Phase II Randomized Trial of Nivolumab With or Without Ipilimumab in Patients With Persistent or Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Phase: PHASE2
Conditions: Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)

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i
SUMMARY OF CHANGES 
 
 
For Protocol Amendment #12 to: NRG-GY003 
 
NCI Protocol #: NRG-GY003 
Local Protocol #: NRG-GY003 
 
NCI Version Date: February 28, 2020 
 
 
 
# 
Section 
Change 
1. 
Title Pages 
• NCI Version Date is now February 28, 2020. 
• Includes Amendments #1-12. 
• Dr. Dmitriy Zamarin is now the Study Chair. 
• Dr. Khleif’s contact information was updated. 
• Dr Powell’s email was updated. 
 
 
ICD 
The only change that was made to the ICD was the NCI Version Date. 
 
 
 
 
 
 
 
 
 

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NRG ONCOLOGY  
 
NRG-GY003 
(ClinicalTrials.gov NCT #02498600) 
 
Includes Amendments #1-12 
Phase II Randomized Trial of Nivolumab with or without Ipilimumab in Patients with 
Persistent or Recurrent Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer  
 
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 (28-FEB-2020) 
Translational Science Co-Chair (28-FEB-2020) 
Dmitriy Zamarin, M.D., Ph.D. 
Samir Khleif, M.D. 
Memorial Sloan Kettering Cancer Center 
MedStar Georgetown University Hospital 
1275 York Ave 
3900 Reservoir Road Northwest 
New York, NY 10065 
Pre-Clinical Science Building GM12B 
646-888-4882 
Washington, DC 20007 
zamarind@mskcc.org  
202-687-9689 
 
snk48@georgetown.edu  
 
 
 
Statistician 
Study Co-Chair 
Michael Sill, Ph.D. 
Carol Aghajanian, MD 
NRG-SDMC-Buffalo Office 
Chief, Gynecologic Medical Oncology 
Roswell Park Cancer Institute 
Memorial Sloan Kettering Cancer Center 
Elm and Carlton Streets 
300 E. 66th St 
Buffalo, NY 14263 
New York NY 10065 
716-845-5702/FAX: 716-845-8393 
646-888-4217/FAX: 646-888-4267 
msill@gogstats.org 
aghajanc@mskcc.org 
 

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Correlative Scientists 
Daniel J. Powell, PhD 
 
University of Pennsylvania 
 
poda@pennmedicine.upenn.edu (28-FEB-2020) 
 
 
 
Translational Scientist (05/22/2017) (02/28/2019) 
 
Heather A Lankes, PhD, MPH 
 
NRG Oncology 
 
Four Penn Ctr., 1600 JFK Blvd., Ste 1020 
 
Philadelphia, PA 19103 
 
215-854-0770/FAX: 215-854-0716 
 
lankesh@nrgoncology.org 
 
 
 
Data Manager and/or Data Operations Center 
(02/13/2017) 
Protocol Coordinator (05/22/2017) 
Izabela Frak, MA 
Meg Colahan, M.A. 
NRG SDMC-Pittsburgh Office 
NRG Oncology 
201 N. Craig St., Suite 500 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
Pittsburgh, PA 15213 
Philadelphia, PA 19103 
412-383-4913/FAX: 412-624-1082 
215-854-0770/FAX: 215-854-0716 
fraki@nrgoncology.org 
colahanm@nrgoncology.org 
 
NCI-Supplied Agents: 
BMS-936558 (Nivolumab, MDX-1106) NSC #748726 
 
 
  Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) NSC #732442 
IND Sponsor:  Division of Cancer Treatment and Diagnosis, NCI (02/22/2016) 
 
Participating Sites 
U.S. 
 Canada 
 Approved International Member Sites 
Document History 
 
Version/Update Date 
 
Amendment 12 
February 28, 2020 
 
Amendment 11 
06/10/2019 
 
Amendment 10 
02/28/2019 
 
Amendment 9 
12/21/2018 
 
Amendment 8 
09/07/2018 
 
Amendment 7 
07/30/2018 
Broadcast Date 
Closure 
07/14/2017 
08/28/2017 
Amendment 6 
07/14/2017 
07/31/2017 
Re-activation and Amendment 5 
04/28/2017 
05/22/2017 
Amendment 4 
01/19/2017 
02/13/2017 
Amendment 3 
02/23/2016 
03/21/2016 
Amendment 2 
02/02/2016 
Amendments #1 and 2 Broadcast 
together: 02/22/2016 
 
 
Amendment 1 
01/25/2016 
Temporary Closure 
05/21/2015 
10/07/2015 
Activation 
05/21/2015 
06/29/2015 
 
 
 
 
TABLE OF CONTENTS 
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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SCHEMA .................................................................................................................................... - 6 - 
1. 
OBJECTIVES ................................................................................................................. - 7 - 
1.1 
Primary Objectives ............................................................................................. - 7 - 
1.2 
Secondary Objectives (09/07/2018) ................................................................... - 7 - 
2. 
BACKGROUND............................................................................................................. - 8 - 
2.1  
Rationale for Immunotherapy ............................................................................ - 8 - 
2.2 
Evasion of Natural Cell-Mediated Immunity ..................................................... - 9 - 
2.3 
Rationale for Combined CTLA-4 and PD-1 Targeting .................................... - 11 - 
2.4 
Nivolumab ........................................................................................................ - 13 - 
2.5 
Ipilimumab ....................................................................................................... - 17 - 
2.6 
Translational Science Background ................................................................... - 33 - 
2.7 
Inclusion of Women and Minorities ................................................................. - 34 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ............ - 34 - 
3.1 
Patient Selection Guidelines ............................................................................. - 34 - 
3.2 
Eligibility Criteria ............................................................................................. - 35 - 
3.3 
Ineligibility Criteria (02/22/2016) .................................................................... - 37 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 41 - 
4.1 
 PRE-TREATMENT ASSESSMENTS (02/22/2016) ..................................... - 41 - 
4.2 
ASSESSMENTS DURING TREATMENT (02/22/2016) ............................... - 42 - 
4.3 
ASSESSMENTS IN FOLLOW UP ................................................................. - 43 - 
5.  
TREATMENT PLAN/Regimen description ................................................................. - 43 - 
5.1 
 Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy 
(02/22/2016) ..................................................................................................... - 44 - 
5.2 
Radiation Therapy ............................................................................................ - 45 - 
5.3 
 Surgery ............................................................................................................ - 45 - 
5.4 
 Device .............................................................................................................. - 45 - 
5.5 
 Imaging ............................................................................................................ - 45 - 
5.6 
Integral Assay/Biomarker ................................................................................. - 45 - 
5.7 
 Intervention Not Otherwise Categorized ......................................................... - 45 - 
5.8 
 General Concomitant Medication and Supportive Care Guidelines ............... - 45 - 
5.9 
Duration of Therapy (Discontinuation Criteria) (02/22/2016) ......................... - 46 - 
6.  
TREATMENT MODIFICATIONS/management (02/22/2016) ................................... - 47 - 
6.1 
Immune-Related Adverse Events (irAEs) General Definition, Monitoring, 
and Management (02/22/2016) ........................................................................ - 48 - 
6.2 
Criteria to Discontinue Protocol Therapy ........................................................ - 59 - 
6.3 
Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions 
(02/22/2016) ..................................................................................................... - 59 - 
6.4 
Treatment of Ipilimumab/Nivolumab-Related Isolated Drug Fever ............................. - 60 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................. - 61 - 
7.1   
Protocol Agents ................................................................................................ - 61 - 

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7.2  
Adverse Events and Serious Adverse Events ................................................... - 61 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP 
Study Agents .................................................................................................... - 61 - 
7.4 
Expedited Reporting of Adverse Events .......................................................... - 70 - 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ......... - 73 - 
8.1 
CTEP Investigator Registration Procedures (05/22/2017) ............................... - 73 - 
8.2 
Oncology Patient Enrollment Network (OPEN) (02/13/2017) (05/22/2017) .. - 75 - 
8.3 
Agent Ordering and Agent Accountability ...................................................... - 76 - 
9. 
DRUG INFORMATION .............................................................................................. - 78 - 
9.1 
Nivolumab (BMS-936558, MDX1106), NSC #748726 .................................. - 78 - 
9.2 
Ipilimumab (MDX-010) (NSC 732442) ........................................................... - 79 - 
10. 
Pathology....................................................................................................................... - 81 - 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL studies ......................................... - 81 - 
11.1 
Reimbursement ................................................................................................. - 81 - 
11.2 
Translational Science (05/22/2017) .................................................................. - 81 - 
11.3 
Quality of Life .................................................................................................. - 85 - 
12. 
DATA AND RECORDS............................................................................................... - 85 - 
12.1 
Data Management/Collection (02/13/2017) ..................................................... - 85 - 
12.2 
Summary of Data Submission (02/13/2017) .................................................... - 85 - 
12.3 
Global Reporting/Monitoring ........................................................................... - 86 - 
13. 
STATISTICAL CONSIDERATIONS .......................................................................... - 86 - 
13.1 
Study Design .................................................................................................... - 86 - 
13.2 
Study Endpoints ............................................................................................... - 92 - 
13.3 
Primary Objectives Study Design .................................................................... - 92 - 
13.4 
Study Monitoring of Primary Objectives ......................................................... - 92 - 
13.5 
Accrual Considerations .................................................................................... - 93 - 
13.6 
Dose Level Guidelines ..................................................................................... - 93 - 
13.7 
Secondary or Exploratory Elements (including correlative science aims) ....... - 93 - 
13.8 
 Exploratory Hypothesis and Endpoints ........................................................... - 98 - 
13.9 
Gender/Ethnicity/Race Distribution ................................................................. - 98 - 
14. 
EVALUATION CRITERIA ......................................................................................... - 98 - 
14.1 
Antitumor Effect – Solid Tumors (02/22/2016) ............................................... - 98 - 
15. 
REFERENCES ............................................................................................................ - 107 - 
APPENDIX I  COLLABORATIVE AGREEMENT ............................................................. - 114 - 
APPENDIX II PERFORMANCE STATUS CRITERIA ....................................................... - 116 - 
APPENDIX III MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 

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SKIN ADVERSE EVENTS ........................................................................................ - 117 - 
APPENDIX IV TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES (05/22/2017)- 124 - 
APPENDIX V – TRANSLATIONAL SCIENCE LABORATORY TESTING PROCEDURES 
(05/22/2017) (09/07/2018) .......................................................................................... - 131 - 
APPENDIX VI—STUDY PARTICIPANT WALLET CARD (07/31/2017) ....................... - 140 - 
 
 
 
 
 
 
 
 
 
 
 
 

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Recurrent or Persistent Epithelial Ovarian, Primary Peritoneal 
or Fallopian Tube Cancer 
Treatment Arm 1 (02/22/2016) 
Nivolumab: Nivolumab 3mg/kg IV 
once every 2 weeks x 4 doses 
(induction phase), followed by 
Nivolumab 3 mg/kg IV every 2 
weeks (maintenance phase), for a 
maximum of 42 doses of 
maintenance therapy, until disease 
progression or until development of 
unacceptable toxicity, whichever 
comes first.  
 
1 Cycle = 4 weeks 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor measurements scheduled according to time period since beginning protocol therapy: every 8 
weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment schedule) 
for the first 8 months; then every 12 weeks (+/- 7 days) thereafter until disease progression is 
confirmed; also repeat at any other time if clinically indicated based on symptoms or physical signs 
suggestive of new or progressive disease. See Section 4 for more details.  
 
 
Treatment Arm 2 (02/22/2016) 
Nivolumab/Ipilimumab: Nivolumab 3mg/kg 
IV and Ipilimumab 1mg/kg IV once every 3 
weeks x 4 doses (induction phase)*, followed 
by Nivolumab 3 mg/kg IV every 2 weeks 
(maintenance phase), for a maximum of 42 
doses of maintenance therapy, until disease 
progression or until development of 
unacceptable toxicity, whichever comes first.  
 
1 Cycle = 3 weeks for induction phase 
1 Cycle = 4 weeks for maintenance phase 
 
* The order of administration is nivolumab, 
followed by ipilimumab 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
1.1.1 
To estimate the proportion of patients who have objective tumor response (complete 
or partial) by modified RECIST 1.1 in patients with persistent or recurrent epithelial 
ovarian, fallopian tube, primary peritoneal cancers, treated with nivolumab or the 
combination of nivolumab and ipilimumab and to assess the difference in ORR 
between patients treated with nivolumab versus those treated with the combination 
of nivolumab and ipilimumab. 
 
1.2 
Secondary Objectives (09/07/2018) 
1.2.1 
To estimate the PFS hazard ratio for patients treated with nivolumab versus those 
treated with the combination of nivolumab and ipilimumab. To estimate and 
compare the duration of OS for patients treated with nivolumab or the combination 
of nivolumab and ipilimumab. PFS by modified RECIST 1.1 will also be examined.  
 
1.2.2  
To determine the frequency and severity of adverse events associated with treatment 
with nivolumab or the combination of nivolumab and ipilimumab as assessed by 
Common Terminology Criteria for Adverse Events (CTCAE). 
 
1.2.3 
To determine whether cellular and molecular laboratory parameters in pre-treatment 
tissue and peripheral blood specimens predict overall survival (OS), tumor response 
by modified RECIST 1.1, and progression-free survival (PFS): (09/07/2018) 
(1) PD-L1 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) 
measured by quantitative immunohistochemistry (IHC); 
(2) Natural anti-tumor immunity in tumor cells and TILs measured using IHC and T 
cell repertoire analyses; 
(3) Tumor “immunogenicity” as determined by the neo-epitope landscape using 
next-generation whole exome sequencing (NGS); 
(4) Anti-tumor immune response in peripheral blood, including serologic responses 
and analysis of T cell receptor (TCR) repertoires by deep sequencing; and 
(5) Shift in quantitative peripheral blood parameters after the first 6 and 12 weeks of 
therapy.  
 
 
 
 
    
 
 

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2. 
BACKGROUND 
2.1  
Rationale for Immunotherapy 
Most epithelial cancers of ovarian, fallopian tube and primary peritoneal origin are 
genetically unstable, aggressive neoplasms accounting for the majority of deaths 
related to gynecologic malignancies.1 Unfortunately, despite front-line therapy 
including surgical resection and combination platinum-taxane chemotherapy, the 
vast majority of patients will recur and ultimately die from disease. Thus, there is a 
great unmet need for the development of complementary and augmentative 
therapeutic approaches. In particular, strategies reversing tumor promoting processes 
involving the interaction between tumor-infiltrating T-cells and the host 
microenvironment may be worthwhile, especially in genetically unstable tumors. 
 
There is abundant evidence that native host anti-tumor cell mediated immune 
mechanisms play a role in controlling malignant progression of epithelial ovarian 
cancer, the majority of which exhibit high grade serous morphology. Investigators at 
the University of Pennsylvania first discovered the impact of anti-tumor immune 
response on overall survival (OS) in patients with newly diagnosed advanced 
epithelial ovarian cancer, where the presence of CD3+ T-cells infiltrating tumor 
islets (intra-tumor T-cells) was found to be a predictor of prolonged OS.2 The five-
year OS rate was 38 percent among patients whose tumors contained CD3+ tumor 
infiltrating lymphocytes (TILs) versus 4.5 percent among patients whose tumors 
contained no CD3+ TILs within tumor islets.  Furthermore, in a Cox proportional 
hazards regression model, the prognostic significance of TIL was independent of 
residual disease after initial surgical cytoreduction, tumor grade, cell type, previous 
receipt of taxane therapy, and age at diagnosis.  Finally, the presence of TILs was 
associated with increased tumor expression of interferon gamma (IFN-γ) and other 
lymphocyte-attracting cytokines. Sato et al. independently showed that the 
accumulation of TILs in ovarian cancers was associated with improved progression-
free survival (PFS) and OS.3 The accumulation of CD8+ TILs, but not CD4+ TILs, 
was shown to predict improved OS, suggesting a role for CD8+ T-cells in tumor 
control. TILs isolated from ovarian cancers can recognize autologous tumor and 
known tumor antigens in vitro,4-8 can exhibit tumor-specific cytolytic activity ex 
vivo9,10 and are oligoclonal in composition.11,12 We demonstrated that tumor-specific 
T-cell precursors are also detected in the peripheral blood of approximately 50% of 
patients with advanced ovarian carcinoma.13 Furthermore, we have shown that TILs 
within epithelial ovarian cancers exhibit tumor-rejecting features in vivo and that 
ovarian cancers can be immunogenic (see below). Thus, naturally arising T 
lymphocytes with anti-tumor potential pre-exist in patients with epithelial ovarian 
cancer and underscore the potential for immunotherapy to affect the natural course 
of Mullerian duct carcinomas in order to improve patient outcome. 
 
Until recently, the immuno-biology of spontaneous tumor-reactive T-cells in ovarian 
cancer was not well-defined, largely due to the difficulty in identification and 
interrogation of responses. Recently, we elucidated CD137 (4-1BB), an activation 
induced TNF receptor family member, as a biomarker for bona fide naturally-
occurring tumor-reactive T-cells in epithelial ovarian cancers.14  CD137+ TILs, but 

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not CD137- TILs, demonstrated HLA-dependent IFN-γ secretion in response to 
autologous tumor stimulation and were capable of controlling epithelial ovarian 
cancer outgrowth in vivo. These results have enabled rapid identification of tumor-
reactive T-cells in this disease. We have now validated the existence of CD137+ 
TILs in ovarian cancer samples via analytical immunohistochemistry (IHC), 
allowing for the quantification of tumor-reactive TILs in biopsied tumor specimens. 
Taken together, we have demonstrated the potency of TILs in the control of 
epithelial ovarian cancer progression and have revealed an important role for CD137 
in the immuno-biology of ovarian cancer, wherein this marker is preferentially 
expressed on the tumor-reactive TIL subset, rationalizing the use of immunotherapy 
to bolster the accumulation of CD137+ TIL. 
 
2.2 
Evasion of Natural Cell-Mediated Immunity 
On the other hand, solid tumors may successfully evade immune attack by blocking 
effector T-cell trafficking into tumor islets and inhibiting effector T-cell activation. 
There are two important parallel mechanisms of tumor induced cell mediated 
immunologic tolerance in ovarian cancer which may operate in a complementary 
fashion and represent candidate therapeutic targets to reverse spontaneous T-cell 
mediated anti-tumor immunity. 
 
First, in general, activation of T-cells requires binding of the T-cell receptor (TCR) 
to antigen in association with major histocompatibility (MHC) molecules, plus co-
stimulation by antigen-presenting cells (APCs).15 Such co-stimulation involves 
binding of CD86 and CD80 on APCs to CD28 on T-cells, and absence of co-
stimulation through CD28 is associated with anergy. Cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4) is a negative regulatory homologue of CD28 found 
on activated T-cells and, by competing with CD28 for CD86 and CD80 binding 
functions as a checkpoint to prevent auto-immunity. CTLA-4 is also expressed 
ubiquitously on a naturally occurring subpopulation of CD4+ regulatory T-cells 
(Treg) constitutively expressing FOXP3 and CD25 (the IL-2 receptor-α chain) and 
thought to inhibit autoimmune pathology, mediate transplantation tolerance, impede 
anti-tumor immunity and prevent the expansion of other T-cells in vivo.16  Treg cells 
require activation via their T-cell receptor (TCR) to become suppressive, and once 
activated inhibit the proliferation of effector T-cells in an antigen-unrestricted 
manner. Cancer cells may secrete chemokines such as CCL22 that specifically 
recruit Treg cells. The paradigm of Treg-mediated immunosuppression in human 
cancer was originally defined in epithelial ovarian cancer.17  In a detailed analysis of 
Treg cells in 104 ovarian carcinoma cases, it was shown that human tumor-
infiltrating Treg cells suppressed tumor-specific T-cell immunity and contributed to 
growth of human tumors in vivo. At all stages of disease, increased accumulation of 
Treg cells in tumor was associated with poor OS. In addition, a high CD8+/Treg 
ratio has been associated with favorable prognosis in epithelial ovarian cancer,3 
suggesting that an abundance of CD8 effector cells may overcome Treg-mediated 
suppression. We therefore hypothesize that those immune therapies that enhance 
CD8+ T-cell accumulation and activity while reducing the population of Treg cells 
will demonstrate anti-tumor activity. Experimental depletion of Treg cells in tumor-

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bearing mice has been shown to improve immune-mediated tumor clearance, 
indicating that strong anti-tumor immunity may require breaking Treg-mediated 
tolerance to tumor antigens.18,19 van Elsas et al showed that treatment with anti-
CTLA-4 antibody promoted tumor rejection and T-cell activation in a mouse model 
of melanoma.20 Experimental work in animal models using this approach ultimately 
led to clinical development of ipilimumab (see full details below in protocol section 
2.5), a CTLA-4 neutralizing humanized monoclonal antibody FDA approved for the 
treatment of metastatic melanoma21 based on a phase III trial demonstrating 
significant prolongation of OS.22 Though the application of CTLA-4 targeted 
therapy with Ipilimumab represents a rational approach in the treatment of advanced 
Mullerian duct adenocarcinomas (particularly high-grade serous cancers), clinical 
trial experience to date for this disease entity has been limited to two patients with 
relapsed epithelial ovarian cancer in the initial phase I study.23 
 
A second mechanism involves signaling through the negative regulatory co-
stimulatory T-cell receptor, human programmed death-1 (PD-1, CD279).24,25  PD-1 
is highly expressed on activated T-cells. The principal ligands for PD-1 are PD-L1 
(B7-H1, CD274),25,26 expressed on tumor cells, antigen-presenting cells and 
dendritic cells and PD-L2 (B7-DC, CD273),27,28 commonly expressed on endothelial 
cells. Ligand binding leads to de-activation of T-cells. PD-L1 is expressed in some 
normal tissues and thought to maintain host T-cell-mediated immunologic tolerance. 
Of note, expression of PD-L1 by a variety of solid tumors has been implicated in 
evasion of anti-tumor immunity. PD-L1 expressed on tumor cells from epithelial 
ovarian cancers has been shown to inhibit anti-cancer immunity.26 A study by 
Hamanishi et al. suggested that expression of both PD-L1 and PD-L2 in human 
ovarian cancers is associated with poor OS and that expression of PD-L1 was 
inversely correlated with the presence of CD8+ (effector) T-cells in tumor islets.29 
The same group also showed in a pre-clinical model that PD-L1 bearing tumors 
inhibited tumor-directed cytotoxic T-cell activity. Maine et al. showed that PD-L1 
was over-expressed on monocytes within ascites of patients with ovarian cancer; 
they demonstrated functional links between PD-L1 expression on monocytes and 
tumor cells.30 Furthermore, blocking the interaction of PD-L1 with PD-1 on T-cells 
has resulted in tumor regression in a mouse epithelial ovarian cancer model.31 We 
recently showed that nearly all human tumor-reactive TILs in epithelial ovarian 
cancer express high levels of PD-1,14 requiring signaling through its ligands (most 
notably PD-1) to suppress T-cell function. Thus, disruption of PD-1/PD-L1 
interaction is a rational strategy for immunotherapy in patients with advanced 
epithelial ovarian cancer.  Nivolumab (see full details below in protocol section 2.4) 
is a humanized monoclonal antibody binding to PD-1 and blocking the interaction 
between PD-1 and its ligands, thus inhibiting PD-1 signal transduction in activated 
T-cells. A phase I dose-finding trial involving 296 patients with multiple non-
gynecologic tumors demonstrated response rates of 18% (14 of 76), 28% (26 of 94) 
and 27% (9 of 33) among patients with non-small-cell lung cancer, melanoma and 
renal-cell cancer, respectively.32 Overall, two-thirds of responses were durable for at 
least one year. Importantly, response in 42 patients with pretreatment tumor 
specimens was associated with tumor expression of PD-L1 by IHC analysis, with no 

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responses in 17 patients bearing PD-L1 (-) tumors and 9 (36%) responses in 25 
patients with PD-L1 (+) tumors. Further rationale for targeting PD-1/PD-L1 pathway 
in gynecologic malignancies was demonstrated in a phase I study of anti-PD-L1 
antibody in patients with advanced cancer, which included 17 patients with ovarian 
cancer.33  Of the ovarian cancer cohort, 22% of the patients had evidence of 
objective response or stable disease, lasting at least 24 weeks.33 
 
2.3 
Rationale for Combined CTLA-4 and PD-1 Targeting 
The non-redundant nature of CTLA-4 and PD-1 mediated T-cell inhibition suggests 
the potential for additive or synergistic anti-tumor activity with dual therapeutic 
targeting. To determine whether concurrent therapy with nivolumab and ipilimumab 
may have applicability for  human epithelial ovarian cancer, we performed 
molecular profiling of IFN-γ+ CD137+ tumor-reactive TILs from fresh tumor 
biopsies, which revealed that the tumor-reactive fraction of TILs in epithelial ovarian 
cancers express both surface PD-1 and CTLA-4 (Figure 1). To model concurrent 
therapy for epithelial ovarian cancer, we showed that blockade of both PD-1 and 
CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in 
two thirds of treated mice.34 Double blockade was associated with increased 
proliferation of antigen-specific effector CD8+ and CD4+ T-cells, antigen-specific 
cytokine release, inhibition of suppressive functions of Treg cells, and up-regulation 
of key signaling molecules critical for T-cell function. In summary, our results 
suggest that clinical activity from concurrent nivolumab and ipilimumab can act in a 
complementary fashion to provide significant clinical activity in epithelial ovarian 
cancer and related malignancies. 
 
 

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Wolchok et al. recently reported the results of a dose-finding trial in advanced 
melanoma which included 53 patients receiving concurrent Nivolumab and 
Ipilimumab.35 The objective response rate was 40%. At maximum doses associated 
with an acceptable level of adverse events, the objective response rate was 53%, and 
all 17 of these patients experienced tumor reduction of at least 80% by modified 
World Health Organization (WHO) criteria.  Callahan et al. are currently conducting 
an open label phase I/II trial of Nivolumab as monotherapy or combined with 
Ipilimumab in advanced or metastatic solid tumors.36  
 
Recently, efficacy and safety results of a phase I clinical trial of Nivolumab in 
women with platinum-resistant ovarian cancer was presented.37 Nivolumab was 
administered every 2 weeks to patients with advanced or relapsed, platinum–
 
Figure 1. Tumor-reactive T-cells in advanced ovarian cancer express PD-1 and CTLA-4.  
(A) A subset of epithelial ovarian cancer CD3+ TILs express activation-induced CD137 
on their surface which is detectable by flow cytometry. (B) Enriched CD137+ TILs are 
the bona fide tumor-reactive TIL subset, and react against autologous tumor cells and 
produce IFN-γ in overnight co-culture. All other TILs (CD137-) do not. (C) Tumor-specific 
CD137+ TILs control human ovarian cancer progression in an immuno-deficient mouse 
model; CD137 TILs do not. (D) Tumor-activated T-cells in a field of tumor cells are 
detectable by IHC using anti-CD137 antibody. CD3, CD8, CD4, FOXP3 and PD-L1 
CD3
Isotype
CD137
TILs
PBL
B.
A.
0
200
400
600
800
1000
1200
IFN-g (pg/mL) 
CD137+ EOC
TILs
CD137- EOC
TILs
EOC sample ID#
E.
C.
0
20
40
60
80
100
120
140
160
180
18
25
32
39
46
52
59
Tumor Volume (mm3)
CD137pos
CD137neg
Days post-inoculation
% IFNg+ CD8 TILs
% CTLA-4+ CD8 TILs
% PD-1+ CD8 TILs
D.

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resistant ovarian cancer. Eighteen patients were treated at two dose levels, 1 (10 
patients) or 3 (8 patients) mg/kg until disease progression or dose limiting toxicity. 
CT imaging was performed every 8 weeks. The majority of women had serous 
tumors (14, serous; 2 endometrioid; 2 clear cell), and 11/18 had received at least 4 
prior chemotherapy regimens. Seven of 18 experienced grade 3-4 adverse events 
possibly related to treatment (rash (n=1), hypothyroidism (n=2), fever (n=1), 
arrhythmia (n=1), arthralgia (n=1), lymphocytopenia (n=1); the distribution did not 
appear to be dose dependent in this dose range. In addition, there were two serious 
adverse events thought possibly to be treatment related. One patient at the 1 mg/kg 
dose level developed grade 3 disorientation and fever, and another at the 3 mg/kg 
dose level developed grade 3 fever in association with deep vein thrombosis. Three 
of 18 (17%) had a confirmed objective response (2 CR [serous, clear cell], 1 PR 
[serous]) with the two complete responses seen at the 3 mg/kg dose.  An additional 5 
(28%) patients demonstrated stable disease. These results provide preliminary 
evidence of single agent activity in patients with highly pre-treated, platinum-
resistant ovarian cancer. 
 
2.4 
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 .38  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.35 
 
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 

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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).38PD-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 phosphatase.   
 
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c).  In transplantable tumor models that 
expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual anti-
LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that 
were largely resistant to single antibody treatment.39 Despite minimal immuno-
pathologic 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,40 renal,41-43 
esophageal, 44gastric,45 ovarian,46 pancreatic,47 lung,48 and other cancers.38 
 
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.   
 
2.4.1  
Nonclinical Development of Nivolumab 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, 
nivolumab alone was well tolerated.38  Combination studies have highlighted the 

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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. 
 
2.4.2 
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 
ovarian cancer.   
 
2.4.2.1 
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.38  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. 
 
2.4.2.2 
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.49  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.50  
In the RCC cohort, median duration of response was 12.9 months for both doses 
with 5 of the 10 responses lasting ≥1 year.51   
 
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 

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weeks for 4 doses (concurrent regimen).35  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.52  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. 
 
2.4.2.3 
Toxicology 
A maximum tolerated dose (MTD) of nivolumab was not defined.32  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,35 grade 3 or 4 treatment-related events were noted in 53% of 
patients.  Skin rash represents the majority of these events. 
  
2.4.2.4 
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.35  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. 
 
 

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2.5 
Ipilimumab 
Ipilimumab (MDX-010, MDX-CTLA4, BMS-734016) is being developed by CTEP 
as an anticancer agent in collaboration with Bristol-Myers-Squibb (BMS).  On March 
25, 2011, the FDA approved ipilimumab injection (YERVOY, BMS) for the 
treatment of unresectable or metastatic melanoma.  Ipilimumab is a human IgG1κ 
monoclonal antibody (mAb); it is specific for human cytotoxic T lymphocyte-
associated antigen-4 (CTLA-4, CD152) expressed on activated T cells.  Ipilimumab 
is now produced and formulated from transfected Chinese hamster ovary (CHO) 
cells.   
 
CTLA-4 is a negative regulator of T-cell responses following T-cell 
stimulation.53,54CTLA-4 knockout mice suffer from a fatal lymphoproliferative 
disorder, supporting the idea that CTLA-4 functions as a negative regulator of T-cell 
responses in vivo.55-57  Disrupting CTLA-4 interaction with its ligands B7-1 (CD80) 
and B7-2 (CD86), which are expressed on antigen-presenting cells (APCs), with 
ipilimumab, augments immune responses.58  In vivo blockade of CTLA-4, utilizing 
anti-CTLA-4 mAb, induced regression of established tumors and enhanced 
antitumor immune responses in several murine tumor models.  Blockade of CTLA-
4-mediated signals is effective in inducing rejection of immunogenic cancers in 
mice.  Moreover, when anti-CTLA-4 mAb is used in conjunction with granulocyte 
macrophage-colony stimulating factor (GM-CSF)-secreting tumor vaccines, poorly 
immunogenic cancers in mice are rejected.  These findings suggest that CTLA-4 
blockade, alone or in combination with antigenic stimulation and other immune 
modulating agents, can induce a potent antitumor response.   
 
2.5.1 
Pharmacology of Ipilimumab 
In vitro studies were performed with ipilimumab to demonstrate that it is specific for 
CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show 
any cross-reactivity with human B7.1 or B7.2 negative cell lines, and stains the 
appropriate cells without non-specific cross-reactivity in normal human tissues.  
Ipilimumab does cross-react with CTLA-4 in non-human primates including 
cynomolgus monkeys.  Blockade of CTLA-4/B7 interactions enhanced T-cell 
responses to CD3 / CD28, peptide antigens, or super-antigens in mice.59-62  CTLA-4 
knockout mice appear to have spontaneously activated T cells evident at 
approximately 1 week after birth, followed by rampant lymphoproliferation and 
lymphadenopathy.  These mice die at approximately 3 weeks of age, either as a 
result of polyclonal T-cell expansion and tissue destruction or as a result of toxic 
shock resulting from lymphokine production.  Genetically engineered mice 
heterozygous for CTLA-4 (CTLA-4+/-), appeared healthy and gave birth to healthy 
CTLA-4+/- heterozygous offspring.  Mated CTLA-4+/- heterozygous mice also 
produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-).  Since 
thymocyte differentiation and selection proceed normally in CTLA-4-deficient mice, 
the rampant T-cell expansion that occurs in the mice indicates that CTLA-4 plays a 
critical role in down-regulating post-thymic T-cell responses in the periphery 
following stimulation of naïve, memory, and effector T cells.62  
 

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2.5.2 
Pharmacokinetics  
The pharmacokinetics (PK) of ipilimumab was studied in 499 patients with 
unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg 
administered once every 3 weeks (q3w) for four doses.  Peak concentration (Cmax), 
trough concentration (Cmin), and area under the curve (AUC) of ipilimumab were 
found to be dose proportional within the dose range examined.  Upon repeated 
dosing of ipilimumab administered q3w, ipilimumab clearance was found to be time-
invariant, and minimal systemic accumulation was observed as evident by an 
accumulation index of 1.5-fold or less.  Ipilimumab steady-state concentration was 
reached by the third dose.  The following mean (percent coefficient of variation) 
parameters were generated through population PK analysis: terminal half-life of 14.7 
days (30.1%); systemic clearance (CL) of 15.3 mL/h (38.5%); and volume of 
distribution at steady-state (Vss) of 7.21 L (10.5%).  The mean (±SD) ipilimumab 
Cmin achieved at steady-state with the 3-mg/kg regimen was 21.8 mcg/mL (±11.2). 
 
Specific Populations: Cross-study analyses were performed on data from patients 
with a variety of conditions, including 420 patients with melanoma who received 
single or multiple infusions of ipilimumab at doses of 0.3, 3, or 10 mg/kg.  The 
effects of various covariates on ipilimumab PK were assessed in population PK 
analyses. 
 
Ipilimumab CL increased with increasing body weight; however, no dose adjustment 
of ipilimumab is required for body weight after administration on a mg/kg basis. 
 
The following factors had no clinically meaningful effect on the CL of ipilimumab: 
age (range 26 to 86 years), gender, concomitant use of budesonide, performance 
status, HLA-A2*0201 status, positive anti-ipilimumab antibody status, prior use of 
systemic anticancer therapy, or baseline lactate dehydrogenase (LDH) levels.  The 
effect of race was not examined as there were insufficient numbers of patients in 
non-Caucasian ethnic groups. 
 
Renal Impairment: Creatinine clearance at baseline did not have a clinically 
important effect on ipilimumab PK in patients with calculated creatinine clearance 
values of 29 mL/min or greater. 
 
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a 
clinically important effect on ipilimumab PK in patients with various degrees of 
hepatic impairment. 
 
2.5.3 
Clinical Pharmacodynamics 
 
In clinical studies, ipilimumab increased absolute lymphocytes counts (ALC) in 
peripheral blood.58  However, CD4+/CD8+ ratio did not appear to be affected.  
Across three phase 2 studies in 463 subjects with advanced melanoma, ipilimumab 
increased ALC in a dose-dependent manner, with the largest increase observed at 10 
mg/kg dose.  ALC continued to increase over time during the induction treatment at 
least until week 12 at the 3 mg/kg and 10 mg/kg dose, but not at the 0.3 mg/kg dose.  

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The slope of ALC increase also suggested the 10 mg/kg dose is more biologically 
active than the 3.0 mg/kg or 0.3 mg/kg dose.   
 
2.5.4 
Mechanism of Action 
The proposed mechanism of action for ipilimumab is T-cell potentiating through 
interference of the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on 
APCs, with subsequent blockade of the inhibitory function of CTLA-4 (Investigator 
Brochure, 2011).  Ipilimumab impacts tumor cells indirectly, and measurable clinical 
effects emerge after the immunological effects.  Tumor infiltration with lymphocytes 
and the associated inflammation is likely the cornerstone of the effect of ipilimumab 
and can manifest in various patterns of clinical activity leading to tumor control.  
These immunologic responses may take time to develop and so tumor responses may 
be delayed and tumor progression may occur during the initial period followed by 
responses.  In some cases, tumor response based on tumor infiltration with immune 
cells may be preceded by an apparent increase in initial tumor volume and/or the 
appearance of new lesions, which may be taken for tumor progression on 
radiological evaluations. Delayed responses following increasing tumor size or 
appearance of new lesions have been seen in approximately 10-20% of patients with 
metastatic melanoma.  For patients who are not experiencing rapid clinical 
deterioration, allowing sufficient time to observe responses including disease 
stabilization or confirmation of progression is recommended; as discussed in the 
section “Overall Risk/Benefit Assessment” may allow better assessment of clinical 
activity and avoid unnecessarily initiating additional therapies in subjects who might 
be benefitting from treatment.  Immune-related (ir) response criteria were developed 
based on these observations in patients with melanoma to systematically categorize 
novel patterns of clinical activity and are currently being prospectively evaluated in 
clinical studies. 
 
2.5.5 
Nonclinical Toxicology  
Please note relevant toxicity for single-agent ipilimumab has been almost 
completely derived from clinical studies.  
 
In a study using cynomolgus macaques, anti-melanocyte responses were observed in 
animals given up to four doses of 10 mg/kg ipilimumab after receiving a melanoma 
cell vaccine.63  Depigmentation has been observed in other nonclinical 
immunotherapy studies that involve treatment with melanoma peptides.64-69  The 
symptoms in animals appear to resemble vitiligo observed in clinical immunotherapy 
trials of melanoma patients and may be an unavoidable consequence of treatment.70 
 
Additional repeat-dose toxicity studies conducted using cynomolgus macaques 
demonstrated that the IV administration of ≤30 mg/kg every 3 days for three doses, 
10 mg/kg weekly for 1 month, 1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly 
for 6 months was generally well tolerated, without significant clinical, immuno-
toxicological, or histo-pathological findings.58  However, when ipilimumab was 
administered in combination with another immuno-modulatory antibody (BMS-
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DNA, two immune-related adverse events (irAEs) were observed:  severe colitis 
requiring euthanasia in one monkey and reversible dermatitis/rash in the inguinal 
area and peripheral lymphadenopathy in another monkey. 
 
Complete information on the pre-clinical toxicology studies can be found in the 
Ipilimumab Investigator Brochure (IB).58  Non-clinical toxicity assessments included 
in vitro cynomolgus monkeys alone and in the presence of vaccines.  Low to 
moderate ADCC activity was noted at concentrations up to 50 mcg/mL.  These data 
are consistent with the requirement of high levels of antigen expression on the 
surface of target cells for efficient ADCC or CDCC.  No mortality or signs of 
toxicity were observed in three independent 14-day intravenous (IV) toxicology 
studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose.  
Furthermore, ipilimumab was evaluated in sub-chronic and chronic toxicology 
studies in cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine and 
Melanoma Vaccine.  Ipilimumab was well tolerated alone or in combination in all 
studies.  There were no significant changes in clinical signs, body weight values, 
clinical pathology values or T-cell activation markers. In addition, there were no 
significant histopathology changes in the stomach or colon. 
 
2.5.6 
Clinical Development of Ipilimumab   
Company-Sponsored Studies 
BMS and Medarex (acquired by BMS in September 2009) have co-sponsored an 
extensive clinical development program for ipilimumab, encompassing more than 
4000 subjects in several cancer types in 33 completed and ongoing studies.58  The 
focus of the clinical program is in melanoma, prostate cancer, and lung cancer, with 
advanced melanoma being the most comprehensively studied indication.  
Ipilimumab is being investigated both as single agent and in combination with other 
modalities such as chemotherapy, radiation therapy, and other immunotherapy. 
 
Phase 3 programs are ongoing in melanoma and prostate cancer (Investigator 
Brochure, 2011).  In the phase 3 combination study of ipilimumab with glycoprotein 
100 (gp100) peptide vaccine (melanoma study MDX010-20), ipilimumab was 
administered at a dose of 3 mg/kg of body weight, with or without gp100 q3w for up 
to four treatments.22  The median overall survival (OS) in the ipilimumab plus gp100 
group was 10.0 months (95% confidence interval [CI], 8.5 to 11.5 months) compared 
with 6.4 months (95% CI, 5.5 to 8.7 months) in the gp100-alone group (hazard ratio 
[HR] for death, 0.68; p<0.001).  Grade 3 or 4 immune related events (irAEs) 
occurred in 10 to 15% of patients treated with ipilimumab and in 3% of patients 
treated with gp100 alone.   
 
A second phase 3 study in melanoma was reported for ipilimumab in combination 
with dacarbazine versus dacarbazine alone in previously untreated advanced 
melanoma.  CA184024 evaluated the addition of 10 mg/kg ipilimumab to 
dacarbazine in patients with previously untreated, metastatic melanoma.  A total of 
502 patients were randomized to receive up to 8 cycles of dacarbazine 850 mg/m2 
q3w, with either ipilimumab 10 mg or placebo for cycles 1-4 and as maintenance 

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after completion of chemotherapy. Ipilimumab AEs were consistent with previous 
studies and predominantly affected skin, GI tract, liver, and the endocrine system.  
Events were managed with established guidelines and were generally responsive to 
dose interruption/discontinuation, corticosteroids and/or other immunosuppressive 
drugs.   
 
There are two ongoing studies of ipilimumab as adjuvant monotherapy for high-risk 
Stage III melanoma (CA184029 and ECOG 1609).  
 
Two phase 3 studies are ongoing in subjects with castration-resistant prostate cancer 
who have received prior chemotherapy (CA184043, ipilimumab in combination with 
radiation therapy) and those who are chemotherapy-naïve (CA184095, ipilimumab 
monotherapy). 
 
An ongoing large phase 2 study (CA184041) is investigating the addition of 
ipilimumab to carboplatin and paclitaxel using two different schedules (concurrent 
and phased) in subjects with non-small cell lung cancer (NSCLC) or small cell lung 
cancer (SCLC).58  The results demonstrate an improved immune-related progression-
free survival (irPFS) for the subjects who received combination therapy with 
paclitaxel/carboplatin/ipilimumab compared with paclitaxel/carboplatin alone.  The 
improvement in irPFS with the combination therapy met the pre-specified protocol 
criteria for significance for both the concurrent and phased schedules (p=0.0935 and 
0.0258, respectively).  Using modified World Health Organization (mWHO) criteria 
(a key secondary endpoint), PFS was significantly improved with the phased 
schedule but not the concurrent schedule (p=0.0240 and 0.2502, respectively). 
 
2.5.7 
Other Clinical Studies with Ipilimumab 
Renal cell carcinoma (RCC) 
Yang and colleagues presented data on a phase 2 study of ipilimumab conducted in 
patients with metastatic RCC.71   Sequential cohorts received either 3 mg/kg 
followed by 1 mg/kg or all doses at 3 mg/kg q3w.  One of 21 patients receiving the 
lower dose had a PR.  Five of 40 patients at the higher dose had PRs (95% CI, cohort 
response rate 4 to 27%) and responses were seen in patients who had previously not 
responded to IL-2.  Thirty-three percent of patients experienced grade 3 or 4 irAEs.  
There was a highly significant association between autoimmune events and tumor 
regression (response rate = 30% with AE, 0% without AE).  The authors concluded 
that CTLA-4 blockade with ipilimumab induced cancer regression in some patients 
with metastatic clear cell renal cancer, even if they had not responded to other 
immunotherapies.   
 
Melanoma (ipilimumab plus bevacizumab) 
At the 2011 ASCO meeting Hodi and colleagues presented results on 21 evaluable 
patients (22 patients enrolled) with unresectable stage III or stage IV melanoma 
treated with the combination of 10 mg/kg ipilimumab and 7.5 mg/kg bevacizumab 
on a phase 1 study.72  AEs included giant cell arteritis (1), hypophysitis (3), 
thyroiditis (4), grade 3-4 hepatitis (2), bilateral uveitis (2), and grade 2 colitis (2); 5 

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patients required systemic steroids and stopped treatment.  All toxicities were 
resolved.  Eight PRs and 6 SDs were observed.  All responses were durable (>6 
months).  Post-treatment biopsies in 12 patients revealed activated vessel 
endothelium with extensive T-cell trafficking non-productive central angiogenesis, 
and peripheral blood monitoring revealed a marked increase in CD4/CCR7/CD45RO 
central memory cells in the majority of patients,  not seen with ipilimumab alone.  
The authors concluded that the combination of ipilimumab with bevacizumab can be 
safely administered with clinical activity and correlatives suggesting synergistic 
effects.  
 
Bladder cancer 
Carthon and colleagues reported immuno-modulatory effects following a brief 
exposure of anti-CTLA-4 in patients with urothelial carcinoma of the bladder 
requiring surgery (BMS study CA184027).73  12 patients were enrolled (six patients 
received 3 mg/kg/dose of ipilimumab and another six patients received 10 
mg/kg/dose for two doses prior to surgery).  The treatment was found to be tolerable 
in the cohort of patients with 11 of 12 patients receiving both doses of antibody.  
Grade 1-2 diarrhea and rash were the most common drug-related AEs.  The only 
noted grade 3 irAEs were ischemic papillopathy and diarrhea, which were both 
responsive to treatment with steroids.   
 
Liakou and colleagues found that CD4 T cells from peripheral blood and tumor 
tissues of all bladder cancer patients treated with anti-CTLA-4 antibody had 
markedly increased expression of inducible co-stimulator (ICOS).74  These 
CD4+ICOShi T cells produced interferon-gamma (IFN-γ) and could recognize the 
tumor antigen NY-ESO-1.  Increase in CD4+ICOShi cells led to an increase in the 
ratio of effector to regulatory T cells.  The authors indicated that these immunologic 
changes were reported in both tumor tissues and peripheral blood as a result of 
treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and 
scheduling of this agent to improve clinical responses.  A sustained increased 
frequency of CD4+ICOShi T cells may serve as a biomarker of anti-CTLA-4 activity 
and/or of clinical benefit for patients who are being treated with this novel agent.73   
 
Pancreatic cancer 
Royal and colleagues presented the results on 27 patients (metastatic disease: 20 and 
locally advanced: 7).75  Three subjects experienced ≥ grade 3 irAEs (colitis:1, 
encephalitis:1, hypophysitis:1).  One subject experienced a delayed response after 
initial progressive disease.  In this subject, new metastases after 2 doses of 
ipilimumab established progressive disease.  However, continued administration of 
the agent per protocol resulted in significant delayed regression of the primary lesion 
and 20 hepatic metastases with normalization of tumor markers and clinically 
significant improvement of performance status.  The investigators concluded that 
single agent ipilimumab at 3.0 mg/kg/dose was ineffective for the treatment of 
advanced pancreatic cancer.  However, a significant delayed response in one subject 
of this trial suggests that immunotherapeutic approaches to pancreatic cancer deserve 
further exploration. 

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2.5.8 
CTEP-Sponsored Studies 
The DCTD, NCI, has sponsored nine studies with ipilimumab including one pilot 
study (NCI #5744, lymphoma), three phase 1 studies (5708 [ovarian], 6082 [solid 
tumors], and 7458 [solid tumors]), one phase 1/2 study (6359 [non-Hodgkin’s 
lymphoma]) with single agent ipilimumab, two phase 1 combination studies in 
prostate cancer with GM-CSF (6032) and with prostate-specific antigen (PSA)-
TRICOM vaccine (7207), one phase 2 combination study of ipilimumab with GM-
CSF (E1608, melanoma) and one phase 3 study (E1609) of adjuvant ipilimumab 
therapy versus high-dose interferon alpha-2b in patients with resected high-risk 
melanoma.   
 
Results from 11 patients (colon, n=3; non-Hodgkin’s lymphoma, n=4; prostate, n=4) 
who received ipilimumab on study 5744 included tumor regression in 2 patients with 
lymphoma; 1 of whom (follicular lymphoma patient) had a partial response (PR) of 
14-month duration.76  Ipilimumab was well tolerated with predominantly grade 1/2 
toxicities.  One drug-related grade 3 AE was observed.  Tregs, as detected by 
expression of CD4+CD25+CD62L+, declined at early time points but rebounded to 
levels at or above baseline values at the time of the next infusion.  The investigators 
concluded that ipilimumab treatment depressed Treg numbers at early time points in 
the treatment cycle but was not accompanied by an increase in vaccine-specific 
CD8+ T-cell responses in these patients previously treated with a variety of 
investigational anticancer vaccines.   
 
Hodi and colleagues reported preliminary results on 20 patients (11 metastatic 
melanoma patients and 9 metastatic ovarian carcinoma patients) on study 5708.77  
None of the 11 patients from the metastatic melanoma cohort manifested grade 3 or 
4 inflammatory toxicities; however, all subjects revealed mild inflammatory 
pathologies associated with low-level constitutional symptoms.  The most common 
toxicity (10/11 subjects) was a grade 1-2 reticular and erythematous rash on the 
trunk and/or extremities that arose between 3 days and 3 weeks after antibody 
administration and then gradually resolved without specific intervention.  Biopsies 
of involved skin revealed low-grade interface dermatitis, minor to moderate 
mononuclear infiltrates surrounding the superficial dermal vasculature, and 
increased mucin deposition in the papillary and reticular dermis.  These pathologic 
features resembled those observed in mild cutaneous forms of systemic lupus 
erythematosus.  Three PRs (range, 21-34+ months) and five events of stable disease 
(SD) (range, 4-25 months) were observed.  One PR and three SDs (2, 4, and 6+ 
months) were observed in the ovarian carcinoma group.  The investigators concluded 
that selective targeting of antitumor regulatory T cells (Treg) may constitute a 
complementary strategy for combination of ipilimumab and GM-CSF-based antigen 
tumor cell vaccine therapy.  
 
Results from 29 patients with malignancies that were recurrent or progressive after 
allogeneic hematopoietic cell transplantation (allo-HCT) demonstrated that drug was 
well tolerated at single doses up to 3 mg/kg.78  Four patients experienced organ-
specific irAEs of reversible grade 3 arthritis, grade 2 hyperthyroidism, dyspnea, and 

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grade 4 pneumonitis.  Three patients had objective responses: one PR lasting for 2 
months, and two durable complete responses (CRs).  Two additional patients with 
Hodgkin’s disease who had evidence of rapid disease progression prior to 
ipilimumab treatment achieved SD for 3 and 6 months, following infusion at the 3 
mg/kg dose level.  Median OS was 24.7 months.  At a 3.0 mg/kg dose, active serum 
concentrations of ipilimumab were maintained for 30 days following a single 
infusion.  Zhou and colleagues reported immuno-phenotypes of peripheral blood T 
cells, including T-cell reconstitution, activation, and Treg expression, in 29 patients 
before and after a single-dose infusion of ipilimumab.79  CTLA-4 blockade by a 
single infusion of ipilimumab increased CD4+ and CD4+HLA-DR+ T lymphocyte 
counts and intracellular CTLA-4 expression at the highest dose level (3.0 mg/kg).  
There was no significant change in Treg cell numbers after ipilimumab infusion.  
These data demonstrate that significant changes in T-cell populations occur on 
exposure to a single dose of ipilimumab.   
 
Harzstark and colleagues reported results on 36 patients80 with hormone refractory 
metastatic prostate cancer.81  Of six patients treated with ipilimumab at a dose of 3 
mg/kg, three patients had confirmed PSA declines of ≥50%, with a time to 
progression (TTP) of 22, 26, and 103 weeks.  One of these patients had a PR in 
hepatic metastases.  Grade 3 IrAEs consisted of rash in five patients, pan-
hypopituitarism in one patient, temporal arteritis in one patient, and diarrhea in three 
patients.  Non-irAEs included grade 3 and 4 cerebrovascular events (one patient 
each), grade 3 angina (one patient), grade 3 atrial fibrillation (one patient), grade 3 
fatigue (four patients), and grade 5 pulmonary embolism (one patient).  One patient 
treated at 10 mg/kg had a PSA decline of ≥50% with a TTP of 39 weeks.  Higher 
doses of treatment with MDX-010 + GM-CSF induced the expansion of activated 
circulating CD25+, CD69+, and CD8+ T cells more frequently than was seen in 
patients who received the same doses of either MDX-010 or GM-CSF alone.82  The 
sera screening with protein arrays showed that the treatment can induce antibody 
responses to the testicular antigen NY-ESO-1.   
 
Patients with metastatic prostate cancer were treated with ProstVac vaccine and 
ipilimumab before chemotherapy.  The median OS for all patients on study was 31.8 
months with a 74% survival probability at 24 months.83  The median Halabi 
predicted OS for all patients was 18.5 months.  There was no significant difference 
in OS at different dose levels of antibody (range 1-10 mg).  A unique effect of the 
vaccines on the rate of tumor growth may be a novel method to evaluate the anti-
tumor effects of the vaccine.84  The authors suggested that the addition of immune 
checkpoint inhibition may augment the clinical benefit of vaccines.  
 
Ansell and colleagues reported data on 18 treated patients with NHL.85  Two clinical 
responses were observed:  one patient with diffuse large B-cell lymphoma (BCL) 
had an ongoing CR (>31 months), and one with follicular lymphoma had a PR 
lasting 19 months.  In 5 of 16 cases tested, T-cell proliferation to recall antigens was 
>2 fold increased after ipilimumab therapy.  The investigators have found that 
blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the 

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doses used.  Ipilimumab has antitumor activity in patients with BCL, resulting in 
durable responses in a minority of patients.  Ipilimumab at 3 mg/kg monthly for 4 
months can be given safely and is the dose recommended for future combination 
studies.   
 
2.5.9 
Clinical Safety   
Safety Experience  
The most common treatment-related AEs (those considered possibly, probably, or 
definitely related to study drug by the investigator) associated with the use of 
ipilimumab were immune related irAEs.58  The irAEs primarily involved the 
gastrointestinal (GI) tract (e.g., diarrhea and colitis) and skin (e.g., pruritus and rash), 
and less frequently, the liver, endocrine glands (including the thyroid, pituitary, and 
adrenal glands) and nervous system.  IrAEs were generally managed with either 
symptomatic therapy (grade 1-2 events), systemic corticosteroids (grade 3-4 events), 
or other immunosuppressive drugs (e.g., infliximab, mycophenolate mofetil) for 
steroid-unresponsive GI or hepatic irAEs, as appropriate.  Management of irAEs was 
usually paired with omission of dosing for mild or moderate events and permanent 
discontinuation for severe irAEs.  Ipilimumab can result in severe and fatal immune-
mediated reactions due to T-cell activation and proliferation.  Fatalities due to GI 
perforation, hepatic failure, toxic epidermal necrolysis, and Guillain-Barre syndrome 
have been reported in clinical trials of ipilimumab.   
 
Clinical trials are conducted under widely varying conditions so that extrapolation to 
novel settings and combinations regarding rates and severity of events may be 
unreliable.  Given the expected rate of toxicity which may require stopping study 
drug but may also be related to a therapeutic immunologic response alternative DLT 
criteria are discussed in section 6.  
 
Min and colleagues reported three patients who received ipilimumab alone or 
combined with bevacizumab therapy and developed thyroiditis, and the first report 
of euthyroid Graves’ ophthalmopathy.86  They recommend that all patients on 
ipilimumab alone or combined with bevacizumab therapy have baseline thyroid 
function tests and careful monitoring for new onset of thyroid disease, particularly 
during the first 3 months of treatment. See specific events in section 5.  
 
Safety Profile of Ipilimumab at a Dose of 10 mg/kg (Phase 2 data) 
The safety profile of ipilimumab as monotherapy over multiple doses at a dose of 10 
mg/kg in 325 subjects was determined from 4 completed melanoma studies.  
Overall, the incidence of grade 3/4 AEs attributable to study drug was 31%.  The 
target organ system, the incidence, and the severity of the most commonly observed 
irAEs vary among studies and with drug combinations.  Typically, the severity but 
not necessarily the overall incidence increases with dose.  Additional information on 
specific events is provided in section 7.1 and the IB:   
 
 

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Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) 
(%) 
High-grade 
(Grade 3 - 4) 
(%) 
Median Time to 
Resolution of 
Grade 2 - 4 
irAEs (weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (e.g., rash, 
pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (e.g., colitis, 
diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (e.g., LFT 
elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (e.g., 
hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
 
Pregnancy 
Preliminary results are available in cynomolgus monkeys.  Pregnant monkeys 
received ipilimumab every 21 days from the onset of organogenesis in the first 
trimester through delivery, at dose levels either 2.6 or 7.2 times higher than the 
clinical dose of 3 mg/kg of ipilimumab (by AUC).  No treatment-related adverse 
effects on reproduction were detected during the first two trimesters of pregnancy.  
Beginning in the third trimester, the ipilimumab groups experienced higher 
incidences of abortion, stillbirth, premature delivery (with corresponding lower birth 
weight), and higher incidences of infant mortality in a dose-related manner 
compared to controls.  Based on animal data, ipilimumab may cause fetal harm.  The 
use of ipilimumab during human pregnancy has not been formally studied in clinical 
trials.  There have been 7 known pregnancies during ipilimumab treatment: in 3 
female subjects and in the partners of 4 male study subjects.  Two (2) of the 3 female 
pregnancies ended with elected terminations.  The third female subject had a history 
of seizures and delivered the baby at 36 weeks gestation.  The baby had respiratory 
complications that resolved by birth week 16.  Three (3) of the 4 partners of male 
study subjects had full term, normal babies.  The fourth baby had small ureters, 
which are expected to grow as the baby matures.  Although these outcomes do not 
indicate that stillbirths or other severe abnormalities will occur, pregnancy should be 
avoided during treatment with ipilimumab.  
 
Immunogenicity 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding 
antibodies against ipilimumab in an electro-chemiluminescent (ECL) based assay.  
This assay has substantial limitations in detecting anti-ipilimumab antibodies in the 
presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with 

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hypersensitivity or anaphylaxis were not reported in these 11 patients nor were 
neutralizing antibodies against ipilimumab detected.  Because trough levels of 
ipilimumab interfere with the ECL assay results, a subset analysis was performed in 
the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable 
patients, who were treated with 0.3 mg/kg dose, tested positive for binding 
antibodies against ipilimumab.  These results are highly dependent on methodology, 
and comparison of incidence of antibodies to ipilimumab with the incidences of 
antibodies to other products may be misleading. 
 
2.5.10 
Study Results and Clinical Efficacy  
The clinical efficacy of ipilimumab as a single agent at a dose of 3 mg/kg 
administered q3w for 4 doses has been established in MDX010-20 (a randomized, 
controlled study in second line, locally advanced/metastatic melanoma), which led to 
approval of ipilimumab by the FDA.  In study CA184024, the addition of 10 mg/kg 
ipilimumab to dacarbazine led to a prolongation of overall survival in patients with 
previously untreated melanoma.  
 
In melanoma studies, disease stabilization in subjects receiving ipilimumab is 
characteristic of anti-tumor activity.  Stable disease, sometimes of long duration, or 
slow steady decline of tumor lesion size over long periods of time, has been 
observed.  Some subjects demonstrate initial tumor volume increase before response, 
possibly due to T-cell infiltration as shown by biopsies or to the time required for 
immunologic activation.  Consequently, an initial determination of progressive 
disease and consequently PFS may not capture all patterns response and may 
underestimate the clinical activity of ipilimumab.  Please see section “Considerations 
for Using Immune-Related Tumor Assessment Criteria (irRC).”  
 
MDX010-20 (Phase 3, 3 mg/kg, previously treated melanoma) 
MDX010-20, a randomized (3:1:1), double-blind, double-dummy study included 
676 randomized subjects with unresectable or metastatic melanoma previously 
treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, 
fotemustine, or carboplatin.  Of these 676 subjects, 403 were randomized to receive 
ipilimumab at 3 mg/kg in combination with an investigational peptide vaccine with 
incomplete Freund’s adjuvant (gp100), 137 were randomized to receive ipilimumab 
at 3 mg/kg, and 136 were randomized to receive gp100 alone.  The study enrolled 
only subjects with HLA A2*0201 genotype; this HLA genotype facilitates the 
immune presentation of the investigational peptide vaccine.  The study excluded 
subjects with active autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. 
 
 

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The OS results are shown in the table below. 
MDX010-20 Overall Survival Results 
 
Ipilimumab 
n = 137 
Ipilimumab + 
gp100 
n = 403 
gp100 
n = 136 
Hazard Ratio (vs gp100) 
 
(95% CI) 
0.66 
(0.51, 0.87) 
0.68 
(0.55, 0.85) 
 
 
p-value 
p = 0.0026a 
p = 0.0004 
 
Hazard Ratio (vs 
ipilimumab) 
 
(95% CI) 
 
1.04 
(0.83, 1.30) 
 
Median (months) 
 
(95% CI) 
10 
(8.0, 13.8) 
10 
(8.5, 11.5) 
6 
(5.5, 8.7) 
a 
Not adjusted for multiple comparisons. 
 
CA184024 (Phase 3, previously untreated melanoma, 10 mg/kg) 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients 
with previously untreated, metastatic melanoma. A total of 502 patients were 
randomized to receive up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either 
ipilimumab 10 mg/kg or placebo cycles 1-4, and as maintenance after completion of 
chemotherapy. 
 
Patients on the ipilimumab arm received a median of 3 ipilimumab induction doses, 
versus 4 placebo induction doses on the placebo arm. A total of 17.4% and 21.1% of 
patients continued to receive maintenance ipilimumab or placebo, for a median of 4 
and 2 doses, respectively. The number of patients who received all 8 dacarbazine 
doses was 12.2% in the ipilimumab arm, and 21.5% in the placebo arm. 
 
The study met its primary end-point of prolonging overall survival in patients treated 
with ipilimumab (HR 0.72 [95% CI, 0.59 – 0.87], median OS 11.2 vs 9.1 months, 
p = 0.0009).  
 
One, two, and three year survival rates were 47.3%, 28.5%, and 20.8% in the 
ipilimumab arm, and 36.3%, 17.9%, and 12.2% in the placebo arm. 
 
PFS, a secondary end-point, was also prolonged by the addition of ipilimumab, HR 
0.76 (95% CI, 0.63 - 0.93). The median PFS was 2.8 months in the ipilimumab vs 
2.6 months in the placebo arm, p = 0.006. 
 
 

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Best overall response rate (BORR) was increased from 10.3% in the placebo arm to 
15.2% in the ipilimumab arm. More importantly, duration of response was more than 
twice as long in the ipilimumab arm (19.3 months) than in the placebo arm (8.1 
months). 
 
10 mg/kg Dosing with Ipilimumab 
Several additional trials studied the efficacy and safety of 10 mg/kg dosing, and 
additional information gained from these trials is listed below: 
A dose of 10 mg/kg may be necessary to ensure blockade of the CTLA-4 pathway; 
in vitro, a concentration of 20 mcg/mL of ipilimumab was the minimal concentration 
able to fully abrogate the binding of CTLA-4 to B7.1 and B7.2.  With a dose of 3 
mg/kg q3w, 30% achieved a trough concentration of ipilimumab greater than 20 
g/mL, compared to 95% of subjects treated at 10 mg/kg q3w. 
 
In addition, in all ipilimumab trials examined to date, mean Absolute Lymphocyte 
Count (ALC) increased after ipilimumab treatment throughout the 12-week 
induction-dosing period, in a dose-dependent manner.  In an analysis of ipilimumab 
at 0.3, 3, or 10 mg/kg in melanoma studies CA184007, CA184008, and CA184022 
combined, the rate of change in ALC after ipilimumab treatment was significantly 
associated with dose (p = 0.0003), with the largest rate at 10 mg/kg ipilimumab.  
Moreover, the rate of change in ALC over the first half of the induction-dosing 
period was significantly associated with clinical activity in these studies (p = 0.009), 
where clinical activity was defined as CR, PR, or prolonged SD (i.e., SD lasting at 
least 6 months from first dose). Although these analyses alone could not determine 
whether the rate of change in ALC was specifically associated with clinical activity 
in response to ipilimumab treatment, as opposed to being generally prognostic, these 
results do suggest a potential benefit to higher rates of ALC increase after 
ipilimumab treatment.  Among the 3 doses evaluated, 10 mg/kg ipilimumab led to 
the greatest such rates. 
 
 

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In the 3 primary studies conducted in advanced melanoma (CA184007, CA184008, 
and CA184022), subjects treated with 10 mg/kg single agent ipilimumab had the 
highest response, disease control rates, median OS as well as 1-year and 2-year 
survival rates compared to lower  doses. The CA184022 data are summarized in the 
table below. 
 
Summary of Phase 2 Response Data in Melanoma (CA184022 see IB ) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - 
% 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - 
% 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
 
2.5.11 
Dose, Schedule, and Regimen 
While optimal doses and schedules for ipilimumab have not yet been determined, in 
proposed proof of principle studies demonstration of efficacy at 10 mg/kg would 
allow future studies to explore biologic and clinical efficacy at lower doses with 
reduced toxicity. For most studies in new combinations or settings, a short phase 1 
component at 3 mg would be appropriate with a 5 or 6 mg/kg dose added as an 
additional cohort if needed.    
 
A recommended dose of 10 mg/kg is proposed by the manufacturer for most studies 
of ipilimumab.  In melanoma, a similar survival benefit was demonstrated in phase 3 
trials at the 3 mg/kg and at 10 mg/kg with DTIC.  However, the incidence of grade 
>3 toxicity was 15 and 25% respectively.   
 
Based on Phase 2 studies, response rates of ipilimumab appear to be dose dependent 
up to 10 mg/kg.  
 
Exposure-response analyses [Cminss Analysis of PK data from patients treated with 
ipilimumab at 0.3 mg/kg (N=47), 3 mg/kg (N=60) and 10 mg/kg (N=311)], showed 
that the target Cminss target threshold of 20 mcg/ml was exceeded in 0%, 30% and 
95% subjects respectively.  The slope of change in absolute lymphocyte count 

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(ALC) correlated with clinical benefit and T-cell activation markers such as HLA-
class II expression may also be dose dependent.  Responses have not been compared 
systematically in randomized phase 2 or phase 3 studies in patients with tumor types 
other than melanoma.  
 
Regarding schedule, the typical schedule for advanced melanoma at present is once 
q3w for four doses followed by a maintenance phase of four doses every 12 weeks.  
Of interest, ipilimumab was evaluated in NSCLC and SCLC using a dose of 10 
mg/kg given concomitantly or following initial paclitaxel/cisplatin.  When used in 
the phased schedule, 10 mg significantly improved irPFS and mWHO defined 
responses but not PFS determined by Response Evaluation Criteria in Solid Tumors 
(RECIST).  There also was a trend for an improvement in OS in both indications.  
Doses less than 10 mg/kg have not been evaluated in either NSCLC or SCLC.  
 
Studies comparing doses in non-melanoma and combinations have not been widely 
done.  There are also no clear data that peak levels, Cmin, AUC, exposure and 
number of doses given, or the occurrence of autoimmune events, predict responses in 
individual patients.  We note that the incidence of specific events such as 
hypophysitis may vary from study to study and with different combinations of 
agents.  The severity and possibly time to onset but not necessarily the frequency of 
events increases with dose.  In addition, there are rare but serious events such as 
toxic epidermal necrolysis (TEN) for which a dose relationship has not been 
established. Case report forms should include data on the prior treatment, timing, 
number of doses, duration of event, response to treatment, and complications to 
allow comparisons among studies.   
 
2.5.12 
Considerations in Using Immune-Related Tumor Assessment Criteria (irRC) 
New endpoint definitions for trials of immunologic agents have been proposed based 
on novel patterns of clinical activity in malignant melanoma.87,88 These alternative 
definitions allow time for immunologically mediated effectors to develop that may 
result in late tumor responses even after initial progression by RECIST.  Also, in 
some patients, tumors necrosis and inflammation may increase tumor size 
radiographically prior to response.  Changing the definitions of OR and PD may alter 
(increase) the number patients achieving responses and the duration of PFS.  
 
On a protocol by protocol basis, investigators and study sponsors have considered 
allowing study treatment to continue during initial progression up to the 12-16 week 
assessment to allow time for responses to be observed, if the patient is clinically 
stable, there is no deterioration in PS, and there is no need for immediate additional 
treatment.  While maintaining standard definitions of progression and response, this 
system has allowed new lesions and some progression beyond 20% increases in 
tumor measurements during the initial treatment period to allow time for responses 
to develop (these delayed tumor responses may be seen in 10-20% of melanoma 
patients who initially progress during the initial treatment cycles and evaluation).  
There has been little to no experience with response patterns with combination 
therapy or in diseases other than melanoma.  It is suggested that standard response 

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definitions be used as the primary endpoint in these studies.   
 
For the purpose of this trial, section 14.1 specifies modifications to RECIST 1.1 
which take into account the possibility of delayed response following evidence of 
increased tumor size by imaging at first re-assessment 8 weeks after initiation of 
treatment. 
 
2.5.13 
Overall Risk/Benefit Assessment 
The unique immune-based mechanism of action is reflected in the clinical patterns of 
anti-cancer activity in some patients.  Ipilimumab affects tumor cells indirectly, and 
measurable clinical effects emerge after the immunological effects.  Tumor 
infiltration with lymphocytes and the associated inflammation (documented by 
biopsy in some subjects) is likely the cornerstone of the effect of ipilimumab and can 
manifest in various patterns of clinical activity leading to tumor control.  In some 
cases, response may be preceded by an apparent increase in initial tumor volume 
and/or the appearance of new lesions, which may be mistaken for tumor progression 
on radiological evaluations.  Therefore, in subjects who are not experiencing rapid 
clinical deterioration, confirmation of progression is recommended, at the 
investigator’s discretion, to better understand the prognosis as well as to avoid 
unnecessarily initiating potentially toxic alternative therapies in subjects who might 
be benefitting from treatment.  Immune-related (ir) response criteria were developed 
based on these observations to systematically categorize novel patterns of clinical 
activity and are currently being prospectively evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some 
instances is associated with slow, steady decline in tumor burden over many months, 
sometimes improving to partial and/or complete responses.  Thus, the immune-based 
mechanism of action of ipilimumab results in durable disease control, sometimes 
with novel patterns of response, which contribute to its improvement in OS. 
 
The immune-based mechanism of action is also reflected in the safety profile.  The 
most common drug-related AEs are immune-mediated, consistent with the 
mechanism of action of the drug and generally medically manageable with topical 
and/or systemic immunosuppressive drugs.  As previously discussed, the immune-
mediated adverse reactions primarily involve the GI tract, skin, liver, endocrine 
glands, and nervous system. 
 
The early diagnosis of immune-mediated adverse reactions is important to initiate 
therapy and minimize complications.  Immune-mediated adverse reactions are 
generally manageable using symptomatic or immunosuppressive therapy as 
recommended through detailed diagnosis and management guidelines, as described 
fully in the current IB.  The management guidelines for general immune-mediated 
adverse reactions and ipilimumab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy are provided in the appendices of the current IB.  
 

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2.6 
Translational Science Background 
 
2.6.1 
PD-L1 Expression (Integrated Biomarker) 
The expression of PD-L1 has been previously demonstrated to be associated with 
improved clinical benefit from therapies targeting the PD-1/PD-L1 pathway89. The 
utility of PD-L1 expression as a predictive biomarker, however, has been debated as 
it is highly dynamic and can be up-regulated in response to immune activating 
factors. In this trial, pre-treatment formalin-fixed, paraffin-embedded (FFPE) tumor 
tissue will be evaluated by immunohistochemistry (IHC) for expression of PD-L1 as 
a predictive biomarker. 
 
2.6.2 
Analysis of Tumor Infiltrating Lymphocytes (TILs; Exploratory Biomarker) 
Immune infiltration of tumors has been demonstrated in multiple studies to be both 
prognostic and predictive of response to immunotherapies, with tumors exhibiting 
inflamed phenotypes being most responsive. Assessment of the immune subsets in 
the tumors will help to establish predictive markers on the basis of pre-treatment 
phenotype as well to determine whether clinical efficacy correlates with the degree 
of infiltration of specific immune cell subsets. In addition, both PD-L1 and 
indoleamine-2,3-dioxygenase (IDO) have been demonstrated to be up-regulated in 
tumors in response to immune infiltration and may serve as negative feedback 
mechanisms90. Other immune checkpoints such as LAG-3 and TIM-3 may serve as 
additional immune inhibitory mechanisms, which may dampen the overall immune 
response. As such, pre-treatment FFPE will be evaluated for the presence of TILs 
and immune markers including CD3, CD4, CD8, FoxP3, CD16, CD68, CD137, 
OX40, GITR, CD40, IDO, LAG3, TIM3, B7-H3, B7-H4, PD-1, CTLA-4, and 
VISTA.  
 
2.6.3 
 
Neo-antigen Landscape (Exploratory Biomarker) 
A recent study by the group at Memorial Sloan Kettering Cancer Center (MSKCC) 
used next-generation whole exome sequencing (NGS) to characterize neo-antigen 
landscape in patients with malignant melanoma and defined particular neo-epitope 
signatures that were highly predictive of clinical benefit from anti-CTLA-4 therapy 
in patients with malignant melanoma (Snyder et al, ASCO Annual Meeting 2014). 
To determine whether specific tumor genetic determinants, including neo-epitope 
signatures influence the response to either treatment, DNA isolated from archived 
tumor samples will be processed for whole exome analysis to assess for specific 
driver mutations and for potential neo-antigens using appropriate bioinformatics 
algorithms developed at MSKCC by Dr. Alexandra Snyder. 
 
2.6.4 
T Cell Receptor (TCR) Repertoires (Exploratory Biomarker) 
Since cancer-testis (CT) antigens may not be present in all patients and may not be 
the immuno-dominant antigens that will determine tumor sensitivity to the immune 
system, the analysis of overall changes in TCR repertoires during therapy may help 
to determine whether certain dominant T cell clones emerge or persist in response to 
therapy. Recently, Cha et al, reported that maintenance of specific T cell clonotypes 
in blood of patients with advanced melanoma treated with ipilimumab was 

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associated with improved survival91. Similar TCR repertoire studies were performed 
in tumors at MSKCC in the setting of a clinical trial in patients with early stage 
breast cancer treated with neoadjuvant cryoablation of breast lesion and ipilimumab, 
where combination therapy demonstrated most significant increase in intra-tumoral 
T cell clones92. Thus, in this trial DNA will be used for TCR repertoire analysis and 
deep sequencing of TCR CDR3 regions (Adaptive Biotechnologies and Dr. Dmitriy 
Zamarin, respectively). 
 
2.6.5 
Tumor-Associated Antigen (TAA) Serologic Responses (Exploratory Biomarker) 
Expression of CT antigens in a large percentage of gynecologic malignancies has 
been reported in multiple studies. Monitoring for early responses to CT antigens and 
TAA such as NY-ESO1, MAGE 4, SOX2, and p53 may help identify the patients 
that are more likely to derive benefit from therapy. As such, pre- and on-treatment 
serum will used for assessment of TAA serologic responses. (05/22/2017) 
 
2.7 
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 or 
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 ovarian, primary peritoneal and fallopian tube 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 Statistics 
and Data Management Center-Pittsburgh Office: 412-624-2666. (02/13/2017) 
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, 
investigators should consider these factors when selecting patients for this trial. 
Investigators also should consider all other relevant factors (medical and non-
medical), as well as the risks and benefits of the study therapy, when deciding if a 
patient is an appropriate candidate for this trial. 
 
3.1.1 
Patients must have the psychological ability and general health that permits 
completion of the study requirements and required follow up. 
 
3.1.2 
Women of childbearing potential should be willing and able to use medically 
acceptable forms of contraception during the trial and for 23 weeks after the last 
dose of drug. 
 
3.1.3 
Submission of tumor tissue is required for all patients. Investigators should check 
with their site Pathology department regarding release of bio-specimens before 
approaching patients about participation in the trial. (See details of bio-specimen 
submissions in Section 11.) 

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3.2 
Eligibility Criteria 
 
A patient cannot be considered eligible for this study unless ALL of the 
following conditions are met. 
 
3.2.1 
Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer with documented disease progression (disease not 
amendable to curative therapy).  Histologic confirmation of the original primary 
tumor is required via the pathology report.  NOTE:  Patients with mucinous 
histology are NOT eligible. Patients with carcinosarcoma histology are NOT 
eligible. (02/22/2016) 
 
3.2.2 
All patients 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. 
 
3.2.3 
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. 
 
3.2.4 
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; (02/22/2016) 
• 
Further protocol-specific assessments: 
▪ Recovery from effects of recent surgery, radiotherapy or chemotherapy 
▪ Free of active infection requiring antibiotics (with the exception of 
uncomplicated UTI) 
▪ Any hormonal therapy directed at the malignant tumor must be 
discontinued at least one week prior to registration 
▪ Any other prior therapy directed at the malignant tumor including 
chemotherapy, targeted agents, biologic agents, immunologic agents, and 
any investigational agents, must be discontinued at least 4 weeks prior to 
registration (6 weeks for nitrosoureas or mitomycin C). 
▪ Any prior radiation therapy must be completed at least 4 weeks prior to 
registration 
▪ At least 4 weeks must have elapsed since major surgery 
 
3.2.5 
Prior Therapy (1–3 Priors allowed as detailed below) (02/22/2016) 
Patients are allowed to have received up to three prior cytotoxic regimens for 
treatment of their epithelial ovarian, fallopian tube, or primary peritoneal cancer. 

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They must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease, possibly including intra-peritoneal therapy, 
consolidation, biologic/targeted (non-cytotoxic) agents or extended therapy 
(maintenance/consolidation) administered after surgical or non-surgical assessment.   
 
Patients are allowed to have received, but are not required to have received, one or 
two cytotoxic regimens for management of recurrent or persistent disease. (For the 
purposes of this study PARP inhibitors given for recurrent or progressive disease 
will be considered cytotoxic.  PARP inhibitors given as maintenance therapy in 
continuation with management of primary disease will not be considered as a 
separate cytotoxic regimen.) If two cytotoxic regimens had been received for 
management of recurrent or persistent disease, one of these regimens would have 
had to contain either a platinum or a taxane agent. (02/22/2016) 
  
3.2.6 
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. 
 
3.2.7 
The trial is open to females only. 
 
3.2.8 
Performance Status of 0, 1 or 2 (see Appendix II) within 28 days prior to 
registration. 
 
3.2.9 
Adequate hematologic function within 14 days prior to registration defined as 
follows: 
• 
ANC ≥ 1,500/ul 
• 
Platelets ≥ 100,000/ul 
 
3.2.10 
Adequate renal function within 14 days prior to registration defined as follows: 
• 
Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN) 
 
3.2.11 
Adequate hepatic function within 14 days prior to registration defined as follows: 
• 
Bilirubin ≤ 1.5 x ULN 
• 
ALT and AST ≤ 3 x ULN 
• 
Albumin ≥ 2.8 g/dL  
 
For patients with Gilbert’s Syndrome, Bilirubin ≤ 3.0 mg/dL is acceptable. 
(02/22/2016) 
 
3.2.12 
Adequate thyroid function within 28 days prior to registration defined as serum TSH 
in normal range. 
 
 

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3.2.13 
The patient or a legally authorized representative must provide study-specific 
informed consent prior to study entry. 
 
3.2.14  
Platinum-Free Interval (PFI) - Patients must have progressed < 12 months after 
completion of their last platinum-based chemotherapy.  The date (platinum free 
interval) should be calculated from the last administered dose of platinum therapy to 
documentation of progression.  
 
3.2.15  
Adequate oxygen saturation via pulse oximeter within 28 days prior to registration 
(i.e., patient can NOT have CTCAE hypoxia grade 2 or greater).  
 
3.2.16  
LVEF ≥ 50% (measured within 28 days of study entry). (02/13/2017) 
 
3.3 
Ineligibility Criteria (02/22/2016) 
 
Patients with one or more of the following conditions are NOT eligible for this 
study. 
 
 
3.3.1 
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. 
 
3.3.2 
History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.3.3 
Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer and other specific malignancies as noted in Section 3.34 
are excluded if there is any evidence of other malignancy being present within the 
last three years (2 years for breast cancer, see Section 3.3.4). Patients are also 
excluded if their previous cancer treatment contraindicates this protocol therapy. 
(12/21/2018) 
 
3.3.4 
Patients who have received prior chemotherapy for any abdominal or pelvic tumor 
OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal 
cancer within the last three years are excluded. Patients may have received prior 
adjuvant chemotherapy and radiotherapy for localized breast cancer, provided that it 
was completed more than 2 years prior to registration, the patient remains free of 
recurrent or metastatic disease and hormonal therapy has been discontinued. Patients 
who have received prior radiotherapy to any portion of the abdominal cavity or 
pelvis or thoracic cavity within the last three years are excluded. Prior radiation for 
localized cancer of the head and neck or skin is permitted, provided that it was 
completed more than three years prior to registration, and the patient remains free of 
recurrent or metastatic disease. 
 
3.3.5 
Patients with uncontrolled illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure and unstable angina pectoris. 

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3.3.6 
Patients with history of organ transplant.  
 
3.3.7 
Patients who are pregnant or nursing.  The effects of nivolumab and ipilimumab on 
the developing 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 or nivolumab + ipilimumab.  
Women must not be breastfeeding. (02/22/2016) 
 
 
Women who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile) do not require contraception. 
 
 
Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization 
(hysterectomy and/or 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. 
 
If, following initiation of the investigational product(s), it is subsequently discovered 
that a study subject is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 6 half-lives after product 
administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for subject safety). The 
investigator must report this event and any outcomes by amendment through CTEP-
AERS (see section 7.1). 
 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (e.g., X-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated. 
In addition, the investigator must report and follow-up on information regarding the 
course of the pregnancy, including perinatal and neonatal outcome. Infants should be 
followed for a minimum of 8 weeks. (02/22/2016) 
 
3.3.8 
History or evidence upon physical examination of CNS disease, including primary 
brain tumor, seizures which are not controlled with non-enzyme inducing 
anticonvulsants, any brain metastases and/or epidural disease, or history of 
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or 
subarachnoid hemorrhage within six months prior to the first date of study treatment.   
 
3.3.9 
In order for patients with known history of testing positive for human 

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immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome 
(AIDS) to be eligible, they must be on a stable highly active antiretroviral therapy 
(HAART) regimen, have CD4 counts > 350, with no detectable viral load on 
quantitative PCR. 
 
 
Patients with treated hepatitis virus infections (Hepatitis B or Hepatitis C) are 
eligible if they have been definitively treated for 6 months, have no detectable viral 
load on quantitative PCR, and LFTs meet eligibility requirements. 
 
3.3.10 
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, 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. 
 
3.3.11 
Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement 
(such as Hashimoto’s thyroiditis), psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger (precipitating 
event). 
 
3.3.12 
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).  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. (02/22/2016) 
 
 

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3.3.13 
Any of the following within 2 months of registration: active peptic ulcer disease, 
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, malabsorption 
syndrome. Any of the following within 6 months of registration: Intra-abdominal 
abscess, gastrointestinal obstruction requiring parenteral hydration and/or nutrition, 
gastrointestinal perforation. Note: complete resolution of an intra-abdominal abscess 
must be confirmed prior to registration even if the abscess occurred more than 6 
months prior to registration. (02/22/2016) 
 
3.3.14 
No planned concomitant, non-protocol directed anti-cancer therapy. 
 
3.3.15 
Grade ≥2 peripheral neuropathy. (02/22/2016) 
 
 

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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
 PRE-TREATMENT ASSESSMENTS (02/22/2016) 
Assessments 
Prior to 
Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
(Cycle 1, Day 1) 
History and Physical 
≤ 28 days 
≤ 28 days 
Vital Signs  
(Blood  
Pressure, Heart Rate, 
Temperature, and Pulse 
Oximeter Oxygen Saturation)  
≤ 28 days 
≤ 28 days 
Echocardiogram (02/13/2017) 
≤ 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 
Electrolytes, including, BUN, 
creatinine, Ca, phosphorus, 
magnesium and glucose 
≤ 14 days 
≤ 14 days 
Bilirubin, ALT, AST, 
Alkaline Phosphatase, 
Albumin 
≤ 14 days 
≤ 14 days 
Hepatitis panel, including 
hepatitis B surface antigen 
and hepatitis C Antibody 
≤ 28 days 
≤ 28 days 
Pregnancy Test (if 
childbearing potential exists)  
≤ 28 days 
≤ 24 hours1 
TSH 
≤ 28 days 
≤ 28 days 
Amylase/Lipase 
≤ 14 days 
≤ 14 days 
CA-125 
 
≤ 28 days 
Radiographic Tumor 
Measurement2 
≤ 28 days 
≤ 28 days 
 
1 The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of 
hCG. 
2 Radiographic tumor measurements should be obtained via imaging of the chest, 
abdomen and pelvis. See RECIST 1.1 for allowable imaging modalities used to assess 
disease at baseline and subsequent assessments. Contrast CT is the preferred modality. 
 
Note:  See section 11.2 for mandatory and optional research specimens calendar  

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4.2 
ASSESSMENTS DURING TREATMENT (02/22/2016) 
Assessments 
Induction 
Phase,1 
Prior to 
Each 
Infusion 
(All 
Infusions 
after Cycle 
1, Day 1)   
Maintenance 
Phase,2 
Prior to 
Each 
Infusion 
Maintenance 
Phase,2 
Prior to 
Every other 
Infusion 
(i.e., prior to 
maintenance 
infusion 1, 3, 
5, ect) 
Timed 
(Treatment 
Cycle 
Independent) 
History and Physical 
≤ 1 day of 
treatment 
≤ 1 day of 
treatment 
 
 
Vital Signs  
(Blood  
Pressure, Heart Rate,   
Temperature and Pulse 
Oximeter Oxygen 
Saturation) 
Day of 
treatment 
Day of 
treatment 
 
 
Performance Status 
≤ 1 day of 
treatment 
≤ 1 day of 
treatment 
 
 
Toxicity Assessment 
(including clinical 
assessment for irAEs)3 
≤ 1 day of 
treatment 
≤ 1 day of 
treatment 
 
 
Concurrent Medications 
≤ 1 day of 
treatment 
≤ 1 day of 
treatment 
 
 
CBC/Differential/Platelets 
≤ 3 days of 
treatment 
≤ 3 days of 
treatment 
 
 
Electrolytes, including, 
BUN, creatinine, Ca, 
phosphorus, magnesium 
and glucose 
≤ 3 days of 
treatment 
≤ 3 days of 
treatment 
 
 
Bilirubin, ALT, AST, 
Alkaline Phosphatase, 
Albumin 
≤ 3 days of 
treatment 
≤ 3 days of 
treatment 
 
 
Amylase/Lipase 
≤ 3 days of 
treatment 
≤ 3 days of 
treatment 
 
 
TSH 
≤ 7 days of 
treatment 
 
≤ 7 days of 
treatment 
 
CA-125 
 
 
≤ 7 days of 
treatment 
 
Radiographic tumor 
measurement 
 
 
 
X4 
Echocardiogram5 
(02/13/2017) 
 
 
 
 
Note:  See section 11.2 for mandatory and optional research specimens calendar 
 

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1Induction phase consists of first 4 infusions, administered either every 2 weeks 
(nivolumab arm) or every 3 weeks (nivolumab plus ipilimumab arm). 
2Maintenance phase consists of every 2 week infusions of nivolumab only, following 
induction phase. 
3Report all adverse events that occur within 30 days of last protocol treatment on the 
Toxicity form for the last cycle of therapy administered. For reporting of delayed 
toxicity, see Section 7. 
4Every 8 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes 
in treatment schedule) for the first 8 months; then every 12 weeks (+/- 7 days) 
thereafter. Radiographic tumor measurements are obtained until disease progression 
is confirmed; at the investigator’s discretion, they can be repeated any other time if 
clinically indicated based on symptoms or physical signs suggestive of new or 
progressive disease. A tool is provided to calculate dates of re-imaging. Utilize same 
imaging modality of abdomen, pelvis and chest (see footnote 2 under Pre-Treatment 
Assessments) as for pre-cycle 1 baseline assessment. Chest imaging is also indicated 
to monitor for evidence of immune pneumonitis. See section 14.1 for guidance 
concerning continuation of treatment in cases of radiologic progression at the first 8 
week (+/- 7 days) CT. (02/22/2016) 
5Indicated for symptoms or physical signs of congestive heart failure or 
cardiomyopathy. (02/13/2017) 
 
4.3 
ASSESSMENTS IN FOLLOW UP 
 
Assessments 
Timed 
Vital Status 
1 
Toxicity Assessment 
2 
Radiographic tumor measurement 
3 
 
1Every 3 months for 2 years and then every 6 months for 3 years. Follow-up Forms 
are collected for the 5-year follow-up period or until study termination.  
2Patients will be followed for 100 days or 16 weeks (based on 5 half lives) from end 
of treatment on Follow Up Adverse Event Reporting Form.  Patients who 
discontinue treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. For reporting of delayed toxicity, see 
Section 7. 
3In the case that protocol directed therapy is discontinued for reasons other than 
disease progression, follow radiographic tumor measurement schedule as defined 
under Assessments During Treatment (until disease progression documented by 
RECIST 1.1 or until patient initiates a subsequent cancer therapy). 
 
5.  
TREATMENT PLAN/REGIMEN DESCRIPTION 
The treatment plan consists of an induction phase in which treatment is administered 
every 2 weeks (nivolumab arm) or every 3 weeks (nivolumab plus ipilimumab arm) 
for 4 total doses, followed by a maintenance phase in which treatment with 
nivolumab only is administered every 2 weeks. Treatment is administered for a 
maximum of 42 doses of maintenance therapy, until disease progression or until 
development of unacceptable toxicity, whichever comes first.  

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5.1 
 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy (02/22/2016) 
 
5.1.1 
Protocol Directed Therapy 
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. 
 
During both induction and maintenance, it will be acceptable for individual infusions 
to be delivered within a 24-hour window before and after the protocol-defined date.  
If the treatment due date is a Friday, and the patient cannot be treated on that Friday, 
then the window for treatment would include the Thursday (1 day earlier than due) 
through the Monday (day 3 past due). 
 
5.1.2 
Nivolumab Regimen 
Nivolumab 3 mg/kg IV every 2 weeks x 4 for induction, followed by nivolumab 3 
mg/kg IV every 2 weeks for a maximum of 42 doses for maintenance. 
 
5.1.3 
Nivolumab plus Ipilimumab Regimen 
Nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg, every 3 weeks x 4 for induction, 
followed by nivolumab 3 mg/kg IV every 2 weeks for a maximum of 42 doses for 
maintenance.   
 
The order of administration is nivolumab, followed by ipilimumab. (02/22/2016) 
 
5.1.4 
Details of Nivolumab Administration (02/28/2019) 
Patients may not be dosed less than 12 days from the previous dose of drug. 
 
The dosing calculations should be based on the actual body weight.  If the patient’s 
weight on the day of dosing differs by >10% from the weight used to calculate the 
original dose, the dose must be recalculated.  All doses should be rounded to the 
nearest milligram or the treating institutional guidelines.  There will be no dose 
modifications allowed. 
Nivolumab is to be administered over approximately 30 minutes as an IV infusion, 
using a volumetric pump with a 0.2-1.2 micron in-line filter at the protocol-specified 
dose.  The drug can be diluted with 0.9% normal saline for delivery but the total 
drug concentration of the solution cannot be below 0.35 mg/mL.  It is not to be 
administered as an IV push or bolus injection.  At the end of the infusion, flush the 
line with a sufficient quantity of normal saline. 
5.1.5  
Details of Ipilimumab Administration 
The dosing calculations should be based on the actual body weight. If the patient’s 
weight on the day of dosing differs by >10% from the weight used to calculate the 
original dose, the dose must be recalculated.  All doses should be rounded to the 
nearest milligram or the treating institutional guidelines.  There will be no dose 
modifications allowed. 

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Ipilimumab is to be administered over approximately 90-minutes as an IV infusion, 
using a volumetric pump with a PVC IV infusion set with an in-line, sterile, non-
pyrogenic, low-protein-binding filter (0.2/1.2 micron) at the protocol-specified dose.  
The drug can be given undiluted or diluted with 0.9% normal saline for delivery with 
the total drug concentration of the solution between 1 mg/mL and 4 mg/mL.  It is not 
to be administered as an IV push or bolus injection.  At the end of the infusion, flush 
the line with a sufficient quantity of normal saline. 
5.2 
Radiation Therapy 
Not Applicable. 
 
5.3 
 
Surgery  
 
 
Not Applicable. 
 
5.4 
 
Device  
Not Applicable. 
 
5.5 
 
Imaging  
 
 
Not Applicable. 
 
5.6 
Integral Assay/Biomarker 
 
 
Not applicable. 
 
5.7 
 
Intervention Not Otherwise Categorized 
Not applicable. 
 
5.8 
 
General Concomitant Medication and Supportive Care Guidelines 
 
5.8.1  
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 and documented on each site’s source documents as concomitant 
medication. Follow guidelines in section 6.0 and Appendix III regarding 
medication and supportive guidelines related to immune adverse effects. Please 
consult Study Chair or Study Co-Chair with questions.  
• Analgesics 
• Antibiotics 
• Anticonvulsants 
• Antiemetics 
• Anticoagulants 
• Antihistamines (as per Appendix III) 
• Corticosteroids +/- mineralocorticoid component (as per Appendix III) 
• Hydration 
• Immunosuppressive agents – other (as per Appendix III) 
• Infliximab (as per Appendix III) 
• Mycophenolate mofetil (as per Appendix III) 

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• Nutritional supplementation 
 
5.8.2 
Prohibited Therapies 
▪ 
Chronic systemic corticosteroids or other immunosuppressive agents for 
conditions other than for hypersensitivity or immune adverse effects 
associated with nivolumab or ipilimumab as specified in the protocol. 
▪ 
Patients in this study may use standard vaccines.  Where possible, routine 
vaccination for influenza, pneumococcal pneumonia should be given prior to 
the start of therapy but may be administered during treatment when clinically 
indicated. Vaccination should be given when there is enough separation to 
distinguish any vaccine reactions from drug toxicity.  There is no experience 
using live attenuated vaccination during nivolumab/ipilimumab therapy, so 
that live vaccine should be used cautiously during treatment. 
▪ 
Concomitant systemic or local anti-cancer medications or treatments are 
prohibited in this study while receiving nivolumab/ipilimumab treatments.  
 
5.9 
Duration of Therapy (Discontinuation Criteria) (02/22/2016) 
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 (NOTE:  the protocol specifies continuation of treatment 
in cases of radiologic progression at the first 8 week (+/- 7 days) CT if all of 
the criteria in section 14.1 are satisfied) 
• Any clinical adverse event, laboratory abnormality, or on study illness which, 
in the judgment of the investigator, presents a substantial clinical risk to the 
subject with continued study drug dosing. 
• Specified unacceptable adverse event(s) defined below and in section 6.1: 
o Any Grade 2 or greater drug-related uveitis, 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. 
o Grade 3 drug related laboratory abnormalities do not require 
treatment discontinuation except Grade 3 drug-related 
thrombocytopenia > 7 days or any grade thrombocytopenia associated 
with bleeding. 
o Any Grade 4 drug laboratory only abnormality with no clinical 
consequence may be managed medically, and treatment may be 
continued at investigator discretion. Examples are: 
▪ Grade 4 lymphopenia  
▪ Isolated Grade 4 electrolyte imbalance/abnormalities that are 
not associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of 
their onset. 
▪ Isolated Grade 4 amylase or lipase abnormalities that are not 
associated with symptoms or clinical manifestations of 
pancreatitis (see Section 6.1). 
• Any patients who require additional immune suppressive treatment beyond 

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steroids.  
• Patient decides to withdraw from study treatment. 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
 
The Study Chair or Co-Chair must be consulted in any case where protocol 
therapy has not been discontinued but where protocol therapy dosing has been 
delayed > 6 weeks in order to determine whether or not protocol therapy may 
be resumed or must be discontinued. 
 
Patients in the combination nivolumab and ipilimumab cohort who experience an 
unacceptable adverse event(s) (defined in section 5.9 and 6.1) during combination 
nivolumab and ipilimumab induction can, following resolution of toxicity to ≤ grade 
1 and permission from the Study Chair or Co-Chair, continue on nivolumab alone to 
complete induction followed by maintenance nivolumab. In these cases, the schedule 
for the induction phase with nivolumab should resume as per the Treatment 1 - 
Nivolumab Regimen in section 5.1.2. In addition, the same management guidelines 
should be followed and any patient with any further unacceptable adverse event(s) 
while receiving nivolumab alone should be taken off study treatment permanently. 
 
Tumor assessments should continue if protocol therapy is discontinued for reasons 
other than disease progression (see protocol section 4). 
 
6.  
TREATMENT MODIFICATIONS/MANAGEMENT (02/22/2016) 
 
No dose reductions or escalations for nivolumab or ipilimumab are permitted 
or specified. In the case of adverse effects, please see guidelines below, 
Appendix III and Section 5.9 for treatment delay/discontinuation and for 
management.  
 
If treatment delay is required, patients should be reassessed weekly.  Doses 
should be considered delayed not missed.  See Section 5.9 for description of 
maximally allowed delay. 
 
 
NOTE: In several places there are differences between protocol directed drug 
treatment delay and discontinuation rules and Appendix III, identified with (^). In 
these cases please follow the protocol specific guidelines in this section (as 
opposed to Appendix III). 
     
The most common adverse effects of nivolumab and ipilimumab are related to their 
mechanisms of action and are auto-immune in nature. Management in cases of 
adverse effects in general depends on organ system involved, grade and duration. 
 
 

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6.1 
Immune-Related Adverse Events (irAEs) General Definition, Monitoring, and 
Management (02/22/2016) 
 
For the purposes of this protocol, an immune-related adverse reaction irAE is 
defined as an adverse reaction of unknown etiology associated with drug exposure 
and consistent with an immune phenomenon. Efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an 
event an irAEs.  Serologic, immunologic, and histologic (biopsy) data should be 
used to support the diagnosis of an immune-related toxicity. Suspected immune-
related adverse reactions must be documented on an AE or SAE form.  
 
Overall, immune-related AEs commonly start within 3 to 10 weeks from initiation of 
therapy and are in most cases successfully managed by delaying doses, discontinuing 
dosing, and/or through administering symptomatic or immunosuppressive therapy, 
including corticosteroids, as mentioned below.  Immune-related AEs generally 
resolved within days to weeks in the majority of subjects. 
 
Patients should be informed of and carefully monitored for evidence of clinically 
significant systemic immune-mediated adverse reactions (e.g., systemic lupus 
erythematosus-like diseases) or organ-specific immune-mediated adverse reaction 
(e.g., rash, colitis, uveitis, hepatitis or thyroid disease). If an immune-mediated 
adverse reaction is noted, appropriate work-up (including biopsy if possible) should 
be performed, and steroid therapy may be considered if clinically necessary.   
 
It is unknown if systemic corticosteroid therapy has an attenuating effect on 
nivolumab or ipilimumab activity. However, clinical anti-tumor responses have been 
maintained in patients treated with corticosteroids and discontinued from 
ipilimumab. If utilized, corticosteroid therapy should be individualized for each 
patient. For example, prior experience suggests that colitis manifested as ≥ grade 3 
diarrhea requires corticosteroid treatment. If an irAE is documented, in general, 
delay protocol therapy and initiate corticosteroids earlier to obtain resolution with 
the possibility for resuming protocol therapy rather than waiting for higher grade 
events. 
 
Below are dose delay tables for both nivolumab and ipilimumab (depending on 
assigned treatment regimen) related to adverse events. Patients may be dose-delayed 
for evaluation and restarted depending on results.  
   
 
Adverse effects algorithms in Appendix III provide schematic representations of the 
guidelines in this section. These guidelines/algorithms should be followed barring 
specific clinical circumstances in which the treating physician indicates variations or 
alternative treatment is needed. In these cases, the investigator must contact the 
Study Chair or Study Co-Chair.  If a patient experiences several adverse events 
where there are conflicting recommendations between the guidelines in this section 
and the appropriate algorithms, the investigator should follow the protocol specific 
guidelines in this section.  

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Investigators should as a rule evaluate suspected adverse effects early, and with 
any suspicion, erring on the side of caution by withholding drug and instituting 
appropriate treatment as indicated in the management tables and following 
event specific guidelines. 
 
Immune-mediated Endocrinopathy. Agents such as ipilimumab and nivolumab can 
cause inflammation of endocrine organs including thyroid (Hashimoto’s thyroiditis 
with positive antibodies) and adrenal glands, hypophysitis, hypopituitarism, and 
resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, LH.  
Hyperthyroid with Graves’ disease and positive antibody has been reported.  Patients 
may present with subtle and nonspecific symptoms.  The most common clinical 
presentation includes headache and fatigue.  Symptoms may also include visual field 
defects, behavioral changes, and electrolyte disturbances including hyponatremia 
and hypotension.  Adrenal crisis as a cause of the patient’s symptoms should be 
excluded.  Based on the available data with known outcome, most of the subjects 
symptomatically improved with hormone replacement therapy.  Long-term hormone 
replacement therapy with hydrocortisone and thyroid hormone will typically be 
required for subjects developing hypophysitis/hypopituitarism after treatment with 
ipilimumab.  Some patients have regained partial function following steroid 
treatment.  
 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism.  Headache is 
often the first symptoms of hypophysitis.  Patients may present with fatigue, 
headache, mental status changes, loss of libido, abdominal pain, unusual bowel 
habits, and hypotension, or nonspecific symptoms which may resemble other causes 
such as brain metastasis or underlying disease.  Unless an alternate etiology has been 
identified, signs or symptoms of endocrinopathy should be considered immune-
mediated and drug withheld pending evaluation.  Patients may demonstrate both 
central (hypophysitis) and peripheral adrenal and thyroid insufficiency.  Evaluation 
of hypophysitis should include pituitary MRI.  
 
In this study, TSH will be performed at baseline prior to initial treatment (see section 
4).  TSH levels, clinical chemistries and clinical assessment is to be performed using 
the schedule in section 4, with further evaluation as clinically indicated.  Monitoring 
TSH may allow early detection of pituitary dysfunction and hypophysitis. Clinical 
monitoring of symptoms may be equally or more sensitive as an initial presentation.  
In a limited number of patients, hypophysitis was diagnosed by imaging studies 
through enlargement of the pituitary gland.   
 
Please see table below and Appendix III related to delays in protocol therapy and 
management related to endocrine related adverse effects.  
 

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Endocrine 
Thyroiditis 
Hypophysitis 
Adrenal 
Insufficiency  
 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Asymptomatic, TSH out of normal range and no evidence of 
hypophysitis. Continue protocol therapy per protocol. If a) TSH < 0.5 x 
lower limit of normal (LLN), b) TSH > 2 x upper limit of normal (ULN), 
or c) TSH consistently otherwise out of range in 2 subsequent 
measurements: Include free thyroxine (fT4) at subsequent cycles and   
consider endocrinology consultation. 
Grade 2 
Symptomatic. Hold protocol therapy pending evaluation and management 
as per Appendix III - Endocrinopathy Management Algorithm. Resume 
protocol therapy if patient on a stable replacement hormone regimen with 
toxicity resolved to ≤ grade 1 and having completed steroid taper (or 
tapered to <10 mg/kg prednisone equivalent) for patient treated with 
steroids. 
. 
Grade 3 
Hold protocol therapy pending evaluation and management as per 
Appendix III - Endocrinopathy Management Algorithm. Resume protocol 
therapy if patient on a stable replacement hormone regimen with toxicity 
resolved to ≤ grade 1 and having completed steroid taper (or tapered to 
<10 mg/kg prednisone equivalent) for patient treated with steroids. 
Grade 4 
Discontinue protocol therapy. 
Notes: 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate pituitary 
functional testing including 8 AM cortisol, 8 AM ACTH, TSH and T4 must be obtained. 
 
Isolated thyroid deficiency may be treated as grade 2 if there are no other associated deficiencies and 
adrenal function is monitored.  
 
Central hypothyroidism should be considered hypophysitis (not thyroiditis). 
Symptomatic pituitary enlargement, exclusive of hormone deficiency, but including severe headache or 
enlarged pituitary on MRI is considered a grade 3 event.   
 
Recommended management: See Endocrinopathy Management Algorithm, Appendix III 
 
Immune-mediated Enterocolitis. The clinical presentation of GI immune-related AEs 
included diarrhea, increase in the frequency of bowel movements, abdominal pain, 
or hematochezia, with or without fever. However inflammation may occur in any 
part of the GI tract including esophagitis and gastritis.  Fatalities due to GI 
perforation have been reported in clinical trials of Ipilimumab in particular. Patients 
should be carefully monitored for GI symptoms that may be indicative of immune-
related colitis, diarrhea, or GI perforation.  Diarrhea or colitis occurring after 
initiation of ipilimumab therapy should be evaluated to exclude infectious or 
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evidence of mucosal inflammation, with or without ulcerations, and lymphocytic 
infiltration. 
 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus or blood in stool, with or without fever) and bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic patients, rule out 
infectious etiologies and consider endoscopic evaluation to establish etiology and for 
persistent or severe symptoms.  C.difficile toxin has been detected in several patients 
with colitis and may be an independent entity or may co-exist with ipilimumab 
induced inflammatory colitis.  
 
See Appendix III (GI Adverse Event Management Algorithm). 
 
Permanently discontinue ipilimumab in patients with severe enterocolitis (see table 
below on Management/Protocol Therapy Modifications for Diarrhea/Enterocolitis 
and Appendix III), and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day 
of methylprednisolone IV or IV equivalent. Upon improvement to grade 1 or less, 
initiate corticosteroid taper and continue to taper over at least one month. In clinical 
trials, rapid corticosteroid tapering of ipilimumab has resulted in recurrence or 
worsening symptoms of enterocolitis in some patients receiving ipilimumab. Patients 
have been treated with anti-TNF agents (e.g., infliximab) for persistent colitis not 
responding to steroids. 
 
Please note autoimmune pancreatitis may cause abdominal pain and should be 
included in all evaluations. Enteritis may occur occasionally with other autoimmune 
events including hepatitis, pancreatitis, and endocrine insufficiency, which should be 
evaluated as clinically indicated. 
 
Diarrhea/ 
Enterocolitis  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy at investigator discretion.  Treat symptoms. 
Monitor closely for worsening symptoms. Educate patient to report 
worsening symptoms immediately.  
Grade 2 
Delay protocol therapy. Treat symptoms. If improves to ≤ Grade 1, 
resume protocol therapy at investigator discretion. Consider steroid 
treatment as clinically indicated if symptoms fail to improve or worsen 
after evaluation and symptomatic treatment.  
Grade 3 
Discontinue protocol therapy 
Grade 4 
Discontinue protocol therapy.  
Notes: 
 
See GI Adverse Event Management Algorithm in Appendix III for NCI CTCAE v4.03 
definitions of diarrhea and colitis by grade and for management of diarrhea/colitis.  
Evaluate for additional causes including C. diff, acute and self-limited infectious and foodborne 
illness, ischemic bowel, diverticulitis, and IBD.  
 

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Other GI - 
Nausea/Vomiting  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
≤ Grade 1 
Continue protocol therapy and monitor.  Symptomatic Treatment. 
Grade 2 
Hold protocol therapy pending evaluation for gastritis, duodenitis and 
other immune adverse events or other causes.  Resume protocol therapy 
after resolution to ≤ Grade 1.   
Grade 3 
Hold protocol therapy pending evaluation until ≤ Grade 1.  Then resume 
protocol therapy. If symptoms do not resolve within 7 days with 
symptomatic treatment, discontinue protocol therapy 
Grade 4 
Discontinue protocol therapy 
Patients with grade 2 or 3 nausea or vomiting should be evaluated for upper GI inflammation 
and other immune related events.  Recommended management: antiemetics. 
 
Immune-mediated Hepatitis and Pancreatitis. Hepatic immune-related AEs are 
mostly clinically silent and manifested as transaminase or bilirubin laboratory 
abnormalities.  Fatal hepatic failure has been reported in clinical trials of 
ipilimumab.  Serum transaminase, bilirubin and lipase levels must be evaluated 
before each protocol directed therapy infusion as early laboratory changes may 
be indicative of emerging immune-related hepatitis/ pancreatitis and elevations 
in liver function tests (LFTs) may develop in the absence of clinical symptoms.  
Increase in LFT or total bilirubin should be evaluated to exclude other causes of 
hepatic injury, including infections, disease progression, or other medications, and 
monitored until resolution.  Liver biopsies from patients who had immune-related 
hepatotoxicity have shown evidence of acute inflammation (neutrophils, 
lymphocytes, and macrophages).  
 
Monitor levels of hepatic transaminases, bilirubin, and lipase and assess patients for 
signs and symptoms of hepatotoxicity/pancreatitis before each protocol directed 
therapy infusion.  In patients with hepatotoxicity, rule out infectious or malignant 
causes and increase frequency of liver function test monitoring until resolution.  
Please see guidelines below in tables related to hepatic transaminase/bilirubin levels 
and pancreatitis/lipase levels. Please also see Appendix III. 
 
 
 
 

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Hepatic 
transaminase, 
bilirubin  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy at investigator discretion. Continue liver 
function tests (LFT) monitoring per section 4.2.  
Grade 2 
Hold protocol therapy. Increase frequency of laboratory monitoring to 
every 3 days.  Consider steroid treatment as clinically indicated if 
symptoms fail to improve or worsen after evaluation and symptomatic 
treatment. If resolves to ≤ Grade 1 or baseline, resume protocol therapy. 
Grade 3 
Discontinue protocol therapy. Manage as per Appendix III – Hepatic 
Adverse Event Management Algorithm. 
Grade 4 
Discontinue protocol therapy. Manage as per Appendix III – Hepatic 
Adverse Event Management Algorithm. 
Notes: 
 
See Hepatic Adverse Event Management Algorithm in Appendix III for NCI CTCAE v. 4.03 
hepatic adverse event grading and management and Opdivo package insert.  
 
Continued treatment (nivolumab or nivolumab + ipilimumab) during active immune mediated 
hepatitis may exacerbate ongoing inflammation.   
 
Holding drug (nivolumab or nivolumab + ipilimumab) to evaluate LFT changes as indicated 
above and in Appendix III and early treatment are mandatory.   
 
LFT changes may occur during steroid tapers from other events and may occur together with 
other GI events including cholecystitis/pancreatitis. 
Recommended management:  see Hepatic AE management algorithm in Appendix III 
 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy and monitor. Asymptomatic lipase/amylase 
elevation, continue protocol therapy and monitor patient clinically. 
Grade 2 
For amylase/lipase elevations only, continue protocol therapy and 
monitor patient clinically. For radiographic findings consistent with 
pancreatitis, hold protocol therapy until resolved. 
 
Grade 3 
Discontinue protocol therapy for development of Grade 3 pancreatitis or 
for new or worsening DM. Evaluate for co-existing 
hepatitis/cholecystitis.   For amylase/lipase elevations only, continue 
protocol therapy and monitor patient clinically.  
Grade 4 
Discontinue protocol therapy for development of Grade 4 pancreatitis or 
for new or worsening DM.   For amylase/lipase elevations only, 
continue protocol therapy and monitor patient clinically. Consider 
imaging if no improvement or worsening. 
 

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Immune-related Neurological Events. Fatal Guillain-Barre syndrome has been 
reported in clinical trials of ipilimumab. Patients may present with muscle weakness 
and myasthenia gravis, cranial nerve palsy (n VII Bell’s palsy), and aseptic 
meningitis and encephalopathy.  Unexplained motor neuropathy, muscle weakness, 
or sensory neuropathy lasting more than 4 days should be evaluated and non-
inflammatory causes such as disease progression, infections, metabolic syndromes, 
nerve entrapment, and medications should be excluded as causes.  
 
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral 
weakness, sensory alterations, or paresthesia.  Please see guidelines below in table 
related to neurologic adverse effects. Please also see Appendix III. 
 
Withhold protocol therapy dosing in patients with any evidence of neuropathy 
pending evaluation.  Permanently discontinue protocol therapy in patients with 
severe neuropathy (interfering with daily activities) such as Guillain-Barré-like 
syndromes.  Institute medical intervention as appropriate for management of 
neuropathy and other neurologic events.  Consider initiation of systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone IV or IV equivalent 
for severe neuropathies.  
 
Neurologic events  
 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Hold protocol therapy pending evaluation and observation^. Then 
resume protocol therapy. 
Grade 2 
Hold protocol therapy pending evaluation and observation until ≤ Grade 
1^. Discontinue protocol therapy if treatment with steroids is required^. 
Otherwise resume protocol therapy.  
Grade 3 
Discontinue protocol therapy  
Grade 4 
Discontinue protocol therapy  
Discontinue protocol therapy for any CNS events including aseptic meningitis, encephalitis, 
symptomatic hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial 
neuropathy (other than peripheral n. VII), GB syndrome, or myasthenia gravis. 
Recommended management:  See Neurologic Adverse Event Management Algorithm in 
Appendix III 
 
 
 

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Pneumonitis 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Hold protocol therapy pending evaluation including pulmonary or ID 
consultation and resolution to baseline, including baseline pO2^.  Then 
resume protocol therapy.   
Grade 2 
Hold protocol therapy pending evaluation including pulmonary or ID 
consultation and resolution to baseline, including baseline pO2.  Then 
resume protocol therapy if lymphocytic pneumonitis is excluded; 
otherwise discontinue protocol therapy.  Consider steroid therapy as 
clinically indicated, see Opdivo package insert for further information. 
Discontinue protocol therapy if steroids required^.  
Grade 3 
Discontinue protocol therapy  
Grade 4 
Discontinue protocol therapy 
Notes: 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, see Opdivo 
package insert for further information.  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.  Consider recommending seasonal influenza killed 
vaccine for all patients. 
Recommended management:  See Pulmonary Adverse Event Management Algorithm in 
Appendix III  
 
Renal Adverse 
Events 
 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy and monitor creatinine weekly 
Grade 2 
Delay protocol therapy, monitor creatinine every 2 – 3 days. Administer 
corticosteroids and manage as directed by the Renal Adverse Event 
Management Algorithm in Appendix III.  
Grade 3 
Delay protocol therapy, monitor creatinine every 2 – 3 days. Administer 
corticosteroids and manage as directed by the Renal Adverse Event 
Management Algorithm in Appendix III.  
Grade 4 
Discontinue protocol therapy. Manage as directed by the Renal Adverse 
Event Management Algorithm in Appendix III. 
Recommended management:  See Renal Adverse Event Management Algorithm in Appendix 
III. 
 
 
 

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Immune-mediated Dermatitis. Skin immune-related Aes presented mostly frequently 
as a rash and/or pruritus.  Some subjects reported vitiligo associated with ipilimumab 
administration.  Fatal toxic epidermal necrolysis has been reported in clinical trials 
of ipilimumab.  
 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus.  
Unless an alternate etiology has been identified, signs or symptoms of dermatitis 
should be considered immune-mediated.   
 
Please see guidelines for management/protocol therapy modifications in the table 
below and Appendix III. (02/22/2016) 
 
Permanently discontinue protocol therapy in patients with Stevens-Johnson 
syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal 
ulceration, or necrotic, bullous, or hemorrhagic manifestations.  Administer systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of methylprednisolone IV or IV 
equivalent.  When dermatitis is controlled, corticosteroid tapering should occur over 
a period of at least 1 month. 
 
Skin Rash and Oral 
Lesions 
 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy. Symptomatic therapy (e.g. antihistamines, 
topical steroids).  
Grade 2 
Continue protocol therapy at investigator discretion. Symptomatic 
therapy (e.g. antihistamines, topical steroids).  
Grade 3 
Hold protocol therapy until ≤ Grade 1. Obtain Dermatology 
consultation, with consideration of skin biopsy.  
Grade 4 
Discontinue protocol therapy.  
Notes: 
 
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 that skin rash typically occurs early and may be followed by additional events particularly 
during steroids tapering. 
 
Recommended management:  See Skin Adverse Event Management Algorithm in Appendix III 
  

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FATIGUE  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Continue protocol therapy 
Grade 2 
Continue protocol therapy 
Grade 3 
Hold protocol therapy.  Resume protocol therapy if ≤ Grade 2 within 7 
days. 
Grade 4 
Discontinue 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 
 
Fever  
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
Grade 1 
Hold protocol therapy until < grade 1.  Then resume protocol therapy  
Grade 2 
Hold protocol therapy until < grade 1.  Then resume protocol therapy  
Grade 3 
Hold protocol therapy until < grade 1.  Then resume protocol therapy  
Grade 4 
Discontinue 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 6.3 regarding Infusion Reactions   
  
Other Immune-mediated Adverse Reactions (e.g. ocular, joint, myocardial, 
pericardial) not addressed above have been observed with agents such as ipilimumab 
and nivolumab. 
 
See the table below regarding delay in protocol therapy related to other adverse 
events. Please refer to Section 5.9 prior to utilizing this table; in some cases specific 
rules in section 5.9 override guidance in this table. 
 
Permanently discontinue ipilimumab for clinically significant or severe immune-
mediated adverse reactions.  Initiate systemic corticosteroids at a dose of 1 to 2 
mg/kg/day methylprednisolone IV or IV equivalent for severe immune-mediated 
adverse reactions. 
 
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or 
episcleritis. 
 
 

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ALL OTHER 
EVENTS 
Management/Next Dose for Nivolumab and combination 
Nivolimab/Ipilimumab 
≤ Grade 1 
Continue protocol therapy at investigator discretion. 
Grade 2 
Consider corticosteroids as clinically indicated. Hold until ≤ grade 1 
OR baseline, then resume protocol therapy. 
Grade 3 
Discontinue protocol therapy 
Grade 4 
Discontinue protocol therapy 
 
Any patient started on corticosteroids initially who is subsequently determined not to 
require steroids treatment for an autoimmune adverse event may resume therapy at 
the discretion of the investigator. In such a case, steroids should be slowly tapered. 
(02/22/2016) 
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) + 
Ipilimumab Cardiac Toxicities (02/13/2017) 
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain 
history EKG, CK (for concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 days.  If troponin and labs normalize may 
resume therapy.   If labs worsen or symptoms develop then treat as 
below.  Hold pending evaluation  
Grade >2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Resume therapy if there is a return to 
baseline and myocarditis is excluded or considered unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest 
Cardiac Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off treatment. 
 
 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
 
 

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6.2 
Criteria to Discontinue Protocol Therapy 
 
Refer to specific guidelines in sections 5.9 and 6.1.  
Tumor assessments should continue if protocol therapy is discontinued for reasons 
other than disease progression (see protocol section 4). 
 
6.3 
Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions (02/22/2016) 
Since nivolumab and ipilimumab contain only human immunoglobulin protein 
sequences, they are 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, 
arthralgia, 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: 
 
For Grade 1 infusion reaction: (Mild transient reaction; infusion interruption not 
indicated; intervention not indicated) 
 
Remain at bedside and monitor subject until recovery from symptoms.  Infusion rate 
may be slowed.  If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion 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 pre-medications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 infusion reaction:  (Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, IV fluids];prophylactic medications indicated for ≤  
24 hours).   
 
Stop the nivolumab/ipilimumab infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 
325 to 1000 mg (acetaminophen); remain at bedside and monitor patient until 
resolution of symptoms.  Corticosteroid or bronchodilator therapy may also be 
administered as appropriate.  If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate.  Monitor patient closely.  If symptoms recur, then no further 

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nivolumab will be administered at that visit.  Administer diphenhydramine 50 mg 
IV, and remain at bedside and monitor the patient until resolution of symptoms.  The 
amount of study drug infused must be recorded on the electronic case report form 
(eCRF).  The following prophylactic pre-medications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and paracetamol 325 to 1000 mg 
acetaminophen should be administered at least 30 minutes before additional 
nivolumab administrations.  If necessary, corticosteroids (recommended dose: up to 
25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 infusion reaction: Grade 3: (Prolonged [e.g., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae); or Grade 4: (Life threatening consequences; urgent 
intervention indicated).  
 
Immediately discontinue infusion of nivolumab/ipilimumab.  Begin an IV infusion 
of normal saline, and treat the subject as follows.  Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 
to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed.  Patient should be monitored until the investigator is comfortable that the 
symptoms will not recur.  Nivolumab/ipilimumab will be permanently discontinued.  
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis.  Remain at bedside and monitor patient until recovery from symptoms.  
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
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 the presentation of systemic inflammation.  Please evaluate accordingly.  
 
6.4 
TREATMENT OF IPILIMUMAB/NIVOLUMAB-RELATED ISOLATED 
DRUG FEVER 
In the event of isolated drug fever, the investigator must use clinical judgment to 
determine if the fever is related to the nivolumab/ipilimumab or to an infectious 
etiology.  If a patient experiences isolated drug fever, for the next dose, pre-
treatment with acetaminophen or non-steroidal anti-inflammatory agent (investigator 
discretion) should be instituted and a repeated antipyretic dose at 6 and 12 hours 
after nivolumab/ipilimumab infusion, should be administered.  The infusion rate will 
remain unchanged for future doses.  If a patient experiences recurrent isolated drug 
fever following premedication and post dosing with an appropriate antipyretic, the 
infusion rate for subsequent dosing should be decreased to 50% of the previous rate.  
If fever recurs following infusion rate change, the investigator should assess the 
patient’s level of discomfort with the event and use clinical judgment to determine if 
the patient should receive further nivolumab/ipilimumab. 
 

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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   
Protocol Agents 
 
Investigational Agents 
The investigational agents administered in NRG-GY003 are: 
Nivolumab:  IND #125336; IND Sponsor:  DCTD, NCI 
Ipilimumab: IND Sponsor:  DCTD, NCI 
For Nivolumab and Ipilimumab, determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in section 7.4.2 of the protocol. 
7.2  
Adverse Events and Serious Adverse Events 
 
7.2.1 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting 
beginning April 1, 2018. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
(07/30/2018)  
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. 
 
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) (02/13/2017) 
(07/30/2018) 
 
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 

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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/aeguidelin
es.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 2.3, June 18, 20181 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 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 insufficiency3 
 
  
 
Hypophysitis3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision  
  
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3 
  
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic neuritis 
retrobulbar)3 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Gastritis 
  
 
 
 Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  

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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)3,6  
  
 
 
Immune system disorders - Other 
(sarcoid granuloma)3  
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase increased3 
(Gr 3)  
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3)  
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 (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)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - Other 
(demyelination myasthenic 
syndrome) 
  
 
 
Nervous system disorders - Other 
(encephalitis)3 
  

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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Nervous system disorders - Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - Other 
(meningoradiculitis)3 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and mediastinal 
disorders - Other (bronchiolitis 
obliterans with organizing 
pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2)  
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2)  
 
 
Skin and subcutaneous disorders -
Other (bullous pemphigoid)  
  
 
Skin and subcutaneous 
disorders - Other (Sweet’s 
Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
 Stevens-Johnson syndrome 
  
 
 
 Toxic epidermal necrolysis 
  
 
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. 
 
3BMS-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. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 

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5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying fever and 
pancytopenia. 
 
6Complications 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. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following administration 
of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing 
during and immediately after administration of nivolumab. 
 
 
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: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
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; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders - Other 
(mouth sores); 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 - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other (protein total 
decreased); 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 
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; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
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. 
 
 
7.3.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Ipilimumab (MDX-010, NSCs 732442 and 720801) (03/21/2016) (02/13/2017) 
(07/30/2018) (06/10/2019) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 

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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/aeguidelin
es.pdf  for further clarification. Frequency is provided based on 2678 patients. 
Below is the CAEPR for Ipilimumab (MDX-010). 
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 2.10, March 29, 20191 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other (episcleritis)2 
 
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis2 (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
 
General disorders and administration 
site conditions - Other (Systemic 
inflammatory response syndrome 
[SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)4 
  
INFECTIONS AND INFESTATIONS 
  
 
 
 Infections and infestations - Other 
(aseptic meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased 
 
  
 
Aspartate aminotransferase increased 
 
  
 
 
Lymphocyte count decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
 
Metabolism and nutrition disorders - 
Other (exacerbation of pre-existing 
diabetes mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle weakness 
  
 
Musculoskeletal and connective tissue 
disorder - Other (polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Ataxia 
  
 
Facial nerve disorder2 
 
  
 
Guillain-Barre syndrome2 
 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Headache 
 
  
 
Myasthenia gravis2 
 
  
 
 
Nervous system disorders - Other 
(immune-mediated encephalitis)2 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - Other (mental 
status changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - Other 
(granulomatous tubulointerstitial 
nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
Respiratory failure 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other (lung 
infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue disorders 
- Other (Sweet's Syndrome) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
 
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. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell activation and 
proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII 
immune response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure 
red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, 
hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal insufficiency), ocular 
manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, 
polymyositis, and Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; 
however, a minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 

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additional treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with subsequent 
IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving allo stem cell 
transplant (SCT) after receiving Ipilimumab (MDX-010).  These complications may occur despite intervening therapy 
between receiving Ipilimumab (MDX-010) and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, 
Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral 
hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Ipilimumab (MDX-010) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other 
(pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac chest 
pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; Platelet 
count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) 
 
 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) 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. 
 
 

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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 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 

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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 
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. 

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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 Malignancies (02/13/2017) 
 
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. 
 
 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
 
8.1 
CTEP Investigator Registration Procedures (05/22/2017) 
 
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 

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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. 
 
 
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 (02/13/2017) 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
8.1.2.1 
IRB Approval:   
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. 
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all 
regulatory criteria including but not limited to:  an active Federal Wide Assurance 
(FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval and compliance with all protocol specific 
requirements.  
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for the 
study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office.  For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the 
CIRB via IRB Manager to indicate their intent to open the study locally.  The 

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CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  
In order for the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory Institution 
are participating in the study.  
 
8.1.2.2 
Requirements for NRG-GY003 Site Registration: (05/22/2017) 
 
 
• 
IRB approval letter (For sites not participating via the NCI CIRB; local IRB 
documentation, and IRB-signed CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration Of 
Exemption Form, or a combination is accepted) 
 
8.1.2.3 
Submitting Regulatory Documents: (05/22/2017) 
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, where they will be entered and tracked in the CTSU 
RSS.  
 
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab → 
Regulatory Submission  
 
 
 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
8.1.2.4 
Checking Your Site’s Registration Status: (05/22/2017) 
 
You can verify your site registration status on the members’ section of the CTSU 
website: 
• 
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 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go  
Note:  The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the Lead 
Network.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or 
their affiliated networks. 
 
8.2 
Oncology Patient Enrollment Network (OPEN) (02/13/2017) (05/22/2017) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 

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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 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.  
  
8.3 
Agent Ordering and Agent Accountability 
 
8.3.1 
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 

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one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
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. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
(05/22/2017) 
 
8.3.2 
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 the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol.  (05/22/2017) 
 
8.3.3 
Investigator Brochure Availability (05/22/2017) 
The current versions of the IBs for PMB-supplied agents will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  Questions about IB access may be directed 
to the PMB IB coordinator at IBCoordinator@mail.nih.gov. 
 
8.3.4 
Useful Links and Contacts (05/22/2017) 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov  
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx   
• 
CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/  
• 
CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov   
• 
PMB IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov  

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PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
9. 
DRUG INFORMATION  
 
9.1 
Nivolumab (BMS-936558, MDX1106), NSC #748726 (02/28/2019) 
 
9.1.1 
Classification: Anti-PD-1MAb 
9.1.2 
M.W.:  146,221 daltons 
9.1.3 
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. 
9.1.4 
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, non-
pyrogenic, single-use, isotonic aqueous solution formulated in sodium citrate, 
sodium chloride, mannitol, diethylenetriamine pentacetic acid (pentetic acid) and 
polysorbate 80 (Tween® 80), and water for injection.  Dilute solutions of 
hydrochloric acid and/or sodium hydroxide may be used for pH adjustment (pH 5.5-
6.5). 
9.1.5 
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 
fluoropolymer film-laminated rubber stoppers and aluminum seals. 
9.1.6 
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. For patients weighing less than 40 kilograms (kg), the total 
volume of infusion must not exceed 4 mL per kg of patient weight. All vials must 
come from the same batch. 
9.1.7 
Storage: Vials of Nivolumab injection must be stored at 2-8°C (36°-46°F) and 
protected from light and freezing. The unopened vials can be stored at room 
temperature (up to 25°C, 77°F) and room light for up to 48 hours.  
9.1.8 
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 

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product be discarded 8 hours after initial entry.  
 
9.1.9 
Route of Administration: Intravenous infusion over 30 minutes.  Do not administer as 
an IV push or bolus injection. 
9.1.10 
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, 
in-line filter. (02/22/2016) 
9.1.11 
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. 
9.1.12 
See Section 7.3.1 for CAEPR for BMS 936558 (Nivolumab) 
 
9.2 
Ipilimumab (MDX-010) (NSC 732442) 
9.2.1 
Chemical Name or Amino Acid Sequence: 4 polypeptide chains, 2 identical heavy 
chains with 447 amino acids and 2 identical light chains consisting of 215 amino acids. 
9.2.2 
Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
9.2.3 
Classification: Human monoclonal antibody 
9.2.4 
M.W.: 147,991 Daltons 
9.2.5 
Mode of Action: Ipilimumab is specific for the CTLA4 antigen expressed on a subset 
of activated T-cells. CTLA4 interaction with the B7 molecule, one of its ligands 
expressed on professional antigen presenting cells, can down-regulate T-cell 
response. Ipilimumab is, thought to act by blocking the interaction of CTLA4 with 
the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell activation.  
The CTLA4/B7 creates the interaction.  
9.2.6 
Description: Ipilimumab is a fully human immunoglobulin (IgG1) with two 
manufacturing processes – ongoing trials have been using substances manufactured 
using Process B.  New clinical trials will be using ipilimumab that is manufactured 
by Process C. The Process C has been developed using a higher producing sub-clone 
of the current Master Cell Bank, and modified cell culture and purification steps.  
 9.2.7 
How Supplied: Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the DCTD/NCI.  
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly 
opalescent, colorless to pale yellow, sterile, non-pyrogenic, single-use, isotonic 
aqueous solution that may contain particles. 
 
Each vial is a Type I flint glass vial with gray butyl stoppers and sealed with aluminum 
seals. 
 
 
Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 

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Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
 
aIncludes 2.6 mL overfill. 
bNitrogen is used to transfer the bulk solution through the pre-filled and sterilizing 
filters into the aseptic area. 
 
9.2.8 
Preparation:  Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, 
USP or 5% Dextrose Injection, USP in concentrations between 1 mg/mL and 4 mg/mL.  
Ipilimumab is stable in a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-
ethylhexyl) phthalate) IV bag or glass container up to 24 hours refrigerated at (20 to 80 
C) or at room temperature/ room light.  
 
Recommended safety measures for preparation and handling include protective 
clothing, gloves, and safety cabinets. 
 
 9.2.9 
Storage: Store intact vials refrigerated at (2° to 8°C), protected from light.  Do not freeze. 
The storage and use conditions recommended for Ipilimumab also apply to the Placebo 
for Ipilimumab Injection. 
 
9.2.10 
Stability: Shelf-life surveillance of the intact vials is ongoing. 
Solution as described above is stable up to 24 hours refrigerated at (2° to 8° C) or at 
room temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  
Use prepared IV solution immediately. Discard partially used vials.  
 
9.2.11 
Route of Administration: Intravenous infusion.  Do not administer ipilimumab as an IV 
push or bolus injection. 
 
9.2.12 
Method of Administration:  Can use a volumetric pump to infuse ipilimumab at the 
protocol-specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, sterile, 
non-pyrogenic, low-protein-binding filter (0.2 micron to 1.2 micron). 
 
9.2.13 
Patient Care Implications:  Monitor patients for immune-related adverse events, e.g., 
rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism.  If you 
suspect toxicity, refer to the protocol guidelines for ruling out other causes. 
9.2.14 
See Section 7.3.2 for CAEPR for Ipilimumab. 
 
 

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10. 
PATHOLOGY   
 
No pathology is required for central pathology review, but pathology reports are 
required. 
 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1 
Reimbursement 
 
See the Funding Sheet found on the CTSU web site (www.ctsu.org). 
 
11.2 
Translational Science (05/22/2017) 
 
11.2.1 
Specimen Requirements 
 
11.2.1.1 
Mandatory Specimen Requirements (05/22/2017) (09/07/2018) 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s specimens as outlined below. 
 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
ARCHIVAL FFPE 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 35 unstained slides (3 charged, 4 
µm† and 32 charged, 5µm) 
Prior to all treatment 
(Preferred FFPE) 
NRG BB-Columbus  within 
8 weeks of registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 35 unstained slides (3 charged, 4 
µm† and 32 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: 35 unstained slides (3 charged, 4 
µm† and 32 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: 35 unstained slides (3 charged, 4 
µm† and 32 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: 35 unstained slides (3 charged, 4 
µm† and 32 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: 35 unstained slides (3 charged, 4 
µm† and 32 charged, 5µm ) 
Prior to study treatment 
(Optional if FP01, FM01, 
FRP01, FRM01, or FPP01 is 
submitted) 
* A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG BB-
Columbus. 
† The 3 charged, 4µm, slides should be cut first as they are required to test the integrated biomarker. If less than 
35 slides are available, please contact BPCBank@nationwidechildrens.org and/or NRG-TR@nrgoncology.org. 
1 NRG BB-Columbus / Protocol NRG-GY003, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, 
Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
11.2.1.2 
Optional Specimen Requirements (05/22/2017) (07/31/2017) (09/07/2018) 

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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. 
PLEASE NOTE that the Pre-Treatment Blood Collections were omitted from the 
following table in the Amendment #5 document in Error.   
 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
PRE-TREATMENT BLOOD COLLECTIONS 
Pre-Treatment DNA Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) tube(s) 
Prior to study treatment 
NRG BB-Columbus the day 
the specimen is collected1 
Pre-treatment Serum (SB01) 
prepared from 7-10mL of blood drawn into plain 
red top tube(s) 
Prior to study treatment 
NRG BB-Columbus within 
14 weeks of registration1 
 
Pre-Treatment Buffy Coat (LB01) 
prepared from 7-10mL of blood drawn into 
purple top (EDTA) tube(s) 
6 WEEK BLOOD COLLECTIONS 
6 Week DNA Whole Blood (WB02) 
7-10mL drawn into purple top (EDTA) tube(s) 
6 weeks after starting study 
treatment 
NRG BB-Columbus the day 
the specimen is collected1 
6 Week Serum (SB02) 
prepared from 7-10mL of blood drawn into plain 
red top tube(s) 
NRG BB-Columbus within 
14 weeks of registration1 
6 Week Buffy Coat (LB02) 
prepared from 7-10mL of blood drawn into 
purple top (EDTA) tube(s) 
12 WEEK BLOOD COLLECTIONS 
12 Week DNA Whole Blood (WB03) 
7-10mL drawn into purple top (EDTA) tube(s) 
12 weeks after starting study 
treatment 
NRG BB-Columbus the day 
the specimen is collected1 
12 Week Serum (SB03) 
prepared from 7-10mL of blood drawn into plain 
red top tube(s) 
NRG BB-Columbus within 
14 weeks of registration1 
12 Week Buffy Coat (LB03) 
prepared from 7-10mL of blood drawn into 
purple top (EDTA) tube(s) 
1 NRG BB-Columbus / Protocol NRG-GY003, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, 
Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
11.2.2 
Specimen Procedures 
A detailed description of specimen procedures can be found in Appendix IV. 
 
 
 

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11.2.3 
Laboratory Testing (05/22/2017) (09/07/2018) 
 
 
Assay details are included in Appendix V. Specimens will be prioritized for testing 
as outlined below. 
 
 
 
 
 
 
Priority 
Specimen 
1 
2 
3 
4 
5 
Buffy Coat 
(LB01-LB03) 
Transcript 
Profiling 
(11.2.3.5) 
- 
 
- 
 
- 
 
- 
DNA (WB01-
WB03) 
TCR 
Repertoire 
(11.2.3.4) 
- 
 
- 
 
- 
 
- 
FFPE (FP01, 
FM01, FRP01, 
FRM01, FPP01, 
FPM01) 
PD-L1* 
(11.2.3.1) 
Neo-
antigen 
(11.2.3.3) 
TIL IHC 
(11.2.3.2) 
Tumor 
transcriptome 
(11.2.3.5) 
TCR repertoire 
(11.2.3.4) 
Serum (SB01-
SB03) 
TAA 
Responses 
(11.2.3.6) 
- 
 
- 
 
- 
 
- 
 
11.2.3.1 
PD-L1 Immunohistochemistry  (05/22/2017) (09/07/2018) 
Three 4µm charged sections of formalin-fixed, paraffin-embedded (FFPE) archival 
tumor will be batch shipped by the NRG BB-Columbus upon trial completion to 
TBD for immuno-histochemical analysis of PD-L1. 
 
11.2.3.2 
Infiltrating Lymphocytes Immunohistochemistry (05/22/2017) (09/07/2018) 
Unstained sections of FFPE archival tumor will be batch shipped by the NRG BB-
Columbus upon trial completion to Dr. Daniel Powell for IHC analysis of tumor 
infiltrating lymphocytes (TILs). Markers to be examined include CD3, CD4, CD8, 
FoxP3, CD16, CD68, CD137, OX40, GITR, CD40, IDO, LAG3, TIM3, B7-H3, B7-
H4, PD-1, CTLA-4, and VISTA.  Quantification of cells in the tumor and invasive 
margin will be included, provided the invasive margin can be identified.   
 
Daniel J Powell Jr, PhD 
University of Pennsylvania 
3400 Civic Center Blvd, Bldg 421 
Smilow Ctr, Rm 08-103 
Philadelphia, PA 19104-5156 
Phone: 215-573-4783 
Email: poda@mail.med.upenn.edu 
 
11.2.3.3 
Neo-antigen Assessment  (05/22/2017) (09/07/2018) 
 
 
Ten 5µm charged sections of FFPE archival tumor collected pre-treatment will be 
batch shipped by the NRG BB-Columbus upon trial completion to Dr. Dmitriy 
Zamarin for DNA extraction and next-generation whole exome sequencing to 
characterize the neo-antigen landscape.  
 

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Dr. Dmitriy Zamarin 
Memorial Sloan Kettering Cancer Center 
Immune Monitoring Facility 
417 East 68th street, Z15-25 
Phone: 646-888-2322 
Email: zamarind@mskcc.org 
 
11.2.3.4 
T Cell Receptor (TCR) Repertoires in Peripheral Blood and Tumors 
(05/22/2017) (09/07/2018) 
DNA isolated from whole blood collected pre-treatment and at 6- and 12-weeks will 
be batch shipped by the NRG BB-Columbus upon trial completion to Dr. Dmitriy 
Zamarin for TCR repertoire analysis.  DNA extracted from tumors for neoantigen 
assessment will be also used for TCR analysis.  If insufficient, ten 5µm charged 
sections of FFPE archival tumor will be batch shipped by the NRG BB-Columbus 
upon trial completion to Dr. Dmitriy Zamarin for deep sequencing of TCR CDR3 
regions. 
 
11.2.3.5 
Immune Transcriptional Profiling inPeripheral Blood  (05/22/2017) (09/07/2018) 
Peripheral blood buffy coats collected pre-treatment and at 6- and 12-weeks will be 
batch shipped by the NRG BB-Columbus upon trial completion to Dr. Dmitriy 
Zamarin for analysis of transcriptional signatures of immune activation by RNA 
sequencing or similar platform.  Amongst these, the expression of the known 
activating co-stimulatory receptors such as 4-1BB (CD137), OX40, GITR, CD40, 
and ICOS, as well as known immune inhibitory proteins such as PD-L1, indoleamine 
dioxygenase (IDO), B7-H3, B7-H4, LAG3, TIM-3, PD-1, CTLA-4, VISTA, and 
BTLA will be assessed. 
11.2.3.6 
Immune Transcriptional Profiling in Tumors (09/07/2018) 
 
Five 5 µm charged sections will be batch shipped by the NRG BB-Columbus 
upon trial completion to Dr. Dmitriy Zamarin for analysis of transcriptional 
signatures of immune activation and correlation of immune signatures with 
signatures of specific tumor driver pathways such as WNT and MYC, which have 
been previously associated with lack of response. Immune deconvolution algorithms 
will be employed to delineate the composition of the tumor microenvironment; these 
data will be compared to the IHC data. Depending on RNA quality, gene expression 
assessment will be performed using either RNA sequencing, Affymetrix Clariom D 
microarray, or HTG EdgeSeq Oncology Biomarker panel, which includes 2560 
transcripts associated with tumor driver pathways and microenvironment.  
 
11.2.3.7 
Tumor-Associated Antigen (TAA) Serologic Responses (05/22/2017) (09/07/2018) 
Serum collected pretreatment and at 6- and 12-weeks of therapy will be batch 
shipped by the NRG BB-Columbus upon trial completion to Dr. Dmitriy Zamarin 
(address above) for assessment of TAA serologic responses. 
 
11.2.4 
Banking Specimens for Future Research 
Details regarding the banking and use of specimens for future research can be found 
in Appendix IV. 

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11.3 
Quality of Life 
Not applicable. 
 
12. 
DATA AND RECORDS 
 
12.1 
Data Management/Collection (02/13/2017) 
 
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. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings) and 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 members’ 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 
Summary of Data Submission (02/13/2017) 
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 timelier 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, timeframes; add if loading of the pathology 
report is required. 

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Summary of Data Submission: Refer to the NRG Oncology member website for the 
table of Required Forms and Materials. 
 
12.3 
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 
 
Primary Efficacy Analysis 
 
Design Summary (05/22/2017) 
 
Approximately 48 patients (24 within each arm) will be recruited during the first 
stage of accrual.  The proportion of patients responding to therapy will be 
determined. If the observed proportion responding on the Nivolumab and 
Ipilimumab arm is greater than the observed proportion on the Nivolumab arm, then 
the trial may (with medical judgment indicating) continue with recruitment of a 
second stage of accrual.  If the observed proportion responding to Nivolumab and 
Ipilimumab is equal to or less than the proportion responding to Nivolumab arm, 
then the trial should stop early and declare the combination regimen unworthy of 
further investigation.  The trial may be amended and continue as a single arm study 
if there is evidence of activity in the Nivolumab arm, based on comparisons to 
historical data. For example, if there are three or more responses in (22-24) or 4 or 
more in (25-29) at the interim analysis, indicating that the upper bound of a 1-sided 
90% CI is ≥25%, then the study could continue as a single arm study with nivolumab 
(see section 13.7.2). 
 
If the randomized study proceeds to the second stage (with an approximate 
cumulative accrual of 48 patients per arm; 96 patients in total), the proportion 
responding in the Nivolumab plus Ipilimumab arm will be compared to the 
proportion responding in the Nivolumab alone arm, using a 2-stage Fisher’s Exact 
Test that conditions on the event that the trial proceeded to the second stage (see 
below for further details). The study’s overall desired unconditional probability of a 
type I error (i.e. a false positive study) is 15%. Operationally this would be like using 
a nominal critical p-value of 15% divided by the probability of going to the second 
stage when the null hypothesis is true (typical tests could reject Ho if the p-value is 
less than 33%).  See below for more details. 
 
Due to data discreteness, the study’s actual alpha=0.114 and beta ≤ 0.196, assuming 
that exactly 24 patients enroll in each arm for each stage.  These operating 
characteristics will change, depending on the realized accrual.  An intent-to-treat 
analysis will be used for this study. 
 

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Design Details and Math Derivation 
 
The study will randomize patients to two treatments, 𝜏0 (the reference group) and 𝜏1 
(the experimental group) in Stage 1.  The realized sample size for 𝜏0 is 𝑛01 and for 
𝜏1 is 𝑛11.  The number of responses to 𝜏0 is 𝑋0, and the number of responses to 𝜏1 is 
𝑋1.  These random variables are assumed to be distributed as binomials: 
 
𝑋0~𝐵𝑖𝑛(𝑛01, 𝑃0) 
𝑋1~𝐵𝑖𝑛(𝑛11, 𝑃1) 
 
If: 
𝑋1
𝑛11
> 𝑋0
𝑛01
 
 
then the trial will proceed to Stage 2.  Again randomize patients to the two 
treatments.  Let the realized sample size for 𝜏0 in Stage 2 be 𝑛02 and for 𝜏1 be 𝑛12.  
The number of responses to 𝜏0 is 𝑌0, and the number of responses to 𝜏1 is 𝑌1.  These 
random variables are assumed to be distributed as binomials: 
 
𝑌0~𝐵𝑖𝑛(𝑛02, 𝑃0) 
𝑌1~𝐵𝑖𝑛(𝑛12, 𝑃1) 
 
Define the following: 
 
𝑍1 = 𝑋1 + 𝑌1 
𝑍0 = 𝑋0 + 𝑌0 
𝑇= 𝑍1 + 𝑍0 
 
The set, 
𝑋1
𝑛11 >
𝑋0
𝑛01, can be stated equivalently as: 
𝑋1 ≥[ 𝑋0
𝑛01
× 𝑛11 + 1] = [𝑎0] 
So,  𝑎0 =
𝑋0
𝑛01 × 𝑛11 + 1, and [𝑎0] is the integer function of 𝑎0. 
 
Now the joint distribution, conditioned on 𝑋1 ≥[𝑎0], can be written as follows: 
 
𝑓(𝑋1, 𝑋0, 𝑌1, 𝑌0|𝑋1 ≥[𝑎0])
= 𝑃−1𝐼𝑋1≥[𝑎0](𝑋0, 𝑋1) (𝑛11
𝑋1 ) (𝑛01
𝑋0 ) (𝑛12
𝑌1 ) (𝑛02
𝑌0 ) 𝑃1
𝑋1+𝑌1𝑄1
𝑛11+𝑛12−𝑋1−𝑌1
× 𝑃0
𝑋0+𝑌0𝑄0
𝑛01+𝑛02−𝑋0−𝑌0 
 
where 𝐼 is an indicator function, 𝑃= 𝑃(𝑋1 ≥[𝑎0]), and 𝑄𝑖= 1 −𝑃𝑖 for 𝑖= 0, 1. 
 
Rewriting in terms of 𝑋1, 𝑋0, 𝑍1, and 𝑍0 gives: 
 

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𝑓(𝑋1, 𝑋0, 𝑍1, 𝑍0|𝑋1 ≥[𝑎0])
= 𝑃−1
∙𝐼𝑋1≥[𝑎0](𝑋0, 𝑋1) (𝑛11
𝑋1 ) (𝑛01
𝑋0 ) (
𝑛12
𝑍1 −𝑋1) (
𝑛02
𝑍0 −𝑋0) 𝑃1
𝑍1𝑄1
𝑛11+𝑛12−𝑍1
× 𝑃0
𝑍0𝑄0
𝑛01+𝑛02−𝑍0 
 
Note that [𝑎0] ≤𝑋1 ≤𝑛11 and 𝑍1 −𝑛12 ≤𝑋1 ≤𝑍1. Conditional on 𝑋1 ≥[𝑎0], we 
know that 𝑋0 ≤𝑛01 −1 since 0 ≤𝑋0 ≤[𝑛01𝑛11
−1𝑋1] −1 = 𝑛01 −1 when 𝑋1 =
𝑛11.  𝑋0 is also restricted by 𝑍0 −𝑛02 ≤𝑋0 ≤𝑍0 from the definition of 𝑍0. 
 
So the mass function can be written strictly in terms of 𝑍1 and 𝑇= 𝑍0 + 𝑍1 by 
integrating out 𝑋0 and 𝑋1 from 𝑓 over their restricted ranges.  The above equation is 
rewritten in exponential format: 
 
𝑓(∙) = 𝑃−1 ∙𝐼∙𝑒𝑥𝑝(𝑍1(𝜃1 −𝜃0) + (𝑍0 + 𝑍1)𝜃0)
×
∑
(𝑛01
𝑥0 ) (
𝑛02
𝑍0 −𝑥0)
∑
(𝑛11
𝑥1 ) (
𝑛12
𝑍1 −𝑥1)
𝑚𝑖𝑛{𝑛11,𝑍1}
𝑥1=𝑚𝑎𝑥{[𝑎0],𝑍1−𝑛12}
𝑚𝑖𝑛{𝑍0,𝑛01−1}
𝑥0=𝑚𝑎𝑥{0,𝑍0−𝑛02}
 
 
 
where 𝜃𝑖= 𝑙𝑛(𝑃𝑖/(1 −𝑃𝑖)) is the log odds for treatment 𝑖, 𝑖= 0,1.  It is important 
to note that the second summation is an “inner loop” that depends on each iteration 
of 𝑥0 through the lower bound of 𝑥1 (i.e. 𝑚𝑎𝑥{[𝑎0], 𝑍1 −𝑛12}). The sufficient 
statistics for 𝜃0 and (𝜃1 −𝜃0) are 𝑇= 𝑍0 + 𝑍1 and 𝑍1, respectively.  Substituting 
𝑇−𝑍1 for 𝑍0 and ∆= 𝜃1 −𝜃0, which is the log odds ratio for response on treatment 
𝜏1 to 𝜏0, into the above function, we get: 
 
𝑓(𝑍1, 𝑇) = 𝑃−1 ∙𝐼
∙𝑒𝑥𝑝(𝑍1∆+ 𝑇𝜃0)
×
∑
(𝑛01
𝑥0 ) (
𝑛02
𝑇−𝑍1 −𝑥0)
𝑚𝑖𝑛{𝑇−𝑍1,𝑛01−1}
𝑥0=𝑚𝑎𝑥{0,𝑇−𝑍1−𝑛02}
∑
(𝑛11
𝑥1 ) (
𝑛12
𝑍1 −𝑥1) .
𝑚𝑖𝑛{𝑛11,𝑍1}
𝑥1=𝑚𝑎𝑥{[𝑎0],𝑍1−𝑛12}
 
 
The nuisance parameter, 𝜃0, is eliminated by conditioning on the realized value of 𝑇.  
That is:  
𝑓(𝑍1|𝑇) = 𝑓(𝑍1, 𝑇)
𝑓(𝑇)  
 
The marginal distribution of T can be found by integrating 𝑍1from the joint 
distribution listed above.  𝑍1 is restricted as follows: 
 
1 ≤𝑍1 ≤𝑛11 + 𝑛12 
𝑇−(𝑛01 −1 + 𝑛02) ≤𝑍1 ≤𝑇 
 
The first set of inequalities stems from the definition of 𝑍1 and remembering that the 

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minimal value of 𝑋1 = 1.  The second set of inequalities stems from the definition of 
𝑇, 𝑍0, and remembering that 𝑋0 ≤𝑛01 −1.  Looking at the joint distribution of 
𝑓(𝑍1, 𝑇), we note, based on summation over 𝑥1, that 𝑍1 ≥[𝑎0].  A lower bound of 
𝑥0 is 𝑇−𝑍1 −𝑛02.  Accordingly, a lower bound for 𝑍1 is [𝑇−𝑍1 −𝑛02 + 1], 
which is recursive.  Setting 𝑍1 ≥𝑇−𝑍1 −𝑛02 + 1, we get 𝑍1 ≥(𝑇−𝑛02 + 1)/2.  
Finally, 𝑍1 ≥[
(𝑇−𝑛02+1)
2
+ 0.5] since 𝑍1 is an integer.  If this definition is not met, 
the summation over 𝑥1 is 0, which means the value of 𝑍1is not an element of its 
sample space. 
 
Therefore, 
 
𝑓(𝑇) =
∑
𝑓(𝑍1, 𝑇)
𝑚𝑖𝑛{𝑛11+𝑛12,𝑇}
𝑍1=𝑚𝑎𝑥{1,𝑇−(𝑛01−1+𝑛02),[(𝑇−𝑛02+1)
2
+0.5]}
 
 
𝑓(𝑇) can also be thought of as a normalization constant, “𝐶𝑁”, for the conditional 
distribution of 𝑍1.  That is, 𝑓(𝑇) = 𝑃−1 ∙𝐼∙𝑒𝑥𝑝(𝑇𝜃0)𝐶𝑁. 
 
𝑓(𝑍1|𝑇) = 𝐶𝑁
−1
∙𝑒𝑥𝑝(𝑍1∆)
×
∑
(𝑛01
𝑥0 ) (
𝑛02
𝑇−𝑍1 −𝑥0)
𝑚𝑖𝑛{𝑇−𝑍1,𝑛01−1}
𝑥0=𝑚𝑎𝑥{0,𝑇−𝑍1−𝑛02}
∑
(𝑛11
𝑥1 ) (
𝑛12
𝑍1 −𝑥1)
𝑚𝑖𝑛{𝑛11,𝑍1}
𝑥1=𝑚𝑎𝑥{[𝑎0],𝑍1−𝑛12}
 
 
The conditional distribution of 𝑓(𝑍1|𝑇) is simpler than the joint distribution since 
the components containing the nuisance parameter, 𝑃−1𝑒𝑥𝑝(𝑇𝜃0), drops out.  The 
conditional distribution of 𝑓(𝑍1|𝑇) only depends on ∆ and the observable statistic, 𝑇. 
 
The cumulative distribution function is given by 𝑃(𝑍1 ≤𝑧1|𝑇) = 𝐹(𝑧1|𝑇), and the 
survival function is provided with 𝑃(𝑍1 ≥𝑧1|𝑇) = 𝑆(𝑧1|𝑇) = 1 −𝐹(𝑧1|𝑇) +
𝑓(𝑧1|𝑇). 
 
Calculating Unconditional Power Using 𝑓(𝑍1|𝑇) 
 
In most applications, the total number of responses is not fixed to 𝑇.  Instead, the 
first and second stage sample sizes are set to a desired target (i.e. 𝑛𝑖𝑗 are fixed for 
𝑖= 0,1;  𝑗= 1,2), and 𝑇 is allowed to vary randomly so that attention can focus on 
the overall probability that 𝑍1 ≥𝑍𝑐 where 𝑍𝑐 is a critical value obtained from 
various survival distributions, 𝑆(𝑍𝑐|𝑇).  One way of obtaining this probability is 
with: 
 
 
𝑃𝑜𝑤𝑒𝑟= 𝑃(𝑍1 ≥𝑍𝑐, 𝑋1 ≥[𝑎0]) = 

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=
∑
𝑃(𝑍1 ≥𝑍𝑐|𝑋1 = 𝑥1, 𝑋0 = 𝑥0, 𝑇= 𝑡)𝑃(𝑇= 𝑡|𝑋1 = 𝑥1, 𝑋0 = 𝑥0)𝑃(𝑋1 = 𝑥1, 𝑋0 = 𝑥0)
𝑋1≥[𝑎0],𝑡∈Ω𝑡
 
 
Specifically, 
 
𝑃(𝑍1 ≥𝑍𝑐, 𝑋1 ≥[𝑎0]) = ∑( ∑
𝑓𝑋0(𝑥0)𝑓𝑋1(𝑥1)
𝑛11
𝑥1=[𝑎0]
{
∑
𝑆(𝑍𝑐|𝑡)𝑓𝑇(𝑡)
𝑥1+𝑥2+𝑛02+𝑛12
𝑡=𝑥1+𝑥2
})
𝑛01−1
𝑥0=0
 
 
where 𝑓𝑋𝑖 are the marginal probability mass functions of 𝑋𝑖, 𝑖= 0, 1, and 𝑓𝑇(𝑡) is the 
conditional mass function of 𝑇 when 𝑋1 = 𝑥1, 𝑋0 = 𝑥0.  The 𝑓𝑋𝑖 are binomial mass 
functions. The 𝑓𝑇(𝑡) probability can be found as follows: 
 
𝑓𝑇(𝑡) =
∑
𝑓𝑌1(𝑡−𝑥1 −𝑥0 −𝑦0)𝑓𝑌0(𝑦0)
𝑚𝑖𝑛{𝑛02,𝑡−𝑥1−𝑥0}
𝑦0=𝑚𝑎𝑥{0,𝑡−𝑥1−𝑥0−𝑛12}
. 
 
Again, the 𝑓𝑌𝑖 are the binomial mass functions of 𝑌𝑖.  
 
Note that cases 𝑋1 < [𝑎0] do not contribute to power.  If the study closes early, then 
it is assumed that the null hypothesis is not rejected. 
 
Approach to an Analysis of the Design 
 
The null hypothesis, 𝐻0: ∆≤0 is tested against 𝐻1: ∆> 0 using 𝑍1 ≥𝑍𝑐 where 𝑍𝑐 is 
a critical value obtained from 𝑆(𝑍𝑐|𝑇).  Under the null hypothesis, 𝑆(𝑍𝑐|𝑇) provides 
the conditional probability of incorrectly rejecting 𝐻0 which implicitly assumes also 
that 𝑋1 ≥[𝑎0] (i.e. 𝑆(𝑍𝑐|𝑇, 𝑋1 ≥[𝑎0])).  Since the 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])} ≤0.50 over 
all values of 𝑃1 ∋𝑃1 = 𝑃0 when 𝑛01 = 𝑛11, a more liberal critical value can be 
utilized from the conditional distribution.  When it is desired to test the null 
hypothesis at an unconditional level of significance, 𝛼, then we can find a 
conditional  𝑍𝑐 so that 𝑆(𝑍𝑐|𝑇) ≤2𝛼.  Then: 
 
𝑆(𝑍𝑐|𝑇) ×  𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])} ≤2𝛼∙𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])} ≤2𝛼∙1
2 = 𝛼 
 
For example, if we want the unconditional level of significance to be 10%, we can 
find 𝑍𝑐 so that the conditional distribution gives 𝑆(𝑍𝑐|𝑇) ≤0.20 because the interim 
analysis will stop the study early and reject 𝐻0 at least 50% of the time. 
 
When 𝑛01 ≠𝑛11, it is not necessarily true that 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])} ≤0.50.  In this 
case, a search for 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])} is necessary and a potentially more 
conservative critical value is needed. 
 
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for rejecting the null hypothesis will be found from the desired unconditional level 
of significance, 𝛼, and 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])}.  Then the smallest value of 𝑍1 will be 
found so that under the null hypothesis, 𝑆(𝑍1|𝑇) ≤𝛼/ 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])}.  Given 
the discreteness of the dataset, this method is still conservative.  That is to say, the 
true size of the test will be less than or equal to 𝛼. 
Probabilities of rejecting 𝐻0 can be explored under various 𝑃0, 𝑃1, and sample sizes 
in order to obtain a design with desired power through simulation or numeric 
computation as shown above. 
 
Implementation: 
 
Stage 1 will accrue 48 patients with approximately half receiving the reference, 𝜏0 
and the others receiving the experimental therapy 𝜏1.  If the proportion responding 
on the experimental therapy is greater than the proportion on the reference, then the 
study will enroll another 48 patients in Stage 2 in a like manner (assuming medical 
judgment indicates).  The unconditional level of significance is 15%.  If the study 
completes accrual to the second stage, then the conditional test will be conducted at 
no more than the 15%/ 𝑚𝑎𝑥{𝑃(𝑋1 ≥[𝑎0])}level of significance.   
 
Assuming that the targeted accruals are achieved, the study’s operating 
characteristics will have a realized size (probability of a type I error) equal to about 
10.4% (when 𝑃0 = 𝑃1 = 0.2) and power=80.4% when 𝑃0 = 0.2 and 𝑃1 = 0.4 (based 
on exact calculations with a conditional level of significance equal to 0.33881).  The 
probability of early termination (PET) is 57.2% when 𝑃0 = 𝑃1 = 0.2 and 8.3% when 
𝑃0 = 0.2 and 𝑃1 = 0.4.  The minimum PET under the null hypothesis is 55.7% when 
𝑃0 = 𝑃1 = 0.5. 
 
13.1.1 
Stratification 
             
Patients will be stratified by their most recent platinum-free interval (PFI) according 
to PFI < 6 months and 6 ≤ PFI < 12 months. 
 
13.1.2 
Randomization 
             
Treatment randomization will be conducted by using permuted blocks within each 
stratum.  The permuted blocks will be of size 2 (e.g. 01|10|10|01|10 etc.). 
 
13.1.3 
Total Accrual 
 
First stage accrual will target 48 patients (24 in each arm).  The second stage of 
accrual will target an additional 48 patients (96 cumulative). 
 
13.1.4  
Justification of Design:  
             
Assuming that the targeted accruals are achieved, the study’s operating 
characteristics will have a realized size (probability of a type I error) equal to about 
10.4% (when 𝑃0 = 𝑃1 = 0.2) and power=80.4% when 𝑃0 = 0.2 and 𝑃1 = 0.4 (based 
on exact calculations).  The probability of early termination (PET) is 57.2% when 
𝑃0 = 𝑃1 = 0.2 and 8.3% when 𝑃0 = 0.2 and 𝑃1 = 0.4.  The minimum PET under the 

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null hypothesis is 55.7% when 𝑃0 = 𝑃1 = 0.5. 
 
13.2 
Study Endpoints 
 
13.2.1  
Primary Endpoints 
The frequency and duration of objective tumor response within 6 months of study 
entry as assessed by modified RECIST v. 1.1 criteria. 
 
13.2.2  
Secondary Endpoints 
            
 
▪ The hazard of having a disease progression or dying (PFS endpoint) by 
treatment. 
 
▪ The duration of overall survival (OS) by treatment arm. 
 
▪ The frequency and severity of adverse events as assessed by CTCAE.           
 
 
13.2.3  
Exploratory Endpoints 
            
 
▪ Natural anti-tumor immunity in TIL and tumor cells assessed with IHC. 
 
▪ Markers of “immunogenicity” as determined by the neo-epitope landscape 
using next-generation whole exome sequencing (NGS). 
 
▪ Assessing the impact of biomarkers on tumor response, PFS, and OS. 
 
13.3 
Primary Objectives Study Design 
 
13.3.1 
Primary Hypothesis and Endpoints 
             
Primary Hypothesis: Ho: P1 ≤ P0 versus Ha: P1 > P0 where P0 is the probability of 
response for the reference regimen (nivolumab) and P1 is the probability of response 
for the combination regimen (nivolumab + ipilimumab). 
 
 
 
The endpoint is tumor response within 6 months of study entry. 
13.3.2 
Definitions of Primary Endpoints and How These Will Be Analyzed 
           
Tumor response is defined according to RECIST v. 1.1.  It will be analyzed 
according to the methods outlined in section 14.1. 
 
13.3.3 
Sample Size and Power Calculations:  
See section 13.1 for power calculations.  The sample size is 48 patients randomized 
to the first stage, and another 48 randomized to the second stage. 
 
 
13.4 
Study Monitoring of Primary Objectives         
  
As this is an intent-to-treat analysis, all randomized patients will be included in these 
analyses. For purpose of timely analysis, we will use tumor response in 6 months as 
the primary endpoint.  If a patient remains on study for more than 6 months with 

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stable disease as the best response, then this patient will be considered as not 
responding to therapy.   
 
The frequency of tumor response will be monitored on a weekly basis.  If a patient is 
still on study and has not had a tumor response within 6 months of study 
randomization (e.g. has stable disease), this patient will be classified as having an 
unknown tumor response.  Patients who do not respond within 6 months will be 
classified as “non-responders,” so all patients should have their tumor responses 
determined by about 6 months of study suspension or closure, depending on 
institutional reporting. 
 
An interim report will be given to the DMC once the first stage data is mature.  Their 
task will be to provide a recommendation for early termination (i.e. study closure), 
continuation, or study amendment.  Final study results will be initially reported to 
the Study Chair and Developmental Therapeutics Chair for review, then to the 
Cancer Therapeutics Evaluation Program (CTEP).  Efficacy information is not 
routinely reported until the data are sufficiently mature. 
 
13.5 
Accrual Considerations 
 
13.5.1 
Accrual Rate: 6 patients per month.  If accrual is too slow, then an amendment to the 
study will be considered. 
 
13.5.2    
Accrual Goal: 48 patients for stage 1, and 96 patients cumulatively for stage 2. 
 
13.5.3 
Study Duration: We anticipate 8 months of accrual for each stage.  The first stage 
may take 11 months.  The interim analysis may take up to 6 or 8 months of follow-
up. 
 
13.5.4 
Estimated Duration for Completion of Primary Endpoint: All of the data should be in 
by 8 months after the closure of the second stage, so the primary endpoint 
completion date should be about 35 months after study opening.   
 
If the study terminates early, the completion date should be about 19 months after 
study activation. 
 
13.6 
Dose Level Guidelines 
 
See Schema. 
 
13.7 
Secondary or Exploratory Elements (including correlative science aims) 
 
13.7.1 
Secondary Hypotheses and Endpoints:  
Ho: HR=1 versus Ha: HR<1 where HR is the hazard ratio of the combination 
regimen to the reference regimen.  The endpoints include those for PFS and OS. 
 
For toxicity, Ho: Odds Ratio of a severe toxicity is equal to one.  The alternative 

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hypothesis is that the odds ratio of a severe toxicity is greater than one (treatment to 
reference regimen).  Endpoints are adverse events classified as severe or not. 
 
For Translational Research, the prognostic impact for the level of biomarker will be 
assessed by testing Ho: HR=1 versus Ha: HR ≠ 1 for biomarker level 1 to level 2 for 
PFS and OS (across both regimens).  Subset analyses will be conducted within each 
treatment regimen.  To assess the predictive value of a biomarker, we note in 
statistical terms, the hazard ratio for progression on the experimental treatment to the 
control treatment depends on the level of biomarker expression (high versus low).  
Using Peterson and George’s notation,93 let Delta1 be the hazard ratio for low levels 
of biomarker expression and Delta2 be the hazard ratio for the high levels of 
biomarker expression.  Ho: 
1
2
/
1

= versus Ha: Δ1/Δ2 ≠1. 
 
13.7.2 
Definitions of Secondary Endpoints and How These Will Be Analyzed 
Secondary Endpoints: 
An analysis on PFS and OS to assess the impact of treatment will be conducted 
using a stratified log-rank test.  In order to obtain 80% power for detecting a 37.5% 
reduction in the hazard rate while testing at the 10% level of significance, it is 
necessary to observe 82 events.  This would require 85% of the patients to have a 
PFS endpoint (82/96), which is feasible.  It is probably not feasible to wait for this 
many events for OS, so the power of the study to detect a similar reduction in the 
hazard of death will likely be smaller.  Given the imprecision of the estimate, the 
point estimate may be emphasized for an indication of promise. 
 
If the study terminates early for lack of promise in the combination regimen (i.e. is 
considered uninteresting), consideration may be given for amending the study to 
further evaluate the nivolumab regimen against a historical control.  If a 1-sided 90% 
CI on the probability of response excludes 25% as an element of the interval, then 
the study will recommend closing the study.  However, if the 90% CI includes 25%, 
then the study could enroll an additional set of patients to evaluate nivolumab 
against a historically interesting RR of 10% versus 25%.  Such a study could be 
powered at nearly 90% with 10% level of significance. (05/22/2017) 
 
Adverse Event Monitoring 
Patients who receive any therapy will be included in the analyses of adverse events.  
Only those who refuse all therapy according to the assigned regimen will be 
excluded from these analyses.  Ineligible patients who receive any study therapy will 
be included. 
Toxicities on this protocol will be reviewed before each semi-annual meeting and 
will also be reviewed by the Study Chairperson in conjunction with the Statistical 
and Data Center.  In some instances, because of unexpectedly severe toxicity, the 
Statistics and Data Management Center in Buffalo may elect, after consultation with 
the Study Chair and the Chair of Developmental Therapeutics, to recommend early 

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closure of a study. 
The frequency and severity of all toxicities are tabulated and summarized for review 
by the Study Chair, Developmental Therapeutics Committee, and the Data 
Monitoring Committee (DMC) in conjunction with each semi-annual meeting.  In 
addition, 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.  If the study is suspended, 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 
DMC.  However, patients currently receiving treatment may continue to receive 
treatment in accordance with protocol guidelines at the discretion of their physicians, 
unless directed otherwise. 
Approximately 24 patients will be accrued to the combination regimen after the first 
stage.  As part of the summary to be presented to the DMC before opening the trial 
to Stage 2, attention will be called and consideration will be given to closing the 
study for reasons of safety if more than 10% of the patients experience grade 4 or 
grade 5 treatment-related adverse events.  The safety of the two arms will be 
compared according to organs or organ systems.  Toxicities will be divided into 
severe versus non-severe events, and the rates of severe toxicities will assessed using 
an exact Chi-square test.  Adverse events that are significant at the 5% level of 
significance will be highlighted in the presentation. 
Translational Research 
Translational research (TR) data can be fairly difficult to analyze statistically for 
various reasons including data that are highly skewed (non-normal) or of ordinal 
quality where differences between observations are not meaningful.  It has become 
customary to dichotomize biomarker data to help overcome these difficulties and 
ease the interpretation of the results. 
 
PD-L1 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) will be 
measured by quantitative immunohistochemistry (IHC).  It is anticipated that data 
will be available by the percent staining positive (PP) and the staining intensity.  A 
histoscore will be derived from these data (i.e. histoscore will be the product of the 
percent staining positive and the staining intensity).  Depending on the distribution 
of the data, Kaplan-Meier curves of PFS and OS will be examined by staining 
intensity or high staining intensity versus low intensity.  The PP and histoscore will 
also be used to construct Kaplan-Meier curves in terms of high versus low values.  
Cox models will be used to assess the potential impact of these values on the hazard 
of death or the hazard of the PFS endpoint (death or disease progression).  The 
biomarker data may be analyzed in dichotomized form or as raw data.  Deviance 
residual plots may be provided to explore potential relationships with the hazard.  
Relationships with response will be assessed using tables and possibly with logistic 
models. 

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For this study, biomarker data will be dichotomized (if feasible) at the median or, 
less commonly, whether or not expression is observed in the patients.  
Dichotomizing at the median tends to have an advantage by increasing the sensitivity 
of the analysis (relative to other cut points) when there is a significant association 
between the biomarker and clinical outcome. 
The marginal probability of detecting a biomarker’s prognostic effects on the hazard 
of death or progression depends on its true hazard ratio,, the level of significance, 
, and the number of events in the study, D , through the normal cumulative 
distribution function (cdf), provided by 
( )
as follows: 
 
/2
Power = 
2
D
z




−






 
 
The equation above holds since we expect ½ of the patients to score high.  This 
study is expecting about 84 PFS endpoints, so the probabilities of detection under 
this assumption are provided in Figure 11.2 (assuming a high proportion of patients 
participating in the TR aspect of this study). 
Figure 
Power as a function of the hazard ratio for patients with high levels of expression 
versus those with low levels of expression when assessed with the entire dataset 
(D=84) 
 
 
 
Often the predictive value of a biomarker is of considerable interest.  Such a 
biomarker could help direct the physician towards one treatment over another 
because the effectiveness of the treatment depends on the level of expression of the 
biomarker.  In statistical terms, the hazard ratio for progression on the experimental 
treatment to the control treatment depends on the level of biomarker expression 
0.0
0.5
1.0
1.5
2.0
2.5
0.2
0.4
0.6
0.8
1.0

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(high versus low).  Using Peterson and George’s notation,93 let Delta1 be the hazard 
ratio for low levels of biomarker expression and Delta2 be the hazard ratio for the 
high levels of biomarker expression.  When 
1
2
/
1

= , the biomarker contains no 
predictive value for treatment effectiveness.  The hazard ratios are the same 
regardless of the level of biomarker expression (however, the biomarker could still 
be prognostic). 
 
Because these tests amount to tests of interaction between treatment and biomarker 
level, the amount of power is drastically reduced.  All analyses will involve the full 
dataset and be exploratory (hypothesis generating) in nature.  The equation for 
calculating power is similar to the one above except the relevant number of events is 
now only 21 (84 events for 2 treatments cut into four cells is 21.93).  Note that 
roughly equal numbers of patients with high levels of biomarker expression are 
expected to be randomized to the treatments; also, the power calculations are robust 
as shown in Table 3 of publication. 
Figure 
Marginal power of tests for detecting predictive biomarkers. 
 
 
TR analyses that examine the impact of changes in biomarker values over time on 
the hazard of progression will be adjusted with the Landmark Method.94  This 
includes peripheral blood parameters after 6 and 12 weeks of therapy.  Patients that 
progress before the last time of tissue collection (in the entire sample) will not be 
included in the analysis.  The starting point will be adjusted from the date of entry.  
Because a number of patients (and some events) will be eliminated, the overall 
power of these analyses will not be as high as described previously.  However, the 
powers listed previously should be fair approximations since the number of patients 
that progress should be few. 
 
Biomarker measures of natural anti-tumor immunity include tumor infiltrating 
lymphocytes (TILs) and T cell repertoire analyses.  TIL IHC analyses will be 
conducted in similar analysis as proposed for the PD-L1.  T cell repertoire analyses 
are being finalized.  Some of the procedures used for collecting biological data are 
0
1
2
3
4
0.2
0.4
0.6
0.8
1.0

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novel and could be subject to change before the trial opens.  Therefore, details of the 
analysis are not fully presented yet. 
 
13.7.3  
Interim Analysis for All Other Endpoints (Goals):  
 
There will also be an informal interim analysis to examine the toxicities of the 
regimens. 
 
13.7.4 
Power Calculations:  
             
See section 13.1. 
 
13.7.5 
Expected Sample Size or Patient Cohorts:  
           
There is one patient cohort accrued in 2 stages.  The expected sample size is 48 to 96 
patients, depending primarily on whether the trial opens to the second stage. 
 
13.8 
 
Exploratory Hypothesis and Endpoints 
See section 13.7 which discusses exploratory analyses. 
 
13.9 
Gender/Ethnicity/Race Distribution 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
1 
 
1 
Not Hispanic or Latino 
95 
 
95 
Ethnic Category: Total of all 
96 
 
96 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
 
1 
Asian 
1 
 
1 
Black or African American 
5 
 
5 
Native Hawaiian or other Pacific 
0 
 
0 
White 
89 
 
89 
Racial Category: Total of all subjects 
96 
 
96 
 
14. 
EVALUATION CRITERIA 
 
14.1 
Antitumor Effect – Solid Tumors (02/22/2016) 
Response and progression will be evaluated in this study using a slightly modified 
version of the international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1).95 Changes in the largest 
diameter (uni-dimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria.  The 
modification to these criteria minimizes the possibility that therapeutic agents that 
induce T cell infiltration into tumors as an early manifestation of anti-tumor effect 
could be erroneously interpreted as disease progression on imaging and result in 
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protocol specifies continuation of treatment in cases of radiologic progression at 
the first 8 week (+/- 7 days) CT if all of the following criteria are satisfied: 
 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative 
treatment 
• Progression limited to an increase of 40% in the sum of diameters of target 
lesions 
• No more than 4 new lesions included in the sum. 
 
For patients who continue treatment in the case of radiologic progression at the 
first 8 week (+/- 7 days) CT: 
• The 8 week CT will serve as the new baseline for subsequent radiologic 
assessments of disease.  (05/22/2017) 
• At any subsequent CT scan patients who have stable disease as compared to 
the 8 week (+/- 7 days) CT scan will be allowed to continue on study 
treatment.  
• Patients who continue treatment in the case of radiologic progression at the 
first 8 week (+/- 7 days) CT, and later experience a PR or CR (as compared 
to baseline CT) will be recorded as delayed responses by the Statistics and 
Data Management Center. 
 
14.1.1 
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. 
  
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/pneumonitis, inflammatory breast 
disease, and abdominal/pelvic masses (identified by physical exam and not CT or 
MRI), are considered as non-measurable.  
 
Notes:  
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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. 
  
14.1.2 
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. 
  
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, 

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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. 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
 
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. 
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA125 
cannot be used to assess response or progression in this study. If CA125 is 
initially above the upper normal limit, it must normalize for a patient to be 

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considered in complete clinical response. Specific guidelines for CA-125 response 
(in recurrent ovarian cancer) have been published [JNCI 96:487-488, 2004]. In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria that are to be integrated with objective tumor assessment for use only in first-
line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases, e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain. 
 
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. 
  
14.1.3 
Response Criteria  
Determination of response should take into consideration all target (See 14.1.3.1) 
and non-target lesions (See 14.1.3.2) and, if appropriate, biomarkers (See 14.1.3.3). 
 
14.1.3.1  
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 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). 
 
Note:  The protocol specifies continuation of treatment in cases of radiologic 
progression at the first 8 week (+/- 7 days) CT if all of the criteria in section 14.1 are 
satisfied. 
  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters (i.e. the 
nadir) while on study.  
 
14.1.3.2  
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). 

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Note: If CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response. 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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). 
  
14.1.3.3 
Evaluation of Biomarkers  
If serum CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response.  
 
Progression cannot be based upon biomarkers, including serum CA-125 and HE4 
for this study. 
  
14.1.3.4 
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. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., 
Target Disease) 
 
 
Target 
Lesions 
Non-Target 
Lesions 
Biomarker 
CA-125 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
Within 
normal limits 
No 
CR 
CR 
Non-CR/Non-PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
Yes 
PD 

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*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Time Point Response for Patients with only Non-Measurable Disease at 
baseline (i.e., Non-Target Disease) 
 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
14.1.3.5 
 
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 
respons
e 
CR 
CR 
C
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 
Non-Target Lesions 
Biomarker 
CA-125 
New Lesions* 
Time Point 
Response 
CR 
Within normal limits 
No 
CR 
CR 
Above normal limits 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
Any value 
No 
Non-CR/non-PD* 
NE 
Any value 
No 
NE 
Unequivocal PD 
Any value 
Yes or No 
PD 
Any 
Any value 
Yes 
PD 

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CR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
PR 
CR 
P
PR 
PR 
P
PR 
SD 
S
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 
N
E
 
 
*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. 
 
14.1.4 
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). 
 

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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 date of study entry, including the baseline 
measurements. 
 
14.1.5 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry 
to time of progression or death, whichever occurs first. 
 
Modified RECIST PFS makes allowances for greater increases in sum of 
dimensions at the 8th week evaluation as stated in Section 14.1. 
 
14.1.6 
Survival 
Survival is defined as the duration of time from study entry to time of death or the 
date of last contact. 
 
 
 

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2010;16:2861-71. 
74. 
Liakou CI, Kamat A, Tang DN, et al. CTLA-4 blockade increases IFNgamma-
producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in 
cancer patients. Proceedings of the National Academy of Sciences of the United 
States of America 2008;105:14987-92. 
75. 
Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-
CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. Journal of 
immunotherapy 2010;33:828-33. 
76. 
O'Mahony D, Morris JC, Quinn C, et al. A pilot study of CTLA-4 blockade after 
cancer vaccine failure in patients with advanced malignancy. Clinical cancer 
research : an official journal of the American Association for Cancer Research 
2007;13:958-64. 
77. 
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody 
blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated 
cancer patients. Proceedings of the National Academy of Sciences of the United 
States of America 2008;105:3005-10. 
78. 
Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to 
treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 
2009;113:1581-8. 
79. 
Zhou J, Bashey A, Zhong R, et al. CTLA-4 blockade following relapse of 
malignancy after allogeneic stem cell transplantation is associated with T cell 
activation but not with increased levels of T regulatory cells. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation 2011;17:682-92. 
80. 
Harzstark AL, Fong L, Weinberg VK, et al. Final results of a phase I study of 
CTLA-4 blockade in combination with GM-CSF for metastatic castration resistant 
prostate cancer (mCRPC). J Clin Oncol 2010;28:A6032. 
81. 
Harzstark ALF, L.; Weinberg, V.K. Final results of a phase I study of CTLA-4 
blockade in combination with GM-CSF for metastatic castration resistant prostate 
cancer (mCRPC). Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2010;28:A6032. 
82. 
Fong L, Kwek SS, O'Brien S, et al. Potentiating endogenous antitumor immunity to 
prostate cancer through combination immunotherapy with CTLA4 blockade and 
GM-CSF. Cancer research 2009;69:609-15. 
83. 
Madan RAM, M.; Arlen, P.M. Overall survival (OS) analysis of a phase l trial of a 
vector-based vaccine (PSA-TRICOM) and ipilimumab (Ipi) in the treatment of 
metastatic castration-resistant prostate cancer (mCRPC).  . In: Genitourinary Cancers 
Symposium; 2010; 2010. p. A38. 
84. 
Stein WD, Gulley JL, Schlom J, et al. Tumor regression and growth rates determined 
in five intramural NCI prostate cancer trials: the growth rate constant as an indicator 
of therapeutic efficacy. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2011;17:907-17. 
85. 
Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-
CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-
Hodgkin lymphoma. Clinical cancer research : an official journal of the American 

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Association for Cancer Research 2009;15:6446-53. 
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Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to 
melanoma biological therapy. Eur J Endocrinol 2011;164:303-7. 
87. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clinical cancer 
research : an official journal of the American Association for Cancer Research 
2009;15:7412-20. 
88. 
Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. Journal of the National Cancer Institute 2010;102:1388-97. 
89. 
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;366:2443-54. 
90. 
Spranger S, Spaapen, R.M., Zha Y., Williams J., Meng, Y., Ha T.T., Gajewski, T.F. 
Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor 
Microenvironment Is Driven by CD8+ T Cells. Science translational medicine 
2013;5:Epub ahead of print. 
91. 
Cha E, Klinger M, Hou Y, et al. Improved survival with T cell clonotype stability 
after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 2014;6:238ra70. 
92. 
Page DB, Diab A, Yuan J, et al. T-cell receptor (TCR) DNA deep sequencing to 
evaluate clonality of tumor-infiltrating lymphocytes (TILs) in early-stage breast 
cancer patients (pts) receiving preoperative cryoablation (cryo) and/or ipilimumab 
(ipi). Journal of Clinical Oncology 2014;32:(suppl; abstr 3021). 
93. 
Peterson B, George SL. Sample size requirements and length of study for testing 
interaction in a 2 x k factorial design when time-to-failure is the outcome 
[corrected]. Controlled clinical trials 1993;14:511-22. 
94. 
Buyse M, Piedbois P. On the relationship between response to treatment and survival 
time. Statistics in medicine 1996;15:2797-812. 
95. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). European journal of cancer 
2009;45:228-47. 
 
 

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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 
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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 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 

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

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APPENDIX IV TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES (05/22/2017) 
(09/07/2018) 
 
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. 
 
Translational science biospecimens should not be submitted until after patient registration 
and Bank ID assignment. 
 
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. If a patient has 
previously been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as 
the previously assigned Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID to a 
patient (Email: support@nrgoncology.org). 
 
II. Requesting Translational Science Specimen Kits 
One single chamber kit will be provided per patient for the collection and shipment of frozen 
specimens. 
 
Sites can order kits online via the Kit Management link 
https://ricapps.nationwidechildrens.org/KitManagement. Each site may order two kits per 
protocol per day (daily max = 6 kits). (02/22/2016) 
 
 
Please contact the NRG BB-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. Kits should 
arrive within 3-5 business days. 
 
Note: Unused materials and kits should be returned to the NRG BB-Columbus. 
 
III. FFPE Tissue Shipped to the NRG BB-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic, recurrent, persistent). 
 
Only one block may be submitted per tissue type. If submitting sections, all sections must be cut 
sequentially from the same block. 
 
All FFPE tissue must be submitted with the corresponding pathology report. 
 
Mandatory FFPE Biospecimen Requirement 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 35 unstained slides (3 charged, 4 µm and 32 charged, 5µm) should 

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be submitted. Note: The 3 charged, 4µm, slides should be cut first as they are required to 
test the integrated biomarker. If less than 35 slides are available, please contact 
BPCBank@nationwidechildrens.org and/or NRG-TR@nrgoncology.org. 
 
Archival FFPE 
Primary (FP01) and metastatic (FM01) 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 
(FRP01) or persistent primary (FPP01), 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 (FRM01) or persistent metastatic (FPM01), respectively. 
 
 
Completing Form TR for FFPE Biospecimens 
The type of specimen (block, slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified.  
 
Note:  Since the “Charged slides” and “Count” fields only accommodate one value, “Count” 
should be entered as the total count of slides (35) at a “Thickness” of 5 µm.  To note submission 
of the 3 charged, 4µm sections required to test the integrated biomarker, check “Other” for 
“Items shipped” (in addition to “Slides”) and specify “three at 4 µm.” (02/22/2016) 
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY - # # #) 
specimen code (section 11.2.1) 
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. Whole Blood Shipped to the NRG BB-Columbus 
1.  Label the lavender/purple top (K2EDTA) collection tube(s) as described below. Multiple 
tubes may be used to collect the required amount. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and 
K2EDTA. 
4. Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. 

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Ship whole blood to the NRG BB-Columbus 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 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 - GY - # # #) 
specimen code (WB # #) 
collection date (mm/dd/yyyy) 
 
V. Serum Shipped to the NRG BB-Columbus 
1.  Label cryovials and a 15mL conical tube as described below. Use 2mL cryovials if serum 
will be shipped to the NRG BB-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 - GY - # # #) 
specimen code (SB # #) 
collection date (mm/dd/yyyy) 
 
VI. Buffy Coat Specimens Shipped to the NRG BB-Columbus 
1.  Label a cryovial and a 15mL conical tube as described below. Use a 2mL cryovial if buffy 
coat will be shipped to the NRG BB-Columbus. 
2.  Draw 7-10mL of blood into lavender/purple top (K2EDTA) tube(s).  
3.  Immediately after collection, gently invert the blood collection tube 5-10 times to mix the 
blood and K2EDTA. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the plasma (top, straw-colored layer) from the buffy coat (middle, white layer) and 
red blood cells (bottom, red layer).  

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5.  Leaving a small amount of plasma above the buffy coat layer, remove the plasma and 
discard. 
6. Transfer the buffy coat layer to a cryovial. Avoid drawing up any red blood cells. 
7. Centrifuge the buffy coat at 1000g for 10 minutes at 4ºC (preferred) or room temperature to 
pellet the cells. 
 
*If a cryovial centrifuge is not available, place the cryovial in a clean 15mL conical tube and 
centrifuge the cryovial in the 15mL conical tube. 
8. Carefully, remove most of the supernatant. 
9.  Immediately freeze the buffy coat 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 Buffy Coat Specimens 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY - # # #) 
specimen code (LB # #) 
collection date (mm/dd/yyyy) 
 
VII. Submitting Form TR 
An electronically completed copy of Form TR must accompany each specimen shipped to the 
NRG BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus 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 

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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@nrgoncology.org). 
 
VIII. Shipping Translational Science Specimens 
Translational science biospecimens should not be shipped until after patient registration 
and Bank ID assignment. 
 
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 BB-Columbus / Protocol NRG-GY003 
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 Specimens 
Frozen specimens should be shipped using the specimen kit provided to the NRG BB-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 Frozen Translational Science Specimens in a Single Chamber Kit  
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place each frozen specimen type and 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. 

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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. Print a pre-paid FedEx air bill using the Kit link 
(https://ricapps.nationwidechildrens.org/KitManagement). 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 
Whole blood specimens should be shipped Priority Overnight to the NRG BB-Columbus 
(address above). 
 
Whole blood specimens can be shipped to the NRG BB-Columbus Monday through Friday for 
Tuesday through Saturday 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 shipment, contact the NRG BB-Columbus 
at BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
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). The NRG BB-Columbus 
does not provide supplies for shipping whole blood.  
 
Shipping Whole Blood Using Your Own Shipping Container 
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. Print a pre-paid FedEx air bill using the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). Attach the air bill. 
8. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-
238-5355. 

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IX. Banking Translational Science Specimens for Future Research 
Specimens will remain in the NRG BB-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 BB-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. 
 
 

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APPENDIX V – TRANSLATIONAL SCIENCE LABORATORY TESTING 
PROCEDURES (05/22/2017) (09/07/2018) 
 
I. PD-L1 Immunohistochemistry 
A. Rationale 
PD-L1 expression has been previously associated with improved clinical benefit from therapies 
targeting the PD-1/PD-L1 pathway. The utility of PD-L1 expression as a predictive biomarker 
has been debated, as it is highly dynamic and can be up-regulated in response to immune 
activating factors. In this trial, archival, formalin-fixed, paraffin-embedded (FFPE) tumor will be 
evaluated by immunohistochemistry (IHC) for expression of PD-L1 as a predictive biomarker. 
B. Laboratory Testing Procedures 
FFPE tumor will be shipped from sites to the NRG BB-Columbus. The NRG BB-Columbus will 
batch ship unstained sections of tumor to TBD for PD-L1 IHC. PD-L1 IHC will be done using 
Bristol Meyers Squibb’s (BMS) proprietary DAKO assay. 
 
II. Infiltrating Lymphocytes Immunohistochemistry 
A. Rationale 
There is abundant evidence that native host anti-tumor cell mediated immune mechanisms play a 
role in controlling malignant progression of epithelial ovarian cancer (EOC), the majority of which 
exhibit high grade serous morphology. Investigators at the University of Pennsylvania (Penn) first 
discovered the impact of anti-tumor immune response on overall survival (OS) in patients with 
newly diagnosed advanced EOC, where the presence of CD3+ tumor-infiltrating lymphocytes 
(TILs; within tumor islets) was found to be a predictor of prolonged OS.(1) Others independently 
showed that the accumulation of TILs in ovarian cancers was associated with improved 
progression-free survival (PFS) and OS.(2) The accumulation of CD8+ TILs, but not CD4+ TILs, 
was shown to predict improved OS, suggesting a role for CD8+ T-cells in tumor control. It is now 
clear that TILs isolated from ovarian cancers can recognize autologous tumor and known tumor 
antigens in vitro,(3-7) can exhibit tumor-specific cytolytic activity ex vivo(8, 9) and are oligoclonal 
in composition.(10, 11) Thus, naturally arising T lymphocytes with anti-tumor potential exist in 
patients with EOC and underscore the potential for immunotherapy to affect the natural course of 
Mullerian duct carcinomas in order to improve patient outcome. 
 
Until recently, the immuno-biology of spontaneous tumor-reactive T-cells in ovarian cancer was 
not well-defined, largely due to the difficulty in identification and interrogation of responses. 
Recently, our research elucidated CD137 (4-1BB), an activation induced TNF receptor family 
member, as a biomarker for bona fide naturally-occurring tumor-reactive T-cells in EOC.(12)  
CD137+ TILs, but not CD137- TILs, demonstrated HLA-dependent IFN-γ secretion in response 
to autologous tumor stimulation and were capable of controlling EOC outgrowth in vivo. These 
results have enabled rapid identification of tumor-reactive T-cells in this disease. We have now 
validated the existence of CD137+ TILs in ovarian cancer samples via analytical IHC, allowing 
for the quantification of tumor-reactive TILs in biopsied tumor specimens. Our results ascribe a 
previously unknown role for CD137 in the immuno-biology of cancer. 
 
On the other hand, solid tumors may successfully evade immune attack by blocking effector T-
cell trafficking into tumor islets and inhibiting effector T-cell activation. There are two important 
parallel mechanisms of tumor induced cell mediated immunologic tolerance in ovarian cancer 

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which may operate in a complementary fashion and represent candidate therapeutic targets to 
reverse spontaneous T-cell mediated anti-tumor immunity. First, in general, activation of T-cells 
requires binding of the T-cell receptor (TCR) to antigen in association with major 
histocompatibility (MHC; HLA) molecules, plus co-stimulation by antigen-presenting cells 
(APCs).(13) Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative regulatory 
homologue of CD28 found on activated T-cells and, by competing with CD28 for binding to CD86 
and CD80 on the APC, functions as a checkpoint to prevent auto-immunity. CTLA-4 is also 
expressed ubiquitously on a naturally-occurring subpopulation of CD4+ regulatory T-cells (Treg) 
constitutively expressing FOXP3 and CD25 (the IL-2 receptor-α chain) and thought to inhibit 
autoimmune pathology, mediate transplantation tolerance, impede anti-tumor immunity in 
vivo.(14)  The paradigm of Treg-mediated immunosuppression in human cancer was originally 
defined in EOC where it was shown that human tumor-infiltrating Treg cells suppressed tumor-
specific T-cell immunity and contributed to growth of human tumors in vivo(15). We therefore 
hypothesize that those immune therapies that enhance CD8+ T-cell accumulation and activity 
while reducing the population of Treg cells will demonstrate anti-tumor activity.  
 
A second mechanism involves signaling through the negative regulatory co-stimulatory T-cell 
receptor, human programmed death-1 (PD-1, CD279)(16, 17).  PD-1 is highly expressed on 
activated T-cells. The principal ligands for PD-1 are PD-L1 (B7-H1, CD274),(17, 18) expressed 
on tumor cells, antigen-presenting cells and dendritic cells and PD-L2 (B7-DC, CD273),(19, 20) 
commonly expressed on endothelial cells. Disruption of PD-1/PD-L1 interaction is a rational 
strategy for immunotherapy in patients with advanced EOC.  Nivolumab is a humanized 
monoclonal antibody binding to PD-1 and blocking the interaction between PD-1 and its ligands, 
thus inhibiting PD-1 signal transduction in activated T-cells. A phase I dose-finding trial involving 
296 patients with multiple non-gynecologic tumors response in 42 patients with pretreatment 
tumor specimens was associated with tumor expression of PD-L1 by IHC analysis, with no 
responses in 17 patients bearing PD-L1 (-) tumors and 9 (36%) responses in 25 patients with PD-
L1 (+) tumors. This provides the rationale for the study of both PD-L1 and PD-1 expression as 
prognostic biomarkers of response. 
 
Still, other markers have shown prognostic value in ovarian cancer. In particular, markers of T 
cell activation (e.g. CD45RO, TIA-1), B cells (CD20), MHC (HLA class I and II), and 
macrophages (CD68) have shown prognostic value (21) but there role as biomarkers of response 
to therapy are unknown. 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 minimally 
both memory helper and activated effector cells would be needed to sustain long-term responses. 
Accordingly, we have place emphasis on understanding the relationships of the tumor, cellular 
infiltrate, and immunologic milieu surrounding each tumor in the context of immune checkpoint 
inhibition. 
B. Laboratory Testing Procedures 
For exploratory TIL IHC biomarker studies, standard operating procedures (SOPs) have been 
produced or are under validation by the Pathology Core Laboratory in Penn’s Department of 
Pathology and Laboratory Medicine. If required, detailed SOPs will be provided at the time of 
specimen distribution and analysis. 
 
Briefly, we anticipate up to 96 pre-treatment tumor specimens to be available for study. IHC will 

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be conducted using FFPE tumors collected at the time of surgical resection or from biopsy. After 
heat-induced antigen retrieval (Bond ER2, 20 minutes), tumor slides will be stained with 
antibody on a Leica Bond III automated staining system using Bond Polymer Refine Detection 
(Leica Microsystems AR9800). Intensity of staining will be scored on a 0-3+ scale, with both the 
percent tumor cells or macrophages staining positive and the cellular pattern (membrane versus 
cytoplasm) analyzed by two GYN pathologists previously trained in pathologic techniques. Each 
reader will be blinded to patient information and provide a pathologic grade from 0-3+ 
depending on the level of staining. Furthermore, analyzers will count the number of positive 
staining cells per section. Each pathologic grade and number of positive cells will be determined 
for the both the stroma and the tumors. 
 
Collectively, we will explore the prognostic and future therapy implications of measuring 
markers with roles in immune function and activity – e.g., PD-1, PD-L1, CTLA-4, CD3, CD4, 
CD8, FOXP3, CD45RO, TAI-1, CD137, HLA class I and Class II, CD68, and indoleamine-2,3-
dioxygenase (IDO). Other immune checkpoints, such as LAG-3 and TIM-3, may serve as 
additional immune inhibitory mechanisms, which may dampen the overall immune response. As 
such, FFPE will be evaluated for the presence of TILs and immune markers including CD16, 
OX40, GITR, CD40, LAG3, TIM3, B7-H3, B7-H4 and VISTA. 
C. References 
1. L. Zhang et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. 
The New England journal of medicine 348, 203 (Jan 16, 2003). 
2. E. Sato et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high 
CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc 
Natl Acad Sci U S A 102, 18538 (Dec 20, 2005). 
3. R. D. Dadmarz et al., Tumor-infiltrating lymphocytes from human ovarian cancer patients 
recognize autologous tumor in an MHC class II-restricted fashion. Cancer J Sci Am 2, 263 
(Sep-Oct, 1996). 
4. B. Fisk, T. L. Blevins, J. T. Wharton, C. G. Ioannides, Identification of an immunodominant 
peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T 
lymphocyte lines. J Exp Med 181, 2109 (Jun 1, 1995). 
5. S. Kooi, R. S. Freedman, J. Rodriguez-Villanueva, C. D. Platsoucas, Cytokine production by 
T-cell lines derived from tumor-infiltrating lymphocytes from patients with ovarian 
carcinoma: tumor-specific immune responses and inhibition of antigen-independent cytokine 
production by ovarian tumor cells. Lymphokine Cytokine Res 12, 429 (Dec, 1993). 
6. G. E. Peoples et al., Ovarian cancer-associated lymphocyte recognition of folate binding 
protein peptides. Ann Surg Oncol 5, 743 (Dec, 1998). 
7. G. E. Peoples et al., Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize 
the same HER2/neu-derived peptide. Proc Natl Acad Sci U S A 92, 432 (Jan 17, 1995). 
8. G. E. Peoples, D. D. Schoof, J. V. Andrews, P. S. Goedegebuure, T. J. Eberlein, T-cell 
recognition of ovarian cancer. Surgery 114, 227 (Aug, 1993). 
9. A. D. Santin et al., Induction of ovarian tumor-specific CD8+ cytotoxic T lymphocytes by 
acid-eluted peptide-pulsed autologous dendritic cells. Obstet Gynecol 96, 422 (Sep, 2000). 
10. E. Halapi et al., Restricted T cell receptor V-beta and J-beta usage in T cells from 
interleukin-2-cultured lymphocytes of ovarian and renal carcinomas. Cancer Immunol 
Immunother 36, 191 (1993). 
11. K. Hayashi et al., Clonal expansion of T cells that are specific for autologous ovarian tumor 

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among tumor-infiltrating T cells in humans. Gynecol Oncol 74, 86 (Jul, 1999). 
12. Q. Ye et al., CD137 accurately identifies and enriches for naturally-occurring tumor-reactive 
T cells in tumor. Clin Cancer Res,  (Sep 17, 2013). 
13. B. W. Tse, A. Collins, M. K. Oehler, A. Zippelius, V. A. Heinzelmann-Schwarz, Antibody-
based immunotherapy for ovarian cancer: where are we at? Ann Oncol,  (Nov 26, 2013). 
14. K. Wing et al., CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271 
(Oct 10, 2008). 
15. T. J. Curiel et al., Specific recruitment of regulatory T cells in ovarian carcinoma fosters 
immune privilege and predicts reduced survival. Nat Med 10, 942 (Sep, 2004). 
16. J. M. Chemnitz, R. V. Parry, K. E. Nichols, C. H. June, J. L. Riley, SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon 
primary human T cell stimulation, but only receptor ligation prevents T cell activation. J 
Immunol 173, 945 (Jul 15, 2004). 
17. G. J. Freeman et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 
family member leads to negative regulation of lymphocyte activation. The Journal of 
experimental medicine 192, 1027 (Oct 2, 2000). 
18. H. Dong, G. Zhu, K. Tamada, L. Chen, B7-H1, a third member of the B7 family, co-
stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5, 1365 (Dec, 1999). 
19. S. Y. Tseng et al., B7-DC, a new dendritic cell molecule with potent costimulatory properties 
for T cells. The Journal of experimental medicine 193, 839 (Apr 2, 2001). 
20. Y. Latchman et al., PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat 
Immunol 2, 261 (Mar, 2001). 
21. K. Milne et al., Systematic analysis of immune infiltrates in high-grade serous ovarian cancer 
reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE 4, e6412 (2009). 
 
III. Identification of genetic determinants of response (09/07/2018) 
A. Rationale 
Studies in other cancers have identified the overall tumor mutational burden (TMB) [4], overall 
HLA diversity of the host [5], and presence of certain genomic alterations [10, 12, 13] to be 
associated with response to PD-1 blockade. To study these parameters as predictors of response 
in EOC, DNA will be isolated from archival tissue and matched blood and subjected to whole 
exome sequencing (WES) using Illumina HiSeq sequencing.  
B. Laboratory Testing Procedures 
1. Pre-treatment FFPE tumor will be processed for DNA isolation and confirmation of 
concentration and purity by OD 260/280. 
2. Matched DNA extracted from peripheral blood will be used for matched normal DNA for 
whole exome sequencing and HLA typing (ATHLATES 
(http://www.broadinstitute.org/scientific-community/science/projects/viral-
genomics/athlates) [2].  
3. WES of tumor and matched normal DNA will be performed using the SureSelect Human All 
Exon 50MB kit (Agilent) for exon capture and sequencing on the HiSeq 2000 platform 
(Illumina) to a goal of 150X coverage. FFPE samples will be sequenced by the commercial 
sequencing facility of the Broad Institute (Broad Institute, Genomics Platform, Cambridge, 
MA). Raw FASTQ files will be generated for subsequent analysis at MSKCC.  
4. Raw sequencing data are mapped to the human reference genome (hg37). Alignment, base-
quality score recalibration, duplicate-read removal, and exclusion of germline variants will 

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be performed using the Genome Analysis Toolkit (GATK) [3]. Known single nucleotide 
polymorphisms (SNPs) will be eliminated [4-6], keeping only novel mutations and those in 
COSMIC. Mutations will be annotated using SnpEffect [7].  
5. Mutations will be analyzed using four callers: Somatic Sniper [8], VarScan [9], Strelka [10] 
and MuTect [11], then filtered by allelic frequency of  each alteration in tumor (>10%) and 
normal (<3%), depth of coverage (≥7X) and call quality and considered positive if called by 
≥2 callers.  All calls made by only one caller will be manually reviewed using IGV [12]. 
6. To assess putative tumor neoantigens, exonic stretches containing each non-synonymous 
mutation are used to generate pairs of 17 amino acid strings: one with the mutation and 
onecorresponding to the wild-type sequence. A “sliding window” approach is then used to 
identify the nonamer within each mutant 17-mer with maximal binding affinity to any 
patient-specific MHC class I allele using NetMHCpan [13]. The binding affinity of each 
mutated and corresponding WT nonamer will be examined with patient-specific MHC I 
alleles.   
7. Presence or absence of putative neoantigens will be further correlated with PFS by using 
Log-Rank test.  
 
IV. T Cell Receptor (TCR) repertoires 
A. Rationale  (05/22/2017) (09/07/2018) 
Since Cancer Testes (CT) antigens may not be present in all patients and may not be the 
immunodominant antigens that will determine tumor sensitivity to the immune system, the 
analysis of overall changes in T cell receptor repertoires during therapy may help to determine 
whether certain dominant T cell clones emerge or persist in response to therapy. Cha et al. 
reported that maintenance of specific T cell clonotypes in blood of patients with advanced 
melanoma treated with ipilimumab was associated with improved survival [14]. Studies of 
immune checkpoint blockade in other cancers have demonstrated that high intratumoral TCR 
clonality prior to treatment was associated with clinical benefit [7, 9]. In addition, those patients 
with low baseline peripheral blood TCR clonality tended to have better progression free and 
overall survival, along with a more pronounced expansion of tumor-associated TCR clones in the 
peripheral blood after the initiation of therapy. To assess whether baseline TCR diversity as well 
as dynamic changes in TCR diversity could predict clinical benefit, TCR repertoires will be 
assessed in archival tumor samples. Similarly, TCR repertoires will be assessed in the peripheral 
blood at baseline, and 6 and 12 weeks post-therapy initiation. DNA will be extracted from 
tumors and peripheral blood using Qiagen kits and will be sent for deep sequencing of CDR3 
regions to Adaptive Biotechnologies. Rearranged TCRbeta CDR3 sequences will be amplified 
and sequenced using Adaptive Biotechnologies’ immunoSEQ platform. To assess whether 
baseline TCR diversity as well as dynamic changes in TCR diversity could predict clinical 
benefit, TCR repertoires will be assessed in archival  tumor samples. Similarly, TCR repertoires 
will be assessed in the peripheral blood at baseline, and 6 and 12 weeks post-therapy initiation.   
B. Laboratory Testing Procedures 
1. DNA will be isolated from FFPE tumor using the Qiagen QIAamp DNA FFPE Tissue kit.  
DNA will be isolated from whole blood by the NRG BB-Columbus. 
2. Isolated DNA will be tested for concentration and purity by spectrophotometry with OD 
measurement at 260 and 280nm. 
3. Per guidelines for the immunoSEQ Assay, 7-8ug of genomic DNA will be shipped to 
Adaptive Biotechnologies for deep level sequencing.  

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4. The information derived from these studies will be used to determine the relative T cell 
density, clonality, and clonal overlap in FFPE tumor obtained pre-treatment. Based on prior 
experience, for tumor and blood T cell repertoire analyses, rare clonotypes (bottom 5%) will 
be avoided. PFS will be correlated with increase in antigen-specific immune responses and 
with persistence or increase in the number of dominant TCR clones and the degree of 
increase in the dominant TCR clones. Each of the parameters will be treated as a continuous 
variable. Relative change in each biomarker from pre-treatment to 6 and 12 weeks will be 
calculated.  
 
V. Transcriptomic analysis of tumor microenvironment (09/07/2018) 
A. Rationale 
Prior studies of gene expression in epithelial ovarian cancer revealed immune transcriptional 
subtype to be associated with improved prognosis. Studies from different cancer types treated 
with immune checkpoint blockade have identified type I and type II IFN signatures to be 
correlated with clinical benefit. Finally, transcriptional signatures indicative of activation of 
specific tumor driver pathways, such as Myc and beta-catenin have been associated with 
immunotherapy resistance. We will use transcriptional analysis of the tumors to analyze several 
parameters. Using bioinformatic deconvolution (e.g. CIBERSORT), predominance of specific 
immune cell subtypes will be calculated in each sample. In addition, we will focus on the 
expression of genes related to cytotoxic T cell function, as well as the known genes related to 
immune inhibition, such as immune checkpoints (e.g. PD-1/PD-L1, LAG-3, VISTA) and 
indoleamine 2,3-dioxygenase (IDO). We will also characterize the expression of SWI/SNF 
components to establish correlation with data generated by WES. Finally, we will analyze the 
expression of putative antigenic targets recognized by the immune system. These include the 
known cancer germline antigens, putative neoantigens identified by WES, and endogenous 
retroviral sequences (ERVs), which have been previously demonstrated to guide tumor immune 
recognition through activation of type I IFN pathway [11, 29]. Expression of these genes will be 
correlated with T cell infiltration and type I and type II IFN signatures.  
 
B. Laboratory testing procedures 
RNA extracted from the archival tissue will undergo quality control using Agilent RNA pico 
chip, processed for sequencing using Illumina Tru-Seq Stranded RNA kit, followed by 
amplification, hybrid capture, and Illumina sequencing. If FFPE RNA does not meet quality 
controls for RNAseq, alternative methods for transcriptome analysis will be utilized. These 
include Clariom D microarray (Thermo Fisher) and targeted RT-PCR panels (available from 
HTG or Nanostring) focusing on immune-related gene expression.  
 
VI. Peripheral Blood Immune Transcriptional Profiling 
A. Rationale 
Peripheral blood biomarkers have been previously reported to be associated with outcomes of 
immunotherapy. The MSKCC research group has recently demonstrated that high percentages of 
peripheral blood myeloid derived suppressor cells (MDSC) have been associated with poor 
prognosis and poor response to ipilimumab in metastatic melanoma [16]. In addition, in studies 
performed by our research group and others, clinical benefit from CTLA-4 blockade was shown 
to be associated with an increase in absolute lymphocyte counts and with sustained upregulation 
of the co-stimulatory molecule inducible costimulator (ICOS) on the surface of T cells [17, 18]. 

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Increases in T cells expressing HLA-DR, ICOS, and ki67 was similarly observed in patients with 
malignant melanoma treated with ipilimumab/nivolumab combination [19]. Emerging from these 
data, in animal models, targeting of ICOS in combination with CTLA-4 blockade resulted in 
significant enhancement in therapeutic efficacy [20].  
 
To gain a broad understanding of the immune changes happening in peripheral blood in response 
to therapy and to extend the peripheral blood analyses to more sites, transcriptional profiling of 
the peripheral blood will be performed by the Nanostring platform using the nCounter 
PanCancer Immune Profiling Panel, which consists of 770 genes related to angiogenesis, 
inflammation, and innate and adaptive immune response.  
B. Laboratory Testing Procedures 
1. Peripheral blood buffy coats will be isolated, frozen on site, and shipped to NRG BB-
Columbus. 
2. One aliquot of pre-treatment and 6 and 12 week buffy coats will be batch shipped to Dr. 
Dmitriy Zamarin (MSKCC). 
3. RNA isolation will be performed using Qiagen RNeasy kit. 
4. Isolated RNA will be tested for concentration and purity by spectrophotometry with OD 
measurement at 260 and 280nm. 
5. RNA will be analyzed on the Nanostring nCounter platform at MSKCC using the PanCancer 
Immune Profiling Panel. 
6. By using unsupervised clustering, associations between specific gene signatures present at 
baseline and on treatment with PFS will be determined. For the genes that demonstrate the 
most significant changes, in univariate analyses, the expression of individual selected gene 
will be treated as a continuous variable and will be correlated with PFS by using minimal p 
value approach. 
 
VII. Tumor-Associated Antigen (TAA) Serologic Responses 
A. Rationale 
Expression of cancer-testis (CT) antigens in a large percentage of gynecologic malignancies has 
been reported in multiple studies. Monitoring for early responses to CT antigens and TAA such 
as NY-ESO1, MAGE 4, SOX2, and p53 may help to identify the patients that are more likely to 
derive benefit from therapy. Serologic responses to the antigens above will be assessed by 
ELISA in pre-treatment blood, as well as the blood collected at 6- and 12 weeks after starting 
study treatment. 
B. Laboratory Testing Procedures 
1. Human serum will be isolated, frozen on site, and shipped to NRG BB-Columbus. 
2. Aliquots of serum will be batch shipped to Dr. Dmitriy Zamarin (MSKCC) for analysis. 
3. Validated ELISAs using diluted sera (1:100, 1:200, 1:400, and 1:800) and 30ng of 
recombinant antigen proteins will be used. Recombinant proteins have been purchased 
commercially and each lot is tested with specific antibody to ensure reproducibility. 
4. For analysis, concentration of antibody to each antigen will be treated as a continuous 
variable. Relative change in each biomarker from pre- to post-treatment at 6 and 12 weeks 
will be calculated. Univariate analyses for each biomarker using a minimum p value 
approach will be used to calculate an optimal cutoff value, using PFS as the outcome 
variable. 
 

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VIII. References 
1. Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N 
Engl J Med, 2014. 371(23): p. 2189-99. 
2. Liu, C., et al., ATHLATES: accurate typing of human leukocyte antigen through exome 
sequencing. Nucleic Acids Res, 2013. 41(14): p. e142. 
3. DePristo, M.A., et al., A framework for variation discovery and genotyping using next-
generation DNA sequencing data. Nat Genet, 2011. 43(5): p. 491-8. 
4. Sherry, S.T., M. Ward, and K. Sirotkin, dbSNP-database for single nucleotide 
polymorphisms and other classes of minor genetic variation. Genome Res, 1999. 9(8): p. 
677-9. 
5. Server, E.V., NHLBI GO Exome Sequencing Project (ESP). 
http://evs.qs.washington.edu/EVS   
6. Via, M., C. Gignoux, and E.G. Burchard, The 1000 Genomes Project: new opportunities for 
research and social challenges. Genome Med, 2010. 2(1): p. 3. 
7. De Baets, G., et al., SNPeffect 4.0: on-line prediction of molecular and structural effects of 
protein-coding variants. Nucleic Acids Res, 2012. 40 (Database issue): p. D935-9. 
8. Larson, D.E., et al., SomaticSniper: identification of somatic point mutations in whole 
genome sequencing data. Bioinformatics, 2012. 28(3): p. 311-7. 
9. Koboldt, D.C., et al., VarScan 2: somatic mutation and copy number alteration discovery in 
cancer by exome sequencing. Genome Res, 2012. 22(3): p. 568-76. 
10. Saunders, C.T., et al., Strelka: accurate somatic small-variant calling from sequenced tumor-
normal sample pairs. Bioinformatics, 2012. 28(14): p. 1811-7. 
11. Cibulskis, K., et al., Sensitive detection of somatic point mutations in impure and 
heterogeneous cancer samples. Nat Biotechnol, 2013. 31(3): p. 213-9. 
12. Robinson, J.T., et al., Integrative genomics viewer. Nat Biotechnol, 2011. 29(1): p. 24-6. 
13. Nielsen, M., et al., NetMHCpan, a method for quantitative predictions of peptide binding to 
any HLA-A and -B locus protein of known sequence. PLoS One, 2007. 2(8): p. e796. 
14. Cha, E., et al., Improved survival with T cell clonotype stability after anti-CTLA-4 treatment 
in cancer patients. Science translational medicine, 2014. 6(238): p. 238ra70. 
15. Page, D.B., et al., T-cell receptor (TCR) DNA deep sequencing to evaluate clonality of 
tumor-infiltrating lymphocytes (TILs) in early-stage breast cancer patients (pts) receiving 
preoperative cryoablation (cryo) and/or ipilimumab (ipi). Journal of Clinical Oncology, 2014. 
32(5s): p. (suppl; abstr 3021). 
16. Kitano, S., et al., Computational algorithm-driven evaluation of monocytic myeloid-derived 
suppressor cell frequency for prediction of clinical outcomes. Cancer immunology research, 
2014. 2(8): p. 812-21. 
17. Carthon, B.C., et al., Preoperative CTLA-4 blockade: tolerability and immune monitoring in 
the setting of a presurgical clinical trial. Clinical cancer research : an official journal of the 
American Association for Cancer Research, 2010. 16(10): p. 2861-71. 
18. Ku, G.Y., et al., Single-institution experience with ipilimumab in advanced melanoma 
patients in the compassionate use setting: lymphocyte count after 2 doses correlates with 
survival. Cancer, 2010. 116(7): p. 1767-75. 
19. Callahan, M., Horak, CE, Curran, MA, Hollman, T, Schaer, DA, Yuan, J, Lesokhin, AM, 
Kitano, S, Hong, Q, Ariyan, CE, Busam, KJ, Feely, W, Jure-Kunkel, M, Grosso, J, Simon, 
JS, Korman, AJ, Wigginton, JM, Gupta, AK, Sznol, M, Wolchok, JD., Peripheral and tumor 

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immune correlates in patients with advanced melanoma treated with combination nivolumab 
(anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. 2013 ASCO Annual Meeting, 2013. 
20. Fan, X., et al., Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 
blockade in cancer immunotherapy. The Journal of experimental medicine, 2014. 211(4): p. 
715-25. 
 
 

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APPENDIX VI—STUDY PARTICIPANT WALLET CARD (07/31/2017) 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agents 
Nivolumab and Ipilimumab.  This clinical trial is sponsored by the NCI.   
Nivolumab and Ipilimumab may interact with other medications.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
  
Before prescribing new medicines, your regular prescribers should go 
to http://medicine.iupui.edu/clinpharm/ddis/ for a list of drugs to 
avoid, or contact your study doctor.   
 
Your study doctor’s name is _____________________________  
and can be contacted at _________________________________.