A Phase II Window of Opportunity Trial of Ipilimumab and Nivolumab in Metastatic Recurrent HER2- Inflammatory Breast Cancer (IBC) The Win Trial
Phase: PHASE2
Conditions: HER2/Neu Negative, Recurrent Inflammatory Breast Carcinoma, Stage IV Breast Cancer, Stage IV Inflammatory Breast Carcinoma
Sponsor: Northwestern University

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
 
CONFIDENTIAL 
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  
Do not disclose or use except as authorized in writing by the study sponsor. 
1 
 
 
A Phase II Window of opportunity trial of Ipilimumab and Nivolumab in 
metastatic recurrent HER2- inflammatory breast cancer (IBC) 
 
THE WIN TRIAL  
 
 
Principal Investigator: William Gradishar, M.D., FACP, FASCO 
Betsy Bramsen Professor of Breast Oncology & Professor of Medicine  
 
 
 
Northwestern University Feinberg School of Medicine 
Division of Hematology / Oncology   
 
 
 
 
676 N. St. Clair Street, Suite 850 
 
 
 
Chicago, IL 60611 
 
 
 
Phone: 312.695.4541 
 
 
 
Fax: 312.695.6189 
 
 
 
Email: w-gradishar@northwestern.edu  
 
 
Sub-Investigator(s): 
Lisa Flaum, MD  
 
 
Massimo Cristofanilli MD, F.A.C.P 
 
 
 
 
Biostatistician: 
Alfred Rademaker Phd 
 
 
 
rademaker@northwestern.edu 
 
Collaborators:  
Kalliopi Siziopikou, MD (Pathologist) 
 
Study Intervention(s):  
Nivolumab (Opdivo) and Ipilimumab (Yervoy) 
 
IND Number/Holder: 
 
N/A (Exempt) 
 
Funding Source:  
Bristol-Myers Squibb 
 
Version Date: 
 
 
March 1, 2018 (Amendment 5) 
 
Coordinating Center:  
Clinical Research Office 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern University 
676 N. St. Clair, Suite 1200 
Chicago, IL  60611 
 
 
 
 
http://cancer.northwestern.edu/CRO/index.cfm 
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NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
2 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................. 5 
STUDY SCHEMA ............................................................................................................................ 7 
STUDY SUMMARY ......................................................................................................................... 8 
1.0 Introduction – BACKGROUND & RATIONALE ...................................................................... 9 
1.1  
Disease Background .......................................................................................... 9 
1.2             Intervention Background & Overview ............................................................ 12 
1.3  
Rationale for the Current Study ...................................................................... 16 
1.4  
Exploratory Studies ......................................................................................... 17 
2.0 OBJECTIVES & endpoints .................................................................................................... 18 
2.1 
Primary Objective & Endpoint ......................................................................... 18 
2.2 
Secondary Objectives & Endpoints................................................................ 18 
2.3 
Exploratory Objectives & Endpoints .............................................................. 18 
3.0 PATIENT ELIGIBILITY ............................................................................................................ 18 
3.1 
Inclusion Criteria .............................................................................................. 19 
3.2 
Exclusion Criteria ............................................................................................. 20 
4.0 TREATMENT PLAN ................................................................................................................ 22 
4.1 
Overview ............................................................................................................ 22 
4.2 
Treatment Administration ................................................................................ 22 
4.3 
Toxicity Management & Dose Delays ............................................................. 24 
4.4 
Treatment with ipilimumab and or nivolumab beyond progression ........... 27 
4.5 
Concomitant Medications/Treatments ........................................................... 28 
4.6 
Duration of Therapy ......................................................................................... 28 
4.7 
Duration of Follow Up ...................................................................................... 28 
4.8 
Removal of Subjects from Study Treatment and/or Study as a Whole ...... 29 
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4.9 
Patient Replacement ........................................................................................ 29 
5.0 STUDY PROCEDURES ........................................................................................................... 30 
6.0 Endpoint assessment ............................................................................................................ 32 
6.1 
Definitions ......................................................................................................... 32 
6.2 
Primary Endpoint.............................................................................................. 32 
6.3 
Secondary Endpoints ...................................................................................... 33 
6.4 
Definitions ......................................................................................................... 33 
6.5 
Disease parameters ......................................................................................... 33 
6.6 
Response Criteria ............................................................................................. 34 
6.7 
Evaluable patients ............................................................................................ 35 
7.0 ADVERSE EVENTS ................................................................................................................ 35 
7.1 
Adverse Event Monitoring ............................................................................... 35 
7.2 
Definitions & Descriptions .............................................................................. 36 
7.3 
Reporting of pregnancy and lactation ........................................................... 37 
7.4 
Adverse Event Reporting ................................................................................ 38 
8.0 DRUG INFORMATION ............................................................................................................ 39 
8.1 
Nivolumab ......................................................................................................... 39 
8.2 
Ipilimumab ......................................................................................................... 42 
9.0 CORRELATIVES/SPECIAL STUDIES .................................................................................... 44 
10.0 STATISTICAL CONSIDERATIONS ...................................................................................... 45 
10.1 
Study Design/Study Endpoints ....................................................................... 45 
10.2 
Sample Size and Accrual ................................................................................. 46 
10.3 
Data Analyses Plans ........................................................................................ 46 
11.0 STUDY MANAGEMENT ........................................................................................................ 46 
11.1 
Institutional Review Board (IRB) Approval and Consent ............................. 46 
11.2 
Amendments ..................................................................................................... 47 
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11.3 
Registration Procedures .................................................................................. 47 
11.5 
Data Management and Monitoring/Auditing .................................................. 47 
11.6 
Adherence to the Protocol .............................................................................. 48 
11.7 
Investigator Obligations .................................................................................. 48 
11.8 
Publication Policy............................................................................................. 49 
REFERENCES ............................................................................................................................... 50 
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NU Study Number: NU 16B07 
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Initial Version Date: June 28th, 2016 
 
5 
Amendment 4: March 1st, 2018 
LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BMS 
Bristol-Myers Squibb 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CNS 
Central Nervous System 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FOCBP 
Females of Childbearing Potential 
HER2 
Human Epidermal growth factor Receptor 2 
H&PE 
History & Physical Exam 
IBC 
Inflammatory Breast Cancer 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Center 
NCI 
National Cancer Institute 
NGS 
Next-Genomic Sequencing 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PD-1 
Programmed Death 1 
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
QAM 
Quality Assurance Monitor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
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SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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NU Study Number: NU 16B07 
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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
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Amendment 4: March 1st, 2018 
STUDY SUMMARY 
 
Title 
A Phase II Window of opportunity trial, of ipilimumab and nivolumab in 
metastatic recurrent HER2- inflammatory breast cancer (IBC) 
Short Title 
The WIN trial  
Version 
3/1/2018 (Amendment 5) 
Study Design 
This is a single arm phase II “window of opportunity” study of nivolumab 
in association with ipilimumab in patients with newly recurrent HER2 
negative IBC. 
Study Center(s) 
Northwestern University 
Objectives 
Primary: 
To assess the progression free survival (PFS), overall response rate 
(ORR) and safety of nivolumab and ipilimumab treatment in patients with 
recurrent/metastatic HER-2 negative IBC 
 
Secondary: 
1. To assess the overall response rate (ORR) and clinical benefit rate 
(CBR) according to RECIST criteria v1.1, 
2. To assess overall survival (OS) in patients with recurrent HER2 
negative IBC treated with nivolumab and ipilimumab 
3. To assess the safety and tolerability of nivolumab and ipilimumab in 
patients with recurrent IBC according to CTCAE v 4.03) 
Sample Size 
29 patients 
Diagnosis & Key 
Eligibility Criteria 
Study population will consist of female patients age 18 or older, Eastern 
Cooperative Oncology Group (ECOG) performance status 0-1, with 
histologically confirmed, recurrent HER2- IBC. Patients need to have 
adequate kidney, bone marrow, and liver functions, and with or without 
radiologically measurable disease according to Response Evaluation 
Criteria of Solid Tumors (RECIST). Patients cannot have a history of 
clinically significant autoimmune diseases or a syndrome that requires 
systemic steroids or immunosuppressive agents. Autoimmune diseases 
include but are not limited to autoimmune hepatitis, systemic lupus 
erythematous, rheumatoid arthritis, inflammatory bowel disease, multiple 
sclerosis, vasculitis, or glomerulonephritis. Patients on treatment with 
prednisone > 10mg daily or equivalent corticosteroid will be excluded. 
Treatment Plan 
Treatment will consist of combination nivolumab and ipilimumab, given 
intravenously until disease progression or intolerable toxicity. Nivolumab 
will be administered at a dose of 240mg every 2 weeks for the first 16 
weeks, and 480mg every 4 weeks starting with Cycle 2 Day 29 (1 cycle 
= 12 weeks). Ipilimumab will be given continuously at 1mg/Kg every 6 
weeks until disease progression or intolerable toxicity. Patients will be 
evaluated for response every 12 weeks by CT, PET/CT or MRI.  
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NU Study Number: NU 16B07 
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Amendment 4: March 1st, 2018 
Statistical Methodology 
We will test the null hypothesis that median PFS is at most 3 months 
versus the alternative that it is at least 6 months. The null corresponds to 
25% PFS at 6 months under the exponential distribution of PFS versus 
an alternative 6 month PFS rate of 50%. The null corresponds to 50% 
PFS at 3 months and the alternative corresponds to 70.71% PFS at 3 
months under the same conditions. The chance of early study 
termination (3 months follow up with 15 patients) is 50% under the null 
and 4.4% under the alternative. Study power is 90% with overall type I 
error of 7%. The design follows: Early stopping designs based on 
progression-free survival at an early time point in the initial cohort 
 
 
1.0 
INTRODUCTION – BACKGROUND & RATIONALE 
 
1.1 
Disease Background 
According to the Surveillance, Epidemiology End Results in the year of 2015 there will an 
estimated 231,840 new cases of breast cancer in the United States.1 Inflammatory breast 
cancer (IBC) is a rare and aggressive form of disease accounting for 1-5 % of all breast 
cancers diagnosed.2 Patients with this disease have much poorer prognosis when 
compared to locally advanced non-IBC (median survival time of 2.9 versus 6.4 years).2 
Lee and Tannenbaum first used the term “inflammatory breast cancer” in 1924 to 
describe this clinical presentation. Subsequently, Haagensen described diagnostic 
criteria for IBC including a rapidly enlarging breast, erythema involving at least one-third 
of the breast, generalized induration, and biopsy proven carcinoma.3 
 
IBC is a clinico-pathological entity characterized by distinct skin changes including diffuse 
erythema and edema (peau-d’orange) often without a clinically evident underlying mass.4 
It is associated with an abrupt onset and rapid progression, with a high risk of axillary 
lymph node involvement and distant metastases at the time of initial diagnosis.5 Despite 
multimodality therapy, survival rates are lower than those for other breast cancers. Its 
aggressive course, together with accumulating molecular and epidemiological data, also 
lends support to the fact that IBC may in fact be a distinct biological entity rather than a 
subtype on the spectrum of locally advanced breast cancer. 
 
Once considered a uniformly fatal disease with fewer than 5% of patients alive at five 
years, management of IBC has evolved significantly over the last forty years. A 
multimodality approach, including primary systemic chemotherapy followed by 
mastectomy and radiation therapy has led to improved survival outcomes.6 The National 
Comprehensive Cancer Center (NCCN) guidelines list the standard approach to IBC as 
neoadjuvant chemotherapy with an anthracycline based regimen and a taxane.7 If HER2 
is overexpressed, trastuzumab for a total of one year is indicated as part of the systemic 
chemotherapy regimen. Mastectomy with axillary lymph node dissection is standard in 
IBC patients who respond to pre-operative chemotherapy. Following surgery, 
postmastectomy radiation is recommended with adjuvant endocrine therapy if indicated.8 
Several studies demonstrated that pathological complete response (pCR) to neoadjuvant 
therapy is the strongest prognostic factor.9,10 Patients with residual disease remain at 
high-risk of disease recurrence and in spite of optimal endocrine or HER-2 adjuvant 
therapies.11,12 The prognosis of metastatic IBC is dismal compared to non-IBC 
irrespective of disease subtype suggesting the need to improve the understanding of 
disease biology for more effective treatments.11  
 
In contrast with non-IBC breast cancer, most patients diagnosed with IBC do not express 
hormone receptor with estrogen receptor been overexpressed in only 30 to 44% of the 
cases.13,14 Her2 hyper-expression on other hand is common in IBC with overexpression 
frequency estimated at about 32-60% on diagnosis.11,15 
 
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NU Study Number: NU 16B07 
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Amendment 4: March 1st, 2018 
Matro colleagues recently reported the largest follow up study on the recurrence pattern 
of IBC in 478 patients with stage III at diagnosis.11 Among the different tumor subtypes, 
56% of patients with triple negative stage III disease subsequently developed 
metastases, compared with 43% of patients with HER2-positive disease and 35% with 
HR-positive disease. This indicates that triple negative tumors represent the most 
common type of recurrent IBC. Furthermore triple negative IBC is associated with poor 
prognosis when compared to Her2 and or HR + disease with dismal prognosis in the 
recurrent setting despite aggressive therapy.16,17 
 
1.1.1 
IBC molecular features 
Regardless of hormone receptor and HER2 expression statuses the distinct 
biologic characteristics typical of IBC are associated with poor outcome, including 
high S-phase fraction, high grade, aneuploidy, lack of estrogen and progesterone 
receptor expression and overexpression of human epidermal growth factor 
receptor 2 (HER2).13,18,19 Inflammatory breast tumors are more likely to have 
mutations in p53, associated with decreased response to chemotherapy and 
decreased survival outcomes.20 Several genes have been identified which are 
thought to contribute to the aggressive nature of IBC. Nuclear factor kappa B 
(NF-kB) related genes which mediate cell migration, invasion and metastasis are 
reported higher in IBC.21 Overexpression of Rhoc GTPase, a member of the RAS 
family of GTP binding proteins, upregulates angiogenic factors (VEGF, bFGF) 
promoting cell motility and invasion.22 IBC is associated with loss of expression of 
Wisp 3, a tumor suppressor gene coding for insulin-like growth factor-binding 
protein related protein (IGFBP-rP9) regulates tumor cell growth and invasion.11,23  
 
1.1.2 Advanced Diagnostics in IBC 
In the last few years the clinical application of next-genomic sequencing (NGS) 
allowed for molecular analysis of metastatic breast cancer, including IBC and 
showed the ability to identify mechanisms of resistance and actionable 
mutations. Palma, Cristofanilli and colleagues recently reported the result of a 
retrospective study involving patients with metastatic IBC that had a diagnostic 
biopsy of metastatic lesion and subsequent NGS by Foundation One™ panels.24 
The analysis revealed a total of 84 unique mutations with a total of 156 
mutational events. The five most commonly mutated genes in order of frequency 
were TP53 (53.33% of patients), PIK3CA mutations or amplification (36.7%), 
MYC amplification (30%), ERBB2 amplification (26.7%) and ZNF217 amp and 
PTEN loss or mutation (16.7%). In total, 21 of 30 patients (70%) had at least one 
actionable mutation. Of these 21 patients, 28.5% were ER+/HER- (Luminal A), 
28.5% ER+/HER+ (Luminal B) and 28.5% ER-/HER- (TNBC) while the remaining 
were ER-/HER+ (HER2+). 9.5% of these 21 patients expressed HER positivity by 
IHC although ERBB2 amplification was not detected. Fourteen 14 of 84 
mutations (16.7%) were actionable and comprised of PIK3CA 
mutations/amplifications, ERBB2 amplifications, AKT mutations and PTEN 
loss/mutations (unpublished data, manuscript submitted for publication).  
 
In a separate study, Hamm, Cristofanilli and colleagues used a custom 
hybridization capture based probe library was designed using Agilent SureDesign 
portal (Agilent Technologies) to analyze 20 IBC specimens.25 This panel captures 
full coding regions of 208 cancer relevant genes and introns of 13 genes to 
detect the substitution, deletions, copy number changes in the 208 targeted 
genes and structural rearrangements in 17 genes. 
 
Analysis of the types of genetic variants revealed that missense mutations were 
the most common variant (73%), followed by frameshifts (8%), splice site 
alterations (6%), nonsense mutations (5.5%), amplifications (5.5%), and In-frame 
insertions-deletions (3%).  In total, NGS identified 391 genetic variants in 19 IBC 
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tissues. In the IBC cohort, the 5 most commonly altered genes are:  TP53 
(altered in 58% [n=11] of IBC tumors), HER2 (amplified in 53% [n=10] of IBC 
tumors), ATM (altered in 53% [n=10] of IBC tumors, APC (altered in 37% [n=7] of 
IBC tumors), and HER3 (altered in 26% [n=5] of IBC tumors).  In total, 47 genes 
have alterations in at least three independent IBC tumor samples.  Pathway 
analysis of the NGS data reveals prominent genomic variation of core biologic 
pathways in multiple IBC tumors.  Genes with reoccurring variants across IBC 
tumors grouped into distinct biologic pathways, and the most frequent gene 
alterations occur in pathways that influence genomic stability/DNA repair, PI3K 
signaling, chromatin modification, and HER signaling.   
 
1.1.3 Immune checkpoints in IBC 
The study from Hamm Cristofanilli and colleagues investigated also the role of 
immune infiltrate and immune checkpoints in relation with genomic 
abnormalities.25  
 
The pathological examination of IBC tissues identified a subset of IBC tumors 
associated with infiltration of immune or inflammatory cells.  To further 
investigate the nature of these infiltrates, CD8 (cytotoxic T cell marker) and 
FOXP3 (T regulatory cell marker) IHC staining was performed on tissues to 
characterize T cells populations present in each tumor. Twelve IBC tumors had 
sufficient tissue for IHC analysis.  Infiltrates stained minimally for FoxP3+ Tregs.  
IHC staining identified the majority of infiltrating cell populations as CD8+ 
cytotoxic T cells.  CD8+ T cells typically localized in associated intra-tumoral and 
contiguous peri-tumoral desmoplastic stroma.  Each tumor was scored by a 
pathologist as high CD8+ (infiltrating cells occupying ≥5% of tumor area occupied 
by tumor cells) or low CD8+ (infiltrating cells occupying <5% of tumor area 
occupied by tumor cells).  High levels of CD8+ infiltration were observed in 5/12 
tumors, and frequently presented as cell aggregates.   Remaining tumors 
generally displayed low levels of single cell spreads of CD8+ cells across tissues, 
which was further confirmed by image analysis of average size of cellular 
aggregates in each tissue.  
 
In order to explore the possible role of PD-L1 in IBC, the investigators performed 
IHC stained of IBC tissues.  Evaluation of PD-L1 staining demonstrated low-
intensity tumor cell staining in 3/12 tumors studied and high-intensity tumor cell 
staining in 1/12 tumors.  Notably all immune cell infiltrates stained positively for 
PD-L1.   Intensity of PD-L1 staining on immune infiltrates was generally high with 
IHC scores typically ranging from 2+ to 3+. To further understand the differences 
in levels of immune cell infiltration between IBC tumors, NGS data was analyzed 
in tumors with high and low levels of immune infiltrate (Due to limited tissue 
availability 12 of 19 IBC samples were available for IHC analysis).  Notably, 
somatic mutation rates were significantly higher in high infiltration vs low 
infiltration tumors (p<0.05).  The authors speculated that this correlation between 
somatic mutation rate and immune cell infiltration might be related to the 
exposure of tumor neo-antigens to the immune system. They next proposed that 
a score (iScore) that combines the somatic mutation rate and average mutant 
allele frequency might better represent the level and variability of neo-antigens 
throughout the bulk of the tumor. The iScore is calculated by multiplying the 
average mutant allele frequency by the total number of somatic mutations in the 
tumor.  Comparison of iScores between high infiltration and low infiltration tumors 
demonstrated high significance in the association between levels of CD8+ 
infiltration and iScore in IBC tumors, suggesting that the iScore may be a reliable 
NGS-based estimate of immune infiltrate in IBC tumors.   
 
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It is important to review that proposed correlation between high mutational 
burden of tumors and clinical benefit from immunotherapy strategies (i.e. 
checkpoint inhibitors anti-CTLA-4 and anti-PD-1 antibodies) is seen in other 
tumors, with remarkable effects seen with tumors displaying the highest rates of 
mutations such as melanoma26,27.This is also illustrated by the anti-tumoral 
immunologic response to anti-PD-1 antibody in patients with colorectal cancer 
and increased mutational burden secondary to mismatch repair deficiency.28 
 
The potential importance of immune checkpoint guided therapy in breast cancer 
is also underscored by recent reports of PD-1 inhibitor activity in non-IBC triple 
negative breast. Pembrolizumab, which is a monoclonal anti-PD-1 antibody was 
tested in a phase Ib trial on 32 female patients with PD-L1 IHC + and heavily 
pretreated metastatic recurrent non-IBC triple negative breast cancer. The 
clinical benefit rate (partial response + disease stabilization rates) was 25.8%.29 
 
1.2 
Intervention Background & Overview 
 
1.2.1 
Nivolumab, ipilimumab and nivolumab/ipilimumab combination 
Nivolumab (BMS-936558, MDX-1106) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HunMab) that is specific for human 
programmed death-1 (PD-1, cluster of differentiation 279 [ cd279]) cell surface 
membrane receptor (Investigator brochure version 2014). PD-1 is a negative 
regulatory molecule that is expressed transiently following T-cell activation and 
on chronically stimulated T cells characterized by an “exhausted” phenotype. 
Nivolumab anti-tumor activity has been investigated in patients with melanoma, 
non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).30-32 The 
combination of nivolumab and ipilimumab (anticytotoxic T lymphocyte associated 
antigen-4 [anti-CTLA-4]) in phase 1/2 trial showed markedly enhanced clinical 
activity with acceptable safety profile in melanoma patients.33 Nivolumab is 
currently FDA approved for BRAF V600 mutation-positive unresectable or 
metastatic melanoma, as a single agent., unresectable or metastatic melanoma, 
in combination with ipilimumab., metastatic non-small cell lung cancer and 
progression on or after platinum-based chemotherapy andAdvanced renal cell 
carcinoma who have received prior anti-angiogenic therapy, the treatment of 
patients with advanced stage non-small cell lung cancer after progression on 
platinum based chemotherapy and patients with metastatic renal cell carcinoma. 
Nivolumab is well tolerated when compared to chemotherapy with rare grade 3 or 
4 toxicities. Nonetheless is has been associated with immune related adverse 
events such as pneumonitis, colitis, which have frequency of less than 5%.30 
 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal 
antibody. Several preclinical studies demonstrated that CTLA-4 blockade could 
augment T cell-mediated immune responses against tumors.34,35 This let to the 
development of ipilimumab, a fully humanized IgG1 monoclonal antibody to 
CTLA-4. Two phase 3 trials demonstrated a durable clinical benefit for 
approximately 20-25% of metastatic melanoma patients with ipilimumab resulting 
in FDA approval of this compound as a first and second-line agent in metastatic 
melanoma.36,37 Ipilimumab has been associated with immune mediated toxicities 
such as diarrhea, colitis, rash, pruritus, hypothyroidism. The risk of grade 3 and 4 
immune-related adverse is estimated at approximately 14%.36  
 
Preclinical data show that the combination blockade of the PD-1/PD-L1- and 
CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would 
otherwise be inactivated to continue to expand and carry out effector functions, 
thereby shifting the tumor microenvironment from suppressive to inflammatory.38 
A recently published phase III on patients with untreated metastatic melanoma 
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Amendment 4: March 1st, 2018 
showed significant PFS in patients treated with the combination of nivolumab and 
ipilimumab when compared to either agent along.39 The combination of 
ipilimumab and nivolumab is now a standard first line option in the treatment of 
metastatic melanoma patients. Grade 3 and 5 treatment-related toxicities were 
described in 55% of patients treated with diarrhea, fatigue, elevations of liver 
enzymes happening in less than 10% of the patients.39 
 
1.2.2 
Clinical development 
 
Nivolumab in combination with ipilimumab is being evaluated in completed and 
ongoing BMS-sponsored clinical trials in melanoma, renal cell carcinomas, 
glioblastomas, lung cancer and gastrointestinal (GI) malignancies including 
colorectal cancer with microsatellite instability (MSI), and triple-negative breast 
cancer (TNBC) with an expanding group of indications (Investigator Brochure 
version 2015). On September 30, 2015, the U. S. Food and Drug Administration 
granted accelerated approval to nivolumab (Opdivo Injection, Bristol-Myers 
Squibb Company) in combination with ipilimumab for the treatment of patients 
with BRAF V600 wild-type, unresectable or metastatic melanoma. 
 
1.2.3 
Clinical efficacy 
Nivolumab and ipilimumab have demonstrated clinical activity as monotherapy 
and as combination therapy in several tumor types. The majority of responses 
was durable and exceeded 6 months (Investigator Brochure version 2015). 
  
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 
mg/kg dose was chosen for expanded cohorts. Among 236 patients, objective 
responses (ORs) (complete or partial responses [CR or PR]) were seen in 
NSCLC, melanoma, and RCC. ORs were observed at all doses. Median OS was 
16.8 months across doses and 20.3 months at the 3 mg/kg dose. Heavily 
pretreated patients with NSCLC treated with nivolumab (1, 3, or 10mg/kg) 
achieved median OS across all dose cohorts of 9.9 months with response rates 
of 17% and median duration of response 17 months 40. In addition, responses 
were similar between both squamous and non-squamous carcinoma cohorts in 
this study. A subsequent phase 3 study compared nivolumab to docetaxel in 
second-line treatment setting of advanced squamous cell carcinoma among 272 
patients. Nivolumab arm demonstrated superior median OS (9 vs 6 months), 1 
year survival rate (42 vs 24%), response rates (20 vs 9%), and significantly lower 
rates of grade 3-4 treatment related adverse events (7 vs 55%) 30. These results 
supported the FDA approval of nivolumab for second-line treatment of advanced 
squamous cell carcinoma following treatment with platinum-based 
chemotherapy.  
 
Nivolumab has also clinically meaningful activity in RCC. A phase II study treated 
168 patients with advanced clear cell RCC with progression after agents 
targeting VEGF pathway at three doses of nivolumab (0.3, 2 and 10mg/kg) 41. 
Median overall survival was 18, 25, and 24 months for the three dose cohorts, 
respectively. More recently 821 patients previously treated with antiangiogenic 
therapy were randomized to either nivolumab (3mg/Kg every 2 weeks) or 
everolims (10mg daily).42 The median overall survival was 25.0 months (95% 
confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months 
(95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab 
versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the 
prespecified criterion for superiority (P≤0.0148). Response rates were in average 
20% with only 11% incidence of grade 3-4 treatment-related adverse events.  
 
The clinical efficacy of ipilimumab monotherapy was assessed in phase 3 trial 
among 676 patients with metastatic progressive melanoma.36 total of 676 HLA-
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
14 
Amendment 4: March 1st, 2018 
A*0201-positive patients with unresectable stage III or IV melanoma, whose 
disease had progressed while they were receiving therapy for metastatic 
disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus 
gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, 
at a dose of 3 mg per kilogram of body weight, was administered with or without 
gp100 every 3 weeks for up to four treatments (induction). Eligible patients could 
receive reinduction therapy. The primary end point was overall survival. The 
median overall survival was 10.0 months among patients receiving ipilimumab 
plus gp100, as compared with 6.4 months among patients receiving gp100 alone 
(hazard ratio for death, 0.68; P<0.001). The median overall survival with 
ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with 
gp100 alone, 0.66; P=0.003). No difference in overall survival was detected 
between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; 
P=0.76). Ipilimumab is now FDA approved for the treatment of patients with 
metastatic unresectable melanoma. 
 
In an advanced melanoma phase 1 study, nivolumab and ipilimumab 
combination was administered IV every 3 weeks for 4 doses followed by 
nivolumab alone every 3 weeks for 4 doses (concurrent regimen) 33. The 
combined treatment was subsequently administered every 12 weeks for up to 8 
doses. In a sequenced regimen, patients previously treated with ipilimumab 
received nivolumab every 2 weeks for up to 48 doses. In the concurrent regimen 
(53 patients), 53% of patients had an OR at doses 1 mg/kg nivolumab and 3 
mg/kg ipilimumab, with tumor reduction of 80% or more (modified World Health 
Organization criteria). In the sequenced-regimen (33 patients), the objective 
response rate (ORR) was 20%. These results demonstrate significant clinical 
activity of nivolumab across multiple histologies with favorable toxicity profile. 
 
In a phase 2 study of nivolumab in combination with ipilimumab vs. ipilimumab 
monotherapy in subjects with previously untreated, unresectable or metastatic 
melanoma, the combination of nivolumab with ipilimumab demonstrated clear 
evidence of clinical activity over ipilimumab monotherapy, as measured by 
statistically significant improvements in ORR and PFS, and a higher proportion of 
subjects with complete responses.32 A phase 3 study of nivolumab monotherapy 
or nivolumab in combination with ipilimumab vs. ipilimumab monotherapy in 
subjects with previously untreated, unresectable or metastatic melanoma, the 
combination of nivolumab with ipilimumab demonstrated clear evidence of clinical 
activity over ipilimumab monotherapy, as measured by statistically significant 
improvements in median PFS in the combination arm (11.5 vs 6.87 vs 2.89 
months) 39 Based on descriptive analyses, the combination of nivolumab with 
ipilimumab demonstrated improved PFS nivolumab and ipilimumab 
monotherapies. 
 
Most recently, nivolumab at 3mg/Kg every 2 weeks combined with ipilimumab at 
1mg/KG every 6 weeks was evaluated in patients with advanced NSCLC in the 
first line setting(CheckMate 012 trial).43 In this trial 4 different combinations of 
nivolumab were compared (nivolumab 1mg/Kg every 3 weeks x 4+ ipilimumab 
1mg/Kg every 3 weeks x 4 followed nivolumab 3mg/Kg every 2 weeks (N=31), 
nivolumab 1mg/Kg every 2 weeks + ipilimumab 1mg/kg every 6 weeks (N=40), 
nivolumab 3mg/Kg every 2 weeks + ipilimumab 1mg/Kg every 12 weeks (n=38) 
and finally nivolumab 3mg/Kg every 2 weeks combined with ipilimumab 1mg/Kg 
every 6 weeks until disease progression (n=46). The efficacy data showed 
response rates of 13, 25, 39 and 31% respectively. These results suggest that 
continuation of dual CTLA4 and PD-1 inhibition can improve clinical outcomes 
when compared to currently used regimen. 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
15 
Amendment 4: March 1st, 2018 
1.2.4 
Clinical Safety 
For nivolumab monotherapy, the safety profile is similar across tumor types 
(investigator brochure v 2015). The only exception is pulmonary inflammation 
adverse events (AEs), which may be numerically greater in subjects with 
NSCLC, because in some cases, it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary symptoms and 
radiographic changes. There is no pattern in the incidence, severity, or causality 
of AEs to nivolumab dose level. Safety data for subjects with previously treated 
advanced or metastatic NSCLC treated with nivolumab monotherapy in 
CA209017 (131 subjects), CA209057 (287 subjects), and CA209063 (117 
subjects) were pooled and safety analyses were performed for these pooled 
subjects who receiving nivolumab monotherapy (a total of 535 
subjects)(investigator brochure v 2015). Based on the pooled analyses, 
nivolumab monotherapy at a dose of 3 mg/kg administered IV Q2W has an 
acceptable safety profile, as demonstrated by the frequency, severity, and types 
of AEs, drug-related deaths, SAEs, and AEs leading to discontinuation. The most 
common adverse events were fatigue (19.6%), decreased appetite (12.3%), 
nausea (12.0%), and asthenia (10.5%). The majority of drug-related AEs were of 
Grade 1-2 in severity. 
 
The toxicity profile of ipilimumab at the dose of 3mg/Kg for 4 doses in previously 
treated patients with metastatic melanoma was assessed in phase 3 trial. One 
hundred and thirty one patients with received ipilimumab as monotherapy, 380 
received it with gp100 peptide, and 132 received gp100 peptide vaccine alone. 
Patients in the study received a median of 4 doses. Ipilimumab was discontinued 
for adverse events in 10% of patients. The most common adverse events in 
patients who received ipilimumab at 3mg/Kg were fatigue (31%), pruritus (23%) 
and rash (22%)(package insert v 2013). The majority of drug-related AEs were of 
Grade 1-2 in severity. 
 
 
In several ongoing clinical trials, the safety of nivolumab in combination with 
ipilimumab is being explored. Most studies are ongoing and, as such, the safety 
profile of nivolumab combinations continues to evolve. The most advanced 
combination under development is nivolumab + ipilimumab in subjects with 
melanoma. Thus far, the combination of both agents results in a safety profile 
with similar types of AEs as either agent alone, but in some cases with a greater 
frequency 33.  
 
Safety data for subjects with previously untreated unresectable or metastatic 
melanoma treated with nivolumab in combination with ipilimumab in phase III 
(313 subjects) and phase II (94subjects) trials were pooled and safety analyses 
were performed for these pooled subjects receiving nivolumab in combination 
with ipilimumab (a total of 407 subjects) as described in the investigator brochure 
BMS-936558/MDX1106 Version No14, 30-Jun-2015.32,39 Based on the pooled 
analyses, nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg administered IV 
Q3W for 4 doses followed by nivolumab 3 mg/kg IV Q2W has an acceptable 
safety profile, as demonstrated by the frequency, severity, and types of AEs, 
drug-related deaths, SAEs, and AEs leading to discontinuation. The most 
frequently reported drug-related AEs of any grade were diarrhea (43.0%), fatigue 
(35.4%), pruritus (33.4%), rash (31.0%), nausea (24.8%), pyrexia (18.7%), ALT 
increased (18.2%), AST increased (16.7%) and decreased appetite (16.2%). The 
most frequently reported drug-related Grade 3-4 AEs (≥ 5% of subjects) were 
colitis (9.6%), diarrhea (8.80%), ALT increased (8.4%), lipase increased (8.4%), 
and AST increased (5.9%). Study drug toxicity was considered responsible for 2 
deaths; 1 subject died of ventricular arrhythmia within 30 days of the last dose 
and the other died of pneumonitis between 31 and 100 days of the last dose. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
16 
Amendment 4: March 1st, 2018 
 
Most recently, nivolumab at 3mg/Kg every 2 weeks combined with ipilimumab at 
1mg/KG every 6 weeks was administered in patients with advanced NSCLC in 
the first line setting.(CheckMate 012 trial)43 In this trial 4 different combinations of 
nivolumab were compared ( nivolumab 1mg/Kg every 3 weeks x 4+ ipilimumab 
1mg/Kg every 3 weeks  x 4 followed nivolumab 3mg/Kg every 2 weeks (N=31), 
nivolumab 1mg/Kg every 2 weeks + ipilimumab 1mg/kg every 6 weeks (N=40), 
nivolumab 3mg/Kg every 2 weeks + ipilimumab 1mg/Kg every 12 weeks (n=38) 
and finally nivolumab 3mg/Kg every 2 weeks combined with ipilimumab 1mg/Kg 
every 6 weeks until disease progression (n=46). Toxicity data favored the latter 
group with estimates of grade 3 and 4 treatment related adverse events 29, 35, 
29 and 28%, respectively. These results indicate that the nivolumab dose of 
3mg/Kg administered every 2 weeks combined with ipilimumab 1mg/Kg every 6 
weeks until disease progression has favorable disease profile and should be 
further explored in future clinical trials.  
 
1.2.5 
Biomarkers 
Significant efforts continue to explore potential tumor cells and 
microenvironment-related biomarkers that could predict response to nivolumab 
and other checkpoint inhibitors. For instance, tumor cell expression of PD-L1 was 
characterized with the use of IHC staining and pharmacodynamics changes in 
the peripheral blood absolute lymphocyte count in the study investigating the 
combination of nivolumab and ipilimumab in melanoma 33. PD-L1 positivity was 
defined as expression in at least 5% of tumor cells. Among patients treated with 
the concurrent regimen of nivolumab and ipilimumab, ORs were observed in 
patients with either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–
negative tumor samples (9 of 22). In the sequenced regimen cohorts, a higher 
number of overall responses were seen among patients with PD-L1–positive 
tumor samples (4 of 8 patients) than among patients with PD-L1–negative tumor 
samples (1 of 13) suggesting the possibility that these tumors have higher 
response rates to the combination. Other biomarkers such as tissue expression 
of PDL-2, interferon-γ (IFN- γ), IDO (indoleamine-pyrrole 2,3-dioxygenase), and 
T cell CD8+ infiltration are also being investigated. However, there is no definitive 
date to support the use of any of these biomarkers to select patients for 
treatment at this time. 
 
1.3 
Rationale for the Current Study 
IBC is associated with significant level of genomic instability. Moreover, the level of 
genomic mutation rate, indicated as iScore is associated with infiltrate of CD8 cytotoxic T 
cells together with PDL-1 staining. Immune checkpoint targeted therapies showed 
significant activity and is currently approved in other solid tumors. The data provide a 
strong rationale for testing of immune checkpoint modulators in metastatic IBC. 
 
1.3.1 
Study design 
The rationale for use of a “window of opportunity” study is based on the fact that 
it allows to assess the efficacy of immunotherapy in IBC when the tumor is still 
unperturbed by other systemic treatments routinely used the metastatic setting. 
 
1.3.2 
Nivolumab flat dose regimen 
The safety and efficacy of 240 mg (combined with 1mg/kg of ipilimumab) Q2W 
flat dose of nivolumab is expected to be similar to the 3 mg/kg Q2W dosing 
regimen. Using the PPK model, exposure of nivolumab at 240 mg flat dose is 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is the 
approximate median body weight in nivolumab clinical trials. Across the various 
tumor types in the clinical program, nivolumab has been shown to be safe and 
well tolerated up to a dose level of 10 mg/kg, and the relationship between 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
17 
Amendment 4: March 1st, 2018 
nivolumab exposure produced by 3 mg/kg and efficacy and safety has been 
found to be relatively flat. Given the similarity of nivolumab PK across tumor 
types and the similar exposures predicted following administration of 240 mg flat 
dose compared to 3 mg/kg, it is expected that the safety and efficacy profile of 
240 mg nivolumab will be similar to that of 3 mg/kg nivolumab. Hence, the flat 
dose of 240 mg nivolumab is under investigation. 
 
1.3.3 
Ipilimumab dose regimen 
Ipilimumab will be administered at 1mg/Kg every 6 weeks until disease 
progression in combination with nivolumab 240mg every 2 weeks. As discussed 
above, this drug combination regimen has been compared with the current FDA 
approved combination regimen of nivolumab 1mg/Kg every 3 weeks x 4 and 
ipilimumab 3mg/Kg every 3 weeks x 4 followed by nivolumab 3mg/Kg every 2 
weeks until disease progression and showed favorable toxicity profile with 
maintained efficacy among patient with lung cancer.43 
 
1.4 
Exploratory Studies 
In the era of personalized therapy appropriate patient selection to immune-check point 
inhibitors remain an elusive goal. There are conflicting data on the predictive value of PD-
L1 expression on PD-1 directed therapy in solid tumors 30,44. Herbst et al showed that 
patients with solid tumors including non-small cell lung cancer and melanoma treated 
with humanized PD-L1 antibody had higher ORR when immunohistochemistry showed 
intense staining for PD-L1 in the tumor 45. The same correlation was not observed on 
stratified analysis according to tumor cell membrane PD-L1 expression of non-small cell 
lung cancer patients treated with nivolumab therapy in the second line setting.30 
 
The most recent archival diagnostic tissue biopsy performed as part of the standard of 
care approach to recurring breast cancer will be obtained for all patients and sent for 
NGS and evaluation of iScore (baseline assessment). The same specimen will be 
assessed for PDL-1 expression. A fresh tissue biopsy will be obtained for all patients 
where archival tissue is not available.  
 
Should repeat tumor tissue biopsy be performed after initiation of treatment on protocol 
as part of standard of care approach, specimens will be sent for NGS, iScore and PDL-1 
staining. Correlations between efficacy endpoints (PFS and ORR) and biomarker 
statuses will be conducted. 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
18 
Amendment 4: March 1st, 2018 
2.0 
OBJECTIVES & ENDPOINTS 
 
2.1 
Primary Objective & Endpoint 
To determine progression free survival (PFS) in patients with newly recurrent HER2 
negative IBC treated with nivolumab and ipilimumab according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v 1.1.46 
The time in months from start of treatment to progression or death will be measured for 
all patients who receive at least one dose of study drug. Patients will be followed up to 2 
years after completion of treatment. 
 
2.2 
Secondary Objectives & Endpoints 
2.2.1 
To assess the overall response rate (ORR) and clinical benefit rate (CBR)  
 
 
according to RECIST criteria v1.1, in patients with recurrent IBC treated with  
 
 
nivolumab and ipilimumab 
 
 
 
 
Overall response rate (ORR) is defined as Complete Response (CR) + Partial 
Response (PR). Clinical benefit rate (CBR) is defined as CR + PR + Stable 
Disease (SD). Patients will have scans every 12 weeks. 
 
2.2.2 
To assess overall survival in patients with recurrent HER2 negative IBC treated 
with nivolumab and ipilimumab. 
 
 
 
Patients will be followed from the start of treatment until 2 years post-treatment or 
 
death, whichever occurs first, and average survival time will be measured. 
 
2.2.3 
To assess the safety and tolerability of nivolumab and ipilimumab in patients with 
recurrent IBC according to the National Cancer Institute Common Terminology 
Criteria Adverse events v 4.03). 
 
 
 
The number, frequency, and severity of adverse events will be collected from 
time of consent until 12 weeks after study treatment.  
 
2.3 
Exploratory Objectives & Endpoints 
2.3.1  
To assess the predictive value of baseline iSCORE and PDL-1 expression using 
archival tissue samples as well as any standard of care tissue obtained during 
study treatment. 
 
 
 
All patients will provide archival or fresh tumor tissue at study registration, and 
 
will have the option to provide tissue from any biopsies performed during study 
 
treatment.  
 
 
3.0 
PATIENT ELIGIBILITY 
The target population for this study is patients with stage IV early recurrence HER2 negative IBC. 
This will be a single center trial conducted at Northwestern University.  
 
A total of 29 subjects will be needed for this trial. Approximately 8 potentially eligible patients are 
seen per month, and it is anticipated that at least 2 per month will be accrued. Potential patients 
may be referred to the Principal Investigator (PI) at Northwestern University, Dr. William 
Gradishar at (312) 695-4541. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11.3 for complete instructions regarding registration procedures. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
19 
Amendment 4: March 1st, 2018 
3.1 
Inclusion Criteria 
 
3.1.1 
Patients must have histologically or cytologically confirmed stage IV breast 
carcinoma with a previous clinical diagnosis of IBC based on the presence of 
inflammatory changes in the involved breast, such as diffuse erythema and 
edema (peau d’orange), with or without an underlying palpable mass involving 
the majority of the skin of the breast. Pathological evidence of dermal lymphatic 
invasion should be noted but is not required for diagnosis. 
 
3.1.2 
Patients must have local or metastatic recurrence of IBC after prior surgery.  
 
3.1.3 
Patients must have a metastatic tumor negative for HER2. The lack of HER2 
overexpression by immunohistochemistry (IHC), is defined as 0 or 1+ where as 
hyperexpression is defined as 3+. If equivocal IHC, 2+, the tumor must be non-
gene amplified by FISH performed upon the primary tumor or metastatic lesion 
(ratio <2 and HER2 copy number <4).47 
 
3.1.4 
Patients may have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension in accordance with RECIST 
criteria v. 1.1 OR non-measurable tumors (see section 6.5). 
 
NOTE: Non-measurable tumors are small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis). Bone lesions, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI) are considered as 
non-measurable.  
 
3.1.5 
Patients must be in consideration for 1st line systemic therapy for recurrent IBC. 
 
 
 
NOTE: Patients must not have received chemotherapy in the metastatic setting, 
 
but adjuvant treatment after surgery is acceptable. 
 
3.1.6 
Patients must have confirmed availability of archival or freshly biopsied tumor 
tissue meeting protocol-defined specifications prior to study enrollment.  
 
3.1.7 
Patients must be female and age ≥ 18 years. 
 
3.1.8 
Patients must exhibit an ECOG status of 0-1. ECOG performance status 2 and 3  
will be allowed only if decline in performance status is thought to be directly 
secondary to breast cancer disease burden by treating physician. 
 
3.1.9 
Patients must have adequate organ and bone marrow function ≤14 days prior to 
registration, as defined below:  
• 
leukocytes  
 
≥ 2,000/mcL 
• 
absolute neutrophil count 
≥ 1,500/mcL, regardless of transfusion or growth 
 
 
 
 
 
 
factor support 
• 
platelets 
 
 
≥ 100,000/mcl, regardless of transfusion or  
 
 
 
 
 
 
growth factor support 
• 
total bilirubin 
 
total bilirubin ≤1.5× institutional upper limit of  
 
 
 
 
normal (ULN) (except patients with Gilbert  
 
 
 
 
Syndrome or liver metastasis, who can have  
 
 
 
 
total bilirubin  <3.0 x ULN)  
• 
AST(SGOT)/ALT(SPGT) 
≤ 2.5 X institutional upper limit of normal (ULN)  
 
 
 
 
(or ≤5 times ULN in case of liver metastasis) 
• 
creatinine  
 
Serum creatinine of < 3.0 X ULN (upper limit of  
 
 
 
 
normal) 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
20 
Amendment 4: March 1st, 2018 
3.1.10 Patients with history of central nervous system (CNS) metastases are eligible if 
CNS disease has been stable for at least 6 weeks prior to study registration in 
the opinion of the investigator and do not require corticosteroids (of any dose) for 
symptomatic management.  
 
NOTE: Patients are not required to have CNS imaging prior to study entry. 
 
3.1.11 Females of childbearing potential (FOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 
hours of registration. 
 
 
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy 
• 
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months) 
 
3.1.12 FOCBP and men who are sexually active with FOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment and the 
designated post-treatment period (see Appendix C for details on appropriate 
contraception methods)  
 
3.1.13 Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients must not have had chemotherapy or radiotherapy ≤ 28 days prior to 
study registration. 
 
3.2.2 
Patients who already received chemotherapy for recurrent metastatic IBC are not 
eligible. 
 
3.2.3 
Patients who have not recovered to ≤ Grade 1 from adverse events due to 
agents administered ≥28 days prior to registration are not eligible. 
 
3.2.4 
Patients may not be receiving any other investigational agents. 
 
3.2.5 
Patients who have had prior exposure to immune checkpoint inhibitors are not 
eligible. Please contact principal investigator, William Gradishar at 312-695-4541 
for specific questions on potential interactions. 
 
 
Mechanism of action 
Agent 
PD-1 monoclonal antibody 
Pembrolizumab, Pidilizumab, MEDI-0680, 
AMP-224, PF-06801591, AMP224, BGB-
A317, PDR001,REGN2810, SHR-1210 
PD-L1 monoclonal antibody  
Durvalumab, avelumab, MDX-1105, 
atezolizumab, MPDL3280A 
CTLA4 monoclonal antibody 
Tremulimumab, abatacept 
OX40  
MEDI6383,MEDI6469, MEDI0562, 
oxelumab, PF-04518600 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
21 
Amendment 4: March 1st, 2018 
3.2.6 
Patients with active autoimmune disease or history of autoimmune disease that 
might recur, which may affect vital organ function or require immune suppressive 
treatment including chronic prolonged systemic corticosteroids (defined as 
corticosteroid use of duration one month or greater), should be excluded. These 
include but are not limited to patients with a history of: 
• 
immune related neurologic disease 
• 
multiple sclerosis 
• 
autoimmune (demyelinating) neuropathy 
• 
Guillain-Barre syndrome 
• 
myasthenia gravis 
• 
systemic autoimmune disease such as SLE 
• 
connective tissue diseases 
• 
scleroderma 
• 
inflammatory bowel disease (IBD) 
• 
Crohn’s 
• 
ulcerative colitis 
• 
patients with a history of toxic epidermal necrolysis (TEN) 
• 
Stevens-Johnson syndrome 
• 
anti-phospholipid syndrome  
• 
leptomeningeal disease 
 
 
NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll. 
 
3.2.7 
Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible:  
 
• 
Ongoing or active infection (including minor localized infections) requiring 
oral or IV treatment 
• 
Symptomatic congestive heart failure, defined as a clinical syndrome 
resulting from any structural or functional cardiac disorder that impairs the 
ability of the ventricle to fill with or eject blood 
• 
Unstable angina pectoris 
• 
Cardiac arrhythmia 
• 
Psychiatric illness/social situations that would limit compliance with study 
requirements 
• 
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints 
 
3.2.8 
Patients should not have any condition requiring systemic treatment with 
corticosteroids (<10mg daily prednisone equivalents) or other 
immunosuppressive medications ≤14 days prior to registration.  
 
 
NOTE: Inhaled or topical steroids and adrenal replacement steroid doses <10mg 
daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.  
 
3.2.9 
Female patients who are pregnant or nursing are not eligible. 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
22 
Amendment 4: March 1st, 2018 
3.2.10. Patients with a history of another malignancy within 3 years prior to registration 
are not eligible for participation, with the following exceptions: 
• adequately treated basal cell or squamous cell skin cancer,  
• in situ cervical cancer  
 
3.2.11 Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) is not permitted. 
 
3.2.12 Any known positive test for Hepatitis B or Hepatitis C virus indicating acute or 
chronic infection is not permitted. 
 
3.2.13 Patients who have received a live attenuated vaccine ≤ 30 days prior to 
registration are not eligible. 
 
 
4.0 
TREATMENT PLAN 
4.1 
Overview 
Nivolumab and ipilimumab combination will be administered intravenously until disease 
progression or intolerable toxicity. Nivolumab will be given at 240mg every 2 weeks for 
the first 16 weeks, and at 480mg every 4 weeks thereafter (starting with C2D29, 1 cycle = 
12 weeks). Ipilimumab will be given at 1mg/Kg every 6 weeks over approximately 90 
minutes. On days when both nivolumab and ipilimumab are administered, nivolumab 
should be given first, followed by ipilimumab about 30 minutes later. Scans will take place 
every 12 weeks for disease assessment. Note: Please refer to section 4.4 for patients 
who may continue treatment after initial progression. 
 
4.2 
Treatment Administration 
 
Treatment Administration Summary 
Agent 
Premedications 
Dose 
Route 
Schedule 
Cycle 
Length 
Supportive 
Therapies 
Nivolumab 
None 
240mg 
IV infusion 
over ~30 
minutes*  
Q2Ws 
12 
weeks  
 
As needed 
480mg 
IV infusion 
over ~60 
minutes 
Q4W’s 
Ipilimumab* 
None 
1mg/Kg  
IV infusion 
over ~90 
minutes*  
 
Q6Ws 
As needed 
*On days when both drugs are administered, nivolumab should be given first, followed by ipilimumab 
~30 minutes later. 
 
4.2.1 
Nivolumab 
 
Treatment will be administered on an outpatient basis. Reported adverse events 
 
and potential risks are described below. No investigational or commercial agents 
 
or therapies other than those described below may be administered with the 
 
intent to treat the patient’s malignancy. 
 
Nivolumab will be administered at a dose of 240mg (combined with ipilimumab) 
as an intravenous infusion over approximately 30 minutes (-5 / +15 minutes) 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
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Initial Version Date: June 28th, 2016 
 
23 
Amendment 4: March 1st, 2018 
every 2 weeks for the first 16 weeks (1 cycle = 12 weeks). Starting with Cycle 2 
Day 29, nivolumab will be given at 480mg IV over approximately 60 minutes (-10 
/ +15  minutes) every 4 weeks until disease progression, unacceptable toxicity, or 
withdrawal of consent.  
NOTE: The first two nivolumab doses of Cycle 2 will be given at 240mg q2weeks.  
There will be no dose escalations or reductions of nivolumab allowed. Subjects 
may be dosed no less than 12 days or 24 days from the previous dose (for 
240mg and 480mg doses, respectively). There are no pre-medications 
recommended for nivolumab on the first cycle. If an acute infusion reaction is 
noted, subjects should be managed according to Section 4.3.3. 
Nivolumab is to be administered as a 30-minute (-5 / +15 minutes) or 60-minute 
(-10 / +15 minutes) IV infusion (for 240mg and 480mg, respectively), using a 
volumetric pump with a 0.2- 1.2 micron low-protein binding in-line filter at the 
protocol-specified dose. The drug can be diluted with 0.9% Sodium Chloride or 
5% Dextrose for delivery but the total drug concentration of the solution cannot 
be below 0.35 mg/mL. It is not to be administered as an IV push or bolus 
injection. At the end of the infusion, flush the line with a sufficient quantity of 
normal saline.  
Subjects will be monitored continuously for AEs while on study. Treatment delay 
or discontinuation will be based on specific laboratory and adverse event criteria.  
 
Early recognition and management may mitigate severe toxicity. Evaluation and 
Management Guidelines were developed to assist investigators and can be 
found in the Investigator Brochure:  
• 
Suspected Pulmonary Toxicity   
• 
Diarrhea and Colitis   
• 
Suspected Hepatotoxicity (including asymptomatic liver function tests [LFT] 
elevations)   
• 
Suspected Endocrinopathy 
• 
Nephrotoxicity 
 
4.2.2 
Ipilimumab  
Ipilimumab will be administered at a dose of 1mg/Kg as an intravenous infusion 
over approximately 90 minutes (-5 / +15 minutes) every 6 weeks until disease 
progression, unacceptable toxicity, or withdrawal of consent. Dosing will be 
based on actual body weight in kg on the day of the infusion. On days when both 
ipilimumab and nivolumab are administered, nivolumab should be given first, 
followed by ipilimumab ~30 minutes later. 
 
There will be no dose escalations or reductions of ipilimumab allowed. There are 
no pre-medications recommended for ipilimumab on the first cycle. If an acute 
infusion reaction is noted subjects should be managed according to Section 
4.3.3.  
 
Ipilimumab is to be administered as a 90-minute IV infusion (a window of -5 / +15 
minutes is allowed), using a volumetric pump with a 0.2/1.2 micron in-line filter at 
the protocol-specified dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration of the solution cannot be below 1 
mg/mL. It is not to be administered as an IV push or bolus injection. At the end of 
the infusion, flush the line with a sufficient quantity of normal saline.  
Subjects will be monitored continuously for AEs while on study. Treatment delays 
or discontinuation will be based on specific laboratory and adverse event criteria.  
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
24 
Amendment 4: March 1st, 2018 
 
Early recognition and management may mitigate severe toxicity. Evaluation and 
Management Guidelines were developed to assist investigators and can be 
found in the Investigator Brochure:  
• 
Suspected Pulmonary Toxicity   
• 
Diarrhea and Colitis   
• 
Suspected Hepatotoxicity (including asymptomatic liver function tests [LFT] 
elevations)   
• 
Suspected Endocrinopathy 
• 
Nephrotoxicity 
 
4.3 
Toxicity Management & Dose Delays 
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table). Toxicity will be assessed 
according to the NCI CTCAE v. 4.03.  
 
4.3.1 
Dose delays: Ipilimumab and/or nivolumab 
There will be no dose modifications allowed for management of toxicities. 
 
Should the treating physician decide to delay treatment given suspicion for a 
 
drug-related side effect,  the side effect should be attributed to one study drug to 
 
the best of the physician’s ability. Either ipilimumab or nivolumab should be 
 
delayed based on this attribution, or both if a definite attribution is not possible. 
 
Both drugs can be held for a maximum of 56 days.  
 
Ipilimumab and/or nivolumab administration should be delayed for the following 
until resolution to ≤ Grade 1:  
• 
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  
o 
Any Grade 3 skin, drug-related adverse event 
o 
Any Grade 3 drug-related laboratory abnormality, with the following 
exceptions for  lymphopenia, leukopenia, AST, ALT, or total bilirubin: 
 
Grade 3 lymphopenia or leukopenia does not require dose 
delay 
 
If a subject has a baseline AST, ALT or total bilirubin that is 
within normal limits, delay dosing for drug-related Grade ≥ 2 
toxicity  
 
If a subject has baseline AST, ALT, or total bilirubin within 
the Grade 1 toxicity range, delay dosing for drug-related 
Grade ≥ 3 toxicity 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the investigator, warrants delaying the dose of study 
medication.  
 
Immunotherapy agents such as nivolumab and ipilimumab are associated with 
AEs that can differ in severity and duration compared to other therapeutic 
classes of medications. Early recognition and management of AEs associated 
with nivolumab can mitigate severe toxicity. Corticosteroids are the primary 
therapy for drug-related AEs. Management algorithms have been developed to 
assist investigators in assessing and managing nivolumab associated AEs, which 
can be found in Appendix D of this protocol. The guidance provided in these 
algorithms should not replace the Investigator’s medical judgment. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
25 
Amendment 4: March 1st, 2018 
4.3.2 
Treatment discontinuation: Ipilimumab and/or nivolumab 
Should the treating physician decide to discontinue treatment given suspicion for 
 
a drug related side effect, the side effect (adverse event) should be attributed to 
 
one study drug to the best of the physician’s ability. Either ipilimumab or 
 
nivolumab should be discontinued based on this attribution, or both if definite 
 
attribution is not possible.  
 
Ipilimumab and/or nivolumab should be discontinued permanently for the 
following: 
• 
 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 
• 
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: 
 
o 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
o 
Grade 3 drug endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
 
o 
Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except: 
  
 
Grade 3 drug-related thrombocytopenia > 7 days or associated 
with bleeding (aside from minor bleeds ≤ Grade 1) requires 
discontinuation 
 
Any drug-related liver function test (LFT) abnormality that meets 
the following criteria require discontinuation: 
• 
AST or ALT > 5-10 x ULN for > 2 weeks 
• 
AST or ALT > 10 xUL 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 xULN and total bilirubin > 2 
x ULN 
  
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation: 
o 
Grade 4 neutropenia < 7 days 
o 
Grade 4 lymphopenia or leukopenia 
o 
Isolated Grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis. PI and Data 
Monitoring Committee (DMC) should be consulted for Grade 4 amylase 
or lipase abnormalities. 
o 
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 endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation. 
  
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
26 
Amendment 4: March 1st, 2018 
Any event that leads to interruption in dosing lasting > 56 days (8 weeks) from the 
previous dose requires discontinuation. 
 
4.3.3 
Treatment of Nivolumab or Ipilimumab-related infusion reactions 
Since both 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. All 
grade 3 or 4 infusion reactions should be reported within 24 hours to the study 
QAM and reported as an SAE if it meets the criteria. Infusion reactions should be 
graded according to NCI CTCAE (Version 4.03) guidelines.  
 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate:  
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Remain at bedside and monitor 
subject until recovery from 
symptoms.  
 
The following prophylactic pre-
medications are recommended 
for future infusions:  
• 
Diphenhydramine 50 mg 
(or equivalent) and/or 
• 
Acetaminophen 325 to 
1000 mg at least 30 
minutes before 
additional nivolumab or 
ipilimumab 
administrations 
Grade 2 
Moderate reaction requires 
therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment [eg, 
antihistamines, non-steroidal 
anti- inflammatory drugs, 
narcotics, corticosteroids, 
bronchodilators, IV fluids]; 
prophylactic medications 
indicated for < 24 hours 
Stop the nivolumab/ipilimumab 
infusion, begin an IV infusion of 
normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 
325 to 1000 mg;  
  
Remain at bedside and monitor 
subject until resolution of 
symptoms.  
 
Corticosteroid and/or 
bronchodilator therapy may also be 
administered as appropriate. If the 
infusion is interrupted, then restart 
the infusion at 50% of the original 
infusion rate when symptoms 
resolve; if no further complications 
ensue after 30 minutes, the rate 
may be increased to 100% of the 
original infusion rate.  
 
Monitor subject closely. If 
symptoms recur, then no further 
nivolumab will be administered at 
that visit. 
 
For future infusions, the following 
prophylactic pre-medications are 
recommended:  
• 
Diphenhydramine 50 mg (or 
equivalent) and/or 
• 
Acetaminophen 325 to 1000 
mg should be administered 
at least 30 minutes before 
nivolumab or ipilimumab 
infusions. If necessary, 
corticosteroids (up to 25 mg 
of SoluCortef or equivalent) 
may be used. 
Grades 3 or 4 
Immediately discontinue infusion of 
nivolumab/ipilimumab infusion. 
 
No subsequent dosing 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
27 
Amendment 4: March 1st, 2018 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Severe reaction, Grade 3: 
prolonged [ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion]; 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae [eg, 
renal impairment, pulmonary 
infiltrates]. Grade 4: Life-
threatening; pressor or 
ventilatory support indicated 
Begin an IV infusion of normal 
saline and treat the subject as 
follows: Recommend 
bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 
to 0.25 mg of a 1:10,000 solution 
injected slowly for IV 
administration, and/or 
diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or 
equivalent), as needed.  
 
Subject should be monitored until 
the Investigator is comfortable that 
the symptoms will not recur. 
Nivolumab or ipilimimuab will be 
permanently discontinued. 
Investigators should follow their 
institutional guidelines for the 
treatment of anaphylaxis. Remain 
at bedside and monitor subject 
until recovery of the symptoms 
 
In case of late-occurring 
hypersensitivity symptoms (eg, 
appearance of a localized or 
generalized pruritus within 1 week 
after treatment), symptomatic 
treatment may be given (eg, oral 
antihistamine or corticosteroids 
 
 
4.4 
Treatment with ipilimumab and or nivolumab beyond progression 
In the event of an initial assessment of PD (based on RECIST Version 1.1), a subject 
may continue to receive the assigned study treatment as long as none of the criteria 
listed below are met. Criteria for discontinuation of investigational product include: 
 
1. Confirmed PD: An initial assessment of PD by RECIST Version 1.1 will be confirmed 
by a repeat evaluation at the next tumor assessment time point, but no sooner than 4 
weeks later (see Section 4.3.1 for disease evaluation).  
2. Meets any of the other investigational product discontinuation criteria (Section 4.1.6)  
3. Clinical symptoms or signs indicating significant PD such as the benefit-risk ratio of 
continuing therapy is no longer justified.  
4. Decline in ECOG performance status. 
5. Threat to vital organs/critical anatomical sites (eg, spinal cord compression) requiring 
urgent alternative medical intervention, and continuation of study therapy would 
prevent institution of such intervention.  
 
If the lesions included in the tumor burden subsequently regress to the extent that the 
criteria for PD are no longer met, then treatment may continue according to the treatment 
schedule.  
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
28 
Amendment 4: March 1st, 2018 
4.5 
Concomitant Medications/Treatments 
4.5.1 
Permitted Medications 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care. All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids. If changes 
occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). A brief (less than 
3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted. Inhaled or topical steroids, 
and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease.  
 
Concomitant palliative and supportive care for disease related symptoms 
(including bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to 
first dose of study therapy.  
 
 
 
 
 
Antihormonal therapy is permitted for patients with hormonal receptor positive  
 
 
IBC. 
 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs. 
 
4.5.2 
Prohibited Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial: 
• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than nivolumab or ipilimumab 
• 
Radiation therapy  
• 
Corticosteroids are not permitted unless they fall under the criteria listed 
in 4.5.1 
 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
o 
Disease progression (please refer to 4.4 for guidance regarding treatment 
beyond progression), 
o 
Intercurrent illness that prevents further administration of treatment, 
o 
Unacceptable adverse event(s) as already described in session. 
 
4.7 
Duration of Follow Up 
All patients will be followed for adverse events for 12 weeks after last dose of nivolumab 
and or ipilimumab, or until the patient starts a new treatment, whichever occurs first. 
Patients who discontinue treatment for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event (i.e. the grade is not changing). If a 
patient stops treatment due to unacceptable adverse event(s) but has not demonstrated 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
29 
Amendment 4: March 1st, 2018 
disease progression, then the patient will be followed with imaging studies every 8 weeks 
until the time of progression radiographically according to RECIST 1.1 criteria. In the 
event that a radiographic response is detected, then this event will be included as a 
response in the final analysis, and the time of progression used in calculation of the 
survival analysis. Patients will be followed for survival status every 3 months for 2 years 
after treatment discontinuation or until death, whichever occurs first. 
 
4.8 
Removal of Subjects from Study Treatment and/or Study as a Whole 
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include: 
• 
Patient voluntarily withdraws from treatment (follow-up permitted) 
• 
Patient withdraws consent (no follow-up permitted) 
• 
Patient is unable to comply with protocol requirements (follow-up permitted) 
• 
Patient demonstrates disease progression (per parameters above, follow-up 
permitted) 
• 
Patient experiences unacceptable toxicity  
• 
Treating physician determines that continuation on the study would not be in 
the patient’s best interest 
• 
Patient becomes pregnant  
• 
Patient develops a second malignancy that requires treatment which would 
interfere with this study 
• 
Patient becomes lost to follow-up (LTF)  
 
4.9 
Patient Replacement 
Any patient who signs consent but does not receive study treatment may be replaced. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
30 
Amendment 4: March 1st, 2018 
5.0 
STUDY PROCEDURES 
 
Screening1 
On Treatment (1 cycle = 12 weeks)12,13 
Off Treatment 
Cycle 1  
(±3 days) 
Cycle 2 
(±3 days) 
Cycle 3+ 
(±3 days) 
End of 
Treatment
14 
Follow
-Up15 
Day of each 
cycle 
1 
15 
29 
43 
57 
71 
1 
15 
29 
43 
57 
71 
1 
15 
29 
43 
57 
71 
Weeks on study 
1 
3 
5 
7 
9 
11 
13 
15 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35
+ 
Assessment or 
Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
ECOG status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
ConMeds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X15 
Scans3 
X 
X3 
 
 
 
 
 
X3 
 
 
 
 
 
X3 
 
 
 
 
 
X 
 
Lesion Photos16 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CBC with diff 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Chemistry panel 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Amylase/Lipase 
X 
X6 
 
 
 
 
 
X6 
 
 
 
 
 
X6 
 
 
 
 
 
X 
 
TSH (free T4) 7 
X 
X7 
 
 
 
 
 
X7 
 
 
 
 
 
X7 
 
 
 
 
 
 
 
Pregnancy test8 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Nivolumab 9 
 
T 
T 
T 
T 
T 
T 
T 
T 
F 
 
F 
 
F 
 
F 
 
F 
 
 
 
Ipilimumab 10 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Tissue collection11 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
T = 240mg nivolumab 
F = 480mg nivolumab  
 
1 CBC with diff and Chemistry panel should be within 14 days of registration; all other screening procedures should take place within 28 days of 
 
registration unless specified otherwise.  
2 Includes vital signs (pulse, blood pressure), height and smoking history (baseline only) and weight. 
3 Imaging must include Chest, Abdomen, and Pelvis as well as a bone scan. Scans may be by CT, PET/CT or MRI (per treating investigator’s 
discretion) with contrast unless strictly contraindicated as well as a bone scan; the same modality used at baseline should be used 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
31 
Amendment 4: March 1st, 2018 
throughout. Tumor assessment should be done at screening, cycle 2 day 1 (± 1 week) and Day 1 of each cycle (every 12 weeks) 
thereafter, regardless of dosing schedule until progression or treatment discontinuation whichever occurs later. Tumor assessments will 
incorporate both RECIST and clinical criteria. Brain MRI is the preferred imaging method for evaluating CNS metastasis, and assessment 
is only required during screening for eligible subjects with symptomatic CNS involvement.  
 
If PD is confirmed at any time, see section 4.4 on how to determine whether patient can be considered for further treatment. If patient 
continues, scans should be obtained every 12 weeks until PD is confirmed by 2 consecutive scans. 
4 CBC with differential will included WBC, ANC, ALC, Platelets, and Hemoglobin. It will be collected within 14 days of registration, every 14 days 
during cycles 1 & 2, and prior to each treatment thereafter (day 1, 29, 43, and 57 of each cycle).   
5 Chemistry panel will include glucose, calcium, albumin, ALT, AST, sodium, potassium, total bilirubin, alk  phos, and creatinine. It will be collected 
 
within 14 days of registration, every 14 days during cycles 1 & 2, and prior to each treatment thereafter (day 1, 29, 43, and 57 of each cycle).  
6 Amylase and lipase will be assessed at screening and Day 1 of each cycle. 
7 TSH will be tested at screening and Day 1 of each cycle. If TSH is abnormal, free T4  
should be tested 
8 Serum or urine test for females of child-bearing potential (FOCBP) within 72 hours of registration. FOCBP are also required to have a negative 
pregnancy test within 24 hours of starting nivolumab and Day 1 of each cycle. 
9 Nivolumab will be administered IV at 240mg over 30 minutes every two weeks in combination with ipilimumab as follows: 
 
Cycle 1, C2D1, & C2D15: 240mg over 30 minutes (-5 / +15 minutes) every 14 days. 
 
Starting with Cycle 2 Day 29: 480mg over 60 minutes (-10 / +15 minutes) every 28 days until PD, intolerability, or withdrawal of consent.  
10 Ipilimumab will be administered IV at 1mg/kg over 90 minutes every six weeks in combination with nivolumab. Dosing will be based on body 
weight measured every 6 weeks, prior to each ipilimumab infusion. Nivolumab will be given before ipilimumab. 
11Archival tissue (or fresh tissue if not available) will be collected at baseline for all patients. If the patient agrees, additional tissue may be 
collected during biopsies performed as standard of care during study participation. Please see separate lab manual for details. 
12Treatment will start within 14 days of registration, and continue until confirmed disease progression, unacceptable toxicity, or withdrawal of 
consent. 
13 Study procedures may take place within 24 hours prior to study treatment.   
14 End of Treatment visit will occur 30 days (± 7 days) after stopping nivolumab or combination treatment,  or 
before 
the 
patient 
starts 
new 
treatment, whichever occurs first. Adverse events will be recorded for up to 12 weeks after stopping treatment. 
15 Patients will be followed and assessed for adverse events every 4 weeks (±7 days) by routine clinic visit for the first 12 weeks after treatment. 
Thereafter, patients will be followed (either by routine clinic visit or by phone) every 3 months for up to 2 years while off treatment to 
document survival and disease progression.  
16 Photographs for disease assessments will be taken by study staff on a study-supplied digital camera.  It is preferred that these photos be taken 
on a white background (wall of patient room) using a ruler measurement when possible. Photographs should not include any identifying 
characteristics 
 
 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
32 
Amendment 4: March 1st, 2018 
6.0 
ENDPOINT ASSESSMENT 
 
6.1 
Definitions 
For the purposes of this study, patients should be re-evaluated for response every 12 
weeks (±1 week). In addition to a baseline scan, confirmatory scans should also be 
obtained 8 weeks following initial documentation of objective response greater than 
Stable Disease (SD). Tumor assessments for all subjects should continue as per protocol 
even if dosing is interrupted. Tumor measurements should be made by the same 
investigator or radiologist for each assessment whenever possible. Changes in tumor 
measurements and tumor responses to guide ongoing study treatment decisions will be 
assessed by the investigator using RECIST. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) 46. Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
High resolution CT with oral/intravenous contrast or contrast-enhanced MRI is the 
preferred imaging modalities for assessing radiographic tumor response. If a subject has 
a known allergy to contrast material, please use local prophylaxis standards to obtain the 
assessment with contrast if at all possible, or use the alternate modality. In cases where 
contrast is strictly contraindicated, a non-contrast scan will suffice. Screening 
assessments should be performed within 28 days of registration. Brain MRI is the 
preferred imaging method for evaluating CNS metastasis, and assessment is required 
during screening in all eligible subjects. All known or suspected sites of disease 
(including CNS if history of CNS metastases) should be assessed at screening and at 
subsequent assessments using the same imaging method and technique. If more than 
one method is used at screening, then the most accurate method according to RECIST 
1.1 should be used when recording data, and should again be used for all subsequent 
assessments. Previously treated CNS metastases are not considered measurable 
lesions for purposes of RECIST determined response. Subjects with a history of brain 
metastasis should have surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated.  
 
6.2 
Primary Endpoint 
Progression free survival defined as time in months from the date of first study treatment 
to the date of disease progression or death from any cause, whichever comes first.  All 
patients who receive at least one dose of nivolumab/ipilimumab combination will be 
included in the primary analyses of PFS. The Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) criteria will be used for objective tumor response assessment 
(when disease is measurable and non-measurable).46 
 
Patients with IBC often do not have measurable disease. For example, patients will 
sometimes have just recurrent skin involvement, pleural effusions, or bone disease. 
Measurable disease is not a requirement for enrollment on the study.  
 
For patients who have only non-measurable disease, unequivocal progression or 
response will be defined after consideration if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD or tumor response for measurable 
disease.  Complete response will be defined as disappearance of non-measurable 
disease. 
 
Clinical and radiological assessments will be performed every 8 weeks (+- 7 days) 
while on treatment and patients will be followed for up to 2 years after completion of 
treatment. 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
33 
Amendment 4: March 1st, 2018 
6.3 
Secondary Endpoints 
 
Overall response rate (ORR, defined as Complete Response (CR) + Partial 
Response (PR)),and Clinical Benefit Rate (CBR, defined as CR + PR + Stable 
Disease (SD)) in patients with newly recurrent IBC treated with nivolumab and 
ipilimumab  
 
Overall survival defined as time in months from the date of first study treatment to the 
date of death. 
 
The number, frequency, and severity of adverse events will be collected from the 
time of consent until 12 weeks after study treatment to evaluate safety of nivolumab 
and ipilimumab in patients with IBC. Adverse events will follow National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
 
6.4 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with nivolumab and or ipilimumab.  
 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one dose of therapy, and have had their 
disease re-evaluated will be considered evaluable for response. These patients will have 
their response classified according to the definitions stated below.  
 
Evaluable non-target disease response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received 
at least one dose of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
6.5 
Disease parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 
cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam 
(such measurements must be clearly documented). All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).  
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and 
in follow-up, only the short axis will be measured and followed.  
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions  
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable.  
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.  
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.  
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
34 
Amendment 4: March 1st, 2018 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. A sum of the diameters (longest for 
non- nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
6.6 
Response Criteria 
6.6.1 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm 
(0.5 cm). (Note: the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
6.6.2 
Evaluation of Non-Target Lesion 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in 
size (<10 mm [<1 cm] short axis).  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.  
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator).  
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
35 
Amendment 4: March 1st, 2018 
6.6.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. Responses will be assessed 
using CT scans or magnetic resonance imaging according to standard RECIST 
1.1 criteria in order to assess disease progression. These criteria will also allow 
for patients who experience an initial disease flare, and as some patients who will 
have a delayed response may experience an initial disease flare, we will allow 
patients to continue receiving nivolumab beyond progression (see section 4.4). 
 
6.6.4 
Duration of response 
 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
  
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
6.7 
Evaluable patients 
All patients who receive at least one dose of nivolumab/ipilimumab combination will be 
evaluable for the secondary endpoints of safety and overall survival (OS). All patients 
who have at least one on-study scan after baseline will be evaluable for the primary 
endpoint of PFS, and secondary endpoints of ORR and CBR.   
 
7.0 
ADVERSE EVENTS 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires High 
Intensity Monitoring, as outlined in the DSMP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations.   
 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• 
any abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
36 
Amendment 4: March 1st, 2018 
observed; or 
• 
death 
 
7.2 
Definitions & Descriptions 
7.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
7.2.2 
Severity of AEs 
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available 
at http://ctep.cancer.gov/reporting/ctc.html 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
• 
Fatal (grade 5): the event caused death. 
 
7.2.3 
Serious Adverse Events (SAEs) 
 
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 12 weeks after the last administration of study drug, must be 
reported upon discovery or occurrence (see section 7.4.3.4 for reporting details). 
 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
• 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
37 
Amendment 4: March 1st, 2018 
• 
Is life-threatening. 
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 in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is associated with an overdose. 
For purposes of this trial, an overdose will be defined as any dose exceeding 
the prescribed dose for nivolumab or ipilimumab by 20% over the prescribed 
dose. No specific information is available on the treatment of overdose of 
nivolumab or ipilimumab. In the event of overdose, nivolumab should be 
discontinued and the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a 
BMS product, the adverse event(s) is reported as a serious adverse event, 
even if no other seriousness criteria are met. 
If a dose of BMS’s product meeting the protocol definition of overdose is 
taken without any associated clinical symptoms or abnormal laboratory 
results, the overdose is reported as a non-serious Event of Clinical Interest 
(ECI), using the terminology “accidental or intentional overdose without 
adverse effect.” 
All reports of overdose with and without an adverse event must be reported 
within 24 hours to the Sponsor and within 2 working days hours to BMS 
Global Safety. 
• 
Is an important medical event. 
 
 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“.  
 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 
 
Progression of the cancer under study is not considered an adverse event unless 
it results in hospitalization or death. 
 
7.2.4 
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) 
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria: 
• 
Is unanticipated in terms of nature, severity, or frequency 
• 
Places the research subject or others at a different or greater risk of harm 
• 
Is deemed to be at least possibly related to participation in the study.    
 
7.3 
Reporting of pregnancy and lactation 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them), including the pregnancy of a male subject's 
female partner that occurs during the trial or within 120 days of completing the trial 
completing the trial, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  All subjects and female partners of male 
subjects who become pregnant must be followed to the completion/termination of the 
pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
38 
Amendment 4: March 1st, 2018 
must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
 
7.4 
Adverse Event Reporting 
7.4.1 
Routine Reporting 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.  
 
7.4.2 
Determining if Expedited Reporting is Required 
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
 
1) 
Identify the type of adverse event using the NCI CTCAE v 4.03. 
 
 
2) 
Grade the adverse event using the NCI CTCAE v 4.03. 
 
 
3) 
Determine whether the adverse event is related to the protocol therapy.   
 
 
 
Attribution categories are as follows: 
• 
Definite: AE is clearly related to the study treatment. 
• 
Probable: AE is likely related to the study treatment. 
• 
Possible: AE may be related to the study treatment. 
• 
Unlikely: AE not likely to be related to the study treatment. 
• 
Unrelated: AE is clearly NOT related to the study treatment. 
 
 
4) 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current protocol 
• 
the drug package insert 
• 
the current Investigator’s Brochure 
 
7.4.3 
Expedited Reporting of SAEs/Other Events 
7.4.3.1 Reporting to the Northwestern University QAM/DMC 
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form, 
provided as a separate document, is required. 
 
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include: 
• 
Protocol description and number(s) 
• 
The patient’s identification number 
• 
A description of the event, severity, treatment, and outcome (if 
known) 
• 
Supportive laboratory results and diagnostics 
• 
The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting. 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
39 
Amendment 4: March 1st, 2018 
7.4.3.2 Reporting to the Northwestern University IRB 
• 
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.  
• 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment) will be promptly reported to the NU IRB within 24 hours of 
notification, per Lurie Cancer Center policy. 
• 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification. 
• 
All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review. 
 
7.4.3.3 Reporting to the FDA  
 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening. 
 
 
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).All other SAEs will be reported on an 
annual basis as part of the annual FDA report. 
 
7.4.3.4 Reporting to BMS 
SAE reports (including death by any cause), regardless of attribution, will 
be reported within 24 hours to BMS Global Safety (using the NU CRO 
SAE Form and referencing the BMS study number, CA 209-782). The 
assigned study coordinator will facilitate all reporting to BMS Global 
Safety and email QA a copy of the report upon completion. BMS Global 
Safety can be notified at: 
 
Email Address: Worldwide.Safety@BMS.com 
 
Facsimile Number: 609-818-3804 
8.0 
DRUG INFORMATION 
8.1 
Nivolumab 
8.1.1 
Other names 
ONO-4538, BMS-936558, or MDX1106, Opdivo 
 
8.1.2 
Classification - type of agent 
Human IgG4 anti-PD-1 monoclonal antibody 
 
8.1.3 
Mode of action 
Nivolumab acts as an immunomodulator by blocking ligand activation of the 
programmed cell death 1 (PD-1) receptor on activated T cells anti-PD1. 
 
8.1.4 
Storage and stability 
Nivolumab solution for infusion (100mg/vial) is a sterile, non-pyrogenic single-
use, isotonic aqueous solution formulated at 10mg/mL. Vials must be stored in 
a secure, limited-access location at 2ºC to 8ºC (36ºF to 46 ºF) and protected 
from light, freezing, and shaking. The product is a clear to opalescent solution, 
which may contain proteinaceous and extraneous particulates. The product is 
intended for IV administration. The drug preparation can be further diluted with 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
40 
Amendment 4: March 1st, 2018 
normal saline or 5% Dextrose in IV containers made of polyvinyl chloride (PVC) 
or non-PVC material. Opened or accessed vials should be immediately used to 
prepare the infusion solution in the IV bag and the infusion solution should be 
immediately administered. If refrigerated, the vials and/or IV bags should be 
allowed to equilibrate to room temperature prior to subsequent use. Nivolumab 
infusion must be completed within 24 hours of preparation. After preparation, 
store the nivolumab infusion either: 
• 
At room temperature for no more than 8 hours from the time of 
preparation. This includes room temperature storage of the infusion in 
the IV container and time for administration of the infusion or 
• 
Under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) for no more than 24 
hours from the time of infusion preparation. 
• 
Do not freeze 
 
 
8.1.5 
Protocol dose specifics 
240mg q2weeks or 480mg q4weeks 
 
8.1.6 
Preparation 
Nivolumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying aseptic 
technique. 
Visually inspect the drug product solution for particulate matter and discoloration 
prior to administration.  Discard if solution is cloudy, if there is pronounced 
discoloration (solution may have a pale-yellow color), or if there is foreign 
paticulate matter other than a few translucent-to-white, amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
Aseptically withdraw the required volume of nivolumab solution into a syringe, 
and dispense into an IV bag.  If multiple vials are needed for a subject, it is 
important to use a separate sterile syringe and needle for each vial to prevent 
problems such as dulling of needle tip, stopper coring, repeated friction of 
plunger against syringe barrel wall. Do not enter into each vial more than once.  
Do not administer study drug as an IV push or bolus injection. 
When the dose is based on patient weight (i.e. mg/kg), nivolumab injection can 
be infused undiluted (10 mg/mL) or diluted with 0.9% sodium chloride injection, 
USP or 5% dextrose injection, USP to protein concentrations as low as 0.35 
mg/mL. When the dose is fixed (e.g. 240 mg, 360 mg, or 480 mg flat dose), 
nivolumab injection can be infused undiluted or diluted so as not to exceed a total 
infusion volume of 120 mL. It is acceptable to add nivolumab solution from the 
vials into an appropriate pre-filled bag of diluent. “Channel” or tube systems 
should not be used to transport prepared infusions of nivolumab. 
 
8.1.7 
Route of administration for this study 
 
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer through a 0.2 micron to 1.2 micron pore size, low-protein binding 
polyethersulfone membrane in-line filter. 
 
At the end of the infusion period, flush the line with a sufficient quantity of 
approved diluents. 
 
8.1.8 
Incompatibilities 
 
No incompatibilities between nivolumab injection and polyvinyl chloride (PVC), 
non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) IV components, or glass bottles 
have been observed.  
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
41 
Amendment 4: March 1st, 2018 
8.1.9 
Availability & Supply  
 
The supply for this study will be investigational – not commercially available. 
Supply will be provided by BMS free of charge. Nivolumab will be supplied as 
100 mg/vial (10mg/mL) packaged in cartons of 5 or 10 vials. Drug is protocol 
specific, but not patient specific. 
 
 
Drug can be ordered using the Drug Request Form provided by BMS. The form 
is provided as a separate document and should be submitted electronically at 
least 7 business days for initial order and at least 14 days for re-supply before 
the expected delivery date. The initial order should be limited to 20 vials. Contact 
and submission details can be found directly on the Drug Request Form. 
Deliveries will be made Tuesday through Friday. 
 
8.1.10 Side effects 
 
Immune-related adverse events have been associated with nivolumab is 
administered intravenously.  
 
 
Below are safety data from 268 subjects with unresectable or metastatic 
melanoma and 117 patients with metastatic squamous NSCLC who received 
nivolumab alone. Related side effects reported in subjects receiving nivolumab 
alone were: 
 
 
Very Frequent – Expected to occur in more than 20% of people (more than 20 
out of 100 people): Fatigue (50%), Dyspnea (38%), Musculoskeletal pain (36%), 
Rash (21%), Increased AST (28%), Increase alkaline phosphatase (22%), 
Hyponatremia (25-38%) 
 
 
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 100 
people): Pruritus (19%), Cough (17%), URI (11%), Peripheral edema (10%), 
Increased ALT (16%), Hyperkalemia (15%) 
 
 
Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): ventricular arrhythmia, iridocyclitis, infusion-related reactions, 
increased amylase, increased lipase, dizziness, peripheral and sensory 
neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis 
 
 
Deaths thought to be related to nivolumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people). 
 
 
For the most recent safety update, please refer to the current Investigator’s 
Brochure or Study Agent Prescribing Information. 
 
 
8.1.11 Safety and monitoring plan 
All participants will be carefully followed for safety. Participants are seen by their 
study doctor and research nurse before each dose of nivolumab (every 2 weeks). 
Safety evaluations at this time include a physical exam, vital signs, performance 
status assessment, and safety laboratory tests. The study team will continuously 
monitor participants for treatment side effects. Participants are instructed to 
inform their study doctor right away if they notice or feel anything different so the 
study doctor can check for side effects. The study doctor may be able to provide 
treatment for side effects. The study doctor may temporarily hold the study drug 
to reduce side effects. The study doctor will permanently stop the study drug if 
side effects are too severe and/or long lasting. All participants will be followed for 
side effects for 12 weeks from their last dose of nivolumab. Participants with 
ongoing side effects will continue to be followed until resolution or stabilization of 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
42 
Amendment 4: March 1st, 2018 
the side effects. Because it is not known if nivolumab will be effective against 
anal cancer, to enrollment will stop after 12 participants are treated with 
nivolumab if none of them have their tumors shrink. Study team conferences will 
be held monthly or more frequently if needed.  
 
8.1.12 Return and Retention of Study Drug 
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from BMS or designee, the amount dispensed to and 
returned by the subjects and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
8.2 
Ipilimumab 
8.2.1 
Other names  
MDX-CTLA-4, MDX-010, Yervoy 
 
8.2.2  
Classification and type agent 
Human IgG1 Kappa anti-CTLA-4monoclonal antibody 
 
8.2.3  
Mode of action 
Ipilimumab acts as an immunomodulator by blocking the interaction between of 
the CTLA-4 receptor and its ligands CD80/CD86. CTLA-4 has been shown 
augment T-cell proliferation and activation. 
 
8.2.4  
Storage and stability 
Ipilimumab solution for infusion (50mg and 200mg vials) is a sterile, non-
pyrogenic single-use, isotonic aqueous solution formulated at 5mg/mL.  
Vials must be stored in a secure, limited-access location at 2ºC to 8ºC (36ºF 
to 46 ºF) and protected from light, freezing, and shaking. The product is a clear 
to opalescent solution, which may contain proteinaceous and extraneous 
particulates. The product is intended for IV administration. The drug preparation 
can be further diluted with normal saline in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. Opened or accessed vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion 
solution should be immediately administered. If refrigerated, the vials and/or IV 
bags should be allowed to equilibrate to room temperature prior to subsequent 
use. Ipilimumab infusion must be completed within 24 hours of preparation. If not 
used immediately, the infusion solution may be stored up to 20 hours under 
refrigeration conditions (2ºC to 8ºC) and used within 4 hours for up to 24 hours. 
Ipilimumab solutions may be stored at room temperature for a cumulative time of 
up to 4 hours. This includes room temperature storage of solution in vials, room 
temperature storage of prepared solution in the syringe and the duration of drug 
administration. 
 
8.2.5  
Protocol dose specifics 
 
1mg/Kg 
 
8.2.6  
Preparation 
Ipilimumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying aseptic 
technique. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
43 
Amendment 4: March 1st, 2018 
Visually inspect the drug product solution for particulate matter and discoloration 
prior to administration.  Discard if solution is cloudy, if there is pronounced 
discoloration (solution may have a pale-yellow color), or if there is foreign 
paticulate matter other than a few translucent-to-white, amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
Aseptically withdraw the required volume of ipilimumab solution into a syringe, 
and dispense into an IV bag.  If multiple vials are needed for a subject, it is 
important to use a separate sterile syringe and needle for each vial to prevent 
problems such as dulling of needle tip, stopper coring, repeated friction of 
plunger against syringe barrel wall. Do not enter into each vial more than once.  
Do not administer study drug as an IV push or bolus injection 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% 
Dextrose Injection solution. It is acceptable to add ipilimumab solution from the 
vials into an appropriate pre-filled bag of diluent. 
Ipilimumab infusion concentration must be between 1 mg/mL to 2 mg/mL per 
package insert. Mix diluted solution by gentle inversion.“Channel” or tube 
systems should not be used to transport prepared infusions of ipilimumab. 
 
8.2.7  
Route of administration for this study 
Intravenous infusion. Do not administer using IV push or bolus. Administer 
through a volumetric pump with a 0.2 to 1.2 micron in-line filter (non pyrogenic 
and low-protein binding). At the end of the infusion, flush the line with a sufficient 
quantity of approved diluents. 
 
8.2.8  
Incompatibilities 
No formal pharmacokinetic drug interaction studies have been conducted with 
ipilimumab 
 
8.2.9  
Availability & Supply 
 
The supply for this study will be investigational – not commercially available. 
Supply will be provided by BMS free of charge. Ipilimumab will be supplied as 
50mg or 200mg/vial (5mg/mL) packaged in cartons of 5 or 10 vials. Drug is 
protocol specific, but not patient specific. 
 
 
Drug can be ordered using the Drug Request Form provided by BMS. The form 
is provided as a separate document and should be submitted electronically at 
least 7 business days for initial order and at least 14 days for re-supply before 
the expected delivery date. The initial order should be limited to 20 vials. Contact 
and submission details can be found directly on the Drug Request Form. 
Deliveries will be made Tuesday through Friday. 
 
8.2.10  Side effects 
 
Immune-related adverse events have been associated with ipilimumab is 
administered intravenously.  
 
Below are safety data from 131 patients with metastatic melanoma who received 
ipilimumab as monotherapy in a phase 3 trial.  
 
 
Very Frequent – Expected to occur in more than 20% of people (more than 20 
out of 100 people):Fatigue (42%), Pruritus (24.4%), Decreased appetite (26.7%) 
Diarrhea (32.8%), Nausea (35.1%),Constipation (20.6%), Vomiting (23.7%),  
 
 
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 100 
people): Abdominal pain (15.3%), pyrexia(12.2%), headache (14.5%), Cough 
(16%), dyspnea (14.5%), anemia (11.5%), rash (19.1) 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
44 
Amendment 4: March 1st, 2018 
 
Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): vitiligo, colitis, hypothyroidism, hypopituitarism and adrenal 
insufficiency, increased aspartate aminotransferase and alanine 
aminotransferase 
 
 
Deaths thought to be related to ipilimumab when given alone were reported in 
approximately 3 % of subjects treated (approximately 4 out 131 people). 
 
 
For the most recent safety update, please refer to the current Investigator’s 
Brochure or Study Agent Prescribing Information. 
 
8.2.11   Safety and monitoring plan 
All participants will be carefully followed for safety. Participants are seen by their 
study team before each dose of ipilimumab (every 2 weeks). Safety evaluations 
at this time include a physical exam, vital signs, performance status assessment, 
and safety laboratory tests. The study team will continuously monitor participants 
for treatment side effects. Participants are instructed to inform their study doctor 
right away if they notice or feel anything different so the study doctor can check 
for side effects. The study doctor may be able to provide treatment for side 
effects. The study doctor may temporarily hold the study drug to reduce side 
effects. The study doctor will permanently stop the study drug if side effects are 
too severe and/or long lasting. All participants will be followed for side effects for 
12 weeks from their last dose of ipilimumab. Participants with ongoing side 
effects will continue to be followed until resolution or stabilization of the side 
effects. Because it is not known if ipilimumab will be effective against anal 
cancer, to enrollment will stop after 12 participants are treated with ipilimumab if 
none of them have their tumors shrink. Study team conferences will be held 
monthly or more frequently if needed.  
 
8.2.12   Return and Retention of Study Drug 
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from BMS or designee, the amount dispensed to and 
returned by the subjects and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
The Win trial correlative studies will identify genomic alterations that mechanistically contribute to 
oncogenic signaling in IBC.  The information from the correlative studies will provide genetic and 
genomic information that may be relevant for the development of targeted and combination 
therapeutic strategies.   The correlative studies will use next-generation sequencing (NGS) 
technologies to characterize tumor genetics and to identify gene expression profiles that may 
contribute to IBC.  The genetic analysis will be used to study the relationship between mutation 
frequency and immune response.  The expression analysis will focus on genes that are related to 
immune cell signaling, with the goal of identifying an immune expression signature that may be 
useful in identifying potential immunotherapy responders. 
 
The archival diagnostic tissue biopsy performed as part of the standard of care approach to 
recurring breast cancer will be obtained for all patients; if no tissue is available, patients will need 
to undergo a biopsy to provide fresh tumor tissue. The sample will be sent for NGS, and 
evaluation of iScore (baseline assessment). The same specimen will be assessed for immune 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
45 
Amendment 4: March 1st, 2018 
infiltrates and PDL-1. Details on sample collection, shipping, and processing are available in a 
separate lab manual. 
 
Repeated tissue biopsy samples will be performed optionally at time of disease progression and 
partial or complete response and only performed when clinically indicated as part of standard of 
care approach. When performed, specimens will be sent for NGS and iScore and PDL-1 staining. 
See separate lab manual for details on processing and shipping of samples. 
 
9.4     
Specimen Banking 
Patient samples collected for this study will be retained at Robert H Lurie Cancer Center 
of Northwestern University Pathology Core Facility. Specimens will be stored indefinitely 
or until they are used up. If future use is denied or withdrawn by the patient, best efforts 
will be made to stop any additional studies and to destroy the specimens. 
 
Dr. William Gradishar will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of Northwestern University. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed 
research. Any data obtained from the use of clinical specimen will be the property of 
Northwestern University for publication and any licensing agreement will be strictly 
adhered to.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:  
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Study Endpoints 
This is a single open label phase II clinical trial; “window of opportunity” study of 
nivolumab in association with ipilimumab in patients with newly recurrent HER2 negative 
IBC. We believe that a Window of Opportunity trial design is the more appropriate for this 
population inasmuch as it allows to assess the efficacy of immunotherapy in IBC when 
the tumor is still unperturbed by other systemic treatments routinely used the metastatic 
setting.48  
 
10.1.1 Primary: 
To determine progression free survival (PFS) in patients with newly recurrent 
HER2 negative IBC treated with nivolumab and ipilimumab 
 
10.1.2 Secondary: 
• 
To assess the overall response rate (ORR, defined as Complete Response 
(CR) + Partial Response (PR)),and Clinical Benefit Rate (CBR, defined as 
CR + PR + Stable Disease (SD)) in patients with newly recurrent IBC treated 
with nivolumab and ipilimumab 
• 
To assess the safety and tolerability of nivolumab and ipilimumab in patients 
with newly recurred IBC 
• 
To assess overall survival (OS).  
10.1.3 Exploratory endpoints:  
• 
To assess the predictive value of baseline iSCORE and  PDL-1 expression 
using archival tissue samples as well as any standard of care tissue obtained 
during study treatment. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
46 
Amendment 4: March 1st, 2018 
 
10.2 
Sample Size and Accrual 
We previously identified 44 patients who were included in a retrospective study of the 
prognostic significance of HER2 status in IBC.  These patients had both HER2 negative 
and HER2 positive disease, developed metastases, and experienced a disease 
progression.  The median time from the first progression of their metastatic disease to the 
second progression event or death was approximately 3 months.  These patients will be 
considered our historical control group. 
Nivolumab ipilimumab combination will be considered of interest for further study if the 
median PFS time is increased to at least 6 months. We will test the null hypothesis that 
median PFS is at most 3 months versus the alternative that it is at least 6 months. The 
null corresponds to 25% PFS at 6 months under the exponential distribution of PFS 
versus an alternative 6 month PFS rate of 50%. The null corresponds to 50% PFS at 3 
months and the alternative corresponds to 70.71% PFS at 3 months under the same 
conditions. 
We will initially recruit and treat 15 patients. If 7 or fewer initial cohort patients are 
progression free at 3 months the study will be terminated for lack of efficacy. If at least 
8/15 are progression-free at 3 months then we will recruit an additional 14 patients for a 
total of 29.  
 
The patients free of progression at 3 months from the initial cohort will remain on study 
until either progression or 6 months evaluation. Second cohort patients will be evaluated 
at 6 months only. If at least 11/29 patients are progression free at 6 months the null 
hypothesis will be rejected.  
 
The chance of early study termination (3 months follow up with 15 patients) is 50% under 
the null and 4.4% under the alternative. Study power is 90% with overall type I error of 
7%. The design follows: Early stopping designs based on progression-free survival at an 
early time point in the initial cohort.49 
 
10.3 
Data Analyses Plans 
Response rates and 95% confidence intervals will be calculated using exact binomial 
probability distributions.  Progression-free survival and overall survival will be analyzed 
using Kaplan-Meier curves.  Adverse events will be summarized descriptively using 
frequencies and percentages.  Statistics will be given on type, severity, frequency and 
attribution of adverse events.  Sample size considerations are described above. 
 
An intention to treat analysis will be done.  In a single group Phase II study, intention to 
treat means that all patients who are evaluated and registered for the study are followed 
and analyzed regardless of (a) whether they were subsequently found to be protocol 
ineligible and (b) the amount of study treatment (nivolumab/ipilimumab) they received.  
To calculate progression-free and overall survival in patients who received 
nivolumab/ipilimumab, times will be taken from the time of study registration.  This 
definition parallels the definition of intention to treat in randomized clinical trials. 
 
 
11.0 STUDY MANAGEMENT 
 
11.1 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
47 
Amendment 4: March 1st, 2018 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
 
 
11.2 
Amendments 
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by BMS. 
Amendments will be distributed by the lead institution (Northwestern) to all affiliate sites 
upon approval by the Northwestern University IRB. 
 
11.3 
Registration Procedures 
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office at Northwestern University 
before enrollment to study. Please contact the assigned Quality Assurance Monitor 
(QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration.   
 
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system. Training on eCRF completion will be provided at the time of site 
activation.  
 
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number: 
• 
Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart) 
• 
Eligibility checklist (signed and dated by the treating physician – upload to NOTIS) 
• 
Eligibility eCRF (complete in NOTIS) 
• 
Copy of the pathology report (upload to NOTIS) 
 
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment. 
 
11.4 
Data Submission 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document). 
Generally, all data are due at the end of each cycle. 
 
11.5 
Data Management and Monitoring/Auditing 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
48 
Amendment 4: March 1st, 2018 
requires high monitoring, as outlined in the DSMP. The assigned QAM, with oversight 
from the Data Monitoring Committee, will monitor this study in accordance with the study 
phase and risk level.  
 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to NOTIS for additional information). The level of risk attributed to this study requires 
High Intensity Monitoring as outlined in the DSMP. The assigned QAM, with oversight 
from the Data Monitoring Committee, will monitor this study in accordance with the study 
phase and risk level.  
 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document).   
 
11.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
 
11.6.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.  
 
11.6.2 Other Protocol Deviations 
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
• 
Is generally noted or recognized after it occurs. 
• 
Has no substantive effect on the risks to research participants. 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.7 
Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
49 
Amendment 4: March 1st, 2018 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.  
 
11.8 
Publication Policy 
This section should be removed if the trial is not rated as a high intensity trial.   
All potential publications and/or data for potential publications (e.g. manuscripts, articles, 
data, text, digrams, abstracts, posters, charts, slides, picture, or clinicaltrials.gov 
releases) must be approved in accordance with the policies and processes set forth in 
the Lurie Cancer Center DSMP. For trials that require high intensity monitoring, the 
assigned QAM will prepare a preliminary data summary (to be approved by the DMC) no 
later than 3 months after the study reaches its primary completion date (the date that the 
final subject is examined or receives an intervention for the purposes of final data 
collection for the primary endpoint). If the investigator’s wish to obtain DMC-approved 
data prior to this point (or prior to the point dictated by study design), the PI must send a 
written request for data to the QAM which includes justification. If the request is 
approved, data will be provided no later than 4 weeks after this request approval. The 
data will be presented to the DMC at their next available meeting, and a final, DMC-
approved dataset will be released along with any DMC decisions regarding publication. 
The investigators are expected to use only DMC-approved data in future publications. 
The investigators should submit a copy of the manuscript to the biostatistician to confirm 
that the DMC-approved data are used appropriately.  Once the biostatistician gives final 
approval, the manuscript may be submitted to external publishers. 
 
NU shall provide BMS with a copy of each Publication at the earliest practicable time, but 
in any event not less than thirty (30) days prior to its submission to a journal, publisher or 
meeting or fifteen (15) days prior to any public disclosure of any manuscript or other 
public disclosure (e.g., presentations). To the extent applicable, BMS personnel shall be 
acknowledged (including authorship where applicable) in accordance with customary 
scientific practice. 
 
 
 
 
 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
50 
Amendment 4: March 1st, 2018 
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Turpin E, Bieche I, Bertheau P, et al. Increased incidence of ERBB2 overexpression and TP53 
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Gonzalez-Angulo AM, Sneige N, Buzdar AU, et al. p53 expression as a prognostic marker in 
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Van Laere SJ, Van der Auwera I, Van den Eynden GG, et al. Nuclear factor-kappaB signature of 
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transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding. Clin Cancer 
Res. 2006;12(11 Pt 1):3249-3256. 
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van Golen KL, Wu ZF, Qiao XT, Bao L, Merajver SD. RhoC GTPase overexpression modulates 
induction of angiogenic factors in breast cells. Neoplasia. 2000;2(5):418-425. 
23. 
Kleer CG, Zhang Y, Pan Q, et al. WISP3 is a novel tumor suppressor gene of inflammatory breast 
cancer. Oncogene. 2002;21(20):3172-3180. 
24. 
Norma A Palma SMA, Kai Wang, Juliann Chmeleiki, Gary Palmer, Deborah Morosini, Jeffrey S 
Ross, Vincent A Miller, Phil J Stephens, Massimo Cristofannilli. Genomic profiling by 
FoundationOne® analysis of inflammatory breast cancer cases reveals a high frequency of 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
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Initial Version Date: June 28th, 2016 
 
51 
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clinically relevant genomic alterations (GA) [abstract]. In: Proceedings of the Thirty-Seventh 
Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. 
Philadelphia (PA): AACR; Cancer Res.75(9 Suppl). 
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Diarmuid Moran CAH, Kakuturu Rao, Patricia Bacon-Trusk, Karen Pry, Victor Velculescu, 
Massimo Cristofanilli, Sarah S. Bacus. . Genomic analysis identifies drug targetable pathways 
and predicts immune infiltration in inflammatory breast cancer tumors. In: Proceedings of the 
106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; 
Philadelphia, PA. Philadelphia (PA): AACR;. 2015. 
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Champiat S, Ferte C, Lebel-Binay S, Eggermont A, Soria JC. Exomics and immunogenics: 
Bridging mutational load and immune checkpoints efficacy. Oncoimmunology. 2014;3(1):e27817. 
27. 
Rosenberg SA. Decade in review-cancer immunotherapy: entering the mainstream of cancer 
treatment. Nat Rev Clin Oncol. 2014;11(11):630-632. 
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Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N 
Engl J Med. 2015;372(26):2509-2520. 
29. 
Nanda R CL, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with 
advanced triple-negative breast cancer. San Antonio Breast Conference. 
30. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135. 
31. 
McDermott DF, Drake CG, Sznol M, et al. Survival, Durable Response, and Long-Term Safety in 
Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin 
Oncol. 2015;33(18):2013-2020. 
32. 
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. N Engl J Med. 2015;372(21):2006-2017. 
33. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N 
Engl J Med. 2013;369(2):122-133. 
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Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. 
Science. 1996;271(5256):1734-1736. 
35. 
van Elsas A, Sutmuller RP, Hurwitz AA, et al. Elucidating the autoimmune and antitumor effector 
mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination 
with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J Exp Med. 
2001;194(4):481-489. 
36. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med. 2010;363(8):711-723. 
37. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526. 
38. 
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc 
Natl Acad Sci U S A. 2010;107(9):4275-4280. 
39. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. 
40. 
Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-
Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated 
Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(18):2004-2012. 
41. 
Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results 
of a Randomized Phase II Trial. J Clin Oncol. 2015;33(13):1430-1437. 
42. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-
Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. 
43. 
Naiyer Rizvi SNG, Jonathan Goldman, Matthew D. Hellmann, Laura Q. Chow, Rosalyn Juergens, 
Hossein Borghaei, Julie Brahmer, Yun Shen, Christopher Harbison, Faith Nathan, Neal E. Ready, 
Scott J. Antonia. Safety and Efficacy of First-line Nivolumab (Anti-programemed Death-1 [PD-1]) 
and Ipilimumab in Non-small cell lung cancer (NSCLC). 16th World conference on Lung cancer 
September 6-0,2015. Denver Colorado USA. 2015. 
44. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. 
45. 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567. 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
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Initial Version Date: June 28th, 2016 
 
52 
Amendment 4: March 1st, 2018 
46. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
47. 
Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor 
receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American 
Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013. 
48. 
Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular 
entities in oncology. Ann Oncol. 2011;22(8):1717-1725. 
49. 
S. Litwin Y-NWaGH. Early stopping designs based on progression-free survival at an early time 
point in the initial cohort. Statistics in Medicine. 2007;26:4400-4415. 
 
 
 
 
 
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Initial Version Date: June 28th, 2016 
 
53 
Amendment 4: March 1st, 2018 
APPENDICES  
 
Appendix A. 
Common Terminology Criteria for Adverse Events V4.0.3 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.3 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
54 
Amendment 4: March 1st, 2018 
 
Appendix B – ECOG Performance Status 
 
The Eastern Cooperative Oncology Group (ECOG) performance status scale 
Grade 
Description 
0 
Normal  activity.  Fully  active,  able  to  carry  on  all  pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
55 
Amendment 4: March 1st, 2018 
Appendix C – Contraception Requirements 
 
Investigators shall counsel FOCBP and male subjects who are sexually active with FOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise FOCBP and male subjects who are sexually active with FOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% per year when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as listed 
below: 
 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
a)  
Male condoms with spermicide 
b) 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by FOCBP 
subject or male subject’s FOCBP partner. Female partners of male subjects participating 
in the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug. 
c) 
Nonhormonal IUDs, such as ParaGard® 
d) 
Tubal ligation 
e) 
Vasectomy. 
f) 
Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
a) 
Diaphragm with spermicide 
b) 
Cervical cap with spermicide 
c) 
Vaginal sponge 
d) 
Male Condom without spermicide* 
e) 
Progestin only pills by FOCBP subject or male subject’s FOCBP partner 
f) 
Female Condom* 
*A male and female condom must not be used together 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
56 
Amendment 4: March 1st, 2018 
Appendix D – Immune-Mediated Adverse Event Management 
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, neurologic 
toxicity, pulmonary toxicity, renal toxicity and skin toxicity 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
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Amendment 4: March 1st, 2018 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
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Amendment 4: March 1st, 2018 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
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Amendment 4: March 1st, 2018 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
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Amendment 4: March 1st, 2018 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
61 
Amendment 4: March 1st, 2018 
 

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
62 
Amendment 4: March 1st, 2018 
Appendix E – Protocol Summary of Changes 
 
Amendment 1 – September 28, 2016  
Approved by Scientific Review Committee October 31, 2016 
Section(s) Affected 
Prior Version 
Amendment 1 Changes 
Rationale 
Cover Page 
Lists “n/a” for IND 
number/holder 
Adds “Exempt” for IND 
number/holder 
Adds Kalliopi Siziopikou as 
sub-I 
Clarification 
Administrative; Kalliopi is 
involved in relevant 
pathology 
Study Schema; Study 
Summary;  
4.1 (Overview);  
4.2 (Treatment 
Administration); 4.2.1 
(Nivolumab); 5.0 
(Study Procedures);  
6.1 (Definitions); 8.1.5 
(Protocol dose 
specifics) 
Nivolumab was to be 
administered at 240mg 
every 2 weeks throughout 
the study 
1 cycle = 2 weeks 
Scans every 8 weeks for 
the first 13 months and 
12 weeks thereafter 
Nivolumab will now be 
administered at 240mg every 
2 weeks for the first 16 weeks 
and 480mg every 4 weeks 
thereafter (starting with 
C2D29) 
1 cycle = 12 weeks 
Scans every 12 weeks 
throughout study 
To align with new BMS 
dosing strategy for 
nivolumab which is under 
investigation 
Eligibility Criteria 
(3.1.9, 3.2.1, 3.2.3, 
3.2.8, 3.2.14) 
n/a 
Replaces ambiguous wording 
with ≤ or ≥ symbols for 
windows 
Replaces # weeks with # 
days for windows 
Adds “prior to registration” to 
unclear windows 
Simplifications for clarity 
4.2.2 (Ipilimumab) 
“Subjects may be dosed 
no less than 12 days from 
the previous dose” 
Removes statement 
Statement was invalid; 
dosing takes place every 6 
weeks, and PI does not 
feel that a minimum 
window between doses is 
necessary 
4.3.1 (Dose Delays: 
Ipilimumab and/or 
Nivolumab) 
“Both drugs can be held 
for a maximum of 28 
days. If the patient is 
receiving clinical benefit 
in the opinion of the 
investigator, this period 
can be extended up to 56 
days with approval from 
the DMC” 
“Both drugs can be held for a 
maximum of 56 days.” 
Removes allowable extension 
After 16 weeks, nivolumab 
doses are always given 28 
days apart, so a dose hold 
will allow for another 28 
days.  
4.3.1 (Dose Delays: 
Ipillimumab and/or 
Nivolumab); Appendix 
D 
n/a 
Adds management algorithms 
for immune-mediated adverse 
events. 
Algorithms were provided 
by BMS as they were 
developed specifically for 
immune-oncology drugs 
5.0 (Study 
Procedures) 
#2: Listed respirations as 
part of vitals 
#4 & 5: CBC & Chem to 
be collected on Day 1 of 
each cycle 
#2: Removes respirations 
#4 & 5: CBC & Chem to be 
collected before each dose 
(Day 1, 29, 43, and 57 after 
Cycle 2) 
To avoid deviations; 
respiration are not 
clinically relevant 
To align with new 
treatment schedule 
7.2.3 (SAEs) 
SAE’s were to be 
reported through 30 days 
after the last study drug 
SAE’s are to be reported for 
12 weeks after the last study 
drug 
Corrects discrepancy 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
63 
Amendment 4: March 1st, 2018 
Adds reference to section 
7.4.3.4 for reporting 
instructions 
7.4.3.4 (Reporting to 
BMS) 
n/a 
n/a 
Listed incorrect reporting 
email for BMS 
Adds that SAE’s are to be 
reported regardless of 
attribution to study drug and 
including death by any cause 
BMS study number should be 
included in the SAE report 
Corrects BMS email 
Clarification 
Clarification 
Discrepancy 
8.1.11 & 8.2.11 
(Safety and Monitoring 
Plan) 
“All participants will be 
followed for side effects 
for 100 days from their 
last dose of nivolumab” 
“All participants will be 
followed for side effects for 12 
weeks from their last dose of 
nivolumab” 
Corrects discrepancy 
Amendment 2 – November 22, 2016  
Approved by Scientific Review Committee: December 1, 2016 
Section(s) Affected 
Prior Version 
Amendment 2 Changes 
Rationale 
Title Page 
Lists excess sub-
Investigators 
Removes the following sub-
investigators: 
Sunandana Chandra 
Maria Matsangou 
Jason Kaplan 
Aparna Kalyan 
Mark Agulnik 
Administrative; sub-I’s no 
longer need to include all 
investigators at the 
Developmental 
Therapeutics Program. 
Current listing only 
includes those who will 
work with breast cancer 
patients 
4.4 (Treatment with 
ipilimumab and/or 
nivolumab beyond 
progression) 
“Patients must provide 
separate consent to 
continue treatment 
despite radiological scans 
indicating PD. Separate 
consent must be obtained 
when progression is first 
detected.” 
Removes this statement to 
require consent beyond 
progression. 
A consent is not available 
for patients to sign in this 
situation. Aligns with other 
protocols, which do not 
require consent to treat 
beyond progression.  
5.0 (Study 
Procedures) 
#3: Scans were to take 
place every 4 cycles for 
the first 13 months and 
every 6 cycles thereafter. 
 
 
 
 
 
Amylase and lipase will 
be assessed at screening 
every 2 cycles starting 
with Cycle 2. 
#3: Scans will take place day 
1 of each cycle (every 12 
weeks) 
 
 
 
 
 
 
Amylase and lipase will be 
assessed at screening and 
Day 1 of each. 
#3: Correction for 
discrepancy; protocol 
previously included 2-
week cycles. Cycle length 
and scan frequency has 
since been changed, and 
the update was not 
changed in this footnote. 
 
#6: Correction for 
discrepancy; protocol 
previously included 2-
week cycles. Cycle length 
has since been changed, 
and the update was not 
changed in this footnote. 
 
 
 
 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
64 
Amendment 4: March 1st, 2018 
Amendment 3 – May 30, 2017  
Approved by Scientific Review Committee: April 25, 2017 and June 28, 2017 
Section(s) Affected 
Prior Version 
Amendment 3 Changes 
Rationale 
Cover Page; 3.0 
(Patient Eligibility);  
3.2.5 (Exclusion 
Criteria);  
9.4 (Specimen 
Banking) 
Listed Ricardo Costa as 
the study PI 
Removes Ricardo Costa and 
adds William Gradishar as PI 
Administrative faculty 
transition; Dr. Costa’s last 
day at Northwestern is 
4/30/17 
Cover Page 
Listed Kalliopi Siziopikou 
as a sub-Investigator 
Removes Kalliopi Siziopikou 
as a sub-Investigator and lists 
her as a “collaborator” 
Administrative 
List of Abbreviations; 
 1.4 (Exploratory 
Studies); 2.3.2 
(Exploratory 
Objectives & 
Endpoints); 5.0 (Study 
Procedures #11); 9.0 
(Correlatives/ Special 
Studies); 9.0 
(Correlatives/ Special 
Studies); 10.1.3 
(Exploratory 
Endpoints) 
Listed objective of 
analyzing ctDNA with 
Guardant Health 
Laboratory performing the 
ctDNA analysis 
Removes references to 
Guardant Health Laboratory 
and all correlative blood 
samples 
Logistical issues with 
Guardant Health 
Laboratories 
3.0 (Patient Eligibility) 
Specified that the study 
would be conducted at 
Northwestern Medicine 
Developmental 
Therapeutics Institute 
(NMDTI) 
Removes reference to 
NMDTI, stating generally that 
the study will take place at 
Northwestern 
Administrative; it is 
possible that patients will 
be seen at locations other 
than NMDTI 
3.1.4 (Inclusion 
Criteria); 3.2.6 
(Exclusion Criteria) 
Leptomeningeal disease 
was listed as non-
measurable 
Removes leptomeningeal 
disease as an example of 
non-measurable disease and 
adds it as an autoimmune 
disease, thus excluding 
leptomeningeal disease 
Per PI, leptomeningeal 
disease should be 
excluded and is not an 
example of non-
measurable disease 
3.2.5 (Exclusion 
Criteria) 
Included a reference to 
cancer.gov  
Removes cancer.gov 
reference 
Inaccurate reference 
3.2.11 (Exclusion 
Criteria) 
Prior cancer was 
excluded “unless patient 
has been disease free for 
3 years” 
Changes language to state 
more clearly that cancers are 
only excluded if within 3 years 
Clarification  
4.2.1 (Nivolumab); 5.0 
(Study Procedures #9) 
Infusion window for 
nivolumab was ±5 
minutes 
Updates infusion windows as 
follows: 
30-minute (-5 / +15 minutes) 
60-minutes (-10 / +15 
minutes) 
To align with updated drug 
information per BMS 
4.2.2 (Ipilimumab); 5.0 
(Study Procedures #9) 
n/a 
Adds an infusion window for 
ipilimumab (-5 / +15 minutes) 
and states that dosing will be 
based on actual body weight 
on the day of the infusion 
Clarifications  
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NU Study Number: NU 16B07 
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Initial Version Date: June 28th, 2016 
 
65 
Amendment 4: March 1st, 2018 
4.3.2 (Treatment 
Discontinuation: 
Ipilimumab and/or 
nivolumab) 
“Upon resolution of the 
adverse event, the 
unrelated study drug may 
be continued” 
Removes statement 
Statement is irrelevant and 
misleading; there was no 
mention in this section of 
delaying the unrelated 
study drug 
5.0 (Study 
Procedures) 
n/a 
 
Adds visit window of ±3 days 
Clarification 
n/a 
Adds a legend to identify “T” 
as 240mg nivolumab and “F” 
as 480mg nivolumab 
Clarification 
#2: n/a 
#2: Adds smoking history as 
part of the physical exam at 
baseline 
PI would like to collect 
smoking history as data 
n/a 
Adds an activity for “Lesion 
Photos” and footnote 16 to 
specify that photos will be 
taken by study staff on a 
study-supplied digital camera, 
preferably on a white 
background 
Photos are part of 
standard IBC lesion 
measurement, and a 
study-supplied camera will 
allow for consistency in 
study measurements. 
6.6.4 (Duration of 
Response) 
Contained a run-on 
sentence to describe the 
timeframe of a CR 
Removes language: 
“category when no lesions 
can be measured is not 
advised” 
Language included 
inadvertently  
9.0 (Correlative 
Studies) 
Samples for NGS and 
iScore were to be sent to 
American Molecular 
Laboratories (AML) 
Removes AML references; 
samples will now be sent to 
GoPath Laboratories 
Administrative – change in 
outside collaboration 
Amendment 4– November 1, 2017 
IRB-Requested Changes: October 31, 2017 
 
Section(s) Affected 
Prior Version 
Changes 
Rationale 
8.1.4 (Storage and 
Stability)   
Nivolumab could be 
stored at room 
temperature for a 
maximum of 4 hours 
Nivolumab can be stored at 
room temperature for a 
maximum of 8 hours 
Updated to align with new 
IB, version 16, per IRB 
request 
8.1.6 (Preparation) 
Included dilution 
instructions with 
concentrations only 
relevant to weight-based 
dosing 
Now includes dilution 
instructions and 
concentrations for both 
weight-based and flat dosing. 
Updated to align with new 
IB, version 16, per IRB 
request. Flat dosing is a 
new strategy available for 
investigational use of 
nivolumab.  
Amendment 5 – March 1st, 2018 
Approved by Scientific Review Committee:  
Section(s) Affected 
Prior Version 
Amendment 5 Changes 
Rationale 
Cover Page 
Sarika Jain and Cesar 
Santa-Maria were listed 
as study sub-I’s 
Removes Sarika Jain and 
Cesar Santa-Maria as sub-I’s 
Administrative due to 
faculty leaving institution  
3.2 (Exclusion Criteria) 
Numbering for exclusion 
criteria skipped #3.2.9 
Renumbers exclusion criteria 
to correct numbering error 
To correct typographical 
error 
9.0 (Correlative/ 
Special Studies) 
Specified locations for 
sample analysis, 
including GoPath 
Laboratories. 
Removes specific locations of 
sample analysis instead 
referring to separate lab 
manual 
Protocol language did not 
align with the plan to have 
IHC for PD-L1 analysis 
performed externally. For 
IRB #: STU00203191-CR0002 Approved by NU IRB for use on or after 5/14/2018 through 5/13/2019.

NU Study Number: NU 16B07 
Other Study Number: CA 209-782  
Initial Version Date: June 28th, 2016 
 
66 
Amendment 4: March 1st, 2018 
simplicity, the protocol will 
remain vague, and the lab 
manual will specify exactly 
where to send each 
sample.  
Appendix D 
Contained outdated AE 
Management Algorithms. 
Specific outdated 
parameters include: 
 
Hepatic: 
• Discontinue for 
AST/ALT >5xULN 
and/or Tbili >3xULN 
Pulmonary (G3-4): 
• Includes example 
immunosuppression 
Renal (G2-3): 
• “Consider renal 
biopsy” 
 
Skin (G3-4): 
• n/a 
 
Updates AE Management 
Algorithms to align with 
nivolumab IB v16. Specific 
changes to AE management 
include: 
Hepatic: 
• Discontinue for AST/ALT > 
5xULN or Tbili > 3xULN 
Pulmonary (G3-4): 
• Removes examples of 
immunosuppression  
Renal (G2-3): 
• “Consider renal biopsy with 
nephrology consult” 
Skin (G3-4): 
Adds footnote: “If SJS/TEN is 
suspected, withhold I-O 
therapy and refer patient for 
specialized care for 
assessment and treatment. If 
SJS or TEN is diagnosed, 
permanently discontinue I-O 
therapy.” 
Updated per BMS for 
consistency with new 
nivolumab IB v16 and 
additional or clarified 
safety measures. 
 
 
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