaluate patients with stable disease to determine whether they respond or not. 
Therefore, the duration for completion of primary endpoint will be approximately 16 
months from activation of the study for the first stage, and 14 months from activation of 
the second stage for the second stage if the study advances to the second stage.   
 
However the study regimen is a very exciting new drug, it is reasonable to project that 
the actual study accrual rate can be as high as 3 patients per months. If the actual accrual 
rate is 3 patients per months, the duration for completion of primary endpoint will be 
approximately 9 months from activation of the study for the first stage, and 8.5 months 
from activation of the second stage for the second stage if the study advances to the 
second stage. 
13.6 
Dose Level Guidelines 
 
Not Applicable. 
13.7 
Secondary or Exploratory Elements (including correlative science aims) 
13.7.1 
Secondary Hypotheses and Endpoints:  
             
There are no specific secondary hypotheses regarding secondary objective. The purpose 
of secondary objective is to describe the survival functions for progression-free survival 

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(PFS) and overall survival (OS). 
13.7.2 
Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
Progression-free survival is defined as the duration of time from study entry to time of 
progression, death, or the date of last contact, whichever occurs first. PFS is censored in 
patients who are alive and have not progressed. 
 
          
Overall survival is defined as the duration of time from study entry to time of death or 
the date of last contact.  OS is censored in patients who are alive.       
 
             
Kaplan-Meier median estimates and curves will be used to describe PFS and OS 
survival functions. 
13.7.3  
Interim Analysis for All Other Endpoints (Goals):  
            
Not Applicable. 
13.7.4 
Power Calculations:  
             
Not Applicable. 
13.7.5 
Expected Sample Size or Patient Cohorts:  
           
Not Applicable. 
13.8 
 
Exploratory Hypothesis and Endpoints 
The corresponding exploratory hypotheses for the study translational science objectives 
are: 
1) Tumor expressions of PD-L1 and PD-1 will be associated respectively with 
objective response, PFS and OS in nivolumab-treated patients.  
2) Immune infiltration related biomarkers (i.e., CD4+, CD8+, FoxP3) in tumor 
specimens will be associated with objective tumor response, PFS and OS in 
nivolumab-treated patients. 
3) The study treatment will change the immune response to HPV 16/18/31/35/45 E7 
antigen in peripheral blood lymphocytes and serum. 
      4)    The study treatment will change the CTC count and the CTC count is associated 
             with objective response, PFS and OS in nivolumab-treated patients.  
 
                         The corresponding exploratory endpoints: 
 See Section 13.2.3. 
 
Spearman’s correlation coefficient will be used to explore the associations of tumor 
expressions of PD-L1, PD-1 and other interested biomarkers with tumor response.  Cox 
proportional hazards (PH) model will be utilized to evaluate the associations of these 
tumor expressions with PFS and OS. These expressions may also be dichotomized into 
high versus low values (cut at the median).  Log-rank tests will be used to assess the 
associations of these dichotomized tumor expressions with PFS and OS. The 
corresponding hazard rations will be estimated by Cox PH models.  Wilcoxon signed 
rank test (for interval or ordinal data) or McNemar’s test (for binary data) may be 
utilized to examine whether the study treatment will change immune response to HPV 
16/18/31/35/45 E7 antigen in peripheral blood lymphocytes and serum by changes in the 
measures of pre- and post-treatment immune response to HPV 16/18/31/35/45 E7. Other 
statistical methods such as time dependent or landmark survival method, mixed model 
or logistic regression will be applied to evaluate the associations between the CTC count 

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and objective response, PFS or OS, and the hypothesis that the study treatment will 
change the CTS count, where it is appropriate. 
 
The purpose of translation science objectives is to explore and possibly generate 
hypotheses for future study. Therefore there will be no adjustment for multiple tests. Due 
to small sample size of this study, exact testing procedure (i.e., exact Spearman 
correlation test, permutation-based log-rank test) may be used where it is appropriate. 
 
13.9 
Gender/Ethnicity/Race Distribution 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
0 
2 
Not Hispanic or Latino 
23 
0 
23 
Ethnic Category: Total of all 
25 
0 
25 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
5 
0 
5 
Native Hawaiian or other Pacific 
0 
0 
0 
White 
20 
0 
20 
Racial Category: Total of all 
25 
0 
25 
 
14. 
EVALUATION CRITERIA 
14.1 
Response Assessment:  RECIST 1.1  
14.1.1 
Antitumor Effect – Solid Tumors 
 
 
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) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST criteria. 
14.1.1.1 
Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >10 mm with 
CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in decimal fractions of centimeters. 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 

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Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short 
axis), are considered non-measurable disease.  Leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal/pelvic masses (identified by physical exam and not CT or MRI), 
are considered as non-measurable. 
 
Notes: 
Bone lesions:  Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described 
above.  Blastic bone lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, and in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
14.1.1.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 

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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
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.  MRI is also acceptable in certain situations (e.g. for body 
scans), but NOT lung.   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline, and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible.  If possible, 
body scans should be performed with breath-hold scanning techniques. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  PET-CT scans are not always done with oral and IV contrast.  In 
addition, the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed.  For these reasons, NRG will 
not allow PET-CT use for RECIST 1.1 response criteria. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible “new” disease).  New 
lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 

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No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
Note:  A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next.  If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases, e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment when measurable disease has met 
criteria for response or stable disease.  This confirmation is necessary to differentiate 
response or stable disease versus progressive disease, as an effusion may be a side effect 
of the treatment. 
14.1.1.3 
Response Criteria 
Determination of response should take into consideration all target (See 14.1.1.3.1) and 
non-target lesions (See 14.1.1.3.2). 
14.1.1.3.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 

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that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Not Evaluable (NE): When at least one target lesion is not evaluated at a particular time 
point. 
 
14.1.1.3.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
 
Not evaluable (NE):  When at least one non-target lesion is not evaluated at a particular 
time point. 
 
Although a clear progression of only “non-target” lesions is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
14.1.1.3.3 
Evaluation of Best Overall (unconfirmed) Response 
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest sum recorded since baseline).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria in some circumstances. 
 
 

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Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
 
 
 
 
 
 
 
 
 
 
 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline 
(i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions* 
Time Point 
Response 
CR 
No 
CR 
CR 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
14.1.1.3.4 
Best Overall Confirmed Response  
Confirmation of CR and PR for determination of best overall response is required 
for studies with a primary endpoint that includes response. 
 
 Confirmed CR and PR for best overall confirmed response 
 
Time Point Response 
First time point 
Time Point Response 
Subsequent time point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD  
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Time Point  
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

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*If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact 
the patient had PR or SD, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR or SD and the best response is PR or SD.  
 
In non-randomized trials where response is part of the primary endpoint, confirmation of 
CR or PR is needed to deem either one the “best overall response.”   Responses (CR 
and PR) require confirmation at greater than or equal to 4 weeks from initial 
documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment or die without objective evidence of disease progression at that time should be 
reported to be off study treatment due to “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
14.1.1.4 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
14.1.1.5 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression, death, or the date of last contact, whichever occurs first. 
14.1.1.6 
Survival 
Survival is defined as the duration of time from study entry to time of death or the date 
of last contact. 
 
15. 
REFERENCES 
 
Brahmer, J.R., L. Horn, S.J. Antonia, et al.  (2013).  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).  J Clin Oncol.  
31:A8030. 

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Chen TT, Ng TH. Optimal flexible designs in phase II clinical trials. Stat Med. 1998; 17: 2301-
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Curran, M.A., W.Montalvo, H.Yagita, et al.  (2010).  PD-1 and CTLA-4 combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within 
B16 melanoma tumors.  Proc Natl Acad Sci U S A.  107: 4275-80. 
 
Dong, H., and L. Chen.  (2003). B7-H1 pathway and its role in the evasion of tumor 
immunity.  J Mol Med (Berl).  81:281-287. 
 
Drake, C.G., D.F. McDermott, M. Sznol, et al.  (2013).  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.  J Clin Oncol.  31:A4514. 
 
Ghazani AA, Castro CM, Gorbatov R, et al.  Sensitive and Direct Detection of 
Circulating Tumor Cells by Multimarker µ-Nuclear Magnetic Resonance. (2012), 14; 5, 
388–395. 
 
Hammers, H.J., E.R. Plimack, J.R. Infante, et al.  (2014). Phase I study of nivolumab in 
combination with ipilimumab in metastatic renal cell carcinoma (mRCC).  J Clin Oncol.  
32:A4504. 
 
Investigator Brochure.  (2014).  Nivolumab, BMS-936558, MDX1106.  Version 13, 21 
July 2014. Bristol-Myers Squibb.  Lawrenceville, NJ.   
 
Ipilimumab Investigator Brochure.  (2014).  BMS-734016, MDX010.  Version 17, 10 
March 2014. Bristol-Myers Squibb.  Wallingford, CT.  
Karim, R., E.S. Jordanova, S.J. Piersma, et al. (2009). Tumor-expressed B7-H1 and B7-
DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical 
carcinoma. Clin Cancer Res. 15:6341-6347. 
 
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes to age. Nature. 480; 
480-489; 2011. 
 
Monk BJ, Sill MW, McMeekin DS, et al.  Phase III trial of four cisplatin-containing 
doublet combinations in stage IVB, recurrent, or persistent cervical carcnoma:  a 
Gynecologic Oncolgoy Group Study. J Clin Oncol 2009;27:4649-55. 
 
Nomi, T., M. Sho, T. Akahori, et al.  (2007). Clinical significance and therapeutic 
potential of the programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer.  Clin Cancer Res.  13:2151-2157. 
 
Ohigashi, Y., M. Sho, Y. Yamada, et al.  (2005). Clinical significance of programmed 
death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal 

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cancer.  Clin Cancer Res.  11:2947-2953. 
 
Ravaggi A. Romani C. Pasinetti B. et al.  Correlation between serological immune 
response analyzed by a new ELISA for HPV-16/18 E7 oncoprotein and clinical 
characteristics of cervical cancer patients. Archives of Virology. 151(10):1899-916, 
2006 Oct. 
 
Rizvi, N.A., S.J. Antonia, L.Q.M. Chow, et al.  (2013).  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).  J 
Clin Oncol.  31:A8072. 
 
Santin AD. Hermonat PL. Ravaggi A. Chiriva-Internati M. Zhan D. Pecorelli S. Parham 
GP. Cannon MJ. Induction of human papillomavirus-specific CD4(+) and CD8(+) 
lymphocytes by E7-pulsed autologous dendritic cells in patients with human 
papillomavirus type 16- and 18-positive cervical cancer. Journal of Virology. 
73(7):5402-10, 1999  
 
Santin AD. Bellone S. Palmieri M. Ravaggi A. Romani C. Tassi R. Roman JJ. Burnett 
A. Pecorelli S. Cannon MJ. HPV16/18 E7-pulsed dendritic cell vaccination in cervical 
cancer patients with recurrent disease refractory to standard treatment modalities. 
Gynecologic Oncology. 100(3):469-78, 2006 
 
Santin AD. Bellone S. Palmieri M. Zanolini A. Ravaggi A. Siegel ER. Roman JJ. 
Pecorelli S. Cannon MJ. Human papillomavirus type 16 and 18 E7-pulsed dendritic cell 
vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial. 
Journal of Virology. 82(4):1968-79, 2008 
 
Sznol, M., H.M. Kluger, F.S. Hodi, et al.  (2013).  Survival and long-term follow-up of 
safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of 
nivolumab (anti-PD-1; BMS-936558; ONO-4538).  J Clin Oncol.  31:ACRA9006. 
 
Taube, J.M., R.A. Anders, G.D. Young, et al.  (2012).  Colocalization of inflammatory 
response with B7-H1 expression in human melanocytic lesions supports an adaptive 
resistance mechanism of immune escape.  Sci Transl Med.  4:127ra137. 
 
Tewari KS, Sill MW, Long HJ, et al.  Improved survival with bevacizumab in advanced 
cervical cancer.  N Engl J Med 2014;370:734-43. 
 
Thompson, R.H., M.D. Gillett, J.C. Cheville, et al.  (2004). Costimulatory B7-H1 in 
renal cell carcinoma patients: Indicator of tumor aggressiveness and potential 
therapeutic target.  Proc Natl Acad Sci U S A.  101:17174-17179. 
 
Thompson, R.H., M.D. Gillett, J.C. Cheville, et al.  (2005).  Costimulatory molecule B7-
H1 in primary and metastatic clear cell renal cell carcinoma.  Cancer.  104:2084-2091. 
 

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Thompson, R.H., S.M. Kuntz, B.C. Leibovich, et al.  (2006).  Tumor B7-H1 is 
associated with poor prognosis in renal cell carcinoma patients with long-term follow-
up.  Cancer Res.  66:3381-3385. 
 
Topalian SL, Hodi FS, Brahmer JR, et al., Safety, Activity, and Immune Correlates of 
Anti–PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454 June 28, 2012DOI: 
10.1056/NEJMoa1200690. 
 
Velcheti V, Schalper KA et al.  Programmed death ligand-1 expression in non-small cell 
lung cancer.  Laboratory Investigation (2014) 94, 107–116. 
 
Wolchok, J.D., H. Kluger, M.K. Callahan, et al.  (2013).  Nivolumab plus ipilimumab in 
advanced melanoma.  N Engl J Med.  369:122-133. 
 
Woo, S.R., M.E. Turnis, M.V. Goldberg, et al.  (2012).  Immune inhibitory molecules 
LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune 
escape.  Cancer Res.  72:917-927. 
 
Wu, C., Y. Zhu, J. Jiang, et al.  (2006). Immunohistochemical localization of 
programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance.  
Acta Histochem.  108:19-24. 
Yang W. Song Y. Lu YL. Sun JZ. Wang HW. Increased expression of programmed 
death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in 
high-risk human papillomavirus-related cervical intraepithelial neoplasia.  Immunology. 
139(4):513-22, 2013 
 
Zitvogel, L., A. Tesniere, and G. Kroemer.  (2006). Cancer despite immunosurveillance: 
immunoselection and immunosubversion.  Nat Rev Immunol.  6:715-727. 
 
 

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APPENDIX I - COLLABORATIVE AGREEMENT 
 
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”): 
 
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. 
 

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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 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. 
 
 
 

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

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

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APPENDIX IV - TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES 
 
I. Obtaining a Bank ID for Translational Science Specimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
specimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that 
a patient has agreed to participate in the translational science component. 
 
A Bank ID can also be obtained online via the Tissue Bank Portal link on the NRG Oncology 
webpage. Obtain the patient’s study ID for all protocols with translational science specimen 
requirements before requesting a Bank ID from the Tissue Bank Portal. Be sure to indicate if 
the patient has a legacy GOG ID when registering. This will ensure the patient is only 
assigned one Bank ID. The GOG ID – Bank ID Lookup on the Tissue Bank Portal can be used to 
search for an existing Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID to a 
patient (Email: support@gogstats.org; Phone: 716-845-7767). 
 
II. Requesting Translational Science Specimen Kits (03/21/2016) 
One single chamber kit will be provided per patient for the collection and shipment of frozen 
serum. 
 
Sites can order kits online via the Kit Management link 
http://ricapps.nationwidechildrens.org/BPCKitManagement/. . Each site may order two kits per 
protocol per day (daily max = 6 kits). 
 
Please contact the NRG Oncology Biospecimen Bank-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. 
 
Note: Unused materials and kits should be returned to the NRG Oncology Biospecimen Bank-
Columbus. 
 
III. Formalin-Fixed, Paraffin-Embedded Tissue Shipped to the NRG Oncology 
Biospecimen Bank-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic, recurrent). Primary and metastatic tumor should be 
collected prior to all treatment. Recurrent and persistent tumor should be collected prior to the 
study treatment. Recurrent or persistent tumor collected from the site of primary disease should 
be labeled recurrent primary or persistent primary, respectively. Recurrent or persistent 
tumor collected from a site other than the site of primary disease (e.g., lymph node) should be 
labeled recurrent metastatic or persistent metastatic, respectively. Only one block may be 
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Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 20 unstained slides (charged, 5µm) should be submitted. All tissue 
sections should be cut sequentially from the same block.  
 
The type of specimen (block or slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
Labeling Formalin-Fixed, Paraffin-Embedded Tissue 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY002) 
specimen code (see protocol section 11) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
IV. Immune Whole Blood Shipped to Yale School of Medicine 
Note: This protocol requires green top (sodium heparin) tubes to collect 30mL whole blood. 
1.  Label the green top (sodium heparin) collection tube(s) as described above. Multiple tubes 
may be used to collect the required amount. 
2. Draw 30mL of blood into the labeled green top (sodium heparin) tube(s). 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and sodium 
heparin. 
4. Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. 
Ship whole blood to Yale School of Medicine the day the specimen is collected. If the whole 
blood absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated 
(4°C) until the specimen can be shipped. 
 
Labeling Immune Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY002) 
specimen code (see protocol section 11) 
collection date (mm/dd/yyyy) 
 
V. CTC Whole Blood Shipped to Massachusetts General Hospital 

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Note: This protocol requires purple top (EDTA) tubes to collect 10mL whole blood. 
1.  Label the purple top (EDTA) collection tube(s) as described above. Multiple tubes may be 
used to collect the required amount. 
2. Draw 10mL of blood into the labeled purple top (EDTA) tube(s). 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and purple 
top (EDTA). 
4. Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. 
Ship whole blood to Massachusetts General Hospital the day the specimen is collected. If the 
whole blood absolutely cannot be shipped the day it is collected, the tube(s) should be 
refrigerated (4°C) until the specimen can be shipped. 
 
Labeling CTC Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY002) 
specimen code (see protocol section 11) 
collection date (mm/dd/yyyy) 
 
VI. Serum Shipped to the NRG Oncology Biospecimen Bank-Columbus 
1.  Label cryovials and a 15mL conical tube as described above. Use 2mL cryovials if serum 
will be shipped to the NRG Oncology Biospecimen Bank-Columbus. 
2. Draw 7-10mL of blood into red top tube(s).  
3.  Allow the blood to clot at 4°C (or in a bucket with ice) for at least 30 minutes but no longer 
than 3 hours. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the serum (top, straw-colored layer) from the red blood cells (bottom, red layer). 
5.  Transfer the serum into a 15mL conical tube and gently mix. 
6. Quickly, evenly dispense (aliquot) the serum into the pre-labeled cryovials and cap the tubes 
securely. Place a minimum of 0.25mL into each cryovial. 
7.  Immediately freeze the serum in an upright position in a -70oC to -80oC freezer or by direct 
exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for 
storage, store and ship on dry ice within 24 hours of collection. 
 
Labeling Serum 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY002) 
specimen code (see protocol section 11) 
collection date (mm/dd/yyyy) 
 
VII. Submitting Form TR 
An electronically completed copy of Form TR must accompany each specimen shipped to the 

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NRG Oncology Biospecimen Bank-Columbus (or alternate laboratory). Handwritten forms will 
not be accepted. 
 
Note: A copy does not need to be sent to the NRG Oncology Biospecimen Bank-Columbus (or 
alternate laboratory) if specimens are not collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the 
“PDF File” link at the top of the form. Clicking this link will generate a PDF of Form TR in a 
“SEDES style” format. Do not use the “Printable Version” or “View PDF” links at the bottom of 
the form or any other method to print the form, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@gogstats.org; Phone: 716-
845-7767). 
 
VIII. Shipping Translational Science Specimens 
An electronically completed copy of Form TR must be included for each translational 
science specimen.  
 
A. FFPE Tissue 
FFPE tissue, an electronically completed copy of Form TR, and a copy of the corresponding 
pathology report should be shipped using your own container at your own expense to: 
 
NRG Oncology Biospecimen Bank-Columbus / Protocol NRG-GY002 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Frozen Serum 
Frozen serum should be shipped using the specimen kit provided to the NRG Oncology 
Biospecimen Bank-Columbus (address above). 
 
Frozen specimens should be shipped Monday through Thursday for Tuesday through Friday 
delivery. Do not ship frozen specimens on Friday or the day before a holiday. Note: Saturday 
delivery is not available for frozen specimens.  
 
Frozen specimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-70oC 
freezer, liquid nitrogen, or direct exposure with dry ice) until the specimens can be shipped. 
 
Shipping Specimens in a Single Chamber Kit to the NRG Oncology Biospecimen Bank-

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Columbus 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen specimens from each time point in a separate zip-lock bag. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Do not put 
more than 25 cryovials in a single chamber kit. Put the secondary envelope into a Tyvek 
envelope. Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen specimens into the kit and fill the chamber to 
the top with dry ice. 
5. Insert a copy of Form TR for each specimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other 
durable sealing tape. Please do not tape the inner chamber.  
7. Legacy GOG sites can print a pre-paid FedEx air bill using the Kit Management application 
(found under Data Entry on the Web Menu page). Non-legacy GOG sites should contact the 
NRG Oncology Biospecimen Bank-Columbus for a pre-paid FedEx air bill. Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
C. Whole Blood 
Immune whole blood specimens should be shipped to: 
 
Dr. Alessandro Santin 
c/o Lisa Patriub 
Yale University School of Medicine 
330 Cedar St, LSOG 305 
New Haven, CT 06520 
Phone: 203-737-4450 
Email: lisa.patriub@yale.edu 
 
CTC whole blood* specimens should be shipped to: 
Dr. Michael Birrer 
c/o Giulia Fulci 
Massachusetts General Hospital 
Jackson 9 
55 Fruit St 
Boston, MA 02114 
Phone: 617-726-6081 
Email: gfulci@partners.org, wei.wei@mgh.harvard.edu 
*Please email MGH prior to shipping CTC whole blood specimens. 
 
Whole blood specimens can be shipped Monday through Thursday for Tuesday through 
Friday delivery. Do not ship whole blood the day before a holiday. Use your own shipping 
container to ship specimens via FedEx priority overnight. 
 
When shipping whole blood specimens, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your immune whole blood shipment, contact 
Lisa Patriub (Phone: 203-737-4450; Email: lisa.patriub@yale.edu). If you have questions 

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regarding your CTC whole blood shipment, contact Giulia Fulci (Phone: 617-726-6081; Email: 
gfulci@partners.org, wei.wei@mgh.harvard.edu). 
 
To ship whole blood specimens you will need (1) a sturdy shipping container (e.g., a cardboard 
or styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a puncture 
and pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, 
and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood specimens from more than one patient, please put each 
specimen in a separate plastic zip-lock bag before placing the specimens in the shipping bag. 
You may include up to four different blood specimens in one biohazard envelope. 
 
If you do not have these materials available at your site, you may order them from any supplier 
(e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container to an Alternate Laboratory 
1. Place the whole blood specimen in a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing 
the envelope. 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
5. Insert a copy of Form TR for each specimen.  
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
7. Attach the pre-paid FedEx air bill provided. 
8. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-
238-5355. 
 
IX. Distributing Translational Science Specimens 
Note: Testing of banked specimens will not occur until an amendment to this treatment protocol 
(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies.  
 
The Statistics and Data Management Center-Buffalo Office and NRG Oncology Biospecimen 
Bank-Columbus (or alternate laboratory) will coordinate the distribution of translational science 
specimens to approved investigators. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of the translational 
science and for keeping accurate records. 
 
Investigators will ensure the results are linked to the appropriate translational science specimen-
specific identifiers and are responsible for transferring relevant laboratory data to the Statistics 
and Data Management Center-Buffalo Office. 
 

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At the discretion of the Chair of the Translational Science-GYN Committee and the Director of 
the NRG Oncology Biospecimen Bank-Columbus, investigators may be required to ship any 
specimens (or by-products) remaining after the completion of the translational science to the 
NRG Oncology Biospecimen Bank-Columbus. 
 
X. Banking Translational Science Specimens for Future Research 
Specimens will remain in the NRG Oncology Biospecimen Bank-Columbus and made available 
for approved research projects if the patient has provided permission for the use of her specimens 
for future health research. The patient’s choices will be recorded on the signed informed consent 
document and electronically via Specimen Consent. At the time of specimen selection for project 
distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her specimens at any time if the 
patient changes her mind. 
 
If the patient revokes permission to use her specimens, the NRG Oncology Biospecimen Bank-
Columbus will destroy or return any remaining specimens. The patient’s specimens will not be 
used for any further research; however, any specimens distributed for research prior to revoking 
consent cannot be returned or destroyed. In addition, the patient cannot be removed from any 
research that has been done with her specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the site’s expense.