Conditions: Advanced Stage Non-small Cell Lung Cancer
Keywords: Nivolumab Lung ipilimumab NSCLC 14-137
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
The purpose of this study is to closely examine tumor and blood samples from patients treated with nivolumab and ipilimumab in order to try to identify why some patients with lung cancers respond and why some patients do not.

Detailed description:

Arms:
arm 1: Patients will begin treatment with nivolumab IV 3mg/kg and ipilimumab 1mg/kg. Treatment with nivolumab will continue every 2 weeks (+/- 3 days) thereafter and treatment with ipilimumab will continue every 6 weeks (+/- 3 days) thereafter. Treatment will continue until protocol-defined toxicity, confirmed progression of disease\*, withdrawal of consent, or death.

Interventions: intervention 1: nivolumab intervention 2: pilimumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-137 A(10) 
Approval date: 02-Dec-2021 
 
 
 
 
MSK PROTOCOL COVER SHEET 
An Exploratory Study to Evaluate the Mediators of Sensitivity and Resistance to 
Nivolumab plus Ipilimumab in Patients with Advanced NSCLCs 
Principal Investigator/Department: Adam Schoenfeld, MD / Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial  Sloan-Kettering  Cancer  Center 
1275 York Avenue 
New York, New York 10065 
 
 
Page 1 of 85 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .........................................................................3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................................4 
3.0 
BACKGROUND AND RATIONALE .......................................................................................5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 14 
4.1 
Design ............................................................................................................................ 14 
4.2 
Intervention ....................................................................................................................... 15 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................. 24 
6.1 
Subject Inclusion Criteria ................................................................................................. 24 
6.2 
Subject Exclusion Criteria ................................................................................................ 25 
7.0 
RECRUITMENT PLAN ......................................................................................................................... 26 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 27 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 28 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 32 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 34 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 46 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 53 
14.0 
BIOSTATISTICS .................................................................................................................. 56 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES57 
15.1 Research Participant Registration ............................................................................................. 57 
15.2 
Randomization ........................................................................................................................ 58 
16.0 
DAT A M ANAGEMENT ISSUES .......................................................................................... 58 
16.1 
Quality Assurance .......................................................................................................... 58 
16.2 
Data and Safety Monitoring ............................................................................................. 58 
17.0 
PROTECTION OF HUMAN SUBJECTS .............................................................................. 59 
17.1 
Privacy ............................................................................................................................ 60 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 60 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 62 
19.0 
REFERENCES ........................................................................................................................... 63 
20.0 
APPENDICES ...................................................................................................................... 70 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: An exploratory study to evaluate the mediators of sensitivity and resistance to nivolumab plus 
ipilimumab in patients with advanced NSCLC 
Study Design: This is an open-label, single-center, single-arm, phase II exploratory study of 
nivolumab 3mg/kg q 2 weeks in combination with ipilimumab 1mg/kg q 6 weeks. The target 
population includes patients with advanced stage NSCLCs. This study aims to examine the factors 
that may contribute to sensitivity or resistance to nivolumab plus ipilimumab in patients with 
advanced NSCLCs. There are several objectives to this study, which are structured around a model 
of T-cell recognition of cancer. 
Eligible patients must have at least one site of disease that is amenable to standard-of-care surgical 
resection or a core needle biopsy. For those undergoing standard of care resection, residual 
measurable disease following resection is required. 
Eligible patients must have had no more than 2 prior regimens of chemotherapy and no prior 
immunotherapy. Patients with EGFR mutations or ALK re-arrangements must have had prior 
tyrosine kinase inhibitors.  Those with auto-immune disease, concurrent treatment with alternative 
anti-cancer therapy or systemic immunosuppressants, or untreated brain metastases are excluded 
from study. 
Patients will have a pre-treatment, standard-of-care tumor resection or tumor biopsy for fresh tissue 
collection. Patients will then start nivolumab 3mg/kg day 1 and continue this every 2 weeks during 
the study protocol. Patient will concurrently start ipilimumab 1mg/kg day 1 and continue this every 6 
weeks during the study protocol. Tissue collection and correlative studies planned described below. 
 
 
Pre- 
Rx 
C1D1 
C2D1 
C2D8 
C3D1 
C4D1 and each cycle 
thereafter 
Nivolumab 
3mg/kg 
X 
X 
X 
X 
Ipilimumab  1 
mg/kg 
X 
X and every 6 weeks thereafter 
Biospecimen collection for analysis 
Tumor resection 
or biopsy 
X 
Tumor biopsy 
X 
Isolation of 
TILs 
X 
PBMCs 
X 
X 
X 
X 
X 
X and every 6 weeks thereafter 
Tumor-based  analysis 


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Mutation 
burden 
X 
Candidate 
neoantigens 
X 
Co-stimulatory 
receptors and 
ligands 
X 
X 
X and every 6 weeks thereafter 
T cell analysis (TILs and/or PBLs) 
Identification of 
antigen-specific 
T-cells 
X 
X 
X 
X and every 6 weeks thereafter 
 
 
Project 
Methods 
Mutation burden 
Whole exome / transcriptome 
Candidate neoantigens 
Bioinformatics 
Co-stim receptors and  ligands 
IHC 
Antigen specific  T-cells 
MHC-multimer  assays 
ICS assays 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Nivolumab produces a response in ~15-20% in patients with advanced NSCLC and the combination 
of PD-1 blockade plus CTLA-4 blockade appears to have a response rate of ~30%(1). We have 
recently demonstrated that somatic mutation burden is associated with response to PD-1 blockade 
monotherapy in a retrospective study (2), but the predictors and mediators of response to nivolumab 
in combination with ipilimumab are not known. In this prospective study, we aim to examine 
mechanisms of sensitivity and resistance to nivolumab plus ipilimumab by dissecting the individual 
components that contribute to T-cell recognition of and response to a cancer cell. 
A cornerstone of cancer immunotherapy is the ability of the adaptive immune system to recognize a 
cancer as foreign, i.e. non-self. One way that a cancer can appear foreign is by the accumulation of 
somatic mutations. Some of these mutations are oncogenic, while others are passengers. But 
irrespective of their oncogenic potential, each of these mutations has the potential to contribute to 
the immunogenicity of a cancer. The primary objective of this study is to explore how these somatic 
mutations in cancer mediate response or resistance to nivolumab plus ipilimumab. To fully 
contextualize the T-cell response to cancer, we will evaluate in parallel the other factors involved in 
T-cell and cancer cell interactions, including expression of co-stimulatory ligands on tumor cells and 
in the tumor microenvironment and expression of exhaustion/activation receptor on T-cells. 
Primary objectives: 
1) Explore the relationship between mutational burden and response to nivolumab plus 
ipilimumab therapy 
2) Identify candidate neoantigens and explore their associations with response to nivolumab 
plus ipilimumab therapy 


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3) Identify neoantigen-specific T-cells using technology such as in vitro using MHC-multimer or 
intracellular cytokine staining. 
Secondary objectives 
1)   Examine MHC and co-stimulatory receptor and ligand expression in tumor-microenvironment 
and explore their relationship with response to nivolumab plus ipilimumab. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
INTRODUCTION TO LUNG CANCERS 
Lung cancer is the most common cancer and leading cause of cancer related death worldwide, 
accounting for more than 1.6 million cases and 1.3 million deaths annually (3). For patients with 
advanced stage non-small cell lung cancer (NSCLCs), the most common form of lung cancer in the 
United States, cytotoxic chemotherapy improves outcomes (4, 5) but durable disease control is 
disappointingly rare – fewer than 5% of patients are alive 5 years later and median survival is ~10 
months (6, 7). Histology-specific chemotherapy (8), maintenance chemotherapy (9-13), the addition 
of bevacizumab (14), and the identification of targetable driver oncogenes (15-20)  have all improved 
outcomes, but there remains an urgent need for better treatment strategies for the majority of  
patients with advanced NSCLCs. T-cell checkpoint inhibitors, particularly those targeting PD1 and 
PDL1, have recently demonstrated promising activity in NSCLCs and represent a new paradigm for 
considering the treatment of patients with lung cancers. 
T-CELL CHECKPOINT INHIBITION  IN NSCLCs 
T-cell checkpoint inhibitors targeting CTLA-4 (ipilimumab (21)), PD-1 (nivolumab, and other similar 
therapies in development (22-25)) and PDL1 (26, 27) have demonstrated effectiveness in advanced 
NSCLCs and validated the importance of cancer immunotherapy in the treatment of patients with 
NSCLCs. 
PD-1 AND PD-L1 
Programmed Cell Death-1 (PD-1; CD279) is a cell surface receptor on T-cells that is induced after T- 
cell activation. When PD-1 engages with its cognate ligands (PDL1, also known as B7-H1, or PD-L2, 
also known as B7-DC), it signals intracellularly in T-cells to inhibit effector T-cell function (28) via 
induction of effector T-cell apoptosis, suppression of effector T-cell proliferation or cytokine 
production (29-32). PDL1 and PD-L2, ligands of PD-1, are expressed not only by APCs but also by 
tumor cells and cells in the tumor microenvironment. An overexpression of PD-1 ligands by tumor 
cells and cells in its microenvironment leading to ineffective tumor infiltrating effector T-cells is 
postulated to be one important mechanism by which tumor cells prevent immune-mediated 
destruction (28, 33). Indeed, overexpression of the PD-L1 within solid tumors has been associated 
with poor prognosis and diminished tumor infiltrating effector T-cells (34-36), including NSCLCs (37, 
38). 
Aimed at reversing the immune inhibitory signals to restore effective tumor directed immune attack, 
multiple anti-PD-1 and anti-PDL1 monoclonal antibodies (mAb) are currently in development. 


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Nivolumab 
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 and PD-L2), 
thereby abrogating inhibitory signals and augmenting the host antitumor response. In an early 
clinical trial, nivolumab demonstrated activity in several tumor types, including melanoma, renal cell 
cancer (RCC), and NSCLCs (22). Treatment was well tolerated, no dose-limiting toxicities were 
observed, three objective responses, including one complete response, were reported. 
 
A second phase I study of 296 patients with advanced solid tumors treated with nivolumab given 
every two weeks in escalating dose cohorts has also been reported (24). 122 patients had 
NSCLCs. 55% had been treated with ≥ 3 prior regimens. Only 8% of those with NSCLCs 
experienced treatment related grade 3-4 toxicity (fatigue, pneumonitis, transaminitis being most 
common), although two patients with NSCLCs died of treatment-related pneumonitis. Of all NSCLC 
patients evaluable for clinical activity [i.e. all doses], 17% has an objective response; in those who 
received 3 or 10mg/kg (the recommended phase II doses), the response rate was 22% (21/96). 
Impressively, the 24-week PFS rate among all NSCLCs patients treated at 3mg/kg was 42-45% 
(23, 39). These results are similar to the ORR and median PFS from achieved with first-line 
platinum-based chemotherapy (ORR ~30%, median PFS ~5 months (8, 14)) and appear 
numerically superior to standard second-line treatment options (including erlotinib, docetaxel, or 
pemetrexed; ORR 3-8%, median PFS 6-8 weeks (40, 41)). 
Since then, nivolumab has since been studied in several studies include two phase 3 studies of 
nivolumab versus docetaxel in patients with advanced NSCLCs previously treated with one line of 
therapy. In both studies, nivolumab significantly improved response rate and overall survival 
compared to docetaxel. As a result, nivolumab has recently been approved by the FDA for patients 
with previously treated squamous cell lung cancers. NCCN has also suggested that nivolumab is 
reasonable therapy for patients with previously treated lung adenocarcinomas, though this has not 
been FDA approved yet. In this context, the recent successes of PD1/PDL1 directed therapy offer 
perhaps the most encouraging results for the treatment of NSCLCs in years. 
Nivolumab plus ipilimumab 
 
Although both CTLA-4 and PD-1 function as inhibitory co-receptors expressed on T cells, their 
ligands and function are distinct. When localized to the T cell surface after antigen-driven TCR- 
mediated T cell activation(42), CTLA-4 binds to CD80 and CD86(43) and prevents effector T cell 
activation and proliferation(44-46) by competitively preventing binding of B7 ligands to the 
costimulatory receptor CD-28(47-50) and inhibition of intracellular signaling pathways(51-53). As 
above, PD-1 is similarly shuttled to the surface of effector T cell upon activation(54), where PD-1 can 
bind to ligands PD-L1(28, 55) and PD-L2(56) and inhibit proliferation(57), cytokine production(58,  
59), and survival(60, 61), characteristic of T cell exhaustion.(62, 63) In this context, CTLA-4 and PD- 
1 can produce differing effects on effector T cells, including inhibition of early activation and 
differentiation by CTLA-4 and modulation of effector function by PD-1 


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Confirming the potential for syngery with these therapies, the combination of nivolumab and 
ipilimumab has produced truly transformative responses for patients with melanoma. Building upon 
an initial phase I dose-escalation study of this combination [Wolchok NEJM 2013], reports of 
randomized Phase II and Phase III studies have recently been reported. The Phase II study was a 
double-blind, randomized study of nivolumab plus ipilimumab compared to ipilimumab in patients 
with advanced melanoma (Postow NEJM 2015). The objective response rate to nivolumab plus 
ipilimumab was 59%, compared to 11% with ipilimumab alone. Among those treated with 
combination therapy, the median change in tumor volume was a 68% decrease and 22% of patients 
achieved a complete response. 
Most recently, a double-blind, phase III,  randomized study of nivolumab plus ipilimumab versus 
nivolumab versus ipilimumab was performed in patients with treatment-naïve advanced melanoma 
(Larkin NEJM 2015). Again, the response rate with combination therapy was 57.6%, compared to 
43.7% in the nivolumab monotherapy arm and 19% in the ipilimumab monotherapy group. 
Progression-free survival also favored combination therapy, with hazard ratio of 0.57 (95% CI 0.43- 
0.76) compared to ipilimumab and 0.74 (95% CI 0.60-0.92) compared to nivolumab. Overall, with 
responses exceeding 50% of the population and median PFS reaching nearly a year, it is clear that 
combination therapy has reshaped the treatment landscape of advanced melanoma and profoundly 
improved the outcomes for these patients. 
Building upon the remarkable activity seen in patients with melanoma, several studies have begun to 
explore this combination in NSCLCs as well. In an initial study of nivolumab and ipilimumab, patients 
with NSCLC were initially treated with two dosing schedules (Nivo1/Ipi3  or Nivo3/Ipi1 every three 
weeks for four doses, followed by Nivo3 every two weeks) (Antonia, ASCO 2014). A total of 49 
patients were treated and frequent toxicity was seen in both groups, with 49% patients experiencing a 
treatment-related grade 3-4 toxicity and 35% of patients discontinuing therapy due to treatment- 
related events. Some responses were seen, but efficacy was difficult to interpret in the setting of the 
rate of toxicity. Subsequently, the study was amended to examine several additional treatment 
regimens, including giving lower doses of both nivolumab and ipilimumab (1mg/kg each) or 
increasing the interval between ipilimumab administration (every 6 or 12 weeks). These data have 
demonstrated the response rate to be ~20-30% across arms and safety to be much better tolerated. 
Nivo 3mg/kg every two weeks plus Ipi 1mg/kg every six weeks has emerged as an optimal dose and 
schedule and will be assessed further in a Phase 3 study of nivolumab plus ipilimumab versus 
nivolumab monotherapy versus chemotherapy has been recently begun .(NCT02477826). 
Additionally,  and with similar result, a dose-escalation study of anti-PD-L1 inhibitor MEDI4736 in 
combination with the CTLA-4 inhibitor tremelimumab in patients with NSCLC was also recently 
reported (Antonia ASCO 2015). 102 patients were treated across 10 dose-escalation cohorts. 
MEDI4736 given at 10mg/kg every two weeks or 3, 10, 15, 20mg/kg every four weeks and 
tremelimumab was given at 1, 3, or 10mg/kg every four weeks. In cohorts of tremelimumab 3 or 
10mg/kg, the rate of treatment-related grade 3-4 toxicity was 50-80% and 34-45% lead to treatment 
discontinuation; therefore these doses were felt to be unacceptable for development. Toxicity was 
more modest in cohorts of tremelimumab 1mg/kg, with grade 3-4 toxicity occurring in 29% of 
patients, and only 7% resulting in discontinuation of therapy. In addition to manageable toxicity 


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with lower doses of tremelimumab, initial efficacy was also promising with objective responses seen 
in 33% of patients and 52% were progression-free 16 weeks after beginning therapy. Phase 3 
studies of MEDI4736 plus tremelimumab versus MEDI4736 versus chemotherapy in untreated, 
advanced NSCLC are planned to begin this year (NCT02453282). 
Overall, early efficacy with combination of CTLA-4 + PD-1/PD-L1 blockade is promising with 
response rates of ~30% that numerically exceeds (nearly double) what has been reported with anti- 
PD-1/PD-L1 monotherapy in NSCLC. However, as it remains a minority of patients who respond to 
either therapy, it remains critical that we examine the determinants of response to combination 
therapy in order to optimize therapy for patients. 
 
Predictors of response to PD-1 blockade 
 
Although robust responses to PD-1 blockade have been seen across many tumor types, it is a 
fraction of patients treated who ultimately respond. Significant recent effort has been dedicated to 
finding predictors of response to anti-PD-1/PD-L1 therapies. Expression of PD-L1 in the tumor 
microenvironment appears to enrich for response, but is neither sensitive nor specific (24, 64-66). 
 
Our group has largely focused on the genomic predictors of response to PD-1 blockade and recently 
reported the results of whole exome sequencing of paired tumor/normal tissue from 34 patients with 
NSCLC who were treated with pembrolizumab as part of a phase I study. Similar to previous series 
of NSCLCs that have been examined with exome sequencing, we found a substantial range in the 
mutation burden of samples, with some tumors harboring as few as 11 somatic non-synonymous 
mutations and others with as many as 1192 mutations. Importantly, somatic mutation burden 
substantially correlated with clinical benefit to treatment with pembrolizumab. Patients with durable 
benefit lasting >6 months (termed "durable clinical benefit," DCB) had significantly higher mutation 
burden compared to those with no durable benefit (NDB) (median 299 vs 127 mutations, p=0.0008). 
Additionally,  the rate of objective response, DCB, and progression-free survival were all significantly 
greater in patients with an elevated mutation burden (59% vs 12%, p=0.01; 79% vs 18%, p=0.001; 
HR 0.19, 95% CI 0.08-0.47, respectively). 
 
We hypothesized that neoantigens, cancer-specific mutated peptides formed as a consequence of 
somatic mutations, may underlie the association between mutation burden and response to T cell 
checkpoint blockade. We applied a computational pipeline recently developed to identify candidate 
neoantigens from cancer exome data (Snyder et al, NEJM 2014) to examine the neoantigen 
landscape of one patient with NSCLC who had an excellent response to pembrolizumab. In 
collaboration with Ton Schumacher’s lab, candidate neoantigens from this patient were synthesized 
and neoantigen-specific T cell reactivity was screen used prospectively collected autologous 
peripheral blood lymphocytes. A neoantigen-specific T cell response to a neoantigen resulting from 
a HERC1 P3278S mutation was detected in the peripheral blood and the increase in neoantigen- 
specific reactivity mirrored the clinical response to pembrolizumab. The T cell response was only 
detectable after starting therapy, increased rapidly initially, and then plateaued at levels just above 
background as tumor regression was maintained over the next year. This is the first neoantigen- 
specific T cell response identified in the peripheral blood of a patient treated with PD-1 blockade. 
 
This data has demonstrated clear differences in response to PD-1 blockade monotherapy based on 
mutation burden and a suggestion that neoantigens may be a fundamental component of directing 
an effective anti-tumor immune response during treatment. However, it is unknown whether a similar 
result will be seen in patients treated with combination PD-1 plus CTLA-4 blockade. There is 


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suggestion from combination studies that there may be a distinct molecular profile of responders to 
combination therapy. For example, in one study of NSCLCs treated with PD-L1 plus CTLA-4 
blockade, there was no difference in response rate by PD-L1 expression in this study(69). However, 
the study of ipilimumab plus nivolumab in NSCLC did show a persistent enrichment of response 
among patients whose tumors expressed PD-L1(1). Ultimately larger sample sizes from the ongoing 
Phase 3 studies will be needed to fully examine the impact of PD-L1 on response to combination 
immunotherapy in patients with NSCLC. 
 
Still, it remains unknown whether mutation or neoantigen burden associate with response to 
combination therapy. More broadly, and most importantly, there are currently no predictive markers 
of response to combination PD-1 plus CTLA-4 blockade. 
 
 
The goal of this study is to evaluate in parallel the individual components that are involved in T-cell 
recognition of lung cancers in order to comprehensively explore the mediators of sensitivity or 
resistance to nivolumab plus ipilimumab in patients with NSCLCs. Due to the multiple planned 
exploratory analyses, this trial is tissue-intensive and will focus on a specific set of patients from 
whom sufficient pre-treatment tissue can be feasibly obtained. Overall, our goals are to examine in 
parallel some of the individual components that are involved in T-cell recognition of lung cancers in 
order to more fully identify the potential mediators of sensitivity or resistance to combination therapy 
in patients with NSCLCs. 
Primary Objectives 
 
1) Mutational  burden: 
 
As above, in patients with lung cancers we have previously demonstrated that response to PD-1 
blockade monotherapy is greatest in patients with elevated somatic mutation burden. The 
examination of mutation burden in PD-1 treated patients was initially spurred by the observation that 
responders to nivolumab were almost exclusively former smokers, whose tumors are characterized 
by substantially greater mutational burden compared to never smokers (76, 77). For example, using 
provisional data available from The Cancer Genomic Atlas project (TCGA) (www.cbioportal.org), we 
found that smoking-related lung adenocarcinomas have on average 370 mutations/sample 
compared to never smokers with 86 mutations/sample (p<0.0001). In contrast, initial results of 
patients with NSCLCs treated with PD-1/PD-L1 plus CTLA-4 blockade suggests that smoking status 
is not associated with response to combination therapy. It remains an open question whether or how 
the molecular landscape of NSCLCs will determine response to combination immunotherapy. 


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We aim to prospectively evaluate the response rate to nivolumab plus ipilimumab in patients whose 
tumors are characterized by either high or low mutation burden. We will also compare the molecular 
landscape of patients treated with combination therapy to our previously generated data of the 
molecular features of patients treated with PD-1 blockade monotherapy. 
 
2) Identification of candidate neoantigens : 
 
Beyond a general increased mutational burden, there may be specific mutations that direct a T-cell 
response to cancer. In particular, non-synonymous somatic missense mutations have the potential   
to give rise to “neoantigens,” which are uniquely expressed in tumor tissue and may direct anti-tumor 
T-cell recognition. 
Neoantigens are tumor-specific antigens and should be differentiated from tumor-associated 
antigens, such as cancer-testis (CT) antigens, which are self-antigens that are expressed  
particularly but not exclusively on cancer cells (78). Although CT-antigen based therapies have been 
attractive targets for cancer immunotherapies (79, 80), none have yet demonstrated significant 
clinical activity in lung cancer (25). This lack of efficacy may be related to the fact that these antigens 
were subjected to thymic tolerance during early development which may restrain the degree to  
which an effective immunologic response can be mounted. By contrast, neoantigens are truly 
cancer-specific (81), are not subject to thymic tolerance, and have the potential to invoke a more 
significant T-cell response (82). 
MSKCC has pioneered the development of bioinformatic methods to identify candidate neoantigens 
using DNA sequencing of tumors. Segal et al (83) evaluated a set of 1152 somatic mutations found 
in 11 colon and 11 breast cancers and used in silico modeling of the predicted binding affinity of 
MHC I to peptide strings containing each mutation. Peptides with high affinity MHC I binding are 
considered effective epitopes for generating a T-cell response and may be important neoantigens. 
This study revealed an average of 7–10 mutated peptides/tumor that were predicted to be effective 
neoantigens. Additionally,  this study demonstrated that it was possible to use cancer genomics to 
identify mutations that are predicted to be immunologically relevant and that the identity and 
spectrum of neoantigens may be unique in each tumor. 
Building on this initial study, several recent pre-clinical studies have highlighted the importance of 
neoantigens and neoantigen-specific T-cells in cancers (84-87). Of note, DuPage et al (85) 
demonstrated in a murine model of lung cancer that neoantigen-specific T-cells quickly infiltrated 
tumors, but the quantity and function of these T-cells waned quickly over time. These functionally 
incompetent antigen-specific T-cells appeared to have an exhausted phenotype, characterized by 
increased expression of PD-1. This result may recapitulate the experience in human lung cancers 
and highlights how T-cell checkpoint blockade may be precisely what is needed to re-establish an 
effective tumor-directed T-cell response. 
In humans, the Schumacher lab at NKI has recently provided proof-of-concept that cancer genomic 
sequencing can be used to identify clinically relevant neoantigens (88). Using tumor (and matched 
normal) tissue from a patient with melanoma who had a durable response to ipilimumab, the authors 
performed whole exome sequencing to identify somatic mutations and found 1075 non- 


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synonymous mutations. This exome data was then combined with RNA expression data to focus 
only on expressed mutations. They then modeled the MHC I binding affinity of each predicted 
mutant protein. Those with high affinity were consider candidate neoantigens and were further 
studied in in vitro studies. Candidate neoantigens were synthesized to generate a large library of 
peptide-MHC  multimers. Using combinatorial coding, autologous T-cells were exposed to the 
peptide-MHC  multimers to evaluate reactive T-cell populations. Two neoantigen-specific T-cell 
responses were identified, including a dominant response (3.3% of CD8+ T cells) against a 
neoantigen derived from the ATR DNA damage response gene. Cultured TILs exposed to the wild- 
type version of ATR had no reactivity, but the addition of the mutant ATRS>L peptide resulted in a 
significant increase in T-cell reactivity. Additionally,  analysis of peripheral blood samples pre- and 
post- treatment with ipilimumab showed a five-fold increase in the frequency of mutant ATRS>L 
specific CD8+ T cells upon treatment. Intriguingly, it is possible (but not proven) that this specific T- 
cell clone may have mediated the tumor regression seen in this patient after treatment with 
ipilimumab. 
These studies have highlighted the importance of neoantigens and neoantigen-specific T-cells in 
mediating T-cell recognition and response to cancers. But these studies also demonstrate the 
complexity of identifying candidate neoantigens and neoantigen-specific T-cells, especially from 
human samples. We have developed a cross-disciplinary, cross-institutional collaboration to bring 
together the technical expertise needed to perform this study. Collectively, the ability to identify 
candidate neoantigens and neoantigen-specific T-cells may represent significant a breakthrough in 
the ability to model the interactions between the adaptive immune system and cancer and in the 
development of more effective (and more personalized) immunotherapies in the future. 
3) Identification of neoantigen-specific T-cells 
Neoantigens may represent to precise targets of the tumor-specific T-cells which are responsible for 
response to nivolumab. To complement and validate the in silico identification of candidate 
neoantigens, we will evaluate the presence of neoantigen-specific T-cells. The Schumacher Lab at 
NKI has developed in vitro methods for identifying neoantigen-specific T-cells using clinically 
relevant tissue materials (88). These methods, termed combinatorial coding, permit examination of 
T-cell reactivity to multiple candidate peptides in parallel. This system builds upon a peptide 
exchange model that uses a conditional peptide ligand that is cleaved in the presence of UV light to 
permit the generation of multiple different peptide-MHC complexes (89-91) and further includes 
fluorochrome-labeled MHC-peptide multimers such that each neoantigen of interest is coded by a 
unique set of fluorochromes (92, 93). 
To evaluate the presence of neoantigen-specific T-cells, candidate neoantigens identified from the 
whole exome/transcriptome analysis above will be synthesized and used to analyze autologous 
intratumoral T-cells and peripheral blood lymphocytes. Autologous  TILs and PBMCs isolated from 
the pre- and on-treatment (if feasible) as well as serial peripheral blood specimens which will be 
analyzed. 
Secondary Objectives 
 
4) MHC and co-stimulatory receptor/ligand expression 
The validity of tumor expression of PD-L1 as a predictive biomarker of response to anti-PD1 mAb is 
a topic of current debate. Tumors expressing PD-L1 contain tumor-infiltrating lymphocytes (TILs) 
that typically express PD-1 (37, 67, 94) but are dysfunctional (32, 95-98). These data support 


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the hypothesis that expression of PD-L1 on tumor cells or cells in the tumor microenvironment may 
be an adaptive mechanism of immune escape by binding to PD-1 on TILs and quieting a tumor- 
directed immune attack. 
In this context, it is further hypothesized that PD-L1 expression is needed for response to anti-PD1 
mAb, while tumors lacking PD-L1 are insensitive to anti-PD1 mAb and evade immune surveillance 
using alternate mechanisms (99). Currently available data suggest PD-L1 expression may enrich for 
response, but is neither necessary nor sufficient (24). We will integrate an evaluation of PD-L1 
expression, MHC expression, as well as other co-stimulatory ligands, in patients treated with 
nivolumab plus ipilimumab using IHC, flow cytometry, or other methods if become available. 
Study Therapy Summary: Nivolumab plus Ipilimumab 
 
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve 
antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN- 
production 2- 
to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased antitumor activity of the 
combination was also observed in 3 of 5 syngeneic murine cancer models. In a murine melanoma 
vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 
and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor 
infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either 
agent alone. 
 
The combination of nivolumab and ipilimumab was evaluated in CA209004 (MDX1106-04),  a Phase 
1b multiple ascending dose study in subjects with treatment-naive and previously treated advanced 
melanoma. Results showed promising activity, with higher, but tolerable toxicity than ipilimumab 
alone.16 Based on these data, CA209069, a phase 2 study, compared the combination to  
ipilimumab alone in treatment-naïve patients with advanced melanoma: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg every 3 weeks x4 followed by nivolumab 3 mg/kg every 2 weeks versus 
ipilimumab 3 mg/kg every 3 weeks x 4.12 In patients with BRAF wild type tumors, the ORR was 61% 
(44/72), including 22% (16/72) complete responses (CR) in the group treated with the combination, 
compared to 11% (4/37) with 0 CRs in those treated with ipilimumab alone. The median PFS was  
not reached in the combination versus 4.4 months for ipilimumab alone (HR=0.4). It should be noted 
that in the combination group, the ORR was independent of PD-L1 expression. In this group, ORR 
was 58% among patients with PD-L1+ tumors and 55% among those with PD-L1- tumors. In 
contrast, in the ipilimumab alone group, the ORR was numerically higher among patients with PD- 
L1+ tumors (18%) compared to those with PD-L1- tumors (4%). 
 
Grade 3-4 treatment-related AEs were reported in 54% of patients receiving the combination 
compared to 24% for ipilimumab alone. Ipilimumab has been shown to have activity in lung cancer. 
A Phase 2 study (CA184041) in subjects with NSCLC or small cell lung cancer (SCLC) investigated 
the addition of ipilimumab to carboplatin and paclitaxel using 2 different schedules (concurrent and 
phased). The phased schedule demonstrated a significant improvement of immune-related 
progression-free survival as well as progression-free survival by modified WHO criteria compared to 
chemotherapy alone, in both NSCLC and SCLC. 
 
Based on the initial data in melanoma, and the activity observed with nivolumab and ipilimumab in 
lung cancer, the nivolumab plus ipilimumab combination has been also evaluated as first-line 
therapy in patients with advanced NSCLC. In CA209012, early combination cohorts evaluated 2 
dosing schedules that were studied in the CA209004 study in melanoma: 
• 
nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 
weeks (arms G and H, n=24); 


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• 
nivolumab 3 mg/kg + ipilimumab 1 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 
weeks (arms I and J, n=25) 
 
These regimens resulted in significant toxicity, with 39% of patients discontinuing treatment due to a 
treatment-related adverse event. 
 
Thus, additional combination cohorts were initiated, using lower doses of both nivolumab and 
ipilimumab, or less frequent dosing of ipilimumab. Data from these cohorts demonstrate that both 
nivolumab 1 mg/kg + ipilimumab 1 mg/kg q 3 weeks with nivolumab maintenance 3 mg/kg q2w (arm 
N in study CA209012), as well as ipilimumab at 1 mg/kg q6w is tolerable, when given with nivolumab 
3 mg/kg q2w (arm Q in study CA209012). 
 
Overall, the safety data are not dissimilar to what has been observed in the nivolumab monotherapy 
arm (arm F in CA209012). Of particular note, the rate of discontinuation due to drug-related AEs was 
13% in arm N and 11% in arm Q compared to 10% in the nivolumab monotherapy arm (arm F). 
 
Arm 
Treatment 
N 
subjects/ 
arm 
Follow- 
up time 
(median, 
wks) 
N 
subjects 
still on 
treatmen 
t 
N 
subjects 
with 
drug- 
related 
AEs 
N 
subjects 
with 
grade 3- 
4 drug- 
related 
AEs 
N 
subjects 
d/c  due 
to drug- 
related 
AEs 
N 
Nivo 1mg/kg plus Ipi 
1mg/kg every three 
weeks x 4, followed by 
nivo 3mg/kg every two 
weeks) 
31 
57 
9 (29%) 
23 
(74%) 
9 (29% 
4 (13%) 
Q 
Nivo 3mg/kg every two 
37 
18 
19 
20 
9 (24%) 
4 (11%) 
weeks plus Ipi 1mg/kg 
(51%) 
(54%) 
every 6 weeks 
F 
Nivo 3mg/kg every two 
52 
62 
5 (10%) 
37 
10 
5 (10%) 
weeks 
(71%) 
(19%) 
 
Based on these data, the following schedule will be evaluated in this study: 
• 
Nivolumab (3 mg/kg every 2 weeks, i.e. the FDA approved dose in pretreated squamous 
NSCLC) with the highest dose and frequency of ipilimumab feasible (1 mg/kg every 6 
weeks). 


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4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
 
 
This will be a single-arm, single-institution, open-label, exploratory trial of combination therapy with 
nivolumab plus ipilimumab in patients with advanced NSCLCs. This is an analyses-intensive trial 
with multiple exploratory aims. Due to the tissue required to perform these analyses, eligible patients 
must have advanced NSCLCs and require a pre-treatment tumor resection as standard of care. 
However, if pre-treatment tumor resection is not clinically indicated as standard of care, patient may 
instead have a pre-treatment tumor biopsy.  For those patients undergoing pretreatment resection, 
patients must also have residual measurable disease following resection. 
The objectives of this exploratory trial are descriptive in nature. 
Primary objectives: 
1) Quantify mutational burden and identify candidate neoantigens: 
a. We will describe the response rate to nivolumab plus ipilimumab in patients with 
“high” and “low” somatic mutational burden (stratified about a median of 
mutations/sample) 
2) We will then identify candidate neoantigens by assessing the antigenicity of each expressed 
somatic mutation using an established bioinformatics platform. We will describe the 
association between the presence of candidate neoantigens and response to combination 
therapy. 
3) Identify neoantigen-specific T-cells: We will describe the ability to identify neoantigen-specific 
T-cells in vitro using MHC-multimer assays or similar technology. 
Secondary objectives 


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1)   Examine MHC and co-stimulatory receptor and ligand expression in tumor- 
microenvironment: We will describe the impact of the tumor expression of MHC, PD-L1, and 
other co-stimulatory ligands and receptors  on response to nivolumab. 
 
4.3 
Intervention 
 
Patients who are eligible and provide study consent will undergo screening procedures and 
evaluation by thoracic surgery (or other appropriate surgical/interventional radiological specialty) to 
discuss and plan standard-of-care surgical resection or biopsy (the biopsy is research non-billable 
unless performed for a standard-of-care reason). 
In those patients undergoing a resection, the CT scan of the chest (+/- abdomen/pelvis depending 
on sites of known disease) which will serve as the baseline for this protocol must be obtained after 
surgical procedure or biopsy has taken place. For those undergoing biopsy, the CT scan be 
performed before or after the biopsy but must be completed during the screening period. Additional 
screening procedures (including blood tests and EKG) may take place before or after surgical 
procedure or biopsy so long as they occur during the screening window. All screening procedures 
(including biopsies if performed) and scans must be done within 28 days of beginning study therapy 
with the exception of those undergoing tumor resections which may be performed within 12 weeks 
(84 days) before beginning study therapy so long as there has been no intervening systemic anti- 
cancer therapy. 
Following resection/biopsy and screening procedures, patients will begin treatment with nivolumab 
IV 3mg/kg and ipilimumab 1mg/kg. Treatment with nivolumab will continue every 2 weeks (+/- 3 
days) thereafter and treatment with ipilimumab will continue every 6 weeks (+/- 3 days) thereafter. 
Each treatment cycle will be defined as below: 
- 
C1D1: Nivolumab 3mg/kg + Ipilimumab 1mg/kg 
- 
C2D1 (+/- 3 days): Nivolumab 3mg/kg 
- 
C3D1 (+/-3 days): Nivolumab 3mg/kg 
- 
C4D1 (+/- 3 days): Nivolumab 3mg/kg + Ipilimumab 1mg/kg 
 
Treatment will continue until protocol-defined toxicity, confirmed progression of disease*, withdrawal 
of consent, or death. 
*Patients who experience initial progressive disease may continue therapy if they are 
experiencing clinical benefit. A CT scan should be repeated no earlier than 4 weeks after 
the first documentation of progressive disease. If there is more than10% additional 
progression compared to baseline (e.g. first scan showed 24% growth relative to 
baseline, second scan shows 36% growth relative to baseline), then study therapy  
should be discontinued. If, instead, <10% further progression is seen, the patient may 
continue study therapy until confirmed progression of disease so long as there is 
continued clinical benefit (detailed in Section 9.0). 


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Protocol-related research blood draws will occur during screening, before treatment on C1D1 (+/- 1 
day), C2D1 (+/- 3 days), C2D8 (+/- 1 day from date of on-treatment biopsy), C3D1 (+/-3 days), C4D1 
(+/- 3 days), C5D1 (+/- 3 days), and at the end-of-study visit. 
In addition to the baseline CT scan, which will occur after pre-treatment surgical resection or biopsy, 
tumor assessments will be performed with CT scans of the chest (+/- abdomen/pelvis depending on 
sites of known disease) every 6 weeks (+/- 1 week) while on treatment for up to 48 weeks. After 48 
weeks, CT scans will be performed every 12 weeks (+/- 1 week). CT scans should occur every 6 (or 
12) weeks throughout the patient’s time on study irrespective of treatment interruptions or delays. 
 
In addition to pre-treatment standard-of-care surgical resection or biopsy, a protocol-mandated 
tumor biopsy will be required at C2D8 (+/- 1 week) for all patients who remain on study at that time. 
The tumor biopsy should be optimally performed on a non-target lesion, if feasible. 
Study Size 
 
30 patients will be treated on this study. Patients who enroll on study but withdrawal study consent 
or for any other reason never receive study therapy will be considered a screen failure and will be 
replaced. Additionally,  in order to be considered eligible for the primary and secondary objectives 
described in this study, patients must receive (1) at least one dose of study therapy and remain on 
study until at least the first radiographic tumor assessment (week 6) or (2) at least one dose of study 
therapy and have clear clinical or radiographic progression prior to the planned first radiographic 
tumor assessment at week 6. Patients who come off study for reasons other than 
clinical/radiographic progression prior to the first radiographic tumor assessment will be replaced. 
4.3 Rationale for dosage of nivolumab plus ipilimumab 
 
The dose and schedule of nivolumab in combination with ipilimumab in this proposed study is 
nivolumab  3 mg/kg every 2 weeks and ipilimumab 1mg/kg every 6 weeks. This dose and schedule 
selection was based on results of safety, efficacy, and exposure-response analyses obtained from 
the CA209-012 study (MSKCC IRB # 11-189). 
4.5 Pre-treatment tumor resection or pre-treatment biopsy 
 
Pre-treatment tumor tissue will be obtained via surgical resection or biopsy from all patients enrolled 
on study. Tumor resections may be performed within 12 weeks (84 days) before beginning study 
therapy so long as there has been no intervening systemic anti-cancer therapy. Biopsies will be 
performed within the 28 day screening window. 
Tumor resections will be standard-of-care. Possible indications may include a painful skin or lymph 
node metastasis or pleural effusions with pleural metastases which require resection and 
pleurodesis. However, if a standard-of-care tumor resection is not clinically indicated, patient may 
still fulfill pre-treatment tumor tissue requirements by having a biopsy which will be considered 
research non-billable unless otherwise indicated. 
Initial processing of tissue from resection: In the case of those patients undergoing pre-treatment 
tumor resections, a portion of resected tumor tissue will be sent to pathology for diagnostic 


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confirmation of NSCLC and any other testing with may be required. A separate portion of tumor 
tissue (at least 1 x 1 x 1cm in aggregate size) will be collected from the OR or procedure room by a 
dedicated research assistant. 
Resected tumor tissue will be delivered directly to the Wolchok Lab in ZRC15 and partitioned into at 
least three parts: 
- 
One portion will be snap frozen for future DNA and RNA extraction. 
- 
One portion will be processed as single-cell suspensions of tumor and infiltrating immune 
cells and then snap frozen for future T-cell assays. 
- 
One portion will be processed as formalin-fixed tissue and will be embedded in paraffin for 
future IHC assays. 
 
And if sufficient tissue is available: 
 
- 
One portion will be processed fresh and infiltrating T-cells will also be isolated. 
 
Initial processing of tissue from biopsy: In the case of those patients undergoing pre-treatment 
biopsies, image-guided core needle tumor biopsies are recommended. 
 
Patient will undergo up to 5 core biopsies, if can be performed safely: 
 
- 
Core #1 and #3 will be snap frozen for future DNA and RNA extraction. 
- 
Core #2 will be placed in formalin, fixed, and embedded in paraffin. 
- 
Core #4 and #5 (or more) will be processed either as snap frozen or as single-cell 
suspensions of tumor and infiltrating immune cells and then snap frozen for future antigen- 
specific T-cell assays. 
If it is only possible to safely obtain fewer than five cores, priority will be given as numbered above. 
 
A research assistant or investigator will be present at the time of the either resection or core biopsy 
to assess with material handling and processing. 
Sufficient material must be collected to permit at least (1) frozen material for DNA/RNA extraction, 
and (2) FFPE material for IHC. Within 5 business days of each collected case, the adequacy of material 
collected with be reviewed  and determination  made regarding  eligibility. 
4.6 On-treatment tumor biopsy 
 
On-treatment tumor tissue will be obtained from all patients enrolled on study on C2D8 (+/- 1 week). 
 
Image-guided core needle tumor biopsies are recommended and the biopsied lesion is preferred not 
to be a target lesion. 
Patients will undergo up to 5 core biopsies, if can be performed safely: 
 
- 
Core #1 and #3 will be snap frozen for future DNA and RNA extraction. 
- 
Core #2 will be placed in formalin, fixed, and embedded in paraffin. 


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- 
Core #4 and #5 (or more) will be processed either as snap frozen or as single-cell 
suspensions of tumor and infiltrating immune cells and then snap frozen for future antigen- 
specific T-cell assays. 
If it is only possible to safely obtain fewer than five cores, priority will be given as numbered above. 
 
A research assistant or investigator will be present at the time of the core biopsy to assess with 
material handling and processing. 
4.7 Tumor-based studies 
 
Tumor (and matched normal) whole exome and transcriptome sequencing for evaluation of 
mutational burden: 
Tumor DNA, matched normal DNA, and tumor RNA will be extracted for whole exome and 
transcriptome analysis. Once DNA has been obtained and extracted, we will perform massively 
parallel sequencing of the whole exome of the tumor tissue and the available normal tissue. 
Genomic DNA will be captured via solution-based hybrid selection and sequenced on the Illumina 
HiSeq platform. Matched normal DNA will also be collected from whole blood and sequenced in 
conjunction with somatic tumor DNA. This is necessary to make variant calls in next-generation 
sequencing assays. It is not the intent of this analysis to utilize these samples to identify germline 
susceptibility mutations. However, in the course of investigating somatic sequence variations, 
germline susceptibility variants may be suggested by comparative germline sequencing. In addition, 
some somatic mutations are themselves directly suggestive of a germline predisposition (e.g. 
BRCA1). 
The following plan will be followed by MSKCC investigators who identify a potentially actionable 
incidental finding in the course of research conducted on samples collected under this protocol: 
In the event an investigator’s research identifies a finding that he or she believes should 
be communicated to the subject (and/or family designee), the investigator shall 
communicate this to the OCR-IRB. The finding will be reviewed by a group convened by 
the IRB to determine whether the incidental finding should be discussed with the subject. 
In the event that group convened by the IRB determines that the finding should be 
discussed with the subject, and the subject has consented to be re-contacted, then the 
treating/consenting physician shall be contacted by the OCR-IRB representative and 
asked to refer the subject to the Clinical Genetics Service for further discussion of th 
research finding. After appropriate counseling and consent, the Clinical Genetics Service 
will request permission to confirm the result in a New York DOH-approved laboratory prior 
to communication of the specific result. If the patient is not available (e.g. deceased), then 
the surrogate designated on the consent will be contacted and the above will occur. 
Germline BAM files will not be separately analyzed in the future without additional informed consent 
(such as responded YES to question 4 on the IRB# 06-107 consent form or consenting to IRB #12- 
245), anonymization, and/or human subjects review by this committee or the IRB. 
The somatic sequencing data will be analyzed for base mutations, insertions, fusions, deletions, copy 
number alterations  and in all target genes. Exon capture will be performed using the SureSelect 


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Human All Exon 50MB kit (Agilent). Enriched exome libraries will be sequenced on the HiSeq 2000 
platform (Illumina) to >100X coverage. Raw sequencing data will be mapped to the human reference 
genome using the BurrowsWheeler Aligner (BWA). All filtered candidates will be annotated and 
manually reviewed (103) using the Integrated Genomic Viewer (IGV) (104). Mutations will be 
annotated using SnpEffect (105). In order to improve quality of calls in these FFPE samples, mutations 
will be analyzed using four callers: Somatic Sniper (106), VarScan (107),  Strelka (108) and MuTect 
(109) then filtered by allelic frequency of each alteration in tumor (>10%) and normal (<3%), depth of 
coverage (≥7X) and call quality. Calls made by only one caller will be manually reviewed using IGV 
(104). 
Whole transcriptome tumor mRNA will be sequenced using next-generation sequencing. Briefly, 
after ribogreen quantification and quality control of Agilent BioAnalyzer  (RIN>7), poly(A) RNA will be 
isolated using Dynabeads® mRNA DIRECT™ Micro Kit(Life Technologies) from 1ug of total RNA. 
mRNA is then fragmentated using RNaseIII and purified. The Fragmented Samples quality and yield 
are evaluated using Agilent BioAnalyzer. Subsequently, the fragmented material will undergo Whole 
transcriptome Library preparation according to the Ion Total RNA-Seq Kit v2 protocol (Life 
Technologies), with 12 to 16 cycles of PCR. Samples will be barcoded, template-positive Ion PI™ 
Ion Sphere™ Particles (ISPs) will be prepared using the ion one touch system II and Ion 
PI™Template OT2 200kit v2 Kit (Life Technologies). Enriched particles will be sequenced on a 
Proton sequencing system using 200bp version 2 chemistry. An average of 70 to 80 million reads 
will be generated per samples. 
Bioinformatic Analysis - identification of candidate neoantigens : 
 
We have developed a bioinformatic pipeline to use whole exome sequencing to identify candidate 
neoantigens. Neoantigens are modeled in silico by examining the components of antigen 
presentation on MHC (antigenicity) (110). Expressed somatic missense mutations are translated into 
pairs of short peptide strings: one including the mutation and one corresponding to the wild-type 
sequence. Next, in silico analysis is performed using NetMHC  (http://www.cbs.dtu.dk/services/  
NetMHC-3.2/   (111, 112)) or similar algorithm to predict the binding affinity of a given peptide for 
patient-specific MHC I. IEDB (http://www.iedb.org (84)) can also used to predict the induction of a T- 
cell response to a given amino acid peptide sequences or that have sequence homology to known 
antigens. Candidate neoantigens of particular interest will be identified by having predicted class I 
MHC binding affinity to patient-specific HLA alleles of at least 500nM. 
The binding affinity of a given candidate neoantigen is dependant in part on the specific MHC I and II 
alleles that are presenting the antigen. Although initial studies restricted analysis to the predicted 
binding affinity to HLA-A*02:01 (83), the most common allele in Caucasians, NetMHC 3.2 is now  
able to predict the nanomolar peptide binding affinity of nearly any human HLA allele (113). Exome 
sequencing done above may not provide sufficient coverage to accurately determine the patient- 
specific HLA allele, so HLA typing may be performed separately using normal DNA. 
Co-stimulatory receptor and ligand expression: 
FFPE tumor tissue collected from pre-treatment tumor resection and on-treatment biopsy will be 
examined for expression of PD-L1 on tumor and microenvironment cells by immunohistochemical 
(IHC) staining with the 28-8 antibody, and/or alternative method(s) if available. 3rd  party vendors 


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have also developed IHC stains which may be used. In addition to PD-L1, there are other surface 
markers that may mediate immunogenicity and selective sensitivity to different immunotherapy 
approaches. These include, but are not limited to, MHC I, MHC II, PD-1, LAG-3, TIM-3  which can 
be examined by IHC, immunofluorescence, and/or flow cytometry. 
 
 
 
 
 
 
 
4.8 Peripheral blood-based studies 
 
Identification of neoantigen-specific TILs and PBMCs: 
To evaluate the presence of neoantigen-specific T-cells from TILs and/or PBMCs, candidate 
neoantigens identified from the whole exome/transcriptome analysis above will be synthesized and 
used to analyze autologous T-cells. Autologous T-cells will be collected in the form of either single 
cell suspensions of T-cells and/or as CD3/CD4/CD8+ selected cells isolated fresh from resected, 
digested tumor tissue and/or PBMCs. 
Isolated T-cells will be frozen and examined at MSKCC or in collaboration with outside investigators 
with relevant expertise (MTA will be obtained). All biospecimens will be anonymized and labeled with 
a unique study ID prior to analysis. Coding linking the identifiers with the unique study ID will be 
retained by the listed investigators at MSKCC, but will not be shared outside of the institution. 
To identify neoantigen-specific T-cells, the Schumacher lab has developed a technology called 
combinatorial coding (89, 93) that permits high-throughput detection of antigen-specific T-cells to 
multiple potential antigens in parallel. Briefly, using synthesized peptides from candidate 
neoantigens, large quantities of fluorochome-labeled peptide-MHC  complexes are generated such 
that each neoantigen is coded by a unique fluorochrome combination. Then, using conditional MHC 
ligands that are cleaved upon exposure to UV-light, empty, peptide-reactive MHC molecules are 
then be exposed autologous T-cells and reactivity of TILs to peptide-MHC complexes will be 
assessed and quantified by flow cytometry. Neoantigen-specific T-cells will be isolated and may be 
expanded and used for future experiments, including treatment of autologous PDX models. 
In addition to these methods, the Wolchok lab has also developed methods for identifying antigen- 
specific T-cell responses by IFN-gamma ELISpot assay, tetramer staining, and ICS assay. These 
assays had been well validated at Immune Monitoring Core at MSKCC (114). 
For the ELISpot assay, multi-screen IP plates will be coated with 10 ug/ml anti-human IFN- gamma T 
cells will be re-stimulated with neoantigen derived peptides, then IFN-gamma production detected 
by addition of biotinylated mouse-anti-human IFN-gamma Ab using the AEC substrate Vector ABC kit 
(Vector Laboratories, Burlingame, CA) and analyzed with an Automated CTL ImmunoSpot Analyzers 
(C.T.L., Shaker Heights, OH). For tetramer staining, HLA-class I-PE labeled tetramers will be loaded 
with neoantigen peptides (Tetramer Core, Lausanne Branch, Ludwig Cancer Research).  5 × 105  cells 
are incubated with 0.5 µl of peptide-loaded tetramer, followed by incubation with antibodies to surface 
markers  (PE-Cy7-CD3, APC-CD27, PerCPCy5.5-CD28 [BD, Pharmingen,  San  Jose,  CA],  APC- 


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AF750-CD8 [eBioscience, San Diego, CA], ECD-CD45RA [Beckman Coulter Inc., Fullerton, CA] and 
FITC-CCR7 [R&D Systems, Minneapolis]). Cells are acquired using a CYAN flow cytometer (Dako 
Cytomation California Inc., Carpinteria, CA) and analyzed using FlowJo software (version10.1; 
TreeStar, Inc.). Intracellular  cytokine staining: Two million cultured autologous patient T cells (PBMC 
or TILs) are incubated with PE-Cy5-CD107a then stimulated with the addition of neoantigen peptides 
followed by Brefeldin A and monensin (BD Bioscience). After staining with pacific blue-CD3, APC- 
AF750-CD8 (Ebioscience) and ECD-CD4 (Beckman Coulter), washing and permeabilizing, the cells 
are stained with FITC-IFN-gamma PE-Cy7-TNF-alpha and APC-IL-2 (BD Pharmingen) and analyzed 
by flow cytometry as described above. 
As improvements in technology and scalability permit, alternative strategies for identifying 
neoantigen-specific T cells in treated patients may be explored. 
 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Product description - Nivolumab 
Description 
Potency 
Primary 
packaging(volu 
me)/label type 
Secondary 
packaging(qty)/labe 
l type 
Appearance 
Storage 
conditions (per 
label) 
“BMS-936558-01 
Solution for Injection” 
Injection drug product 
is a sterile, non- 
pyrogenic, single-use, 
isotonic aqueous 
solution formulated at 
10 mg/mL 
100mg 
(10mg/mL) 
10 mL per 
vial/Open-label 
10 vials per 
carton/Open-label 
Clear to 
opalescent 
colorless to pale 
yellow liquid. May 
contain particles. 
2 to 8 degrees 
Celsius. 
Protect from 
light and 
freezing. 
Ipilimumab Solution 
for Injection 
200 mg (5 
mg/ml) 
40 ml vial 
4 vials per 
carton/Open-label 
Clear, colorless to 
pale yellow liquid. 
May contain 
particles 
2 to 8 degrees 
Celsius. 
Protect from 
light and 
freezing. 
 
 
Ordering of Nivolumab and Ipilimumab 
 
Following submission and approval of the required regulatory documents, a supply of nivolumab and 
ipilimumab may be ordered from by completing a Drug Request Form. The first request may take 
place upon screening of the first patient. 
Nivolumab vials (10 mL) are shipped in quantities of ten. The initial order should be limited to 20 vials 
(2 cartons of 10 vials each). Ipilimumab vials (40 mL) are shipped in quantities of four. Allow 5 business 
days for shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but 
not patient specific. All drug product will be shipped by courier in a temperature-controlled container. 
It is possible that sites may have more than one nivolumab clinical study ongoing at the same time. It 
is imperative that only drug product designated for this protocol number be used for this study. 
Drug re-supply request form should be submitted electronically business days before the expected 
delivery date.  Deliveries will be made Tuesday through Friday. 


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When assessing need for resupply, institutions should keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of request. Drug is not 
patient-specific. Be sure to check with your pharmacy regarding existing investigational stock to 
assure optimal use of drug on hand. 
Storage of Nivolumab and Ipilimumab 
 
Nivolumab and Ipilimumab should be stored in a secure area according to local regulations. 
Temperature monitoring of the storage area must be performed by site as per local practice and 
any temperature deviations reported to Sponsor. The product storage manager should ensure 
that the study drug is stored in accordance with the environmental conditions (temperature, light, 
and humidity) as described in the Investigator’s Brochures. Nivolumab and Ipilimumab vials must 
be stored at a temperature between 2°C and 8°C and should be protected from light and  
freezing. These products do not contain anti-microbial preservative nor bacteriostatic agent so 
care must be taken to assure drug sterility. 
After nivolumab has been prepared for administration, the total storage time (combination of 
refrigeration and room temperature) is not to exceed 24 hours. IV bags containing undiluted and 
diluted solutions of nivolumab injection prepared for dosing may be stored up to 20 hours in a 
refrigerator at 2°-8°C (36°-46°F) and used within 4 hours at room temperature and under room light. 
The maximum 4-hour period under room temperature and room light conditions for undiluted and 
diluted solutions of Nivolumab injection in the IV bag should be inclusive of the product 
administration period. 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. 
After ipilimumab has been prepared for administration, the total storage time (combination of 
refrigeration and room temperature) is not to exceed 24 hours. IV bags containing undiluted and 
diluted solutions of ipilimumab injection prepared for dosing may be stored up to 24 hours in a 
refrigerator at 2°C to 8°C or at room temperature/room light. The maximum 24 hour period under 
room temperature and room light conditions for undiluted and diluted solutions of ipilimumab 
injection in the IV bag should be inclusive of the product administration period. 
Detailed instructions on prepared drug storage and use can be found in the Investigator 
Brouchures, under “Recommended Storage and Use Conditions.” 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as described in the Investigator’s 
Brochure. 
Dispensing of Nivolumab and Ipilimumab 
 
It is the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational  product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
Nivolumab and ipilimumab product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 


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administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g., required diluents, administration sets). 
Nivolumab and Ipilimumab Dosing 
 
Patients will receive treatment with nivolumab as a 30 minute infusion 3 mg/kg every 2 weeks and 
ipilimumab as a 30 minute infusion 1 mg/kg every 6 weeks, starting on Day 1, until progression, 
unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first. 
 
 
 
When nivolumab and ipilimumab are to 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. 
 
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. 
 
Dosing calculations should be based on the body weight assessed during screening. 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 per local standards for rounding. 
 
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. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab and/or ipilimumab 
administration. If an acute infusion reaction is noted, subjects should be managed according to 
Section 11.4. 
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment. See Sections 11.5-11.7 for more details regarding 
dose delays, retreatment, and discontinuations. 
Destruction of Nivolumab and Ipilimumab 
 
Study drugs supplied by BMS such as partially used study drug containers, vials and syringes may 
be destroyed on site and their disposition should be recorded on an investigational drug 
accountability form according to the institution’s SOP. 
On-site destruction is allowed provided the following minimal standards are met: 
 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances. 


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• 
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request. 
• 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
• 
Accountability and disposal records are complete, up-to-date, and available for BMS to 
review throughout the clinical trial period. 
 
 
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. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.2 
Subject Inclusion Criteria 
 
1. Patient must be capable, willing, and able to provide written, informed consent. 
2. ≥ 18 years old. 
3. Advanced stage NSCLC 
4. Previously treated with no more than two lines of prior systemic therapy for advanced stage 
lung cancer. 
a. Patients who previously received neoadjuvant, concurrent, or adjuvant chemotherapy 
for localized NSCLC and then recurred within 6 months of completing chemotherapy 
may be considered as having received one line of prior therapy 
b. Maintenance therapy does not count as a separate line of therapy 
5. Patients must: 
a. Be scheduled to undergo a standard-of-care resection of tumor tissue as part of 
treatment plan prior to beginning study therapy OR have pre-treatment biopsy. 
Patients may not have intervening systemic anti-cancer therapy between the time of 
resection/biopsy and treatment with nivolumab. 
b. Have collection of adequate pre-treatment tissue for correlative analysis defined as 
sufficient material for 1) frozen tissue for DNA/RNA extraction, 2) FFPE material for 
IHC. Adequacy of collected material will be determined within 5 business days of 
each collected case. 
c. Have measurable by RECIST v1.1 (those undergoing pre-treatment resection must 
have imaging assessment after resection to determine measurability) 
i. Previously irradiated sites of tumor may be considered measurable if there is 
radiographic progression at that site subsequent to the time of completing 
radiation. 


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d. Have a safely biopsiable tumor lesion 
6. ECOG performance status of 0-1. 
7. Adequate hematologic, renal, and/or hepatic function (following criteria must be met within 28 
days of C1D1): 
a. WBC ≥ 2,000/ul 
b. ANC ≥ 1,500/ul 
c. Hemoglobin ≥ 9.0 g/dl 
d. Platelet count ≥ 100,000/ul 
e. Total bilirubin ≤ 1.5 x ULN (unless evidence of Gilbert’s syndrome, in which case, 
direct bilirubin must be ≤ 1.0 x ULN) 
f. 
AST and ALT ≤ 3 x UNL (unless elevated transaminases are felt to be directly related 
to metastatic disease involving the liver, in which case AST and ALT must be ≤ 5x 
ULN) 
g. Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance of ≥ 40 mL/min 
calculated using the formula of Cockcroft and Gault: (140-Age) • Mass (kg)/(72 • 
creatinine mg/dL); multiply by 0.85 if female 
8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy 
test (minimum  sensitivity  25 IU/L or equivalent units  of  HCG)  within 3 days prior to the 
start of study drug. 
9. Effective contraception: 
h. Women of childbearing potential must agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 23 weeks (5 
half-lives plus 30 days, the duration of an ovulatory cycle) after the last dose of 
nivolumab, or agree to completely abstain from heterosexual intercourse. 
i. 
Male subjects, even if surgically sterilized (i.e., status post vasectomy) must agree to 
1 of the following:  practice effective barrier contraception during the entire study 
treatment period and through 31 weeks (5 half-lives plus 90 days, the duration of 
sperm turnover) after the last dose of study drug, or completely abstain from 
heterosexual intercourse. 
6.3 
Subject Exclusion Criteria 
 
10. Patients who are pregnant or lactating. 
11. Presence of activating EGFR mutations or ALK re-arrangement unless previously treated 
with standard TKI therapy. All patients with adenocarcinoma histology must be tested for 
EGFR and ALK status. 
12. History of allergy to study drug components or history of severe hypersensitivity reaction of 
any monoclonal antibody. 
13. Prior treatment with immune checkpoint inhibitor, including (but not limited to) those targeting 
PD-1, PD-L1, PD-L2, CTLA-4, CD137, GITR, TIM3, LAG3, or OX40 
14. Any systemic anti-cancer therapy within 3 weeks prior to C1D1 of study therapy 


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j. 
Exception is made for patients with EGFR or ALK re-arrangements who must have 
stopped TKI therapy at least 7 days prior to C1D1 
15. Patients who have not previously been treated with platinum-based based doublet 
chemotherapy and who, in the judgment of the investigator, have rapidly progressive disease 
such that serious complications may arise from disease progression within the next 12 weeks 
will be excluded 
16. Non-CNS radiotherapy within 1 week prior to C1D1 of study therapy 
17. Active infection requiring therapy 
18. Prior or current systemic immunosuppressive therapy (> 10 mg/day prednisone equivalents) 
within 1 week prior to C1D1 of study therapy. Inhaled, ocular, intra-articular, intranasal, and 
topical corticosteroids are permitted in absence of active autoimmune disease. 
k. Adrenal replacement doses are permitted in the absence of active autoimmune 
disease. 
19. Patients with known or suspected history of autoimmune disease. Subjects with type I 
diabetes melitis, hypothyroidism only requiring hormone replacement, resolved childhood 
asthma/atopy, patients with asthma requiring intermittent bronchodilator therapy, 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. 
20. Other active malignancy requiring concurrent intervention. 
21. Patients with previous malignancies  (except  non-melanoma  skin  cancers, and  the 
following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are 
excluded unless definitive therapy has been completed at least 1 year prior to study entry 
and the patient is now without evidence of disease from that malignancy and no additional 
therapy is required or anticipated to be required during the study period. 
22. Known untreated brain or leptomeningeal metastasis. 
l. 
Patients with brain metastases are eligible if metastases have been adequately 
treated and neurologically returned to baseline (except for residual signs or 
symptoms related to the CNS treatment) for at least two weeks prior to C1D1. 
23. Patients with interstitial lung disease that is symptomatic or may interfere with the detection 
or management of suspected drug-related pulmonary toxicity. 
24. Any positive test for HIV 
25. Any positive test for HCV RNA or HBsAg. 
 
7.0 
RECRUITMENT PLAN 
 
A member of the patient’s treatment team, the protocol investigator or research team at Memorial 
Sloan-Kettering Cancer Center will identify potential research participants. If the investigator is a part 
of the treatment team, s/he will screen the patient as to eligibility, and will discuss the study and the 
possibility of enrollment in the research study with the patient. The preliminary screen of eligibility 
will be confirmation of the diagnosis of NSCLC, ascertaining the exact stage of the disease, and 
confirmation of the presence of appropriate need for pre-treatment tumor resection. 


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Potential subjects that meet these basic criteria may be referred by their treating physician to the 
investigator/research staff of the study. Minorities and women are well represented in the thoracic 
oncology clinics, and we expect that they will be well represented in the trial accrual. The principal 
investigator will be available to all patients for further questions and information through a contact 
number which will be provided on the consent form itself. 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical records 
at MSKCC in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. 
8.1 
PRETREATMENT EVALUATION 
 
All aspects of the screening evaluation should be completed within four weeks of starting treatment 
unless otherwise noted. 
• 
Documented (or suspected) histologic/pathologic diagnosis of NSCLCs and 
radiographic/pathologic  evidence of advanced stage disease 
o Patients who are highly suspected to have advanced stage NSCLCs and who are 
planned for a standard-of-care diagnostic tumor resection or biopsy may also be 
enrolled. Patients who are confirmed to have advanced stage NSCLCs will be eligible 
to continue with screening procedures. Those who are found after surgery/biopsy to 
not have advanced stage NSCLCs will not be eligible continue with screening 
procedures and may not receive study therapy. 
 
• 
Standard-of-care tumor resection or pre-treatment biopsy (resection within 12 weeks of 
beginning nivolumab plus ipilimumab, biopsy within screening period) and successful 
collection of sufficient pre-treatment tumor tissue for planned correlative studies. If patient is 
a candidate for a standard-of-care tumor resection, patient will be consented to a separate 
screening consent to permit collection of tissue at the time of the procedure, in addition to 
tissue that will be collected for routine pathology evaluation. 
• 
Full medical history. 
• 
Physical examination, complete vital signs (pulse, blood pressure, temperature, respiratory 
rate, oxygen saturation), as well as weight and height. 
• 
12-lead electrocardiogram (EKG) recorded at MSKCC at any point in the last 3 months. 
• 
Performance status by ECOG. 
• 
Baseline tumor assessment with CT scans at least of the chest (+/- abdomen/pelvis 
depending on sites of known disease) but should also include all known non-CNS sites of 
disease. Tumor burden must be measurable using RECIST 1.1. IV and PO contrast is 
preferred but not required. 
o For those undergoing resection, the screening CT scan which will be used for the 
baseline tumor measurements during this protocol should be obtained after the 
patient has completed the pre-treatment tumor resection. Other screening 


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assessments may be completed prior to or after tumor resection, so long as they 
occur during the screening period. 
• 
Serum or urine pregnancy test for women of childbearing potential must be performed within 
3 days prior to the initial administration of study therapy. 
• 
Complete blood count with differential. 
• 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, bilirubin, alkaline 
phosphatase, ALT, AST), magnesium, LDH, amylase, lipase 
• 
HIV antibody, Hepatitis B surface antigen, Hepatitis C antibody (with RNA if antibody is 
positive) 
• 
Thyroid function test (TSH, with reflexive free T4/T3 if TSH is abnormal). 
• 
Research blood: 
o Germline DNA 
o PBMCs 
9.1 
TREATMENT/INTERVENTION PLAN 
 
This protocol is an open-label, single-arm, phase 2 trial of nivolumab plus ipilimumab patients with 
advanced NSCLCs. 
Nivolumab and Ipilimumab 
 
Patients will receive treatment with nivolumab at a dose of 3 mg/kg as a 30-minute IV infusion, on 
Day 1 of each treatment cycle every 2 weeks. Patient will receive treatment with ipilimumab at a 
dose of 1 mg/kg as a 30 minute infusion every 6 weeks. The second infusion on combination 
treatment days will always be ipilimumab and will start approximately 30 minutes after completion of 
the nivolumab infusion. This treatment schedule will continue until progression, unacceptable 
toxicity, withdrawal of consent, or the study ends, whichever occurs first. 
Dosing calculations should be based on the body weight at time of screening visit. It is not 
necessary to re-calculate the dose if the patient’s weight is within 10% of baseline weight or prior 
dose weight. All doses should be rounded to the nearest milligram. 
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed. Patients may 
be dosed no less than 12 days from the previous dose. There are no premedications recommended 
for nivolumab on the first cycle. 
Patients should be carefully monitored for infusion reactions during nivolumab and ipilimumab 
administration. If an acute infusion reaction is noted, subjects should be managed according to 
Section 11.4. 
Doses of nivolumab or ipilimumab may be interrupted, delayed, or discontinued depending on how 
well the subject tolerates the treatment. See Sections 11.5-11.7 for more details regarding dose 
delays, retreatment, and discontinuations. 
Cycle 1 Day 1: Initiation of nivolumab plus ipilimumab 


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At each study visit, performance status, vital signs (including oxygen saturation), a physical exam, 
toxicity evaluation, review of current medications and blood tests will be performed. Blood tests must 
be performed on the day of the study visit. 
Nivolumab 3mg/kg IV and ipilimumab 1mg/kg will be initiated on cycle 1, day 1. 
 
 
 
 
 
Cycle 2 Day 1 (+/- 3 days) – Treatment visit, blood collection, toxicity visit 
 
At each drug-administration visit, performance status, vital signs (including oxygen saturation), a 
physical exam, toxicity evaluation, review of current medications and blood tests will be performed. 
Blood tests must be performed on the day of the study visit or within the 2 days prior to the study 
visit. 
Patient will be treated with Nivolumab 3mg/kg IV alone on Cycle 2 Day 1. 
 
Cycle 2 Day 8 (should be same day as C2D8 biopsy, +/- 1 day from date of biopsy) – Research 
blood collection 
 
Patients will have research blood collection on C2D8. 
Cycle 2 Day 8 (+/- 1 week) – On-treatment tumor biopsy 
An on-treatment tumor biopsy of (ideally) a non-target lesion will occur on C2D8 (+/- 1 week, i.e. 
during week 3-4 of study treatment). Acceptable samples include core needle biopsies for tumor 
tissue or lymph nodes or excisional, incisional, punch, or forceps biopsies for cutaneous or 
subcutaneous lesions. The safest and most feasible tissue biopsy is preferred and will be at the 
discretion of the treating physician. For core needle biopsies, five cores are preferred but at least 
three cores should be obtained; 1 will be fixed in formalin, 3 will be immediately frozen and then 
stored, and 1 will be processed fresh to isolate CD4/CD8+ cells prior to freezing. 
 
Cycle 3 Day 1 (+/- 3 days) – Treatment visit, toxicity visit 
 
At each drug-administration visit, performance status, vital signs (including oxygen saturation), a 
physical exam, toxicity evaluation, review of current medications and safety blood tests will be 
performed. Blood tests must be performed on the day of the study visit or within the 2 days prior to 
the study visit. Research bloods will be collected at C3D1 visit. 
Patient will be treated with Nivolumab 3mg/kg alone on C3D1. 
Cycle 4 Day 1 (+/- 3 days) – Treatment visit, toxicity visit 
At each drug-administration visit, performance status, vital signs (including oxygen saturation), a 
physical exam, toxicity evaluation, review of current medications and safety blood tests will be 
performed. Blood tests must be performed on the day of the study visit or within the 2 days prior to 
the study visit. Research bloods will be collected at C4D1 visit. 


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Patient will be treated with both Nivolumab 3mg/kg and Ipilimumab 1mg/kg on C4D1. 
Subsequent study visits 
Patients will return for nivolumab administration, blood collection, and toxicity visit every two weeks 
(+/- 3 days) thereafter. Patient will be treated with both nivolumab and ipilimumab on Day 1 of every 
third cycle (i.e. every six weeks, +/- 3 days). Performance status, vital signs (including oxygen 
saturation), a physical exam, toxicity evaluation, review of current medications, and blood tests will 
be performed at each visit. Research bloods will be collected at C5D1 and at end-of-treatment visit. 
Blood tests must be performed on the day of the study visit or within the 2 days prior to the study 
visit. 
 
Tumor assessment with CT scan – Beginning W eek 6 (+/- 1 week) 
 
Tumor assessments must include at least CT scans of the chest (+/- abdomen/pelvis depending on 
sites of known disease). IV (and PO, if abdomen/pelvic CT obtained) contrast is preferred but not 
required. Bone or PET scans are not adequate for assessment of RECIST 1.1 response in target 
lesions. The same radiographic procedure should be used to assess disease sites at screening 
should be used throughout the study (e.g. the same contrast protocol for CT scans). All known sites 
of disease must be documents at screening and re-assessed at each subsequent tumor evaluation 
(with exception of CNS lesions which do not need to be examined at each assessment). Scans 
should be performed and response assessed by RECIST v1.1 prior to patient’s next study visit to 
determine if treatment should be continued. 
Tumor assessments will be performed after 6 weeks (+/- 1 week) and subsequently every six week 
(+/- 1 week) while on study until week 48. After week 48, tumor assessments will be conducted 
every 12 weeks (+/- 1 week).  Additional tumor assessments may be performed at the discretion of 
the treating physician. 
 
Toxicity monitoring and adverse events 
 
Patients should be assessed for toxicity at least every 2 weeks so long as patient remains on study. 
Safety blood tests must be performed on the day of the study visit or within the 2 days prior to the 
study visit. 
Toxicity will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI CTCAE v4.0. 
Follow-up Assessments Prior to Progression of Disease 
 
Patients who discontinue study treatment early for reasons other than disease progression (e.g. 
toxicity) should continue to undergo scheduled tumor assessments per protocol until the patient 
experiences confirmed progression, starts new anti-cancer treatment, withdraws consent, or dies, 
whichever occurs first. 
 
Treatment beyond Disease Progression: 


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Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD (115). Subjects  treated  with nivolumab plus 
ipilimumab  will  be  permitted  to  continue  nivolumab plus ipilimumab  treatment  beyond initial 
RECIST 1.1 defined PD, assessed by the investigator, as long as they meet the following criteria: 
• 
Investigator-assessed clinical benefit, and do not have rapid disease progression. 
• 
Tolerance of study drug 
• 
Stable performance status 
• 
Treatment beyond  progression will not delay  an imminent intervention  to prevent 
serious complications of disease progression (e.g., CNS metastases) 
• 
Subject provides written informed consent prior to receiving additional nivolumab treatment 
acknowledging the possibility of any reasonably foreseeable risks or discomforts, as well as 
the possibility of alternative treatment options. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
If the investigator feels that the nivolumab plus ipilimumab subject continues to achieve clinical 
benefit by continuing treatment, the subject should remain on the trial and continue to receive 
monitoring according to the Study Calendar in Section 10.0. A radiographic assessment/CT scan 
should be performed no earlier than 4 weeks after original PD to determine whether there has been 
a decrease in the tumor size or continued PD. 
For the subjects who continue nivolumab plus ipilimumab study therapy beyond progression, 
further progression is defined as an additional 10% increase in tumor burden compared to baseline 
above the degree of progression determined at the time of initial PD (e.g. if progression of disease 
is determined with 24% growth from baseline and a subsequent confirmatory scan shows 33% 
growth compared to baseline (but 9% growth compared to initial PD) patient an continue on  
therapy. However, if there is 36% growth compared to baseline (and 12% growth compared to initial 
PD, patient should be discontinued from study treatment). This includes an increase in the sum of 
diameters of all target lesions and/or the development of new measurable lesions. 
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 volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of   
at least 15 mm). 
Nivolumab/ipilimumab treatment should be discontinued permanently upon documentation of 
further progression. 
Palliative Local Therapy 
 
Palliative local therapy, including palliative (limited-field) radiation therapy and palliative  surgical 
resection, is permitted prior to discontinuation of study treatment if the following criteria are met: 


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1) 
The subject is considered to have clinically or radiographically progressed at the 
time of palliative local therapy and meets criteria to continue with treatment beyond 
progression in the section above. 
2) 
The lesion planned for palliative local radiation is not a target lesion used for 
assessing radiographic response 
3) 
The case is discussed with the PI-Sponsor prior to the initiation of palliative local 
therapy. Palliative therapy must be clearly documented as such in the study 
record. 
The potential for overlapping toxicities with radiotherapy and nivolumab plus ipilimumab currently is 
not known. If palliative radiotherapy is required for a tumor lesion, study therapy 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. 
Follow-up Assessments after Last Dose of Study Treatment 
 
Patients will be followed for safety for 100 days following their last dose of study treatment. Patients 
who have an ongoing study-treatment related adverse event at the time of study completion or at 
discontinuation from the study will be followed until one of the following occurs: the event has 
resolved to baseline grade, the event is assessed by the study doctor as stable, new anti-cancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that the study treatment or participation was not the cause of the AE. 
All patients will be followed for survival and subsequent anti-cancer therapy approximately every 3 
months until death, loss to follow-up, or study termination. 
End of Study 
 
The end of study is defined as the date of the last follow-up visit of the last patient enrolled and is 
expected to occur approximately 4 months after the last patient enters the study. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Screening 
C1D1 
C2D1 
C2D8 
C3D1 
Each cycle 
thereafter 
Day 1 
Final visit14 
Within 28 
days of 
C1D1 
unless 
otherwise 
noted 
+/- 3 
days 
See note 
below13 
+/- 3 days 
+/- 3 days 
100 days 
after last 
dose of 
study 
therapy (+/- 
2 weeks) 
Informed screening 
consent1 
X 
Informed treatment 
consent 
X 
History2, Physical 
3,4,5 
X 
X 
X 
X 
X 
X 


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Pregnancy test for 
WOCBP6 
X6 
Comprehensive 
metabolic panel, 
Mg, LDH, amylase, 
lipase7 
X 
X 
X 
X 
X 
X 
Complete blood 
count7 
X 
X 
X 
X 
X 
X 
Thyroid function 
test8 
X 
X 
Every third 
cycle 
X 
Hepatitis B, C, HIV 
X 
EKG 
X 
Adverse event 
assessment and 
attribution9 
X 
X 
X 
X 
X 
X 
Radiographic tumor 
assessment10 
X 
Every 6 (or 12) 
weeks 10 
X 
Research blood 
tests 
X11 
X12 
X12 
X13 
X12 
C4D1, C5D1 12 
X12 
Pre-treatment 
tumor resection or 
biopsy 
X 
(resection 
permitted 
within 12 
weeks) 
Biopsy 
X13 
Nivolumab 3mg/kg 
q 2 weeks 
X 
X 
X 
X 
Ipilimumab 1 mg/kg 
q 6 weeks 
C1D1 and every 6 weeks (+/- 3 days) 
 
1 Patients will be consented separately for screening consent by either medical oncologist or thoracic 
surgeon. 
2 Medical history includes baseline symptoms as well as detailed history of prior cancer therapies 
including start and stop dates, disease progression during or after therapy, as well as 
discontinuations due to intolerability or any other serious illness 
3 Body height to be measured at screening only 
4 Vital signs include weight, temperature, pulse, blood pressure, and oxygen saturation 
5 Full physical exam for baseline and end of study visit. Other study visit physical exams may be 
symptom directed. 
6 Applicable for women of childbearing potential. Serum or urine beta-HCG test within 3 days before 
the first dose of study drug. 
7 Screening safety blood tests (CBC and CMP) must be done within 28 days of C1D1. Subsequent 
safety blood tests may be performed the day of the study visit or within 2 days prior to the study visit. 
8 Thyroid function tests (TSH, reflexive free T4/free T3 if TSH is abnormal) should be performed at 
baseline, C4D1, and then D1 of every third cycle thereafter. 
9 Adverse events will be graded and attributed using CTCAE 4.0 


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10  Tumor assessments will be performed with CT scan of the chest (+/- abdomen/pelvis depending 
on sites of known disease) but should also include all known sites of cancer (with exception of 
previously treated CNS lesions which do not need to be examined at each assessment). Scheduled 
on-treatment tumor assessments should begin 6 weeks after beginning nivolumab and continue 
thereafter every 6 weeks irrespective of dose interruptions or delays during the first 48 weeks of 
treatment, and every 12 weeks thereafter. Tumor assessments have a window of +/- 1 week from 
scheduled day. If an appropriate imaging study is done for an unrelated reason, it can be used for 
disease assessment. 
11 At screening, research bloods will be drawn for a) germline sequencing as a companion to somatic 
tumor DNA sequencing (1 blue top tube), b) T-cell subsets (4 CTP tubes) 
12 At C1D1, C2D1, C2D8, C3D1, C4D1, C5D1 and end-of-treatment, research bloods will be drawn 
for T-cell subsets (4 CTP tubes). 
13 The window for the on-treatment biopsy will be +/- 1 week from the date of C2D8. The 
corresponding research blood draw should be the same day of the on-treatment biopsy, +/- 1 day 
from the date of the biopsy [The +/- 1 day window should be applied to the date of the biopsy, not 
the date of C2D8]. 
14All patients will be followed for survival and subsequent anti-cancer therapy approximately every 3 
months until death, loss to follow-up, or study termination. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 Nivolumab and Ipilimumab toxicity overview 
 
Nivolumab and Ipilimumab are currently in clinical development and both have been FDA-approved 
for use as monotherapies respectively. The entire safety profile of nivolumab plus ipilimumab is not 
known at this time. Measures will be taken to ensure the safety of the patients participating in this 
trial, including the use of stringent inclusion and exclusion criteria and close monitoring. Toxicity 
grading will be performed in accordance with NCI CTCAE 4.0. If toxicities are encountered, 
adjustments will be made to the study treatment as detailed in the sections below. All AEs and SAEs 
will be recorded during the trial and for up to 100 days after the last dose of study treatment. 
 
11.2 Risks associated with nivolumab 
 
Likely 
 
• 
Fatigue 
• 
Skin changes including: rash, itching, hives, dry skin, or redness 
• 
Diarrhea 
• 
Nausea 
• 
Abdominal pain 
• 
Decreased appetite 
• 
Low red blood cells 
• 
Joint pain or stiffness 
 
Less Likely 


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• 
Bowel inflammation 
• 
Liver function blood test abnormalities 
• 
Loss of color (pigment) from areas of skin 
• 
Dry mouth 
• 
Vomiting 
• 
Weight loss 
• 
Thyroid gland abnormalities 
• 
Blood chemistry abnormalities, including low blood phosphate, magnesium, and potassium 
levels. 
• 
High blood uric acid level 
• 
Lung inflammation 
• 
Cough 
• 
Dizziness 
• 
Headache 
• 
Low white blood cell 
• 
Chills 
• 
Muscle soreness, weakness, stiffness, spasms, or paralysis 
• 
Pain in arms or legs 
• 
Tingling, burning, or numbness in hands and feet 
• 
Shortness of breath 
• 
Abnormal taste 
• 
Flushing 
• 
High or low blood pressure 
• 
Allergic reaction during or between study drug infusions 
• 
Increased sensitivity of skin to sunlight 
• 
Constipation 
• 
Difficulty swallowing 
• 
Heartburn 
• 
Low blood platelets (may increase risk of bleeding) 
 
Rare but serious 
• 
Low blood oxygen level 
• 
Acute lung injury or failure 
• 
Collection of fluid around the lungs 
• 
Inflammation of the appendix 
• 
Increase in inflammatory blood proteins (e.g., lipase) 
• 
Adrenal gland abnormalities 
• 
Pituitary gland inflammation 
• 
Changes in vision, inflammation of the eye (or optic nerve), or bleeding into the eye 
• 
Swelling of the optic disc 
• 
Liver inflammation 
• 
Acute kidney injury or failure 


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• 
Inflammation of the mouth and lining of the digestive tract 
• 
Swelling of the face, arms, or legs 
• 
Inflammation of the pancreas 
• 
Back pain 
• 
Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis) 
• 
Chest discomfort 
• 
Heart palpitations 
• 
Inflammation of the heart or its lining 
• 
Collection of fluid around the heart 
• 
Increased blood sugar 
• 
Dehydration 
• 
Infections: including sepsis, lung infections, and skin infections 
• 
Decreased movement of the intestines 
• 
Confusion 
• 
Inflammation of the optic nerve 
• 
Inflammation or loss of the lining of the brain and spinal cord 
• 
Abnormal brain function due to brain inflammation 
• 
Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal organ 
involvement (including liver, kidney, and lung) 
• 
Myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, and 
swallowing muscles 
• 
Muscle breakdown or inflammation in the muscle 
• 
Toxic epidermal necrolysis, a potentially fatal disease characterized by blistering and peeling 
of the top layer of the skin resembling a severe burn, has occurred in patients who received 
nivolumab treatment 
• 
Rhabdomyolysis (muscle fiber released into the blood stream which could damage your 
kidney) and polymyolsis (chronic inflammation with muscle weakness) has been reported in 
one patient 
• 
Lung inflammation (pneumonitis) 
• 
Death 
 
 
11.2 Risks associated with ipilimumab 
 
Likely 
 
• 
Fever 
• 
Nausea and/or vomiting 
• 
Rash 
• 
Diarrhea 
• 
Inflammation of the colon 
• 
Increased liver enzymes 
• Fatigue 


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• 
Skin itchiness 
• 
Decreased appetite 
• 
Abdominal pain 
• 
Headache 
• 
Constipation 
• 
Adrenal gland abnormalities 
• 
Pituitary gland abnormalities 
• 
Colitis 
 
Most of the side effects are mild and may be treated with common medications. 
 
Less Likely 
 
• 
Chills 
• 
Weakness 
• 
Muscle pain 
• 
Redness of skin 
 
Rare but Serious 
 
• 
Decrease in hormones of pituitary gland 
• 
Allergic reactions 
• 
Inflammation of the liver 
• 
Inflammation of the pituitary gland 
• 
Decreased red blood cells 
• 
Loss of color from areas of skin 
• 
Decreased or blurry vision, or inflammation of the eye 
• 
Numbness or tingling 
• 
Inflammation of the membrane surrounding the spinal cord and brain 
• 
Inflammation of the kidneys 
• 
Joint pain 
• 
Death 
 
11.3 Risks associated with Nivolumab and Ipilimumab Combined Therapy 
 
Likely, Some May Be Serious 
 
• 
Fatigue 
• 
Fever and/or chills 
• 
Flu-like feeling 
• 
Skin changes including dryness, rash, or itching 
• 
Vitiligo (loss of pigment or color in the skin) 
• 
Diarrhea 
• 
Nausea and/or vomiting 
• 
Abdominal Pain 


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• 
Bowel Inflammation 
• 
Dry Mouth 
• 
Liver function blood test abnormalities 
• 
Cough 
• 
Shortness of breath 
• 
Headache 
• 
Dizziness 
• 
Lung inflammation (pneumonitis) 
• 
Joint pain or stiffness 
• 
Decreased appetite 
• 
Lowe blood pressure 
• 
Inflammation of the thyroid 
• 
Muscle soreness, weakness, stiffness, or spasms 
• 
Increase in inflammatory blood proteins (e.g. lipase) 
 
Lung Inflammation: It is possible that nivolumab may cause inflammation of the tissues of the lung. 
This adverse effect has been reported in approximately 3% of patients treated with nivolumab. 
Although many patients are have no symptoms from this lung inflammation, some patients have 
developed mild to severe symptoms and 2 patients have died as a result of their lung inflammation. 
Symptoms of lung inflammation may include difficulty breathing, fever, or fatigue. Your doctor and 
nurse will watch you closely for signs that might show you are developing lung inflammation. 
Please inform your doctor or nurse at once if you experience anyof the following: 
 
• 
Any new or increased shortness of breath 
• 
Any new or increased chest pain 
• 
Any new or increased cough or any significant change in your type of cough 
• 
Any increase in the amount of supplemental oxygen you require 
• 
Any fever, fatigue, or other symptoms that occur at the same time as changes to your 
breathing or other lung symptoms. 
If you start to develop symptoms concerning for lung inflammation, your doctor will ask you to return 
to clinic to perform regular tests including physical exams, measurement of oxygen levels, 
pulmonary function tests, blood tests, bronchoscopy, and/or CT scans. This may require treatment 
with steroids or other immune suppressive medicines as well as holding nivolumab. You may even 
require hospitalization. 
Kidney inflammation: It is possible that nivolumab may cause kidney damage due to inflammation 
in the kidneys. This is very rare. You should let your doctor know if you notice any decreased 
amount of urine, difficulty urinating, sudden weight gain, increased tiredness, increased thirst or 
inability to tolerate liquids. This may require treatment with steroids and holding nivolumab. 
Reproductive risks 


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Patients should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  It is 
important you understand that you need to use birth control while on this study. 
11.3 Management Algorithms for Unique Nivolumab/Ipilimumab-Related Toxicities 
 
Nivolumab and Ipilimumab are associated with AEs that can differ in severity and duration than 
AEs caused by other therapeutic classes. 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 appendix 1-7 or in the current Investigator Brochure. 
11.4 Management of Nivolumab or Ipilimumab-Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
 
Infusion reactions should be graded according to NCI CTCAE (Version 4.0) guidelines. 
Treatment recommendations are provided below and may be modified as appropriate: 
• 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
o 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/paracetamol 325 to 1000 mg at least 30 
minutes before additional nivolumab administrations. 
• 
For  Grade  2  symptoms: (moderate reaction  required  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): 
o Stop infusion, begin an IV infusion of normal saline, 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 


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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 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). 
o For future infusions of therapy associated with infusion reaction, the following 
prophylactic premedications are recommended: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg should be 
administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of Solu-Cortef or equivalent) may be used. 
• 
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): 
o Immediately discontinue infusion of study drug. 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. The 
study drug that is associated with infusion reaction 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. 
o 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). 
 
11.5 Dose Delay Criteria 
 
Dose delay criteria apply for all drug-related events (regardless of whether or not the event is 
attributed to nivolumab, ipilimumab or both). 
Nivolumab and ipilimumab administration should be delayed for the following: 
 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay. 
• 
Any Grade 3 skin, drug-related adverse event 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase: 
o Grade 3 lymphopenia does not require dose delay 


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o If a subject has a baseline AST, ALT or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥ 2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity 
o Any  Grade  ≥ 3 drug-related  amylase or lipase abnormality that  is not associated 
with symptoms or  clinical manifestations  of pancreatitis  does  not  require  dose 
delay. 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
Patients who require delay of nivolumab or ipilimumab should be re-evaluated weekly or more 
frequently if clinically indicated. Both drugs should be delayed until re-treatment criteria are met (per 
Section 11.7). 
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 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. 
 
Dose delay  of nivolumab which results in treatment interruption of > 6 weeks or ipilimumab for > 12 
weeks require treatment discontinuation, with exceptions as noted in Section 13.0 
 
11.6 Dose Reduction Criteria 
 
There will be no dose reductions for nivolumab or ipilimumab. 
11.7 Criteria to resume treatment 
Patients may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade 1 ≤ 
or baseline, with the following exceptions: 
• 
Patients may resume treatment in the presence of Grade 2 fatigue 
• 
Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity 
• 
Patients  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 
• 
Patients  with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation 
parameters (Section 13.0) should have treatment permanently discontinued 


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• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed 
• 
Drug-related endocrinopathies adequately  controlled with only physiologic hormone 
replacement may resume treatment 
• 
Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
10 
mg/day. 
• 
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. 
• 
In instances in which toxicity if felt to be exclusively related to ipilimumab, treatment with 
nivolumab alone may be resumed after retreatment criteria are met and after discussion with 
PI-Sponsor. 
 
11.8 Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product during the course of a study and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered related 
to the medicinal product. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
product are not considered AEs after administration of the study product unless they reoccur after 
the patient has recovered from the pre-existing condition or they represent an exacerbation in 
intensity or frequency. 
11.9 Laboratory AEs 
 
For this protocol, an abnormal laboratory value will not be assessed as an AE unless: 
 
• 
The laboratory test result is clinically significant or meets the definition of an SAE 
• 
The laboratory test result leads interruption or discontinuation in study treatment 
• 
Any laboratory test result requires a specific correlative therapy/therapeutic  intervention. 
 
Laboratory AEs will be reported by the clinical term rather than the laboratory term (e.g. anemia, 
rather than low hemoglobin). 
11.10 Adverse Event Documentation 


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Adverse events will use the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE). This study will utilize the CTCAE Version 4.0 for 
adverse event reporting. 
Documentation of each adverse event must be supported by an entry in the patient’s file. Each event 
should be described in detail along with start and stop dates, severity, relationship to investigational 
product as judged by the Investigator, action taken and outcome. 
 
11.11 Causality of AEs 
 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
• 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
• 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
11.12 Serious Adverse Event 
Reporting of SAEs is detailed in Section 17.2. 
 
Clarification should be made between the terms serious and severe because they are not the same. 
The term severe is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as a severe headache). This is not the same as serious, which is based 
on the patient/event outcome or an action criterion described above, and is usually associated with 
events that pose a threat to a patient’s life or functioning.  A severe AE does not necessarily need to 
be considered serious.  For example, persistent nausea of several hours duration may be 
considered severe nausea but may not be considered an SAE. On the other hand, a stroke resulting 
in only a minor degree of disability may be considered mild but would be defined as an SAE based 
on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
Following the patient’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol- 
specified procedures. All SAEs must be collected that occur during the screening period and  within 
100 days of discontinuation  of dosing. If  applicable, SAEs  must be collected that relate to any 
later protocol-specified procedure (e.g., a follow-up skin biopsy). All SAEs should be followed to 
resolution or stabilization. 
A Serious Adverse Event or Reaction is any AE occurring at any dose that: 
 
• 
Results in death 


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• 
Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization EXCEPT 
as noted below 
• 
Results in persistent or significant disability/incapacity (defined as substantial 
disruption of a person’s ability to conduct normal life’s functions). 
• 
Results in a congenital anomaly / birth defect 
 
• 
Results in anaphylaxis related to study drug 
 
• 
Results in an important medical event that may not be immediately life threatening or 
result in death or hospitalization, but may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above 
(example: intensive treatment in an emergency room or at home for bronchospasm, 
convulsions that do not result in hospitalization). Medical and scientific judgment 
should be exercised in deciding whether some events should be considered as 
serious because their quick reporting to the sponsor may be of interest for the overall 
conduct of the study. 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, or drug-induced 
liver injury. 
• 
Results in suspected transmission of an infectious agent (pathologic or 
nonpathologic) via the study drug 
Hospitalization: Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered an SAE, UNLESS at least one of the following exceptions 
is/are met: 
• 
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 for a planned medical/surgical procedure as part of the study protocol 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g. 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). 
It should be noted that invasive treatment during any hospitalization may fulfil the criteria of 
‘medically important’ and as such may be reportable as a serious adverse event dependant 


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on clinical judgement.  In addition where local regulatory authorities specifically require a 
more stringent definition, the local regulation takes precedent. 
Pregnancies occurring in study patients/sexual partner(s) will be treated procedurally as 
SAEs and patient is required to immediately discontinue the trial medication. Overdoses and 
Potential Drug Induced Liver Injury (DILI) should also be reported as an SAE. 
 
11.13 Pregnancy 
 
If, following initiation of nivolumab or ipilimumab, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 6 half lives after product administration, nivolumab and ipilimumab will both be 
permanently discontinued. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures described in Section 17.2.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance 
Form [provided upon request from BMS]. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
 
11.14 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 17.2.1 for reporting details.). 
11.15 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 (see Section 17.2.1 for reporting details). 
Potential drug induced liver injury is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline  phosphatase) 
AND 


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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. 
11.16 Events NOT to be reported as SAEs 
 
For this study, the following are not classified as serious adverse events 
 
• 
Progression or deterioration of the malignancy under study (including new metastatic 
lesions) or death due to disease progression. 
• 
Hospitalization for the performance of protocol-required procedures or administration of 
study treatment, including any hospitalization required for pre-treatment tumor resection. 
However, hospitalization or a prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE. 
• 
Hospitalization or procedures planned prior to start of study therapy, including any 
hospitalization required for pre-treatment tumor resection. A pre-planned procedure must 
be documented in the source documents. However, hospitalization or prolonged 
hospitalization for a complication remains to be reported as an SAE. 
 
• 
An elective hospitalization for a pre-existing condition unrelated to the studied indication. 
 
• 
Hospital admission that is not associated with an adverse event (e.g. social 
hospitalization for purpose of respite care). 
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of 
such transfusions remains to be reported as an SAE. 
• 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Best overall response rate (confirmed partial + complete response) will be assessed as part of this 
study. Tumor response will be assessed using RECIST 1.1. All responses must be confirmed on 
subsequent scan to be considered a true response. 
The same CT method with the same technique (i.e. with or without contrast) should be used to 
characterize each identified and reported lesion at baseline and every 6 weeks (+/- 1 week) 
thereafter while on study until week 48. After week 48, tumor assessments will be conducted every 
12 weeks (+/- 1 week). Tumor assessments should be scheduled irrespective of dose 
delays/treatment interruptions. Designated radiologists/physician will be responsible for 
interpretation of the study imaging according to RECIST 1.1. 


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A CT scan of the chest or CT chest (+/- abdomen/pelvis depending on sites of known disease) with 
or without contrast will be performed to demonstrate all known areas of measurable disease. The 
baseline study will occur no more than 4 weeks prior to first study drug administration. An alternative 
imaging test, including MRI, can also be used in patients with contraindications to radiographic 
contrast media used in CT scans. PET scans or bone scans are not adequate for assessment of 
RECIST 1.1 response in target lesions. All patients must have at least one measurable disease 
lesion by CT or MRI. 
 
Target Lesions: 
 
All measurable lesions, up to a maximum of 5 lesions 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, should be representative of all involved organs, and should 
lend themselves to reproducible repeat measurements. All other lesions (or sites of disease) should 
be identified as non-target lesions and should also be recorded at baseline as well. All baseline 
evaluations should be performed as close as possible to the start of treatment and never more than 
28 days prior to beginning treatment. 
All measurements should be recorded in millimeters. 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 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 pathological lymph nodes should be identified as non- 
target lesions and should be also recorded at baseline. Measurements are not required and these 
lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.” In 
addition, it is possible to record multiple non-target lesions involving the same organ as a single item 
(e.g. “multiple enlarged pelvic lymph nodes”). 
Tumor Response Evaluation: 
 
Definitions of response in target and non-target lesions are described in Table 12.1 and 12.2 below. 
Table 12.3 provides overall responses for all possible combinations of tumor responses in target and 
non-target lesions. 
 
 
Table 12.1: Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial response (PR) 
At least a 30% decrease in the sum of the 
diameters of the target lesions 
Progressive disease (PD): 
At least a 20% increase in the sum of the 
diameter of the target lesions or the 
appearance of one or more new lesions 
Stable disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD 


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Table 12.2: Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions 
Incomplete response/Stable disease (SD): 
Persistence of one or more non-target 
lesions 
Progressive disease (PD): 
Appearance of one or more new lesion 
and/or unequivocal progression of existing 
non-target lesion 
 
 
Table 12.3: Combinations of responses 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Evaluation of Non-Target Lesions: 
 
Although some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non- 
pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) above the normal limits. 
 
Progressive Disease (PD): Unequivocal  progression of  existing  non-target lesions  (Note: the 
appearance of one or more new lesions is also considered progression). To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
 
Confirmation of Scans 
 
Verification of Response: Initial observations of response will be confirmed by repeat scans which 
should be performed no earlier than 4 weeks after the original observation to ensure that responses 
identified are not the result of measurement error. After an initial PR or CR is noted, the subsequent 
protocol-specified tumor assessment may serve as the confirmation. 
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date 


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of the initial scan. If repeat scans do not confirm PD, then the subject is considered not to have 
progressive disease per RECIST 1.1. 
Best Overall Response: 
 
The best overall response is determined once all the data for a subject is known. It is defined as the 
best response designation recorded between the date of first treatment and the date of objectively 
documented progression per RECIST v1.1 or the date of initiating subsequent therapy, whichever 
occurs first. For subjects without documented progression or subsequent therapy, all available 
response designations will contribute to the BOR assessment. The subjects best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. 
 
Modifications  to RECIST v1.1: Immune-related Response Criteria 
 
Immune-related response criteria using uni-dimensional measurements are used to describe tumor 
shrinkage following RECIST-defined disease progression. The methodology is the same as 
described above for RECIST except: 
 
1. New lesions do not automatically denote disease progression 
2. The measurements of longest diameter of new measureable lesions are included in the sum 
of the measurements of the original target les ions. 
 
Best immune-related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (>/= 30% reduction from baseline). 
 
Continuation of treatment despite radiographic progressive disease 
 
Patients who experience initial progressive disease may continue therapy if they are 
experiencing clinical benefit. The date of progression for calculation of PFS will remain the first 
CT scan that demonstrates progression (if it is confirmed on subsequent scan, as above). 
For the subjects who continue nivolumab and ipilimumab study therapy beyond progression, 
further progression is defined as an additional 10% increase in tumor burden volume (relative to 
baseline) above the degree of progression identified at the time of initial PD. This includes an 
increase in the sum of diameters of all target lesions and/or the development of new measurable 
lesions. 
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 volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of   
at least 15 mm). 
 
Discontinuation of treatment in absence of objective progression of disease 


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Early death is defined as having no repeat tumor assessments following initiation of study therapy 
resulting from death of the patient due to disease or treatment. Patients with global deterioration of 
health status requiring discontinuation of treatment without objective evidence of disease 
progression will be recorded as “symptomatic deterioration.” This is a reason for stopping therapy, 
but is NOT objective progressive disease. Every effort will be made to document objective 
progression even after discontinuation of treatment. 
 
Special Considerations regarding lesion measurability: 
 
Bone lesions: 
 
• 
Bone scan, PET scan, or plain fils are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described by RECIST v1.1. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• 
“Cystic lesions” though to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described by RECIST v1.1. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other local- 
regional therapy, may be considered measurable ONLY if there is documented progression 
in that lesion. 
Clinical lesions: 
 
• 
Clinical lesions (e.g. biopsy confirmed skin metastasis) will only be considered measurable 
when they are superficial and larger than 10mm in longest diameter. For the case of skin 
lesions, documentation by serial color photography using a ruler to measure the size of the 
lesion is suggested. However, if non-clinical lesions are present in the same patient, these 
are preferred for selection as target lesions. 
Lesions that spit or coalesce on treatment: 


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• 
When non-nodal lesions “fragment,” the longest diameters of the fragmented portions should 
be added together to calculate the total lesion sum. Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If lesions have coalesced such that they are no 
longer separable, the vector of the longest diameter in this instanced should be the maximal 
longest diameter for the “coalesced lesion.” 
Lesions which become too small to measure: 
 
• 
If the radiologist is able to provide an actual measurement, that should be recorded, even if 
below 5 mm. 
• 
However, when a lesion becomes difficult to assign an exact measurement, then: 
o If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0. 
o If the lesion (including lymph nodes) is believed to be present and is faintly seen, but 
too small to characterize, a default value of 5mm should be assigned. 
Non-measurable lesions: 
 
• 
The following are considered non-measurable lesions: 
o Small lesions with longest diameter <10mm or pathologic lymph nodes with ≥ 10 to < 
15 mm short axis 
o Leptomeningeal  disease 
o Ascites 
o Pleural or pericardial effusion 
o Lymphangitic involvement of skin or lung 
o Abdominal masses/organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques 
 
Special Considerations for New Lesions: 
 
The appearance of new malignant lesions denotes disease 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). New lesions may be defined by any modality (i.e. CT, PET, MRI, clinical exam). The finding of 
a new lesion should be unequivocal (i.e. not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to possibly represent something other than tumor 
[e.g. pneumonitis or a “new” bone lesion that may simply be healing or flare or a pre-existing 
lesion]). This is particularly important when the patient’s baseline lesions show partial or complete 
response. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered to be a new lesion and will constitute progression. 
If a new lesion is equivocal, for example because of small size or indeterminate etiology, therapy 
may be continued and follow-up examination will clarify if it represents new disease. If repeat scans 
confirm that the new lesion represented malignant disease, the progression should be declared 
using the date of the initial scan. 


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Special Considerations for Pleural/Pericardial Effusions and Ascites: 
 
As above, pleural/pericardial effusions and ascites are considered non-measureable lesions. The 
appearance of new or worsening pleural/pericardial effusions or ascites does not necessarily 
constitute unequivocal progression unless cytologically proven to be of malignant origin since some 
effusions may be a therapy-related toxicity or related to other medical conditions. 
If a new or worsening pleural/pericardial effusion or ascites is determined to be unequivocally related 
to progressive disease (e.g. cytopathologic confirmation of new effusion or change from “trace” to 
“large” effusion), then this is consistent with progression and treatment would be discontinued. 
If a new or worsening pleural/pericardial effusion or ascites is equivocal, for example because of 
small size or indeterminate etiology, therapy may be continued and follow-up examination or 
cytopathologic analysis will clarify if it represents new disease. If repeat scans or procedures confirm 
that the new lesion represented malignant disease, the progression should be declared using the 
date of the initial scan. 
Definitions 
 
Evaluation of best overall response: The best overall response is the best response recorded from 
the start of treatment until disease progression, as defined in Table 12.3. 
Evaluable for toxicity: All patients who receive at least one dose of study therapy will be evaluable 
for toxicity which will be assessed according to CTCAE v4.0 as well as by documentation of dose 
delay/adjustments that are required. 
Evaluable for objective response: All patients who receive at least one dose of study therapy will be 
included in the modified intent-to-treat analysis of efficacy. Patients who come off study for any 
reason prior to the first radiographic tumor assessment will be treated as having progressive 
disease. 
Evaluable for primary/secondary objectives: In order to be considered eligible for the primary and 
secondary objectives described in this study, patients must receive (1) at least one dose of study 
therapy and remain on study until at least the first radiographic tumor assessment (week 6) or (2) at 
least one dose of study therapy and have clear clinical or radiographic progression prior to the 
planned first radiographic tumor assessment at week 6. Patients who come off study for reasons 
other than clinical/radiographic progression prior to the first radiographic tumor assessment will be 
replaced. 
Progression free survival (PFS) is defined as the duration of time from beginning study therapy 
(C1D1) to time of progression or death, whichever occurs first. Clinical deterioration  consistent with 
progressive disease in absence of radiographic evidence of progression (“clinical progression”) will 
be considered progression for purposes of determining PFS. In patients who continue on study 
therapy after an initial scan demonstrates progressive disease, if repeat scans confirm PD, then 
progression should be declared using the date of the initial scan. If repeat scans do not confirm PD, 
then the subject will not be considered to have progression at the initial scan. Patients who enroll but 
do not receive any study therapy will not be included in the PFS analysis. Patients who started a 


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subsequent anti-cancer therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment prior to initiation of the subsequent anti-cancer therapy. Patients who 
discontinue from therapy and withdraw consent for follow-up without a prior reported progression will 
also be censored at the last evaluable tumor assessment prior to withdrawal of consent. 
Overall survival (OS) is defined as the duration of time from beginning study therapy (C1D1) to time 
of death. Patients who enroll but do not receive any study therapy will not be included in the OS 
analysis. 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Nivolumab and ipilimumab treatment should be permanently discontinued for the following reasons 
and the specific reasons for removal from study will be documented: 
• 
Patient withdrawal of consent at any time 
 
o Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented. 
However, patients will not be followed for any reason after consent has been 
withdrawn. 
• 
Termination of the study by MSKCC or BMS for any reason 
 
• 
Radiographic progression: Confirmed disease progression per RECIST v1.1. 
 
o Patients who experience initial progressive disease may continue therapy if they are 
experiencing clinical benefit. A CT scan should be repeated no more than 6 weeks 
after the first documentation of progressive disease. If there is at least 10% more 
progression (e.g. first scan showed 24% growth relative to baseline, second scan 
shows 36% growth relative to baseline), then study therapy should be discontinued. 
If, instead, <10% further progression is seen, the patient may continue study therapy 
until confirmed progression of disease so long as there is continued clinical benefit. 
• 
Clinical progression: Symptomatic deterioration attributed to disease progression as 
determined by the investigator after integrated assessment of radiographic data, biopsy 
results, and clinical status. 
• 
Other conditions: Any medical condition that may jeopardize the patient’s safety if he or she 
continues on study treatment. 
• 
Pregnancy 
 
• 
New therapies: Use of another systemic anti-cancer therapy. 
 
o Cases in which patients experience a mixed response requiring local therapy (e.g. 
surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control 
of tumor growth or symptoms may still be eligible to continue study treatment so long 


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as such therapy is not directed at a target lesion used for assessment of radiographic 
progression per RECIST v1.1 Such cases must be discussed with and approved by 
the Sponsor-PI. 
Certain toxicities, specific to each drug: 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 ipilimumab but not for nivolumab, treatment with nivolumab may continue if 
ipilimumab is discontinued. If a subject in any of the nivolumab/ipilimumab combination arms 
meets criteria for discontinuation and investigator is unable to determine whether the event is 
related to both or one study drug, the subject should discontinue both nivolumab and 
ipilimumab and be taken off the treatment phase of the study. 
 
Nivolumab dose discontinuation: 
 
o Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment 
o Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, infusion reactions, and endocrinopathies: 
▪ 
Grade 3  drug-related  uveitis,  pneumonitis,  bronchospasm, hypersensitivity 
reaction,  or infusion reaction of any duration requires discontinuation 
▪ 
Grade  3  drug-related  endocrinopathies  adequately   controlled  with  only 
physiologic hormone replacement do not require discontinuation 
▪ 
Grade 3 drug-related laboratory  abnormalities  do not require treatment 
discontinuation except: 
• 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
• 
Any  drug-related liver function  test (LFT) abnormality that meets the 
following criteria requires discontinuation: 
o AST or ALT > 10x  ULN 
o AST or ALT > 5-10x for > 2 weeks 
o Total bilirubin > 5x ULN 
o Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
o Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
▪ 
Grade 4 neutropenia ≤ 7 days 
▪ 
Grade 4 lymphopenia or leukopenia 
▪ 
Isolated Grade 4 amylase or lipase abnormalities that is not associated with 
symptoms or clinical manifestations of pancreatitis. 
▪ 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae   and   are   corrected  with  
supplementation/appropriate 
management  within 72 hours of their onset 
▪ 
Grade  4  drug-related  endocrinopathies  adequately   controlled  with  only 
physiologic hormone replacement do not require discontinuation 


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o Any event that leads to delay in dosing lasting > 6 weeks from the previous dose 
requires discontinuation, with the following exceptions: 
▪ 
Dosing  delays  to  allow  for  prolonged  steroid  tapers  to  manage  drug- 
related  adverse events are allowed. Tumor assessments should continue as 
per protocol even if dosing is delayed. 
▪ 
Dosing delays lasting > 6 weeks from the previous dose that occur for non- 
study-drug-related reasons may be allowed. Tumor assessments should 
continue as per protocol even if dosing is delayed. 
o Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing. 
 
 
Ipilimumab  dose discontinuation: 
 
o Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment 
o Any Grade  3 bronchospasm or other hypersensitivity reaction 
o Any  Grade  3 non-skin,  drug-related  adverse  event with the following exceptions  
for laboratory abnormalities, grade 3 nausea and/or vomiting, grade 3 neutropenia or 
thrombocytopenia, and symptomatic endocrinopathies which resolved (with or without 
hormone substitution) 
o Any  drug-related liver function  test (LFT) abnormality that meets the following 
criteria requires discontinuation: 
▪ 
AST or ALT > 8x  ULN 
▪ 
Total bilirubin > 5x ULN 
▪ 
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
o Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
▪ 
Grade 4 neutropenia ≤ 7 days 
▪ 
Grade 4 lymphopenia or leukopenia 
▪ 
Isolated Grade 4 amylase or lipase abnormalities that is not associated with 
symptoms or clinical manifestations of pancreatitis. 
▪ 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae   and   are   corrected  with  
supplementation/appropriate 
management  within 72 hours of their onset 
▪ 
Grade  4  drug-related  endocrinopathies  adequately   controlled  with  only 
physiologic hormone replacement do not require discontinuation 
o Any event that leads to delay in dosing lasting > 6 weeks from the previous dose 
requires discontinuation, with the following exceptions: 
▪ 
Dosing  delays  to  allow  for  prolonged  steroid  tapers  to  manage  drug- 
related  adverse events are allowed. Tumor assessments should continue as 
per protocol even if dosing is delayed. 


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▪ 
Dosing delays lasting > 6 weeks from the previous dose that occur for non- 
study-drug-related reasons may be allowed. Tumor assessments should 
continue as per protocol even if dosing is delayed. 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing. 
14.0 
BIOSTATISTICS 
 
This study will enroll thirty patients with advanced NSCLCs, who will receive nivolumab plus 
ipilimumab therapy following standard-of-care resection of tumor tissue. In order to be considered 
eligible for the primary and secondary objectives described in this study, patients must receive (1) at 
least one dose of study therapy and remain on study until at least the first radiographic tumor 
assessment (week 6) or (2) at least one dose of study therapy and have clear clinical or radiographic 
progression prior to the planned first radiographic tumor assessment at week 6. Patients who come 
off study for reasons other than clinical/radiographic progression prior to the first radiographic tumor 
assessment will be replaced. 
 
 
The sample size is based on feasibility and budgetary considerations, as well as generating 
sufficient preliminary data to more specifically inform a larger study of sufficient power. In the 
thoracic surgery service, there is an average of 1-3 cases per week of patients with advanced stage 
disease who undergo intervention or resection of a metastatic site of disease and who may be 
eligible for this trial. We would expect that 20-40% of such patients would be willing to participate in 
this study and therefore anticipate an accrual rate of 1-2 patients per month, or 20 patients/year. We 
therefore expect to complete accrual in 18 months. Due to the limited sample size and to the 
heterogeneity of the patient population (both smokers and never smokers permitted, no restriction 
related to PD-L1 expression), we will not be able to draw definitive conclusions regarding the effect 
of specific factors and mechanisms. The nature of this study is descriptive and exploratory. Any 
hypotheses generated will need to be further confirmed. Response to nivolumab will be evaluated 
using RECIST criteria and patients will be classified as either responders (CR or PR at any time 
during nivolumab treatment) or non-responders. 
Primary objective 1: In each tumor sample, we will quantify the mutational burden (number of 
somatic, non-synonymous mutations detected through whole exome sequencing) and investigate 
graphically its relationship with response to nivolumab plus ipilimumab. We will describe the burden 
of mutations for responders and non-responders using summary statistics, and compare it (in an 
exploratory analysis) using Wilcoxon rank sum test. Depending on the number of responses, we 
may also perform logistic regression with mutational burden as a covariate and/or use Cox 
regression to analyze PFS and OS with mutational burden as a covariate. We expect that higher 
burden of somatic mutations will show an indication of positive association with response to 
nivolumab plus ipilimumab. Patients will be stratified into mutation “high” and “low” groups based on 
the median number of non-synonymous mutations/sample in patients with NSCLCs, and we will 
report objective response rate along with exact 95% confidence intervals in the low and high burden 
groups, respectively. Because this is not an established categorization, we will graphically 


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investigate whether other types of functional relationship between the burden of mutation and 
response might be more appropriate. 
Primary Objectives 2: Identification of candidate neoantigens 
 
Candidate neoantigens will be broadly defined as those mutations that generate peptides that have 
<500nM binding affinity to patient specific MHC class I alleles. Analysis may be further refined by IEDB 
or in vitro methods to identify relevant neoantigens that are predicted to elicit T-cell response. Using 
these methods, a list of candidate neoantigens will be generated and we will use non-parametric 
Wilcoxon tests to compare responders vs non-responders with respect to the quantity of putative 
neoantigens. Those neoantigens significantly associated with response status (controlling for a false- 
discovery rate of 5%) will be validated in further studies. Data will be compared to TCGA data to see 
if there are mutated sequences enriched in either the responder or non-responder group. 
 
Primary Objective 3: Identification  of neoantigen-specific T-cells. 
 
The presence of neoantigen-specific peripheral blood and (if possible) intratumoral T-cells will be 
quantified in pre- and on-treatment specimens. We will present these data graphically and 
summarize them for responders and non-responders. We are interested in observing whether 
neoantigen-specific T-cells exhibit patterns of change between the two evaluations that are different 
between responders and non-responders. The presence of neoantigen-specific lymphocytes will be 
quantified in samples collected at baseline and serially while on treatment. Their trajectory will be 
presented graphically, summarized separately for responders and non-responders, and compared 
using mixed-effects models for longitudinal data. 
Secondary objectives: Tumor expression of co-stimulatory ligands and receptors and MHC 
expression will be analyzed and quantified in pre-treatment and on-treatment tissue samples. All 
measures, as well as percent changes between values pre- and during treatment, will be 
summarized separately for responders versus non-responders. Association between pre-treatment 
values and response will be explored using Wilcoxon rank sum test in order to investigate the 
predictive potential. 
Exploratory analyses: Additional  post-hoc, exploratory assessments are expected and may be 
performed. Much such as, but not limited to, logistic regression and graphical summaries may be 
used to assess associations between various potential biomarker measures and clinical efficacy. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
 
Confirm eligibility  as defined in the section entitled  Inclusion/Exclusion  Criteria. Obtain informed 
consent, by following  procedures  defined in section entitled  Informed  Consent Procedures. 
During the registration  process registering  individuals  will be required to complete a protocol 
specific Eligibility  Checklist. The individual  signing the Eligibility  Checklist is confirming whether 
or not the participant  is eligible  to enroll in the study. Study staff are responsible  for 


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ensuring that all institutional  requirements  necessary to enroll a participant  to the study have 
been completed.  See related Clinical Research Policy and Procedure #401 (Protocol Participant 
Registration). 
15.3 
Randomization 
 
N/A 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. The data collected for this study will be entered into a secure database (Clinical Research 
Database (CRDB). Source documentation will be available to support the computerized patient 
record. The principal investigator will maintain ultimate responsibility for the clinical trial. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action.  Random-sample data quality and protocol 
compliance audits will be conducted by the study team, at a minimum of two times per year, or more 
frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/patientsafety/dsm -guidelines /page1 
 
The DSM Plans at MSKCC were established and are monitored by the Clinical Research 
Administration. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet 
at:  
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%20A  
ssurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 


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committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional  Review Board. 
During the protocol development and review process, each protocol will be assessed for its level or 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be reviewed 
with the participant, including a discussion of the possible toxicities and side effects. Alternative, 
non-protocol, treatment options will be discussed with the patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient may withdraw consent at any time. 
The study is designed with careful safety monitoring for toxicity including physician visits. Specific 
guidelines for symptom management are in place to protect the study participant. 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the all of the 
inclusion and none of the exclusion criteria will be eligible. At least 30 patients will will be enrolled. 
Patients eligible will be 18 years of age or older with a ECOG performance status ≤ 1. Both men and 
women and members of all ethnic groups are eligible for this trial. Pregnant and breast-feeding 
women are excluded from this study. This protocol does not include children because the number of 
children is expected to be limited for the patient population expected to be accrued onto this study. 
Also, the majority of children are already accessed by a nationwide pediatric cancer research 
network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion 
of Children as Participants in Research Involving  Human Subjects. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. Participation 
in the trial is voluntary. All patients will be required to sign a statement of informed consent, which 
must conform to IRB guidelines. The informed consent procedure is described in Section 18.0. 
Possible Toxicities/Side-Effects: There are risks associated with treatment as described in Section 
11.0; however, patients screened for enrollment will be deemed appropriate for treatment 
independent of this study. 
Benefits: Based on data from a Phase I trial, nivolumab plus ipilimumab appears to benefit some 
patients with lung cancers. At present, it is unknown what the predictors of that response are.  The 
goal of this study is to evaluate the potential somatic genetic predictors of objective response to 
nivolumab plus ipilimumab in patients with lung cancer. 
Costs:  Patients will be charged for physician visits, routine laboratory tests, and radiologic studies 
required for monitoring their condition. Pre-treatment tumor resections will be performed as 
standard-of-care. 
The cost of research-only biopsies, nivolumab, as well as tumor tissue based- and blood based- 
exploratory correlatives will be covered by research funds. 


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Alternatives: For patients considering this trial as second-line therapy, docetaxel or erlotinib could be 
alternative standard options. Nivolumab would also be a standard option for patients with squamous 
cell lung cancer. For patients considering this trial as third-line therapy or beyond, there are no 
standard treatment alternatives. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. Patients’ names and any other identifying information will not be used in 
reports or publications resulting from this study. Other authorized agencies and appropriate internal 
personnel (e.g. qualified monitors from MSKCC) and external personnel (e.g. qualified monitors from 
BMS (the manufacturer of nivolumab and ipilimumab), its authorized agents, the FDA, and/or other 
governmental agencies) may review patient records as required. 
Future Contact: Participants will not be routinely told of the results from research assays (e.g. DNA 
sequencing). With their permission, the participant and/or family members may be contacted in the 
future to ask if they are interested in learning about potential findings of inherited risks for cancer 
that may have been an outcome of the research assay testing of their samples. 
Patient safety: Patients are monitored by physicians and oncology nurses who are very familiar with 
clinical trials. In the case of an adverse reaction, immediate medical attention is available. In the 
evenings and weekends, we have a 24-hour urgent care facility for outpatients. The PI or co-PI will 
also be available at all times to organize any necessary intervention. 
Monitoring of data to ensure safety: This study is to be monitored by the institutional IRB. This 
incorporates an independent data and safety monitoring board established by arrangement with the 
National Cancer Institute. The analysis of safety will include all patients. Adverse events, including   
all toxic effects of treatment, will be tabulated individually,  and summarized by severity and causality. 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 


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• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
17.2.1  Procedures for Reporting Serious Adverse Events (SAEs) to Drug Sponsor 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol- 
specified procedures. Adverse events (AEs) may be spontaneously reported by the patient and/or in 
response to an open question from study personnel or revealed by observation, physical 
examination, or other diagnostic procedures must be reported to BMS (or designee).  AEs which are 
serious must be reported to BMS (or designee) from study enrollment up to and including 100 days 
after administration of the last dose of nivolumab.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as one comprehensive event.  Any SAE that occurs 
at any time after completion of nivolumab treatment or after the designated follow-up period that the 
investigator and/or sub-investigator consider to be related to any study drug must be reported to the 
BMS Worldwide Safety (or designee). The investigator should report any SAE that occurs after 
these time periods and that is believed to be related to study drug or protocol-specified procedure. 
This is an investigator-initiated study.  The principal investigator Adam Schoenfeld, MD, who may 
also sometimes be referred to as the sponsor-investigator, is conducting the study and acting as the 
sponsor. Therefore, the legal/ethical obligations of the principal investigator include both those of a 
sponsor and those of an investigator. 
 
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 


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(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/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
SAE Fax Number: 609-818-3804 
SAE Email Address: Worldwide.Safety@BMS.com 
 
The study period during which adverse events will be reported is from the initiation of study procedures 
to the end of the study treatment follow-up, defined as 100 days following the last administration of 
nivolumab treatment. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in 
its intensity or relationship to study drug or if new information becomes available, a follow-up SAE 
report should be sent to BMS using the same procedure used for transmitting the initial SAE report. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent forms indicating their consent to 
participate. 
These consent forms meet the requirements of the Code of Federal Regulations and the Institutional 
Review Board/Privacy Board of this Center. The consent forms will include the following: 
1. 
The nature and objectives, potential risks and benefits of the intended study. 
2. 
The length of study and the likely follow-up required. 
3. 
Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. 
The name of the investigator(s) responsible for the protocol. 


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5. 
The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
This study will have two consents: one for screening prior to surgical resection of tumor tissue. This 
consent form will discuss that the surgical procedure will be performed as standard-of-care, but that 
tumor tissue will be collected for research. If sufficient tissue can be collected, the patient will be 
invited to participate in the main treatment part of this study and, if they agree and sign the second 
treatment consent, will begin screening procedures for the treatment part of this study. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consents, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
19.0 
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20.0 
APPENDICES 
 
Appendix 1: Endocrinopathy management algorithm 


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\ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2: GI adverse event management algorithm 


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Appendix 3: Hepatic adverse event management algorithm 


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Appendix 4: Neurological adverse event management algorithm 


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Appendix 5: Pulmonary adverse event management algorithm 


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Appendix 6: Renal adverse event management algorithm 


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Appendix 7: Skin adverse event management algorithm 


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