Clinical trial NCT03420521
Conditions: Neuroendocrine Tumors Carcinoid Tumor
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2018-03-09; Completion date: 2021-11-24
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm open-label design study looking at Nivolumab plus Ipilimumab in patients with Advanced Neuroendocrine Tumors. Patients will be dosed Nivolumab 240mg IV over 60 minutes every 2 weeks (Q2W) and Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W). One cycle will include 3 doses of Nivolumab and 1 dose of Ipilimumab. The objective of this study is to evaluate the objective response rate of combination Nivolumab and Ipilimumab in advanced, well-differentiated neuroendocrine tumors. Durability of response, and progression free survival (PFS) will also be described.

Detailed description:
Subjects with progressive, non-functional advanced or metastatic thoracic, GI or pancreatic well-differentiated neuroendocrine tumors (NET) have few treatment options. The only FDA approved treatment regimen offers little response potential. In currently unpublished data with inhibitory immune checkpoint agents, patients with NET have shown promising clinical benefit. This therapy offers a novel approach to potentially provide long term benefit, but must be further explored. The safety profile of nivolumab plus ipilimumab is characterized by immune-related toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies (Nivolumab, Ipilimumab Investigator's Brochures). The frequencies and intensities of these events in the combination are variable and depend on the specific doses and schedule used. In the dosing schedules selected, these events were mostly low grade and manageable with the use of corticosteroids. Nivolumab and ipilimumab combination therapy has shown improved efficacy over either agent alone in melanoma. Rationale for Single Arm Design This study will use a single arm open-label design. The objective of this study is to evaluate the objective response rate of combination nivolumab and ipilimumab in advanced, well-differentiated neuroendocrine tumors. Durability of response, and PFS will also be described.

Arms: arm 1: Nivolumab 240 mg IV over 60 minutes every 2 weeks (Q2W) Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W)
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: 240mg IV over 60 minutes Q2W intervention 2: 1mg/kg IV over 30 minutes Q6W

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
J17156 / Version 6.4 / November 23, 2021  
Study Title: An Open-Label, Single Arm Phase II Study of Nivolumab in Combination with 
Ipilimumab in Subjects with Advanced Neuroendocrine Tumors 
 
 
Johns Hopkins Protocol #:  
J17156 / IRB00151698 
 
BMS Protocol #: 
CA209-9JL 
 
 
Principal Investigator: 
Christine L. Hann, MD, PhD 
 
Associate Professor of Oncology 
Johns Hopkins University School of Medicine 
 
201 N. Broadway, Room 8123 
 
Baltimore, MD 21287 
 
Phone: (410) 502-0678 
 
Fax: (410) 614-9334 
 
Email: chann1@jhmi.edu 
 
  
 
Lead UAD Study Coordinator  
& Lead Regulatory:  
Amanda Barnes, BS, CCRP 
 
Clinical Research Program Specialist 
 
201 N. Broadway, Suite 8120 
 
Baltimore, MD 21287 
 
Phone: (410) 502-8737 
 
Email: abarne13@jhmi.edu  
 
Lead UAD Research Nurse:  
Joanne Riemer, RN 
 
CO Sr. Research Nurse III 
 
201 N. Broadway, Suite 8120  
 
Phone: (443) 287-4114 
 
Email: Jriemer3@jhmi.edu 
 
 
IND #:  136301 
 
IND Sponsor:  Julie R. Brahmer, MD 
 
 
Supplied Agents:  
 
Nivolumab (BMS-936558) 
Ipilimumab (NSC #732442) 
 
Protocol Type / Version # / Version Date:   
Original/ Version 1/ December 22, 2016 
 
 
 
 
 
Revision/ Version 2/ March 31, 2017
 
 
 
 
 
Revision/ Version 3/July 28, 2017 


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Revision/ Version 3.1/August 14, 2017 
Revision/ Version 3.2/September 1, 2017 
Revision/ Version 3.3/November 17, 2017 
Revision/ Version 4.0/ April 26, 2019 
Revision/ Version 4.1/ July 10, 2019 
Revision/ Version 4.2/ July 16, 2019 
Revision/ Version 4.3/ July 24, 2019 
Revision/ Version 5.0/ September 25, 2019 
Revision/ Version 6.0/ March 5, 2020 
Revision/ Version 6.1/ April 17, 2020 
Revision/ Version 6.2/ July 27, 2020 
Revision/ Version 6.3/ May 25, 2021 
Revision/ Version 6.4/ November 23, 2021 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
Objectives ............................................................................................................................6 
1.1 
Primary Objective ....................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
1.4 
Study Design ............................................................................................................6 
STUDY SCHEMA...........................................................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Neuroendocrine tumors (NETs) ...............................................................................7 
2.2 
PD-L1 Expression in NETs .....................................................................................8 
2.3 
Nivolumab and Ipilimumab .....................................................................................9 
2.4 
Study Rationale ......................................................................................................10 
3. 
PATIENT SELECTION ..................................................................................................112 
 
Eligibility Criteria ..................................................................................................11 
 
Exclusion Criteria ................................................................................................123 
3.3 
Inclusion of Women and Minorities ....................................................................145 
 
4. 
TREATMENT PLAN ........................................................................................................14 
4.1 
Agent Administration ...........................................................................................146 
4.2 
General Concomitant Medication and Supportive Care Guidelines ......................15 
4.3 
Dosing Criteria .......................................................................................................18 
4.4 
Definition of an Overdose for this Protocol ...........................................................18 
4.5 
Contraception, Use in Pregnancy, Use in Nursing ................................................18 
4.6 
Duration of Therapy ...............................................................................................18 
4.7 
Off Study/Safety Follow-up Visit ..........................................................................18 
4.8 
Duration of Follow Up ...........................................................................................18 
4.9 
Criteria for Removal from Study Treatment ..........................................................18 
4.10 
Treatment Beyond Progression ..............................................................................19 
4.11 
Duration of Study ...................................................................................................19 
5. 
DOSING REDUCTIONS/DOSE DELAYS ......................................................................19 
5.1 
Dose Reductions ....................................................................................................19 
5.2 
Dosing Delays ........................................................................................................20 
5.3 
Treatment Beyond Progression ..............................................................................22 
5.4 
Management Algorithms for Immuno-Oncology Agents ......................................24 
5.5 
Management of Nivolumab or Ipilimumab Infusion Reactions ............................24 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................25 
6.1 
Definitions..............................................................................................................26 
6.2 
Relationship ...........................................................................................................27 
6.3 
Expectedness ..........................................................................................................28 
6.4 
Handling of Expedited Safety Reports ..................................................................28 


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6.5 
Reporting................................................................................................................29 
6.6 
Adverse Events of Interest ...................................................................................301 
7. 
PHARMACEUTICAL INFORMATION ..........................................................................32 
7.1 
Product Information Table .....................................................................................32 
7.2 
Nivolumab..............................................................................................................32 
7.3 
Ipilimumab .............................................................................................................35 
8. 
Correlative Studies collection and handling ..................................................................37 
8.1 
Tumor Tissue Studies ............................................................................................37 
8.2 
Serum and Plasma Marker Studies ........................................................................39 
9. 
STUDY CALENDAR .....................................................................................................401 
10. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................42 
10.1 
Data Management ..................................................................................................42 
10.2 
Safety Meetings .....................................................................................................42 
10.3 
Monitoring .............................................................................................................43 
11. 
MEASUREMENT OF EFFECT........................................................................................43 
 
Antitumor Effect ....................................................................................................43 
12. 
STATISTICAL CONSIDERATIONS ...............................................................................48 
12.1 
Study Design/Endpoints.........................................................................................48 
12.2 
Sample Size/Accrual Rate ......................................................................................48 
12.3 
Analysis and Summary of Endpoints .....................................................................48 
12.4 
Efficacy Analyses ..................................................................................................50 
APPENDIX 1 ECOG PERFORMANCE STATUS .......................................................................54 
APPENDIX 2 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ............................................................................................................................55 
 
 
 
 
 
 


 
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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To determine the objective response rate (ORR) of advanced, progressive, well-
differentiated nonfunctional NET of the lung, pancreas or gastrointestinal (GI) tract 
treated with nivolumab plus ipilimumab. 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess safety and tolerability of nivolumab plus ipilimumab by quantification of 
treatment dose interruptions and characterization of toxicities of the combination of 
nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional 
NET of the lung, pancreas or GI tract. 
 
1.2.2 To assess efficacy via progression free survival (PFS) at 6 months, 12 and 24 months of 
the combination of nivolumab and ipilimumab in subjects with advanced well-
differentiated nonfunctional NET of the lung, pancreas or GI tract. 
 
1.2.3 To further assess efficacy via median PFS, disease control rate (DCR), duration of 
response (DOR) and overall survival (OS) of the combination of nivolumab and 
ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the 
lung, pancreas or GI tract. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To assess immunogenicity, response characteristics, and predictors of toxicity of 
nivolumab in combination with ipilimumab by evaluating peripheral blood mononuclear 
cells (PBMCs), sera, plasma and tumor samples collected in treated subjects. 
 
1.4 
Study Design 
The study population will include subjects with advanced thoracic, GI and pancreatic 
neuroendocrine tumors. We propose an open-label, single arm phase 2 study of 
nivolumab in combination with ipilimumab. All subjects will be assigned to receive 
Nivolumab: 240 mg IV q2 weeks plus ipilimumab: 1 mg/kg IV q6 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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STUDY SCHEMA 
 
 
 
2. BACKGROUND 
 
2.1 
Neuroendocrine tumors (NETs) 
 
Well-differentiated neuroendocrine tumors (NETs), often referred to as carcinoid tumors, 
are a heterogeneous group of malignancies originating in neuroendocrine cells throughout 
the body(1).  They are anatomically, functionally and histopathologically distinguished in 
an effort to optimize their care.  Based on population-based registries, about 51% of 
NETs originate in the gastrointestinal (GI) tract , 27% in the lungs and 6% in the 
pancreas(1).   Functional NETs cause carcinoid syndrome, due to hormonal 
hypersecretion.  In the ~25% of patients with functional NETs, symptoms are often 
managed by a somatostatin analogue, such as octreotide or lanreotide.  These medications 
have also been shown to delay tumor progression in advanced GI NETs (2, 3); as such 
they are commonly used in this disease setting, although are not FDA-approved for this 
indication.  Nonfunctional NET (~70%) patients often develop symptoms due to tumor 
growth, such as intestinal obstruction, pain and bleeding for GI NETs, and asthma, 
chronic obstructive pulmonary disease and pneumonia for lung NETs (4-7).  At 
presentation, 5-44% of patients with GI NET and 28% of patients with lung NET have 
advanced disease, and progression is typically associated with poor outcomes. Advanced 
or metastatic NETs, irrespective of function or histopathologic grade, are incurable with 
current treatment regimens.   
 
Recently, everolimus has been FDA approved for the treatment of progressive, well-
differentiated nonfunctional pancreatic, bronchopulmonary and GI NETs [Everolimus 
FDA]. The RADIANT trials were integral to this treatment approval. RADIANT-1 was a 
Phase II trial that evaluated Everolimus in patients with metastatic pancreatic NETs with 
Nivo 240 mg Q2wks + Ipi 1mg/kg Q6wks 
Enrollment by tumor site of origin 
Advanced or metastatic non-functional, well differentiated thoracic, GI or pancreatic NET 
No prior PD-1/PD-L1/CTLA-4 therapy 
ECOG PS 0-1 
Treat until disease progression or unacceptable toxicity 


 
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disease progression after cytotoxic chemotherapy; results revealed median progression 
free survival (mPFS) of 9.7-16.7 months as stratified by prior octreotide therapy (8). 
RADIANT-2 was a Phase III trial that evaluated Everolimus in advanced, non-functional 
NETs of the lung or GI tract which revealed mPFS of 11 months as compared to 3.9 
months in the placebo group (9).  RADIANT-3 was a Phase III trial that evaluated 
Everolimus in advanced, low-grade or intermediate grade pancreatic NET that revealed 
an 11 month mPFS compared to 4.6 months with placebo (10).  RADIANT-4 was a 
Phase III trial that evaluated Everolimus in advanced, non-functional NETs of the lung or 
GI NET that reported an 11 month mPFS compared to a 3.9 month mPFS with placebo 
(11). 
 
Thoracic NETs are histopathologically subdivided into typical carcinoid (TC) and 
atypical carcinoid (AC) tumors(12) and comprise 2.2% of lung cancers diagnosed in the 
US annually (7, 13).  AC is the more common and more aggressive phenotype.  There is 
a paucity of data regarding systemic therapy for advanced thoracic NET disease outside 
of the recently published RADIANT-4, and is based mainly on small retrospective series 
and subgroup analyses of predominant gastrointestinal neuroendocrine tumor clinical 
trials, leading to a lack of definitive data for systemic regimen recommendations outside 
of everolimus placebo (11).  Forde et al., reported on a systematic analysis of thoracic 
NET patients at Johns Hopkins. The response rate to platinum plus etoposide 
chemotherapy for both advanced TC and AC was 23.5% (14). 
 
GI NETs arise in the stomach, intestine, appendix, colon or rectum with an incidence of 
approximately 8000 cases annually in the US(15). The 5-yr OS rates in advanced well 
and moderately-differentiated neuroendocrine tumors range from 14-54% by anatomic 
location.  The PROMID study showed an improvement in time to tumor progression in 
advanced midgut NET patients treated with octretotide LAR (long acting release (2) The 
recent advances of use of Everolimus in the RADIANT series have shown improved 
outcomes in some endpoints, leading to FDA approval, but does not frequently cause a 
response with tumor shrinkage (9, 11). 
 
Pancreatic NETs account for <4% of all pancreatic cancers; about half of them are 
functional, benign tumors.  Non-functional pancreatic NETs are more likely to be 
malignant.  The CLARINET trial showing significant improvement in PFS in pancreatic 
NET patients treated with lanreotide vs. placebo (3).  Based on the results of RADIANT-
1 and RADIANT-3, everolimus is FDA-approved and commonly used in advanced 
pancreatic NET (8, 10).  Sunitinib can also be used in this patient population (16).    
2.2 
PD-L1 Expression in NETs  
PD-L1 staining in gastro-entero-pancreatic (GEP) NETs has been reported in by Kim et 
al.; of 24 foregut GEP-NETs, PD-L1 staining was observed in 21.9%,  was significantly 
associated with high-grade classification and predicted for poorer survival (17). In a 
series of 66 GEP NETs, Pinato et al., reported a lower rate of PD-L1 staining ( 9%) but 
high  PD-L2 (50%) (18). Fan et al., reported high PD-L1 (59%) and PD-1 (51%) staining 
in pulmonary NET tissue compared to cancer-adjacent tissue from 80 cases (19). 
Multivariate analyses revealed that expression of PD-L1 and PD-1 were negatively 
associated with survival time.  


 
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2.3 
Nivolumab and Ipilimumab 
Immunotherapeutic approaches have demonstrated clinical efficacy in several cancer 
types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma 
(RCC), head and neck cancer, bladder and hormone-refractory prostate cancer (20). 
Tumors modulate and evade the host immune response through a number of mechanisms, 
including down regulation of tumor-specific antigen expression and presentation, 
secretion of anti-inflammatory cytokines, and upregulation of inhibitory ligands. T cell 
checkpoint regulators such as CTLA-4 and programmed death-1 (PD-1, CD279) are cell 
surface molecules that, when engaged by their cognate ligands, induce signaling cascades 
down-regulating T cell activation and proliferation.  PD-1 and CTLA-4 are both co-
inhibitory molecules, but evidence suggests that they use distinct mechanisms to limit T 
cell activation.  
CTLA-4 mediated signals are inhibitory to T cell-dependent immune responses (21).  
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen 
expressed on a subset of T cells from human and nonhuman primates. The proposed 
mechanism of action for ipilimumab is interference of the interaction of CTLA-4 with B7 
molecules on APCs, with subsequent blockade of the inhibitory modulation of T-cell 
activation promoted by the CTLA 4/B7 interaction. Ipilimumab was approved by FDA 
for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic 
melanoma. 
Nivolumab  (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 
on activated immune cells and disrupts engagement of the receptor with its ligands PD-
L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals 
and augmenting the host antitumor response. In clinical trials, nivolumab has 
demonstrated activity in several tumor types, including melanoma, renal cell cancer 
(RCC), and NSCLC leading to widespread FDA-approval (22).  
 
2.3.1 Combination treatment with nivolumab and ipilimumab 
Multiple studies in several cancer types have evaluated the safety and efficacy of 
combination on nivolumab and ipilimumab. In both melanoma and non-small cell 
lung cancer (NSCLC) these data show that the combination of nivolumab and 
ipilimumab is well tolerated and associated with promising durable responses. In 
melanoma, CA209004 (MDC1106-04) was a phase Ib study in subjects with 
previously treated advanced melanoma. CA209069 and CA209067, a phase 2 and 
phase 3 studies, respectively, in treatment- naïve subjects with advanced melanoma 
(23, 24). This final study reported significantly improved PFS and ORR with the 
combination of nivolumab and ipilimumab versus ipilimumab alone in previously 
untreated melanoma. The mPFS was 6.9 mos in the nivolumab group compared with 
11.5 mos in the nivolumab-plus-ipilimumab group.  
CA209012, was an open-label, phase 1, multicohort study in treatment-naïve subjects 
with advanced NSCLC. In this study, multiple dosing regimens were explored. The 
final report included 78 patients randomly assigned to: 1) nivolumab 3mg/kg every 2 
weeks plus ipilimumab 1mg/kg every 6 weeks or 2) nivolumab 3mg/kg every 2 weeks 
plus ipilimumab 1mg/kg every 12 weeks (25).  


 
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Grade 3-4 treatment related AEs were reported in 37% and 33% of subjects 
respectively, most commonly increased lipase, pneumonitis and adrenal insufficiency, 
colitis. Confirmed responses were reported in 47% in the ipilimumab 6 week cohort 
and 38% of the ipilimumab 12-week cohort. 
 
2.4 
Study Rationale 
Subjects with progressive, non-functional advanced or metastatic thoracic, GI or 
pancreatic well-differentiated NETs are have few treatment options. The only FDA 
approved treatment regimen offers little response potential. In currently unpublished data 
with inhibitory immune checkpoint agents, patients with NET have shown promising 
clinical benefit. This therapy offers a novel approach to potentially provide long term 
benefit, but must be further explored.  
The safety profile of nivolumab plus ipilimumab is characterized by immune-related 
toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies 
(Nivolumab, Ipilimumab Investigator’s Brochures).   The  frequencies  and  intensities  of  
these  events  in  the  combination  are variable and depend on the specific doses and 
schedule used.  In the dosing schedules selected, these events were mostly low grade and 
manageable with the use of corticosteroids. Nivolumab and ipilimumab combination 
therapy has shown improved efficacy over either agent alone in melanoma. 
 
2.4.1 Rationale for Single Arm Design 
This study will use a single arm open-label design. The objective of this study is to 
evaluate the objective response rate of combination nivolumab and ipilimumab in 
advanced, well-differentiated neuroendocrine tumors. Durability of response, and PFS 
will also be described.  
Response rates to everolimus, the only FDA approved regimen for this patient 
population, are well documented in the RADIANT trials. The ORR to everolimus in 
advanced, progressive low-intermediate grade pancreatic NET was 5% (vs. 2% with 
placebo), and 2% in advanced, progressive well-differentiated nonfunctional lung and 
GI NET (vs. 1% with placebo) (10, 11).  
 
2.4.2  Rationale for Exploratory Correlative Studies 
 
Exploratory correlative studies will be performed to evaluate immune system activation 
and for potential biomarker identification.  The specific studies proposed include: 1) 
assessment of immune cell composition by IHC, gene expression profiling and cytokine 
production within the TME; 2) whole genome or exome sequencing to assess mutational 
load and potentially identify predictors of response or resistance; 3) plasma-based 
markers to correlate with response. 
  
Paired pre-treatment and on treatment core biopsies will be mandatory for patients on 
the part 2 of this study and optional for patients on part 1. Biopsies at time of 
progression will be optional. Blood samples will be collected prior to treatment and 
during treatment as described in the study calendar. 


 
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2.4.2.1 
Tissue studies 
 
Tumor Microenvironment (TME) Analysis 
Quantification, qualification and distribution of immune cell infiltrates may 
correlate to response and clinical outcome. The densities and distribution of 
effector T cells (Teff) including CD8, CD45RO, CXCR3 and CD69+ cells; 
expression of immune suppressive signals including PD-1, PD-L1, PD-L2, 
LAG3, TIM3, and IDO1; immune activation signals including CD137(4-1BB), 
4-1BBL, OX40, OX40L,  CD40, and CD40L  on T cells and macrophages, and 
the expression of T helper cell differentiation markers including Tbet (for Th1), 
GATA3 (for Th2), ROR γ T (for Th17), and Foxp3 (for Treg) have been found to 
be clinically relevant (Lutz et al. 2014).  The balance between Teff and 
regulatory T cell (Treg) function is an area of active study as well.  
 
Quantitative Gene Expression 
Evaluation of the balance between various immune cell types (Th1 vs. Th2; M1 
vs M2; Teff vs. Treg) is imperative to understand the qualitative and quantitative 
effect of dual checkpoint blockade. The expression signatures of certain genes 
already found to be potentially linked to clinical benefit in other tumor types 
should be compared to the gene expression signatures found to correlate with 
response in NET patients. Intra-tumoral cytokine array analysis will also further 
describe the immunogenic tumor microenvironment. 
 
Intratumoral Antigen Specific T cell Response  
Tumor antigen-specific T cells that traffic into the tumor are the most relevant T 
cells to study when evaluating antitumor immune responses.  Both peripheral 
(peripheral blood lymphocytes, (PBL)) and tumor-infiltrating lymphocytes (TIL) 
T-cell receptor (TCR) repertoires will identify T cells that expand following 
treatment. Peripheral and TIL TCR repertoire comparisons will be used to 
identify any T cell clones that are induced or expanded in PBL by combination 
treatment and also enriched in TIL.  This data will be used to determine if T cells 
in PBL and TIL undergo clonal expansion following treatment, and if so, 
whether the T cell clones traffic to the carcinoid TME.    
 
Whole exome sequencing to detect somatic alterations  
Next generation sequencing may be performed to identify of genomic correlates 
of response and resistance. Nonsynonymous missense mutations identified will 
be used to predict mutant peptides and generate a neoantigen signature for each 
tumor using a computational pipeline we have developed. A separate targeted 
capture and sequencing analysis of the TCR will be performed to assess T cell 
clonality 
 
2.4.2.2 
Serum and Plasma Studies:  
Various factors that may impact the immunomodulatory properties and efficacy 
of nivolumab and ipilimumab will be investigated in peripheral blood specimens 


 
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taken from all subjects prior to or during treatment. Data from these 
investigations will be evaluated for associations with response, survival, and/or 
safety (adverse event) data. Plasma samples will be obtained at baseline, on 
treatment and at progression.  
 
Circulating Tumor DNA (ctDNA) 
Non-invasive genomic approaches to determine somatic mutations that detect 
residual disease are being developed at our institution. Cancer-specific genomic 
alterations in circulating cell free DNA (ctDNA) are being evaluated for potential 
to assess ability to predict disease response or progression prior to conventional 
CT imaging. Peripheral tumor-specific mutations found following disease 
progression can be compared to the patient’s genomic tumor profile to evaluate 
for potential matching resistance mutations.  
 
 
3. PATIENT SELECTION 
 
 
Eligibility Criteria  
 
3.1.1 Subjects with histologically confirmed advanced, progressive, well-differentiated 
nonfunctional NET of the pancreas, lung or gastrointestinal (GI) tract per the 8th 
International Association for the Study of Lung Cancer classification (IASLC) or the 
American Joint Committee on Cancer (AJCC) Staging Handbook, 7th edition. 
Progession must be documented over the prior 12 months. 
 
3.1.2 Measurable disease by CT or MRI per RECIST 1.1 criteria (Appendix 3); radiographic 
tumor assessment performed within 28 days before treatment. Target lesions may be 
located in a previously irradiated field if there is documented (radiographic) disease 
progression in that site after the completion of radiation therapy. 
 
3.1.3 Prior therapy, including everolimus, octreotide, surgery, chemoradiation, is all permitted 
after being properly noted. This prior therapy must have been completed at least 28 days 
prior to study enrollment. 
 
3.1.4  Patients with lung NETs must have progressed after at least 1 line of therapy.  Patients 
with GI NETs must have had at least 2 lines of prior therapy.  
 
3.1.5 Subjects are to have tumor tissue sample available at central lab for PD -L1 IHC testing 
during the screening period. Subjects can initiate therapy before the result of IHC 
testing.  
 
3.1.6 (Stage 2 only) Subjects must be willing to undergo 2 sets of core needle biopsies (pre-
treatment and at 6-8 weeks on therapy) if there are lesions amenable to biopsy. Subjects 
without a lesion amendable to biopsy will still be permitted to enroll provided they have 
an archival tumor sample for PD-L1 IHC testing. An optional core biopsy will be 
requested at progression. 
 


 
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3.1.7 ECOG performance status ≤ 1 (see Appendix 1)  
 
3.1.8 Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 
weeks prior to treatment. Subjects with symptomatic tumor lesions at baseline that may 
require palliative radiotherapy within 4 weeks of first treatment are strongly encouraged 
to receive palliative radiotherapy prior to treatment. 
 
3.1.9 Patients must have normal organ and marrow function as defined below: 
-  WBC 
≥1,500/mcL 
-  absolute neutrophil count 
≥1,000/mcL 
-  hemoglobin 
≥ 8.0 g/dL 
-  platelets 
≥75,000/mcL 
-  total bilirubin 
 
≤ 1.5 x institutional ULN (patients with Gilbert’s 
syndrome may have serum bilirubin ≤ 3 x ULN) 
-  AST/ALT 
≤ 3 × institutional ULN (≤ 5 x ULN in the presence 
of liver metastases) 
-  creatinine  
 
≤ 1.5 × institutional ULN or creatinine clearance 
(CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault 
formula below): 
 
Female:  
CrCl = (140 - age in years) x weight in kg x 0.85 
                     72 x serum creatinine in mg/dL 
 
Male:  
CrCl = (140 - age in years) x weight in kg x 1.00  
                      72 x serum creatinine in mg/dL  
 
 
3.1.10 Age ≥18 years of age 
 
3.1.11 Patients must have recovered from adverse events due to prior treatment to ≤ grade 1, 
except for alopecia and sensory neuropathy ≤ grade 2.  
 
3.1.12 Patients must be able to understand and the willingness to sign a written informed 
consent document. 
 
 
Exclusion Criteria 
 
3.2.1 Subjects with poorly differentiated or small cell carcinoma histology 
 
3.2.2 Subjects with disease that is amenable to surgical resection. 
 
3.2.3 Subjects with history of or active symptoms of carcinoid or hormonal syndromes are 
permitted if symptoms are controlled with a somatostatin analog. 
 


 
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3.2.4 Hepatic intra-arterial embolization or peptide receptor radionuclide therapy (PRRT) 
within 4-8 weeks; cryoablation, radiofrequency ablation or trans-arterial 
chemoembolization of hepatic metastases within ≤ 4 weeks of study enrollment 
 
3.2.5 Subjects with symptomatic untreated CNS metastases are excluded.  
 
3.2.5.1 
Subjects are eligible if CNS metastases are asymptomatic or adequately treated and 
subjects are neurologically returned to baseline (except for residual signs or 
symptoms related to the CNS treatment) for at least 2 weeks prior to first 
treatment.  
3.2.5.2 
In addition, subjects must be either off corticosteroids, or on a stable or decreasing 
dose of <10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first 
treatment. 
 
3.2.6 Subjects with carcinomatous meningitis 
 
3.2.7 Subjects must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before first treatment. 
 
3.2.8 Pregnant or breast-feeding women 
 
3.2.9 Women of child-bearing potential, who are biologically able to conceive, and not 
employing two forms of highly effective contraception.  Highly effective contraception 
must be used throughout the trial and up to 8 weeks after the last dose of study drug (e.g. 
male condom with spermicidal; diaphragm with spermicide; intra-uterine device).  
Women of child-bearing potential, defined as sexually mature women who have not 
undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive 
months), must have a negative serum pregnancy test ≤ 14 days prior to starting study 
drug. 
 
3.2.10 Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
 
3.2.11 Other active malignancy requiring concurrent intervention. 
 
3.2.12 Subjects with a  condition  requiring  systemic  treatment  with  either  corticosteroids  
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within  
14 days of first treatment. Inhaled or topical steroids, and adrenal replacement steroid 10 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
 
3.2.13 Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity. 
 


 
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3.2.14 Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
 
3.2.15 Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interferes with the 
interpretation of safety results. 
 
3.2.16 Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways 
 
3.2.17 Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection 
 
3.2.18 History of allergy or hypersensitivity to study drug components 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. TREATMENT PLAN 
 
4.1 
Agent Administration 
 
4.1.1 Study Treatment: all subjects will receive the following: 
 
Table 1: Regimen Description 
REGIMEN DESCRIPTION 
Agent 
Premedication 
Dose 
Route 
Frequency 
Cycle 
Length 
Nivolumab 
No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.5 
240 mg 
IV over 
30 minutes* 
Every 2 
weeks 
6 weeks 
(42 days) 
Ipilimumab 
No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.5 
1 mg/kg 
IV over 
30 minutes* 
Every 6 
weeks 
*Infusion times are approximate (+/- 10 min) and may be adjusted based on subject tolerability.  
 
4.1.2 Cycle length 
One cycle is defined as 42 days. 
 


 
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4.1.3 Dosing 
Nivolumab and ipilimumab will be administered on the same day. Separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. 
The second infusion will always be ipilimumab and will start no sooner than 30 
minutes after completion of the nivolumab infusion. Subjects who require small 
volumes may infuse over < 60 minutes but no less than 20 minutes. 
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% 
Dextrose solution. 
Dosing calculations for ipilimumab should be based on the body weight. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to 
calculate the prior dose, the dose must be recalculated. All doses should be rounded to 
the nearest milligram. There will be no dose modifications allowed. 
Subjects may be dosed with nivolumab no less than 12 days from the previous dose. 
There are no premedications recommended. 
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued 
depending on how well the subject tolerates the treatment. For more details, see 
Section 5.2 (dose delays). 
 
4.2 
General Concomitant Medication and Supportive Care Guidelines 
 
4.2.1 Prohibited and/or Restricted Treatments  
 
4.2.1.1 Systemic immunosuppressive agents are prohibited during the study, unless they 
are utilized to treat an adverse event. Allopurinol to prevent gout flares is allowed. 
 
4.2.1.2 Concurrent administration of any anti-cancer therapies (investigational or 
approved) is also prohibited with the exception of subjects in the survival period of 
the study. This includes somatostatin analogues. 
 
4.2.1.3 Any medicinal herbal preparation unless prescribed by the treating physician. All 
concomitant medications including prescribed medicinal herbal preparations must 
be documented. 
 
4.2.1.4 G-CSF (granulocyte-colony stimulating factor) will be permitted. However, the use 
of these agents is allowed as per their respective label indications/institutional 
guidelines to treat neutropenia that occurs on study. G-CSF must not be used for 
the treatment of cancer or for any primary prophylaxis while on study. 
 
4.2.1.5 Any non-oncology live viral vaccine therapies used for the prevention of infectious 
diseases within 12 weeks prior to study drug is prohibited. The use of the 
inactivated seasonal influenza vaccine will be permitted on study without 
restriction. 
 


 
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4.2.1.6 Alcohol consumption while on study is strongly discouraged due to the potential to 
confound interpretation of hepatotoxic events. 
 
4.2.1.7 Routine use of acetaminophen use is strongly discouraged 
 
4.2.2 Permitted Therapy 
 
4.2.2.1 Regular concomitant use of bisphosphonates and RANK-L inhibitors for 
prevention or reduction of skeletal-related events in patients with bone metastases 
is allowed if initiated prior to first dose of study therapy.  
 
4.2.2.2 Subjects are permitted the use of anti-emetic medications (with the exception of 
dexamethasone and/or other systemically administered steroids) at the treating 
physician’s discretion. 
 
4.2.2.3 Subjects are permitted the use of full-dose anti-coagulation (i.e. warfarin, 
enoxaparin, rivaroxaban, etc.) at the treating physician’s discretion. 
 
4.2.2.4 Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  
 
4.2.2.5 Adrenal replacement steroid doses < 10 mg daily prednisone are permitted.  
 
4.2.2.6 A brief (less than 2 weeks) 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 a contact allergen) is permitted. 
 
4.2.2.7 Palliative local therapy, including palliative radiation therapy- and palliative 
surgical resection, is permitted prior to discontinuation of study treatment for 
subjects who do not have evidence of overall clinical or radiographic progression 
per RECIST 1.1.  
Subjects requiring palliative local therapy should be evaluated for objective 
evidence of disease progression prior to the initiation of such therapy, particularly 
if the most recent tumor assessment was more than 4 weeks prior to the start of 
local therapy. If progression per RECISTv1.1 is identified on any tumor 
assessments prior to the initiation of palliative local therapy, then subjects must 
either discontinue study drug treatment or they must meet criteria to continue 
treatment beyond progression (Section 5.3) in order to resume immunotherapy 
after palliative local therapy. 
The potential for overlapping toxicities with radiotherapy and nivolumab plus 
ipilimumab currently is not known; however, anecdotal data suggests that it is 
tolerable. As concurrent radiotherapy  and nivolumab /ipilimumab have not been 
formally evaluated, in cases where palliative radiotherapy is required for a tumor 
lesion, then nivolumab /ipilimumab should be withheld for at least 1 week before, 
during, and 1 week after radiation. Subjects should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs should resolve 
to Grade <=1 prior to resuming nivolumab or ipilimumab.  


 
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4.3 
Dosing Criteria 
To account for drug quantities supplied within each vial and to minimize wasted unused 
investigational drug, pharmacy may adjust the calculated drug dose +/- 10% for each 
patient.  All patients dosed within these parameters will be considered dosed at full dose. 
 
4.4 
Definition of an Overdose for this Protocol 
Patients dosed > 10% above their calculated drug dose will be considered over-dosed. 
 
4.5 
Contraception, Use in Pregnancy, Use in Nursing 
See Section 3.2.8 
 
4.6 
Duration of Therapy 
Treatment will be continued for up to 2 years or discontinuation due to toxicity, 
withdrawal of consent, or study closure. Subjects may discontinue either drug and remain 
on the other agent if certain circumstances are met (Section 5.2.7). 
 
4.7 
Off Study/Safety Follow-up Visit 
The post-treatment follow-up begins when the decision to discontinue a subject from all 
treatment is made. 
Subjects who discontinue treatment for reasons other than disease progression will 
continue to have tumor assessments (if clinically feasible) according to the schedule in 
Section 9 until progression is confirmed. 
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a 
minimum of 100 days after the last dose of study medication. 
 
4.8 
Duration of Follow Up 
After completion of the first two follow-up visits, subjects will be followed every 3 
months for survival until death, withdrawal of consent, or study closure. Survival follow-
up visits may be performed by phone or email contact or office visit (Section 9). At that 
time of this request, each subject will be contacted to determine their survival status 
unless the subject had withdrawn consent for all contact. 
Study assessments are to be collected as outlined in study calendar in Section 9. 
 
4.9 
Criteria for Removal from Study Treatment 
Patients will be removed from the study for any of the following reasons: 
 Disease progression as defined in Section 11. 
 Patient non-compliance or request to withdraw from all therapy and follow up. Patients 
who withdraw from therapy only may continue to be followed for study specified follow 
up secondary endpoints. 
 Pregnancy. 
 Unacceptable toxicity that in the treating physician’s discretion places the patient at risk 


 
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for future significant harm. 
 Intercurrent illness that prevents continuation of therapy or follow up. 
 
4.10 
Treatment Beyond Progression 
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression is 
permitted if the subject has investigator-assessed clinical benefit and is tolerating 
treatment, as specified in Section 6.3 
 
4.11 
Duration of Study 
The analysis of the primary endpoint ORR will be performed six months after the last subject’s 
first treatment. Additional survival follow-up may continue for up to 5 years from the primary 
analysis. The study will end once survival follow-up has concluded. 
 
5. DOSING REDUCTIONS/DOSE DELAYS 
 
5.1 
Dose Reductions 
 
Recommended Dose Modifications for OPDIVO (Nivolumab) 
 
Adverse Reaction 
Severity
*
Dose Modification 
 
 
 
Colitis 
Grade 2 diarrhea or colitis 
Withhold dosea 
 
Grade 3 diarrhea or colitis 
Withhold dosea when 
administered as a single agent 
Permanently discontinue when 
administered with ipilimumab 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dosea 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
 
 
 
Hepatitis 
AST or ALT > 3 - 5 x ULN or  
total bilirubin > 1.5 - 3 x ULN 
Withhold dosea 
AST or ALT > 5 ULN or  
total bilirubin > 3 x ULN 
Permanently discontinue 
 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dosea 
Grade 4 hypophysitis 
Permanently discontinue 
 
Adrenal 
Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dosea 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 
Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Withhold dosea 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and 
Renal Dysfunction 
Serum creatinine > 1.5 – 6 x  ULN 
Withhold dosea 
Serum creatinine > 6 x ULN 
Permanently discontinue 


 
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Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal necrolysis 
(TEN) 
Withhold dosea 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
 
Encephalitis 
New-onset moderate or severe neurologic signs 
or symptoms 
Withhold dosea 
Immune-mediated encephalitis 
Permanently discontinue 
 
 
 
 
Other 
Other Grade 3 adverse reaction:  
     First occurrence 
 
Recurrence of same Grade 3 adverse 
reactions 
 
Withhold dosea  
 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for ≥ 10 mg per day prednisone 
or equivalent for > 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
* Toxicity was graded per NCI CTCAE v4. 
a  Resume treatment when adverse reaction improves to Grade 0 or 1. 
 
Recommended Treatment Modifications for Immune-Mediated Adverse Reactions of YERVOY 
(Ipilimumab) 
Target/Organ 
System 
Adverse Reaction 
Treatment Modification 
 
 
 
Endocrine 
Symptomatic endocrinopathy 
Withhold dose 
 
Resume in patients with complete or 
partial resolution of adverse reactions 
(Grade 0 to 1) and who are receiving  
< 7.5 mg prednisone or equivalent per 
day. 
• Symptomatic reactions lasting 6 weeks or 
longer 
• Inability to reduce corticosteroid dose to 
< 7.5 mg prednisone or equivalent per 
day 
Permanently discontinue 
Ophthalmologic  
 
 
Grade 2 through 4 reactions 
• not improving to Grade 1 within 2 
weeks while receiving topical therapy 
or  
• requiring systemic treatment 
Permanently discontinue  
 
 
 
 
All Other  
 
Grade 2 
Withhold dose 
 
Resume in patients with complete or 
partial resolution of adverse reactions 
(Grade 0 to 1) and who are receiving  
< 7.5 mg prednisone or equivalent per 
day. 


 
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• Grade 2 reactions lasting 6 weeks or 
longer 
• Inability to reduce corticosteroid dose 
to 7.5 mg prednisone or equivalent per 
day 
• Grade 3 or 4 
Permanently discontinue 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be 
used to grade adverse events. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study. 
Patients will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit for 
the duration of their participation in the study. 
Due to the prolonged half-life associated with monoclonal antibodies, no dose reductions 
of either study agent are planned. 
 
5.2 
Dosing Delays 
 In addition to the dose modifications in 6.1, any AE, laboratory abnormality or 
inter-current illness which, in the judgment of the investigator, warrants delaying 
the dose of study medication. 
 
Subjects that have drug-related toxicities that meet the criteria for dose delay, should 
have both drugs (ipilimumab and Nivolumab) delayed until retreatment criteria are met.  
 
Tumor assessments for all subjects should continue as per protocol even if dosing is 
delayed. 
 
5.2.1 Criteria for Permanent Discontinuation of Nivolumab and Ipilimumab 
 
 In addition to the treatment discontinuation parameters in 6.1, any treatment-
related event that leads to delay in dosing lasting >12 weeks from ipilimumab 
dosing OR > 6 weeks from nivolumab dosing requires discontinuation, with the 
following exceptions: 
o Dosing delays within those time frames to allow for prolonged steroid 
tapers to manage drug-related adverse events are allowed.  
o Dosing delays lasting >12 weeks of ipilimumab or > 6 weeks of 
nivolumab from the previous dose that occur for non-drug-related 
reasons may be allowed. 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the participant 
with continued dosing. 
 
Periodic study visits to assess safety and laboratory studies should also continue every 
6 weeks or more frequently if clinically indicated during such dosing delays. 
 


 
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5.2.2 Criteria to Resume Nivolumab  Dosing 
 Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by the IND Sponsor. 
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
 Any Grade 3 drug-related laboratory abnormality (except lymphopenia, AST, ALT, 
or total bilirubin or asymptotic lipase or amylase). Any Grade ≥ 3 drug-related 
amylase or lipase abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis does not require does delay. The IND Sponsor should 
be consulted prior to resuming nivolumab in such subjects. 
 
5.2.3 Criteria to Resume Ipilimumab Dosing 
 Subjects may resume treatment in the presence of Grade 2 fatigue. 
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT or total bilirubin. 
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the IND Sponsor. 
 Treatment-related dose delay of ipilimumab which results in no ipilimumab dosing 
for > 12 weeks requires ipilimumab discontinuation. 
 Ipilimumab may not be resumed sooner than 6 weeks (+/- 5days) after the prior 
ipilimumab dose. 
 In general, subjects who meet criteria to resume ipilimumab will also have met 
criteria to resume nivolumab, so it should be feasible to synchronize dosing of both 
drugs when resuming ipilimumab. In order to facilitate this, the dosing days of 
nivolumab and  ipilimumab may be adjusted within the permitted +/- 5 day window, 
as long as consecutive nivolumab doses are given at least 12 days apart. 
 Any Grade 3 drug-related laboratory abnormality (except lymphopenia, AST, ALT, 
or total bilirubin or asymptotic lipase or amylase). Any Grade ≥ 3 drug-related 
amylase or lipase abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis does not require does delay. The IND Sponsor should 
be consulted prior to resuming nivolumab in such subjects. 
 
5.2.4 Rescheduling: 
Nivolumab may be delayed until the next planned ipilimumab dose if the next 
ipilimumab dose is scheduled within the next 12 days. This will permit periodic 
ipilimumab dosing to be synchronized with nivolumab dosing. 
Ipilimumab should be dosed at the specified interval regardless of any delays in 
intervening nivolumab doses. However, in order to maintain periodic synchronized 
dosing of ipilimumab and nivolumab, the dosing days of nivolumab  and ipilimumab 
may be adjusted within the permitted +/- 5 day window, as  long as  consecutive  
nivolumab doses  are  given at  least  12 days apart. Ipilimumab may be delayed 


 
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beyond the 5 day window if needed to synchronize with the next nivolumab dose. 
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, 
then subsequent ipilimumab doses should rescheduled to maintain the 6 week interval 
between consecutive ipilimumab doses. 
 
5.2.5 Continuing Nivolumab or Ipilimumab as monotherapy: 
 
The assessment for discontinuation of nivolumab should be made separately from the 
assessment made for discontinuation of ipilimumab. Although there is overlap among 
the discontinuation criteria, if discontinuation criteria are met for nivolumab or 
ipilimumab (Drug 1) but not for the other (Drug 2), treatment with Drug 1 may continue 
if Drug 2 is discontinued.  
 
5.3 
Treatment Beyond Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD (26).  
Subjects will be permitted to continue on nivolumab + ipilimumab for treatment beyond 
initial RECIST 1.1 defined PD as long as they meet the following criteria: 
 Investigator-assessed clinical benefit and no rapid disease progression 
 Subject is tolerating study treatment 
 Stable performance status 
 Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
The decision to continue treatment beyond initial investigator-assessed progression 
should be discussed with the IND Sponsor and documented in the study records. A 
follow-up scan should be performed within six (6) weeks +/- 5 days of original PD to 
determine whether there has been a decrease in the tumor size, or continued progression 
of disease. Subsequent scans should be performed every twelve (12) weeks until further 
progression is determined. 
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring 
according to the Time and Events Schedule on study calendar (Section 9). 
For the subjects who continue study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden from time of initial PD. This 
includes an increase in the sum of diameters of all target lesions and/ or the diameters of 
new measurable lesions compared to the time of initial PD. Nivolumab and ipilimumab 
treatment should be discontinued permanently upon documentation of further 
progression. 
New lesions are considered measureable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes which must have a short 
axis of at least 15 mm). Any new lesion considered non-measureable at the time of initial 
progression may become measureable and therefore included in the tumor burden if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes which 


 
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must have a short axis of at least 15 mm). In situations where the relative increase in total 
tumor burden by 10% is solely due to inclusion of new lesions which become 
measurable, these new lesions must demonstrate an absolute increase of at least 5 mm. 
 
5.4 
Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Early recognition and management 
of AEs associated with immuno-oncology agents may mitigate severe toxicity.  
 
Management Algorithms have been developed to assist investigators in assessing and 
managing the following groups of AEs: 
 Gastrointestinal 
 Renal 
 Pulmonary 
 Hepatic 
 Endocrinopathy 
 Skin 
 Neurological 
The above algorithms are found in both the Nivolumab and Ipilimumab Investigator 
Brochures, as well as in Appendix 2. 
 
5.5 
Management of Nivolumab or Ipilimumab Infusion Reactions 
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, pruritus, arthralgias, hypo- or hypertension, bronchospasm, or 
other symptoms. All Grade 3 or 4 infusion reactions should be reported within 24 hours 
to the IND Sponsor and 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 appropriate: 
 
5.5.1 For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention 
not indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes 
before additional nivolumab or ipilimumab administrations. 
 
5.5.2 For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≥ 24 hours) 
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, 


 
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and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor subject 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion 
at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur, then no further 
nivolumab or ipilimumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should 
be administered at least 30 minutes before nivolumab or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
 
5.5.3 For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence 
of symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: Life threatening; 
pressor or ventilatory support indicated) 
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion 
of normal saline and treat the subject as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 
0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab or ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. 
In 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). 
 
6. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for adverse 
event reporting that can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate. 
 


 
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All AEs and SAEs experienced by subjects will be collected and reported from the first dose of 
nivolumab, throughout the study, and will only be followed for 4 weeks unless related to the 
investigational agent. All SAEs will be collected for 100 days after the last dose of nivolumab. 
Subjects who have an ongoing AE related to the study procedures and/or medication(s) may 
continue to be periodically contacted by a member of the study staff until the event is resolved 
or determined to be irreversible by the investigator. 
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all grade 3 
and 4 clinical laboratory results that represent an increase in severity from baseline will be 
reported as adverse events. A grade 1 or 2 clinical laboratory abnormality should be 
 
6.1 
Definitions  
 
6.1.1 Adverse Event 
An adverse event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
administered study drug and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of study drug, whether or not considered related to the study drug. 
BMS will be reporting adverse events to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320. 
 
6.1.2 Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 results in death  
 is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
 requires  inpatient  hospitalization  or  causes  prolongation  of  existing  
hospitalization (see NOTE below)  
 results in persistent or significant disability/incapacity  
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)  
 Potential drug induced liver injury (DILI) is also considered an important medical 
event. (See Section 6.5.3 for the definition of potential DILI.) 
 Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) 
via the study drug is an SAE. 


 
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 Although pregnancy, overdose, cancer, and potential drug induced liver injury 
(DILI) are not always serious by regulatory definition, these events must be handled 
as SAEs.  (See Section 6.5.4 for reporting pregnancies). 
Any component of a study endpoint that is considered related to study therapy (e.g., 
death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported) should be reported as SAE (see Section 6.5 for reporting details). 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical 
studies: 
 a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 elective surgery, planned prior to signing consent admissions as per protocol for a 
planned medical/surgical procedure  
 routine health assessment requiring admission for  baseline/trending  of  health  
status  (e.g., routine colonoscopy) medical/surgical admission other than to remedy 
ill health and planned prior to entry into the study. Appropriate documentation is 
required in these cases admission encountered for another life circumstance that 
carries no bearing on health status and requires no medical/surgical intervention 
(e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason). Admission for administration of anticancer therapy in the 
absence of any other SAEs  
 
6.2 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
principal investigator according to the following definitions:  
 No (unrelated, not related, no relation):  The time course between the administration 
of study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration - The event should occur 
after the study drug is given. The length of time from study drug exposure to event 
should be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might be recognized to cause the event in question.  


 
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 Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known 
pharmacologic properties (absorption, distribution, metabolism, and excretion) of the 
study drug should be considered.  
 
6.3 
Expectedness 
Expected adverse events are those which are expected to occur, according to previous 
clinical experience, and are listed in the Investigator Brochure. The expectedness of an 
SAE will be assessed by the Principal Investigator. 
 
Unexpected adverse event: An adverse event which varies in nature, intensity, or 
frequency from information on the investigational drug/agent provided in the 
Investigator’s Brochure, package insert, or safety reports. Any adverse event that is not 
included in the informed consent is considered “unexpected”.  
Expected (known) adverse event: An adverse event which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected,” only if it is included 
in the informed consent document as a risk. 
 
6.4 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS and the IND Sponsor will notify investigators 
of all reported SAEs that are suspected (related to the investigational product) and 
unexpected (i.e., not previously described in the IB). In the European Union (EU), an 
event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction 
(SUSAR). Investigator notification of these events will be in the form of an expedited 
safety report (ESR).  
 
Other important findings which may be reported by the as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with 
study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (e.g., animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor decision to end or temporarily halt a clinical study for 
safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC for 
the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator 
and IRB/IEC will determine if the informed consent requires revision. The investigator 
should also comply with the IRB/IEC procedures for reporting any other safety 
information.  
 
In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports).  


 
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6.5 
Reporting 
 
6.5.1 General 
 
All SAEs, regardless of causality to study drug and/or administration device, will be 
reported promptly to the Principal Investigator (e-mail: Chann1@jhmi.edu and Lead Study 
Coordinator), within 24 hours of recognition of the event. If this falls on a weekend or 
holiday, an email notification is acceptable but must be followed by an SAE reporting form 
on the next business day. 
 
The principal investigator will notify the appropriate regulatory agencies of any serious 
adverse event due to any cause during the course of this investigation. These include the 
Johns Hopkins Cancer Center Data and Safety Monitoring Committee, and the Johns 
Hopkins Medical Institutional Review Board (JHM-IRB) of The Johns Hopkins Medical 
Institutions. The required reporting time period is 3 days for fatal events, and 10 days for all 
other events. 
 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. 
BMS will be provided with a simultaneous copy of all adverse events filed with the FDA.  
 
SAEs should be reported on MedWatch Form 3500A or similar form. It MUST include the 
institutional AND BMS study ID [per study Agreement] 
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
The Lead Study Coordinator shall fax or e-mail the SAEs to BMS at: 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
SAE Email Address: Worldwide.Safety@BMS.com 
 
 
6.5.2 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs. 


 
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6.5.3 Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event.  All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs. Potential drug induced liver injury is defined as: 
 
1) ALT or AST elevation > 3 times the institutional upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times the institutional ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
6.5.4 Pregnancy Reporting 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 23 weeks days 
of completing the trial. This also includes the pregnancy of a male subject's female 
partner who has provided written consent to provide information regarding pregnancy 
that occurs during the trial or within 31 weeks days of completing the trial. All 
subjects who become pregnant must be followed to the completion/termination of the 
pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as SAEs (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported to the IND 
sponsor and BMS. 
 
6.5.5 Institutional Review Board (IRB) 
All serious adverse events will be reported to the IRB per institutional standards 
within 3 business days of recognition of the adverse event if the event is related and 
expected, related and unexpected, or related and fatal or life-threatening due to 
administration of the investigational product. Follow-up information will be 
submitted to the IRB as soon as relevant information is available. 
 
6.5.6 Food and Drug Administration (FDA) 
All reporting to the FDA will be completed by the IND Sponsor (Julie R. Brahmer, 
MD, MSc; fax: (410) 550-54457; e-mail: brahmju@jhmi.edu) 
 
6.5.3.1 Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:  The Sponsor is required to notify the 
FDA of any fatal or life-threatening adverse event that is unexpected and assessed 
by the investigator to be possibly related to the investigational agent.  Such reports 
are to be telephoned or faxed (301-796-9845) to the FDA within 7 calendar days of 


 
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first learning of the event.  Follow-up information will be submitted to the FDA as 
soon as relevant information is available. 
15 Calendar-Day Written Report:  The Sponsor is required to notify the FDA of 
any serious adverse event that is unexpected and possibly related to the 
investigational agent in a written IND Safety Report.   
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
 
6.5.3.2 IND Annual Reports 
In accordance with the regulation 21 CFR § 312.33, the Sponsor shall within 60 days 
of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR § 312.33 for a list of the elements required for the annual 
report.  All IND annual reports will be submitted to the FDA by the Sponsor-
Investigator. 
 
6.6 
Adverse Events of Interest 
 
6.6.1 Definition of immune-mediated adverse events (IMAEs) 
Immune-mediated AEs are specific events (that include pneumonitis, diarrhea/colitis, 
hepatitis, nephritis/renal dysfunction, rash, and endocrine (adrenal insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis) for 
which subjects received immunosuppressive medication for treatment of the event, 
with the exception  of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, 
hypophysitis, diabetes mellitus, adrenal insufficiency), which are included regardless 
of treatment since these events are often managed without immunosuppression. 
IMAEs include events, regardless of causality, occurring within 100 days of the last 
dose.  
Table 2 below provides a summary of the IMAEs category and their respective 
Preferred Terms (PTs).  
 
Table 2: Preferred Terms Included in Analysis of IMAEs to Support Warnings and Precautions
IMAE Category 
Preferred Terms included under IMAE Category
Pneumonitis 
Pneumonitis, Interstitial lung disease 
Diarrhea/Colitis 
Diarrhea, Colitis, Enterocolitis 


 
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Table 2: Preferred Terms Included in Analysis of IMAEs to Support Warnings and Precautions
IMAE Category 
Preferred Terms included under IMAE Category
Hepatitis 
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune 
Hepatitis, AST increased, ALT increased, Bilirubin 
increased, ALP increased 
Adrenal insufficiency 
Adrenal Insufficiency 
Hypothyroidism/Thyroiditis 
Hypothyroidism, Thyroiditis, Thyroiditis acute 
(collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency) 
Hyperthyroidism 
Hyperthyroidism 
Hypophysitis 
Hypophysitis 
Diabetes mellitus 
Diabetes mellitus, Diabetic Ketoacidosis 
Nephritis and renal dysfunction 
Nephritis, Nephritis allergic, Tubulointerstitial nephritis 
 
7. PHARMACEUTICAL INFORMATION  
 
7.1 
Product Information Table  
 
Table 3: 
                             Product Description 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumaba 
100 mg 
(10 
mg/mL) 
10 mL vial 
5 vials per 
carton/ Open-
label 
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles 
2 to 8°C. Protect form 
light and freezing 
Ipilimumab 
Solution for 
Injection 
200 mg 
(5 
mg/mL) 
40 mL vial 
5 vials per 
carton/Open-
label 
Clear, colorless to 
pale yellow liquid. 
May contain 
particles 
2 to 8°C. Protect from 
light and freezing. 
*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
7.2 
Nivolumab 
 
7.2.1 Agent Accountability 
The IND sponsor or the Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, 


 
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storage, handling, distribution and usage of investigational product in accordance 
with the protocol and any applicable laws and regulations. 
 
7.2.2 Mode of Action 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds 
to the PD-1 cell surface membrane receptor, a negative regulatory molecule expressed 
by activated T and B lymphocytes. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T cell responses to both 
foreign antigens as well as self-antigens. 
 
7.2.3 Description 
Nivolumab Injection, 100 mg/vial (10 mg/mL) is a clear to opalescent, colorless to 
pale, yellow liquid; light (few) particulates may be present. The drug product is a 
sterile, nonpyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL 
in sodium citrate, sodium chloride, mannitol, diethylenetriamine pentacetic acid and 
polysorbate 80 (Tween™ 80), pH 6.0 and includes a 0.7-mL overfill to account for 
vial, needle, and syringe (VNS) holdup. It is supplied in 10-cc type I flint glass vials, 
stoppered with butyl rubber stoppers and sealed with aluminum seals. 
 
7.2.4 Packaging and Labeling Information  
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Open-label cartons will be supplied with 5 vials per carton.  
 
7.2.5 Preparation 
Nivolumab injection should infused undiluted (10 mg/mL) or be diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an 
infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total 
volume of infusion must not exceed 160 mL. Care must be taken to assure sterility of 
the prepared solution as the product does not contain any anti-microbial preservative 
or bacteriostatic agent. No incompatibilities between nivolumab and polyolefin bags 
have been observed. Recommended safety measures for preparation and handling of 
nivolumab include laboratory coats and gloves. Detailed instructions on the 
preparation of nivolumab for administration will be provided in the Procedures 
Manual. 
 
7.2.6 Storage 
Clinical supplies must be stored in a secure, limited-access location. Nivolumab vials 
must be stored at a temperature of 2°C to 8°C and should be protected from light and 
freezing. If stored in a glass front refrigerator, vials should be stored in the carton. 
Receipt and dispensing of trial medication must be recorded by an authorized person 
at the trial site.  
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 


 
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7.2.7 Stability 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°-8°C, 36°-46°F) for up to 24 hours, and a maximum of 8 
hours of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) and 
room light. The maximum 8-hour period under room temperature and room light 
conditions includes the product administration period.  
 
7.2.8 Route of Administration 
Nivolumab is to be administered as a 30 minute IV infusion, using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. 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.  
 
7.2.9 Subject Care Implications 
The overall safety experience with nivolumab is based on experience in 
approximately 1500 subjects as either a monotherapy or in combination with other 
therapeutics. In general for monotherapy, the safety profile is similar across tumor 
types. The one exception is pulmonary inflammation AEs which may be numerically 
greater in subjects with NSCLC possibly because in some cases it can be difficult to 
distinguish between nivolumab-related and unrelated causes of pulmonary symptoms 
and radiographic changes. The most frequently reported treatment related AE is 
fatigue which is almost always low grade. 
Most related AEs are thought to be due to the effects of inflammatory cells on 
specific tissues. A variety of PTs have been used to describe similar kinds of organ-
related AEs with the result being that AE frequency tables organized by PTs can lead 
to underestimation of the frequency of similar kinds of organ-related AEs. To address 
this issue, select AE categories were created. Select AE categories group together the 
most common and impactful PTs by organ category. These categories include the 
following: pulmonary, gastrointestinal, hepatic, dermatologic, endocrine, and renal 
AEs. It is also useful to consider the management of nivolumab-related AEs by organ 
category as the diagnostic workup often requires excluding other potential diagnoses 
and when appropriate instituting specific management principles as outlined in this 
protocol and Appendix 2. 
 
7.2.10 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from BMS or designee, the amount dispensed to, and returned by the 
subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable 
federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. BMS will be notified of all destruction of 


 
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study drug. 
 
7.3 
Ipilimumab 
 
7.3.1 Agent Accountability 
The IND sponsor or the Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, 
storage, handling, distribution and usage of investigational product in accordance 
with the protocol and any applicable laws and regulations. 
7.3.2 Mode of Action 
Ipilimumab is a fully human immunoglobulin (IgG1) that is specific for the CTLA-4 
antigen expressed on a subset of activated T-cells. CTLA-4 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 CTLA-4 with the B7 ligand, resulting in a blockade of the inhibitory 
effect of T-cell activation.  The CTLA-4/B7 creates the interaction. 
 
7.3.3 Description 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly 
opalescent, colorless to pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous 
solution that may contain particles. Ipilimumab injection, 200 mg/40 mL, is supplied in 
50-cc Type I flint glass vials, stoppered with gray butyl stoppers and sealed with aluminum 
seals. The drug product is formulated at a concentration of 5 mg/mL at a pH of 7.0. in 
sodium chloride, TRIS-hydrochloride, diethylenetriamine pentacetic acid, mannitol, 
polysorbate 80 (Tween™ 80), and water, and includes a 0.7-mL overfill to account for 
vial, needle, and syringe (VNS) holdup. 
 
7.3.4 Packaging and Labeling Information  
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Open-label cartons will be supplied with 5 vials per carton.  
 
7.3.5 Preparation 
The drug can be diluted with 0.9% normal saline or 5% Dextrose Injection to 
concentrations between 1 mg/mL and 4 mg/mL. It is not to be administered as an IV 
push or bolus injection. Care must be taken to assure sterility of the prepared solutions, 
since the drug product does not contain any antimicrobial preservatives or bacteriostatic 
agents. Recommended safety measures for preparation and handling of ipilimumab 
include laboratory coats and gloves. Detailed instructions on the preparation of 
ipilimumab for administration will be provided in the Pharmacy Manual. 
 
7.3.6 Storage 
Clinical supplies must be stored in a secure, limited-access location. Ipilimumab vials 
must be stored at a temperature of 2°C to 8°C and should be protected from light and 
freezing. If stored in a glass front refrigerator, vials should be stored in the carton.  


 
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Receipt and dispensing of trial medication must be recorded by an authorized person 
at the trial site.  
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 
7.3.7 Stability 
The administration of ipilimumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored in IV 
infusion bags (PVC, non-PVC/non-DEHP) or glass infusion containers under 
refrigeration conditions (2°-8°C, 36°-46°F) with protection from light and from 
freezing or at temperature/room light (20-25°C, 68-77°F) for up to 24 hours. This 
would include any time in transit and the total time for infusion. 
 
7.3.8 Route of Administration 
Ipilimumab is to be administered as a 30 minute IV infusion, using a volumetric pump 
with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. 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 (approximately 30-50mL). 
 
7.3.9 Subject Care Implications 
The overall safety experience with ipilimumab is based on experience in approximately 
19,500 subjects as either a monotherapy or in combination with other therapeutics. The 
safety profile of ipilimumab is generally consistent across these trials with a) the majority 
adverse events (AEs) being inflammatory in nature, which is consistent with the proposed 
mechanism of action of ipilimumab; b) the same types of such immune-mediated events 
in the gastrointestinal (GI) tract (eg, diarrhea and colitis), skin (eg, pruritus and rash), liver 
(eg, transaminase elevations), endocrine glands (including the thyroid, pituitary and 
adrenal glands, manifested by hypothyroidism, hypophysitis with hypopituitarism, or 
adrenal insufficiency, respectively), and nervous system (eg, motor neuropathy with or 
without sensory neuropathy) being reported; and c) most of these events being manageable 
using symptomatic or immuno-suppressive therapy as recommended through detailed 
diagnosis and management guidelines as outlined in this protocol and Appendix 2. 
 
7.3.10 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from BMS or designee, the amount dispensed to, and returned by the 
subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable 
federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. BMS will be notified of all destruction of 
study drug. 
 


 
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8. Correlative Studies collection and handling 
Correlative studies will be performed to evaluate immune system activation and for potential 
biomarker identification. A variety of factors that could potentially predict clinical response to 
nivolumab and ipilimumab will be investigated in tumor specimens and in peripheral blood 
obtained prior to first dose of study drug, on study and potentially progression, as outlined in the 
Study Calendar.  Baseline and on treatment tumor assessment of response, immune reactivity 
and gene expression will be performed on all patients during the second stage of this trial. 
Plasma samples will be collected on all patients for ctDNA and immunogenicity studies.  
 
8.1 
Tumor Tissue Studies 
Archival or recently collected FFPE tumor tissue (in the form of paraffin embedded block or 
unstained slides, as described in Section 8.1.1) collected prior to enrollment, will be 
requested for all patients participating in this study.   
 
Pre-treatment and on-treatment biopsies of patients on Stage 2 will also be collected as per 
the Study Calendar. A biopsy sample of subjects who experience progression at any time 
while on treatment is optional, but strongly encouraged for the purposes of understanding 
mechanisms of resistance to therapy. 
 
Several analyses will be completed and are described briefly below.  
 
8.1.1 Tumor Tissue Handling 
 
A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (preferred) or 10 
unstained slides of tumor sample (archival or recent) for biomarker evaluation must be 
available and submitted for correlative studies in order for a subject to be enrolled as 
described in the Laboratory Manual. If fewer than 10 slides are available, the Principal 
Investigator may still approve enrollment of subjects upon review of the case. 
Excisional, incisional or core needle biopsies are strongly preferred, however samples 
collected via endobronchial ultrasound (EBUS) guided biopsy (using a 22g needle or 
larger) and transbronchial lung biopsy (TBLB) are acceptable. In certain cases, the 
Principal Investigator may approve submission of samples collected via other methods. 
 
If a new biopsy is taken (i.e. no archival tissue is available), up to 5 core biopsies are 
recommended at baseline. Otherwise, up to 4 core biopsies should be collected at 
baseline and at other time points per the Study Calendar. An assessment of biopsy 
quality by a pathologist is encouraged at the time of the procedure. The tumor tissue that 
is obtained from these biopsies will be allocated to FFPE, fresh frozen and for RNA later 
as described in the Laboratory Manual. The investigator, in consultation with the 
radiology staff, must determine the degree of risk associated with the procedure and find 
it acceptable. Biopsies may be done with local anesthesia or conscious sedation. 
Institutional guidelines for the safe performance of biopsies should be followed. 
Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy 
specimen. However, if a surgical procedure is performed for a clinical indication, excess 
tumor tissue may be used for research purposes with the consent of the subject. 
 


 
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A pathology report should be provided with tumor samples. 
 
8.1.2 Tumor microenvironment (TME) analysis by IHC 
 
Immunohistochemistry (IHC) will be used to assess the number and composition of 
immune infiltrates in order to define the immune cell subsets present within FFPE 
tumor tissue before, during and after exposure to therapy. These IHC analyses will 
include, but not necessarily be limited to, the following markers relevant to the PD-
L1/PD-1 and CTLA-4 pathways will be performed on FFPE slides of treated patients: 
densities and distribution of effector T cells (Teff) including CD8, CD45RO, CXCR3 
and CD69+ cells, expression of immune suppressive signals including PD-1, PD-L1, 
PD-L2, LAG3, TIM3, and IDO1,  immune activation signals including CD137(4-
1BB), 4-1BBL, OX40, OX40L,  CD40, and CD40L  on T cells and macrophages, and 
the expression of T helper cell differentiation markers including Tbet (for Th1), 
GATA3 (for Th2), ROR γ T (for Th17), and Foxp3 (for Treg) will be assessed as 
previously described (Lutz et al. 2014).   
 
Quantification of IHC on immune markers will be conducted by Aperio’s Immune 
Analysis Software Program as described previously (Lutz et al. 2014) and will be 
supervised by an on-site pathologist. A specific evaluation will be whether the 
combination of nivolumab and ipilimumab collaboratively suppress the Treg pathway 
and enhance effector T cell infiltration. 
 
8.1.3 Genomic assessment and gene expression  
 
DNA or RNA extracted from tumor provided may be used for whole genome or 
exome sequencing to identify mutational load and transcriptional expression. 
Sequencing of pre- and on-treatment biopsies may be compared to evaluate for 
predictors of response or resistance. Gene expression will be quantified by nanostring 
assays to assess whether the combination of nivolumab and ipilimumab influences 
immune cells within the tumor microenvironment.  The gene expression signatures 
listed in Table 4 and the signature found to correlate with responses to the study 
treatment will be evaluated.  
 
Next-generation sequencing may be used to examine the TCR repertoire in peripheral 
blood lymphocytes (PBL) and TIL from FFPE sections from the pre- or on-treatment 
biopsies, to identify if TCR clonal expansion is taking place. TCR repertoires in PBL 
vs TIL may also be compared from the same patients to identify any T cell clones that 
are induced or expanded in PBL by combination treatment and also enriched in TIL.  
This data may be used to determine if T cells in PBL and TIL undergo clonal 
expansion following treatment, and if so, whether the T cell clones traffic to the 
carcinoid TME.    
 
Nonsynonymous missense mutations identified may be used to predict mutant 
peptides and generate a neoantigen signature for each tumor using a computational 
pipeline we have developed. A separate targeted capture and sequencing analysis of 
the T cell receptor may be performed to assess T cell clonality. 


 
J17156 / Version 6.3/ May 25, 2021 
38 
 
 
 
 
 
 
 
8.1.4 Cytokine arrays 
If fresh frozen biopsy specimens are available, they may be used in a cytokine array 
analysis by a well-established protocol in the Zheng Lab using a commercially 
available cytokine protein array (R&D).  
 
8.2 
Serum and Plasma Marker Studies 
Various factors may impact the immunomodulatory properties and efficacy of nivolumab 
and ipilimumab will be investigated in peripheral blood specimens taken from all subjects 
prior to or during treatment. Data from these investigations will be evaluated for 
associations with response, survival, and/or safety (adverse event) data. Plasma samples will 
be obtained at time-points indicated in the Study Calendar (Section 9). Non-invasive 
genomic approaches may be used in order to determine somatic mutations that detect 
residual disease in the patient’s circulation.  
 
Several analyses will be completed and are described briefly below. 
 
8.2.1 circulating tumor DNA (ctDNA)  
Using blood samples collected prospectively after initiation of study treatment, 
measurements of cancer-specific genomic alterations in ctDNA may be analyzed to 
assess if they can predict disease progression prior to conventional CT imaging. 
Comparison of detection of somatic mutations in ctDNA and the sensitivity and 
specificity of the plasma analysis approach for detection of somatic alterations may 
be evaluated by comparison of the mutation data from the plasma to the sequence 
information obtained from analysis of the matching tumor samples.  
 
Table 4. Immune-Related Gene Expression Signatures (27). 
IFN γ 
Expanded Immune 
TCR Signaling 
De Novo 
IDO1 
CXCL10 
CXCL9 
HLA-DRA 
STAT1 
IFNG 
CD3D NKG7 
IDO1 HLA-E 
CIITA CXCR6 
CD3E LAG3 
CCL5 TAGAP 
GZMK CXCL10 
CD2 STAT1 
HLA-DRA GZMB 
CXCL13 
IL2RG 
EOSMES 
CD27 
TIGIT 
CD8A 
CD3D 
GRAP2 
LCK 
PTPRCAP 
CD4 
CCL5  
IL2RB IKZF3 
CD3G CD74 
IKZF3 SAMHD1 CD38 
HLA-DPB1 TIGIT 
CRTAM 
CD27 IL2RB CD8A 
AMICA1 TARP CXCL9 
CD74 CD3D HLA-C 
LY9 CD3G GPR18  
CD4 HLA-B IL18 
HLA-DRA IGJ CX3CR1 
B2M IRF1 CXCL10 
IGSF6 BST2 SIT1 
FASLG PTPN7 LCK 
IFN  interferon; TCR = T-cell receptor 
 


 
J17156 / Version 6.3/ May 25, 2021 
39 
 
Tumor- specific mutations found in the circulation after disease progression may be 
compared to the genomic profile of the recurrent tumors and the presence of matching 
resistance mutations in ctDNA may be confirmed. 
 
8.2.2 Peripheral Blood Mononuclear Cells (PBMCs) 
PBMCs taken at time points on Study Calendar (Section 9) may be analyzed by flow 
cytometry or other methods (e.g., ELIspot) to assess immune cell activity. 
8.2.3 Serum Soluble Factors 
To understand the prevalence of circulating proteins and the impact they may have on 
the clinical activity of nivolumab and ipilimumab, the protein concentrations of a panel 
of cytokines, chemokines, and other relevant immunomodulatory, serum-soluble factors 
(e.g., soluble PD-L1) may be investigated at baseline and during treatment. 
 
8.2.4 Single Nucleotide Polymorphisms (SNPs) 
Whole blood will be collected from all subjects prior to treatment to generate genomic 
DNA for SNP analyses and serve as a reference for tumor mutational profiling. These 
analyses will focus on SNPs within genes associated with PD-1 and other 
immunoregulatory signaling pathways to determine if natural variation within those 
genes is associated with response to nivolumab and/or with AEs during treatment. 
 
 


 
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40 
 
9. STUDY CALENDAR 
 
 
Screening 
(0-28 day 
pre-dose) 
Cycle 1 
Cycle 2, 3, etc.  
End of 
Treatment 
(EOT) 
Assessmentn 
Follow-Up 
Visit 30 days 
post EOT/ 
90 days post 
EOT 
Survival/ 
FU visitsl 
D1 
D15 
D29 
D1 
D15 
D29 
 
CLINICAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs, Height (baseline), 
Weight, O2 Sat 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height (baseline), Weight, O2 
Sat 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, plts 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Serum chemistrya 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Hepatitis Panelb 
X 
 
 
 
 
 
 
 
 
 
TSH, Free T4, Free T3c 
X 
 
 
 
X 
 
 
X 
 
 
EKG 
X 
Xf 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP 
only)d 
X 
X 
 
 
X 
 
 
 
 
 
Tumor Assessment/Imaginge 
X 
 
 
 
X 
 
 
 
Xm 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
Nivolumab 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
 
 
Ipilimumab 
 
Xg 
 
 
Xg 
 
 
 
 
 
CORRELATIVE 
STUDIES 
 
 
 
 
 
 
 
 
 
 
Archival Tumorh 
X 
 
 
 
 
 
 
 
 
 
Fresh Tumor Biopsyi (Second 
stage only) 
X 
 
 
 
X 
 
 
 
 
 
Plasma for Immunogenecity 
Studies (Second stage only)j 
 
X 
X 
X 
X 
 
 
 
X 
 
Plasma for ctDNA 
 (Second stage only)j 
 
X 
X 
X 
X 
 
 
 
X 
 
OTHER ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Symptom/Toxicity 
Assessmentj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
J17156 / Version 6.3/ May 25, 2021 
41 
 
Survival Status/Subsequent 
Therapy 
 
 
 
 
 
 
 
 
 
X 
 
 
a: LDH, AST, ALT, ALP, T. bili, BUN or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, 
glucose, amylase, lipase, TSH, Free T4, Free T3, within 14 days prior to first dose. 
b: Hep B/C (HBV sAg, HCV antibody or HCV RNA), within 28 days prior to first dose. 
c: Thyroid Function Testing to be evaluated every 6 weeks 
d: A serum or urine pregnancy testing is required prior to study enrollment/registration, also within 24 hours prior to D1 
(and extension to 72 hours may be granted if unable to obtain within 24 hrs). Must be reassessed every 4 weeks. 
e: CT scan of the chest and other relevant sites as well as MRI brain with gadolinium (or CT scan brain with contrast if 
MRI is contraindicated) will be performed ≤ 4 weeks prior to the start of therapy. For subsequent scans, may be done 
within +/- 7 days of intended visit. 
f. Within 72 hrs prior to dosing to include CBC w/ differential, AST, ALT, ALP, T. bili, BUN or serum urea level, 
creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, amylase, lipase, TSH (with reflexive Free T4 and 
Free T3). Note: C1D1 labs do not need to be repeated if they were performed within 14 days of dosing. 
g. All treatments may be performed +/- 2 days of the intended treatment administration dates schedule for all cycles.  
h: Recent sample or archival obtained. One (1) formalin-fixed paraffin embedded tumor tissue block or a minimum of 10 
unstained tumor tissue sections are acceptable. 
i: Mandatory fresh tissue will be collected for biomarker studies at baseline and on treatment (week 6-8) for patients 
enrolled in the second stage of the study.  
j: Immunogenecity samples should be collected just before the administration of the first drug (preferably within 30 
minutes). 
k: Adverse event evaluation as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
l: Survival follow-up may be done via phone call for survival status and subsequent therapy 
m: CT if the subject came off study for reasons other than PD 
n: EOT assessments do not need to be repeated if performed within 14 days 
o. In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-
person clinical trial visits or portions of clinical trial visits where determined to be appropriate and where determined 
by the investigator not to increase the participant’s risks. Prior to initiating telemedicine for study visits the study 
team will explain to the participant, what a telemedicine visit entails and confirm that the study participant is in 
agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with 
the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit 
will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved 
by the Health System and within licensing restrictions. 
 
 
10. DATA REPORTING / REGULATORY REQUIREMENTS 
 
10.1 
Data Management 
 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed at least annually by the Sidney Kimmel Comprehensive Cancer Center Data 
Safety Monitoring Board (SKCCC DSMB).  The SKCCC DSMB Recommendation letter 
will state the timeline for the next required review.  The SKCCC DSMB will review aspects 
of this trial that are outlined in the responsibilities section of the Data and Safety Monitoring 
Board (DSMB) Guidance. If the committee decides that amendments should be made to this 
trial, recommendations will be made in writing to the Study Principal Investigator.  The 
study team will submit modifications to the IRB within 60 days of receipt from the DSMB.  
The Associate Director of Clinical Research, will arbitrate any disagreements between the 
DSMB and the study Principal Investigator.  These changes may include early termination 
of accrual if deemed appropriate.  
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-


 
J17156 / Version 6.3/ May 25, 2021 
42 
 
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of 
monitoring.  
10.2 
Safety Meetings 
Scheduled meetings will take place at least on a monthly basis with the frequency 
dependent on the rate of subject accrual and will include the principal investigator, study 
coordinator(s), data manager(s), sub-investigators (as appropriate), collaborators (as 
appropriate), and biostatisticians (as appropriate) involved with the conduct of the 
protocol. During these meetings matters related to the following will be discussed: safety 
of protocol participants, validity and integrity of the data, enrollment rate relative to 
expectation, characteristics of participants, retention of participants, adherence to 
protocol (potential or real protocol violations), data completeness, and progress of data 
for objectives. 
 
10.3 
Monitoring 
The PI shall internally monitor the progress of the trial, including review and 
confirmation of all safety/treatment-related outcomes, response assessments, safety 
reports and/or any related source documentation.  
 
11. MEASUREMENT OF EFFECT 
 
 
Antitumor Effect  
For the purposes of this study, patients should be re-evaluated every 6 weeks.  In addition 
to a baseline scan, confirmatory scans will also be obtained 6 (not less than 4) weeks 
following initial documentation of an objective response. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).  Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
11.1.1 Definitions 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 


 
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11.1.2 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 ≥20 mm (≥2 
cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). Tumor lesions that are situated in a previously irradiated area may 
only be considered measurable if they are growing on pre-treatment imaging. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to 
<15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease.   
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
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, but 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.  
 
11.1.3 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. 


 
J17156 / Version 6.3/ May 25, 2021 
44 
 
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 (≥1 cm) 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
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 (0.5 cm) or less.  If 
CT scans have slice thickness greater than 5 mm (0.5 cm), 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).   
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, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should be performed with breath-hold scanning techniques, 
if possible. 
 
11.1.4 Response Criteria 
 
11.1.4.1 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 (<1 cm). 
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 (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 


 
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Stable Disease (SD).  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 
size (<10 mm [<1 cm] short axis). 
Note:  If tumor markers are initially above the upper normal limit, they 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) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only 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). 
 
11.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Table 5: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/ 
Non-PD/ 
not evaluated 
No 
PR 
SD 
Non-CR/ 
No 
SD 
Documented at least once 


 
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46 
 
Non-PD/ 
not evaluated 
≥4 wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
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. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment.
 
 
 
For Patients with Non-Measurable Disease 
(i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘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 
 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 


 
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11.1.6 Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
There is no independent or central review of the radiology assessments planned for 
this trial. It is the responsibility of each Principal Investigator to ensure that tumor 
assessments are reported per the RECIST 1.1 criteria outlined above.  
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
This is an open label, phase II clinical trial of nivolumab and ipilimumab in subjects with 
advanced, well-differentiated nonfunctional NET of the pancreas, lung or gastrointestinal 
(GI) tract. The primary endpoint is ORR defined as RECIST 1.1 partial response (PR) or 
complete response (CR).  
Simon two-stage design (28) was used to evaluate the primary endpoint, with details as 
described in section 12.2.   
 
12.2 
Sample Size/Accrual Rate 
The optimal two-stage design to test the null hypothesis that P ≤ 0.050 versus the 
alternative that P ≥ 0.150 has an expected sample size of 29.51 and a probability of early 
termination of 0.736. If the regimen is actually not effective, there is a 0.097 probability 
of concluding that it is (the target for this value was 0.100). If the regimen is actually 
effective, there is a 0.199 probability of concluding that it is not (the target for this value 
was 0.200). After testing the drug on 20 patients in the first stage, the trial will be 
terminated if 1 or fewer respond. If the trial goes on to the second stage, a total of 56 
patients will be studied. If the total number responding is less than or equal to 4, the 
regimen is rejected. 
Assuming a 15% screening failure rate, it is estimated that approximately 64 subjects will 
be enrolled in order to achieve 56 treated subjects.  
 
12.3 
 Analysis and Summary of Endpoints 
 
12.3.1 Primary Endpoints 
The primary endpoint is ORR (per RECIST v1.1 criteria) among all treated subjects. 
All treated subjects is defined as all subjects who received at least one complete dose 
of nivolumab and ipilimumab. ORR is defined as the number of subjects with a best 
overall response (BOR) of confirmed CR or PR, divided by the number of treated 
subjects. 
BOR is defined as the best response designation, recorded between baseline and the 
date of objectively documented progression per RECIST 1.1 or the date of initiation 
of palliative local therapy or the date of initiation of subsequent anticancer therapy, 


 
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whichever occurs first. For subjects without documented progression or palliative 
local therapy or subsequent anti-cancer therapy, all available response designations 
will contribute to the BOR determination. For subjects who continue treatment 
beyond progression, the BOR will be determined based on response designations 
recorded up to the time of the initial RECIST 1.1-defined progression. 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point of >= 4 weeks later. 
Further characterization of the response will include time to objective response (time 
from first dosing date to first CR or PR) and depth of response (maximum tumor 
shrinkage in target lesions). 
The analysis of the primary endpoint ORR will be performed six months after the last 
subject’s first treatment. 
 
12.3.2 Secondary Endpoints 
Secondary endpoints include safety and tolerability of study treatment; PFS, DCR, 
DOR and OS in the all treated subjects population. 
Safety and tolerability objectives will be measured by the incidence of adverse events, 
serious events, deaths, and laboratory abnormalities. Dates and duration of study 
treatment delays will also be described.  
PFS is defined as the time from first dose to the date of the first documented tumor 
progression (per RECIST 1.1), or death due to any cause. Clinical deterioration in the 
absence of radiographic evidence is not considered progression for purposes of 
determining PFS. Subjects who die without a reported prior progression will be 
considered to have progressed on the date of their death. Subjects who did  not  
progress or  die  will  be  censored  on  the  date  of  their  last  evaluable  tumor 
assessment. 
Subjects who did not have any on study tumor assessments and did not die will be 
censored on the first dosing date. Subjects who started any palliative local therapy or 
subsequent anti-cancer therapy without a prior reported progression will be censored 
at the last evaluable tumor assessment prior to initiation of the palliative local therapy 
or subsequent anti-cancer therapy, whichever procedure occurred first. PFS rate at 6 
months is defined as the rate from Kaplan-Meier estimate 6 months after first dosing 
date. 
Disease control rate is defined as the number of subjects with a BOR (per RECIST 
v1.1 criteria) of confirmed CR or PR or SD (stable disease), divided by the number of 
treated subjects. 
Duration of response will be summarized among subjects with objective response in 
and is measured from the time at which the criteria for objective response are first met 
until the date of a progression event (according to the definition of PFS). Subjects 
with objective response who does not have a progression event will be censored at the 
same time they were censored under the definition of PFS. 
Overall survival is defined as the time from first dosing date to the date of death. A 
subject who has not died will be censored at last known alive date. The overall 


 
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survival rate at 6 months is the rate from Kaplan-Meier estimate 6 months after 
dosing date. 
 
12.3.3 Exploratory Endpoint(s) 
All biomarker measures, T-cell response, immune phenotype and inflammatory 
response evaluation will be listed, tabulated, and where appropriate plotted. Tumor 
tissue IHC, functional analysis and genomic analysis will be listed, tabulated and 
where appropriate plotted. For the continuous data, summary statistics and the 
corresponding changes (or percent changes) from baseline will be provided at each 
time-point of assessment as well as for the changes from baseline to the peak value. 
Categorical data will be summarized as appropriate. Subjects will be grouped by dose 
level or clinical response. As this is an open-label study without a control treatment, 
statistical analyses will be done to aid in the understanding of the results. The 
associations of biomarkers with dose, clinical response, or time-to-event endpoints 
may be assessed using the appropriate statistical methods (analysis of variance 
[ANOVA], categorical, or survival model), depending on the endpoint. Correlation of 
baseline expression levels or changes in expression levels with response or time-to-
event endpoints will identify potential responsive (or resistant) subgroups. 
The ctDNA and IMG objectives will be measured from serum concentration. 
Response characteristics will be summarized descriptively and are further described 
in the statistical analysis plan. 
Other exploratory endpoints are discussed in details in the statistical analysis plan. 
 
12.4 
Efficacy Analyses 
 
12.4.1 Methods for Primary Endpoints 
Among all treated subjects, the ORR will be summarized by binomial response rates 
and their corresponding two-sided 95% exact CIs using Clopper-Pearson method. The 
null hypothesis will be rejected if the 2-sided 95% CI lower bound for the ORR 
radiology assessed estimate is greater than 15%. 
To further characterize the response: time to objective response, depth of response 
and BOR by response category will be summarized using descriptive statistics. 
 
12.4.2 Methods for Secondary Endpoints 
Secondary endpoints will be evaluated based on the treated population. 
Time to event distribution will be estimated using Kaplan Meier techniques. This will 
be done for PFS. Median PFS along with 95% CI will be constructed based on a log-
log transformed CI for the survivor function. Rates at fixed time points (e.g., PFS at 6 
and 12 months) will be derived from the Kaplan Meier estimate and corresponding 
confidence interval will be derived based on Greenwood formula for variance 
derivation and on log-log transformation applied on the survivor function. 
The DCR will be summarized for subjects who achieve confirmed PR or CR using 
the Kaplan-Meier (KM) product-limit method. Median values of DCR, along with 


 
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95% CI will be constructed based on a log-log transformed CI for the survivor 
function.  
The DOR will be summarized for subjects who achieve confirmed PR or CR using 
the Kaplan-Meier (KM) product-limit method. Median values of DOR, along with 
95% CI will be constructed based on a log-log transformed CI for the survivor 
function. 
 
12.4.3 Safety Analyses 
Safety analysis will be performed in all treated subjects. Descriptive statistics of 
safety will be presented using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. All on-study AEs, drug-related 
AEs, SAEs and drug-related SAEs, AEs and drug-related AEs leading to drug 
discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by 
system organ class and preferred term, based on MedDRA terminology. On-study lab 
parameters including hematology, coagulation, chemistry, liver function and renal 
function will be summarized using worst grade per NCI CTCAE v 4.0 criteria. 
Frequency, management and resolution of IMAEs will be analyzed. A tabular 
summary of the incidence of overall IMAEs (by preferred term) and serious IMAEs 
will be performed. A descriptive analysis of IMAEs including time-to-onset, severity, 
duration, action taken with the study drug, dosing delays of the study drug, 
corticosteroid details, re-challenge information and outcome of the AE will be 
individually characterized by IMAE category (Section 6.6.1). 
 
 
 
 


 
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APPENDIX 1 
ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS a 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g.,, light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655. 


 
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APPENDIX 2 
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented 
by discussions with the IND Sponsor. The guidance applies to all immuno-oncology agents 
and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non inflammatory etiologies should be considered and 
appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be 
taken into account when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic 
or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used.


 
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