Phase II Study of Nivolumab and Ipilimumab for Treatment of Metastatic/Recurrent Adenoid Cystic Carcinoma of All Anatomic Sites of Origin and Non-adenoid Cystic Carcinoma Malignant Tumors of the Salivary Gland
Phase: PHASE2
Conditions: Major Salivary Gland Carcinoma, Minor Salivary Gland Carcinoma, Recurrent Salivary Gland Carcinoma, Stage IV Major Salivary Gland Carcinoma, Stage IVA Major Salivary Gland Carcinoma, Stage IVB Major Salivary Gland Carcinoma, Stage IVC Major Salivary Gland Carcinoma
Sponsor: Northwestern University

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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
1
Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid 
cystic carcinoma of all anatomic sites of origin and non-adenoid cystic carcinoma 
malignant tumors of the salivary gland
Principal Investigator:
Young Chae, MD, MPH, MBA
Co-Director, Early Phase Clinical Trials Unit 
Developmental Therapeutics - Lurie Cancer Center 
Associate Professor of Hematology and Oncology
Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer 
Center of Northwestern University
645 N. Michigan Ave, Suite 1006
Chicago Illinois 60611
Fax: (312) 472 0564
Phone: (312) 926-4248
Email: ychae@nm.org
Biostatistician:
Borko Jovanovic, PhD
Study Intervention(s):
Nivolumab (Opdivo) and Ipilimumamb (Yervoy)
IND Number:
IND-exempt
IND Holder:
IND-exempt
Funding Source:
Bristol-Myers Squibb
Version Date:
October 6, 2022,Amend 8 
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
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS...............................................................................................................5
STUDY SCHEMA.............................................................................................................................7
STUDY SUMMARY..........................................................................................................................8
1.0
Introduction – BACKGROUND & RATIONALE ...............................................................10
1.1
Disease Background ......................................................................................................10
1.2
Intervention Background & Overview.............................................................................11
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.......................................................................................................19
3.1
Inclusion Criteria.............................................................................................................19
3.2
Exclusion Criteria ...........................................................................................................20
4.0
TREATMENT PLAN...........................................................................................................23
4.1
Overview ........................................................................................................................23
4.2
Treatment Administration ...............................................................................................23
4.3
Toxicity Management & Dose Delays/Modifications.......................................................24
4.4
Treatment with ipilimumab and or nivolumab beyond progression..................................28
4.5
Concomitant Medications/Treatments ............................................................................29
4.6
Duration of Therapy .......................................................................................................30
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
3
4.7
Duration of Follow Up.....................................................................................................30
4.8
Removal of Subjects from Study Treatment and/or Study as a Whole ..........................30
4.9
Patient Replacement ......................................................................................................31
5.0
STUDY PROCEDURES .....................................................................................................32
6.0
Endpoint assessment.......................................................................................................35
6.1
Definitions ......................................................................................................................35
6.2
Primary Endpoint............................................................................................................35
6.3
Secondary Endpoints .....................................................................................................35
6.4
Definitions ......................................................................................................................36
6.5
Disease parameters .......................................................................................................36
6.6
Response Criteria...........................................................................................................37
6.7
Immune-related related response criteria.......................................................................38
6.8
Evaluable patients..........................................................................................................38
7.0
ADVERSE EVENTS...........................................................................................................39
7.1
Adverse Event Monitoring ..............................................................................................39
7.2
Definitions & Descriptions ..............................................................................................39
7.3
Reporting of pregnancy and lactation.............................................................................41
7.4
Adverse Event Reporting ...............................................................................................41
8.0
DRUG INFORMATION.......................................................................................................43
8.1
Nivolumab ......................................................................................................................43
8.2
Ipilimumab......................................................................................................................45
9.0
CORRELATIVES/SPECIAL STUDIES...............................................................................49
9.1
Specimen Banking .........................................................................................................50
10.0
STATISTICAL CONSIDERATIONS...................................................................................50
10.1
Study Design/Study Endpoints.......................................................................................50
10.2
Sample Size and Accrual ...............................................................................................51
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
4
10.3
Data Analyses Plans ......................................................................................................51
11.0
STUDY MANAGEMENT REFERENCES...........................................................................51
11.1
Institutional Review Board (IRB) Approval and Consent................................................51
11.2
Amendments ..................................................................................................................52
11.3
Registration Procedures.................................................................................................52
11.5
Data Management and Monitoring/Auditing ...................................................................53
11.6
Adherence to the Protocol..............................................................................................53
11.7
Investigator Obligations..................................................................................................54
11.8
Publication Policy ...........................................................................................................54
References ....................................................................................................................................55
APPENDICES ................................................................................................................................57
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
5
LIST OF ABBREVIATIONS
ACC
Adenoid Cystic Carcinoma
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CMP
Comprehensive Metabolic Panel
CNS
Central Nervous System
CR
Complete Response
CT
Computed Tomography
CTAs
Cancer/Testis Antigens
CTCAE
Common Terminology Criteria for Adverse Events 
CTLA-4
Cytotoxic T Lymphocyte Associated Antigen-4 
DCR
Disease Control Rate
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board 
ECOG
Eastern Cooperative Oncology Group 
GI
Gastrointestinal
H&PE
History & Physical Exam 
HunMab
Human Monoclonal Antibody 
IFN-γ
Interferon-γ
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL-2
Interleukin-2
irRECIST
Immune-Related Response Evaluation Criteria in Solid Tumors 
IV (or iv)
Intravenously
LAK
Lymphocyte-Activated Killer
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute 
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate or Objective Response Rate 
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells 
PD
Progressive Disease
PD-1
Programmed Death Receptor-1
PD-L1
PD Ligand-1
PFS
Progression Free Survival
PFSR
Progression Free Survival Rate 
PO (or p.o.)
Per os/by mouth/orally
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
6
PPK
Population Pharmacokinetics
PR
Partial Response
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase 
SPGT
Serum Glutamic Pyruvic Transaminase 
TNF-α
Tumor Necrosis Factor-α
WBC
White Blood Cells
WT1
Wilm’s Tumor 1
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
7
Tumor tissue 
collection if available
Response Assessment every 12 weeks (Day 1 of each cycle, ±7 days)
1 cycle = 12 weeks / 84 days
Nivolumab will be given as follows:
240mg IV every 14 days for 8 doses (Cycle 1 + Cycle 2 Days 1 & 15),
480mg IV every 28 days starting with Cycle 2 Day 29 (Day 1, 29, and 57 of each 
cycle thereafter)
Ipilimumab will be given at 1mg/Kg IV every 42 days (Day 1 and 43 of each cycle)
Treat until disease progression, intolerable 
toxicity, or withdrawal of consent
Treatment discontinuation (unless patient meets criteria 
for treatment beyond progression, listed in section 4.4)
STUDY SCHEMA
Up to 43 patients will be enrolled with metastatic/recurrent ACC of any site of origin with 
evidence of disease progression who are not candidates for curative surgical or radiation 
therapy. An exploratory cohort of 20 patients with non-ACC of major or minor salivary 
glands will be enrolled concurrently.
**The first 15 ACC patients will be assessed for safety, and ACC accrual will be terminated if ≥ 7 patients 
are withdrawn after <24 weeks of treatment for any reason other than withdrawal of consent. Otherwise, 
enrollment will continue for a total of 43 ACC patients. The exploratory cohort of 20 non-ACC MSGT’s will 
follow an independent accrual process to ACC and will also be assessed for safety; if >2 of the first 10 
non-ACC patients are withdrawn after <24 weeks of treatment, the non-ACC cohort will be closed to 
accrual.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
8
STUDY SUMMARY
Title
Phase II study of nivolumab and ipilimumab for treatment of 
metastatic/recurrent adenoid cystic carcinoma of all anatomic sites of 
origin and non-adenoid cystic carcinoma malignant tumors of the salivary
gland
Version
October 6, 2022, Amendment 8
Study Design
Simon two-stage single arm multi-center phase II clinical trial
Study Center(s)
Northwestern University
Objectives
Primary:
(1) To assess median progression-free survival (PFS) as well as 
PFS at 6 and 12 months in patients with recurrent or metastatic 
adenoid cystic carcinoma treated with a combination of 
nivolumab and ipilimumab.
Secondary:
(1) To assess the efficacy of nivolumab and ipilimumab according to 
response rate (RR), disease control rate (DCR) or clinical benefit 
rate (CBR) at 6 and 12 months- defined as sum of CR, PR, and 
SD, overall survival (OS) and progression free survival (PFS) in 
the above population using RECIST criteria.
(2) To assess the efficacy of nivolumab and ipilimumab according to 
ORR, DCR, PFS, and OS in the above population using 
immune-related RECIST (irRECIST) criteria.
(3) To assess the safety and tolerability profile of nivolumab and 
ipilimumab therapy in the above population using CTCAE 
version 4.03
Exploratory:
(1) To assess the immune-related biomarkers and their association 
with treatment response
(2) To assess activity of nivolumab and ipilimumab in non-ACC 
malignant salivary gland tumors (MSGTs) using OS, PFS, CBR, 
and ORR
Sample Size
63 [43 patients with ACC plus 20 patients with non-ACC 
MSGT(exploratory group)]
Diagnosis & Key 
Eligibility Criteria
Study population will consist of patients age 18 or older, Eastern 
Cooperative Oncology Group (ECOG) performance status 0-2, with 
metastatic/recurrent adenoid cystic carcinoma (ACC) of salivary and non- 
salivary gland origin, as well as non-adenoid cystic carcinomas (non-ACC) 
of major or minor salivary glands who are not surgical or radiation 
candidates with evidence of disease progression. Disease progression is 
defined as one of the following occurring within the 6 months prior to study 
entry:
(1)At least a 20% increase in radiologically or clinically measurable lesions 
(2)Appearance of any new lesions or
(3)Symptomatic and/or deterioration in clinical status
Patients cannot have a history of clinically significant autoimmune 
diseases or a syndrome that requires systemic steroids or 
immunosuppressive agents. Patients on treatment with prednisone >
10mg daily or equivalent corticosteroid will be excluded.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
9
Treatment Plan
Eligible patients will be started on nivolumab 240mg IV every 14 days for 
the first 8 doses and 480mg IV every 28 days starting with Cycle 2 Day 
29 (1 cycle = 12 weeks / 84 days). Ipilimumab 1mg/kg IV will be given q 
6 weeks starting at Cycle 1 Day 1 until disease progression, 
unacceptable toxicity or withdrawal of consent. Patients will have 
response assessments every 12 weeks (each cycle).
Statistical Methodology
The main outcome is median Progression Free Survival (PFS) as well as 
PFS at 6 and 12 months. The optimal two-stage design to test the null 
hypothesis that P<=0.450 versus the alternative that P>=0.650 has an 
expected sample size of 24.70 and a probability of early termination of 
0.654. If the drug is actually not effective, there is a 0.048 probability of 
concluding that it is (the target for this value was 0.050). If the drug is 
actually effective, there is a 0.196 probability of concluding that it is not 
(the target for this value was 0.200). After testing the drug on 15 ACC 
patients in the first stage, ACC accrual will be terminated if 7 or more 
patients are withdrawn from the study after <24 weeks of treatment for 
any reason other than withdrawal of consent (this includes PD, toxicity, 
intolerance etc.). If the trial goes on to the second stage, a total of 43 
patients will be studied. If the total number responding (where response 
is defined as stable disease or better) is less than or equal to 24, the drug 
is rejected. An additional exploratory group of 20 patients with non-ACC 
MSGT will be added concurrently with ACC patients for a total samples 
size of 63 patients. An additional safety analysis will take place for non- 
ACC patients; if >2 of 10 non-ACC patients are withdrawn after <24 
weeks of treatment, accrual of non-ACC patients will discontinue. 
Response rates and 95% confidence intervals will be calculated using 
exact 
binomial 
probability 
distributions 
for 
discrete 
outcomes. 
Progression-free survival and overall survival will be graphically depicted 
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.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
10
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
Adenoid cystic carcinoma (ACC) is a rare cancer most often occurring in the salivary 
glands. The cancer can also arise in other locations including the breast, skin, respiratory 
system, and reproductive organs.1 ACC has a tendency for delayed recurrence and 
metastasis after initial treatment.2 Five, ten, and fifteen year survival rates after surgical 
resection have been reported as 77.3%, 59.6%, and 44.9%, respectively, with close to half 
of the patients dying from ACC, as opposed to other causes, at long-term follow-up.3 
Because of its rarity and distinctive clinical features, the pathophysiology of ACC remains 
understudied, resulting in fewer evidence based therapies compared to other cancers.
Currently there is no standard of care systemic treatment for ACC other than repeated 
surgical resection for locoregional control for early stage disease. In advanced stage, 
conventional chemotherapy can be considered as first-line therapy with only modest 
benefit as is the case with cisplatin and 5-FU. ACC is one of the rare cancers with 
significantly high unmet need that awaits breakthrough in its treatment methodology. Due 
to its rarity, there are no disease specific agents specifically designed for the treatment of 
ACC. When we performed comprehensive analysis of the clinical trials that enrolled ACC, 
only 5.5% (22 out of 397 total patients enrolled) objective response rate was found.4
The newest armamentaria in cancer treatment are cancer immunotherapies. In ACC, 
cancer vaccination and adoptive immunotherapy using LAK/cytokines have been tried in a 
small number of clinical trials that showed encouraging results. An in vitro study of adoptive 
immunotherapy for the ACC cell line was performed in 1996 by a Chinese group.5 This 
group investigated the susceptibility of ACC cells to lymphocyte-activated killer (LAK) cells 
under the influence of cytokines, Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). 
It was confirmed that LAK cells showed cytotoxicity against ACC cells. Also, they 
concluded both TNF-α and IFN-γ could enhance this cytotoxic process. Previously, it was 
reported that these cytokines induced tumor differentiation and apoptosis.6,7
In line with this, a clinical trial using adoptive immunotherapy with chemoradiation was 
performed on 2 maxillary ACC patients in Japan.8 Both patients were given radiation, 5-FU 
and peplomycin followed by intra-arterial injection of LAK cells, interleukin-2 (IL-2) and IFN- 
γ on day 7. Two weeks after the initiation of the treatment, significant tumor regression was 
observed. 3 weeks after finishing the treatment, a CT scan revealed tumor reduction with 
new bone formation of the sinus walls in both patients. Furthermore, those patients showed 
a good quality of life according to the report, meaning that this regimen was well tolerated. 
Even though the mechanism was not fully understood, it could be assumed that cytokine- 
induced cell apoptosis and cytotoxic effect of LAK cells contributed to tumor regression. 
This study result necessitates further trials to confirm the effect of immunotherapy in ACC.
Cancer vaccination, another immunologic approach targeting the specific cancer antigens, 
has also been attempted in ACC.9,10 A hypothesis regarding Cancer/testis antigens (CTAs) 
as a potential target of immunotherapy was suggested based on the finding that CTAs 
were highly expressed in a subset of ACC cells, but not in normal cells. Similar to CTAs, 
WT1 (Wilm’s tumor 1) antibodies and WT1-specific cytotoxic T cells were observed in many 
cancer patients, suggesting WT1 protein could be a target of cancer vaccination.9 In a 
phase I clinical trial performed in Japan, WT1 peptide vaccination was used on ACC 
patients with pulmonary metastasis. A significant suppression of the tumor growth was 
shown during treatment (1 year), while rapid tumor growth and new metastases occurred 
after the withdrawal of therapy. This trial implicated the role of immune system in the 
treatment of ACC.11
The recent whole exome and genome sequencing of ACC has led to new compelling 
discoveries. Ho et al. analyzed sequences of 60 ACC tumors paired with normal DNA
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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28,29
samples. The study revealed genomic alterations in the pathways associated with 
MYB/MYC, chromatin remodeling, tyrosine kinase signaling, and DNA damage/check point 
signaling.12 Errors in the DNA repair system cause genomic instability, which may be 
associated with malignant transformation of cells. Some of these mutations have also been 
noted in ACC.13 The whole genome sequencing revealed more mutated genes involved in 
DNA damage signaling pathway, in a 27% prevalence of the sample cohort. Those include 
BRCA1, ATM, TXNIP, PRKDC and TP53.12 TP53 is a tumor suppressor gene, which 
regulates cell death and DNA repair. It is the most frequently mutated gene in cancers, 
occurring in up to 75% of invasive cancers.14 Somatic mutations in TP53 as well as related 
genes (e.g. UHRF1) were identified in ACC.12,15 In addition, a recent study demonstrated 
that down-regulation of p53 induced increased perineural invasion activity of ACC in vitro
16. Recent evidence showed DNA repair pathway defect suggesting higher somatic 
mutation burden translates into better immune checkpoint inhibitor response.17 Frequent 
mutations in DNA damage repair genes and chromatin remodeling genes and a wide array 
of somatic alterations may results in a significant number of neoepitope peptides derived 
from these altered genes, eliciting the generation of specific cytotoxic T cells.18,19
Building upon this scientific rationale supporting the potential for immunotherapies in ACC 
(arising in any anatomic site) and the immeasurable clinical need for novel treatments in 
this population, we hypothesize that immune checkpoint blockade can be a powerful 
potential therapeutic strategy for patients with ACC that require active clinical investigation. 
Effective disease control with immune checkpoint inhibitors as monotherapy or in 
combination (i.e., CTLA4 and PD-1/PD-L1 inhibitors) was observed in several types of 
cancer in including cutaneous melanoma, squamous cell carcinoma of head and neck.20-
23. The encouraging results from these trials should pave the way for other malignancies 
such as ACC24. Therefore, we suggest the use of nivolumab and ipilimumab in ACC 
with high unmet need and potential for response with these agents.
In addition, malignant salivary gland tumors (MSGTs), including ACC and non-ACC 
account for less than 1% of all cancers, and 6% to 7% of cancers of the head and neck.25-
27 Unlike ACC, non-ACC MSGTs are a heterogeneous group with distinct histologies and 
variable biologic behavior. Patients with recurrent or metastatic non-ACC MSGTs may 
achieve objective response rates ranging from 10-30% with single agent chemotherapy, 
mostly first line, and 29-50% ORR with combination chemotherapy in the same setting. 
Duration of response is typically limited between 3 to 9 months.  .
There are no standard of care therapeutic options for non- ACC MSGT following 
progression of disease on first line therapy. Given this, patients with progressive non-ACC 
MSGT are in need for novel therapies and make good candidates for trials of investigational 
new drugs. Therefore, we propose the use of Nivolumab and ipilimumab combination 
therapy in non-ACC malignant salivary gland tumors (MSGTs) as an exploratory 
objective.
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).22,30,31 The
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NU Study Number: NU 16N03
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Amendment 8: 10/6/2022
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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.32 Nivolumab is 
currently FDA approved for BRAF V600 mutation-positive unresectable or 
metastatic melanoma, as a single agent in unresectable or metastatic melanoma, 
in combination with ipilimumab, metastatic non-small cell lung cancer and 
progression on or after platinum-based chemotherapy and advanced 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.33,34 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.35,36 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%.35
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.37 
A recently published phase III on patients with untreated metastatic melanoma 
showed significant PFS in patients treated with the combination of nivolumab and 
ipilimumab when compared to either agent along.38 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, and elevation of liver 
enzymes happening in less than 10% of the patients.38
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
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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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 39. 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) 40.
Median overall survival was 18, 25, and 24 months for the three dose cohorts, 
respectively. More recently 821 patients previously treated with anti-angiogenic 
therapy were randomized to either nivolumab (3mg/Kg every 2 weeks) or 
everolimus (10mg daily).41 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.35 total of 676 HLA- 
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) 32. 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 of 1 mg/kg nivolumab and 3 
mg/kg of 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
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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.22 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).38 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).23 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.
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
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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.32
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-2015.22,38 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.
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).23 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 immunohistochemistry (IHC) staining and 
pharmacodynamics changes in the peripheral blood absolute lymphocyte count 
in the study investigating the combination of nivolumab and ipilimumab in 
melanoma.32 PD-L1 positivity was defined as expression in at least 5% of tumor 
cells. Among patients treated with the concurrent regimen of nivolumab and
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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
Monoclonal antibodies immune checkpoint inhibitors have shown evidence of antitumor 
efficacy among various solid tumors as discussed below. Recent evidence showed 
significant correlation between higher somatic mutation burden and better immune 
checkpoint inhibitor response.17 Frequent mutations in DNA damage repair genes and 
chromatin remodeling genes and a wide array of somatic alterations found from the 
recent genomic sequencing studies in ACC may result in a significant number of 
neoepitope peptides derived from these altered genes, eliciting the generation of specific 
cytotoxic T cells.18,19 Also results from early phase clinical trial support that activation of 
the immune system through vaccination may indeed results suppression of the adenoid 
cystic tumor growth.11
1.3.1
Study design
The rationale for use of a phase II study is based on the fact that it allows for 
evaluation of anti-tumor efficacy of nivolumab combined with ipilimumab in 
patients with recurrent/metastatic adenoid cystic carcinomas. Patients with non- 
ACC who also have recurrent/metastatic disease will be studied as part of an 
exploratory objective but will not be included in our statistical analysis. To our 
knowledge this is the first study to address this question.
1.3.2
Nivolumab flat dose regimen
The safety and efficacy of 240 mg (monotherapy) Q2W flat dose of nivolumab 
has recently received FDA approval and is expected to be similar to the 3 mg/kg 
Q2W dosing regimen. Using the population PK (PPK) model, exposure of 
nivolumab at 240 mg flat doses 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 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 doses compared to 1mg/kg and 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.
In addition, nivolumab 480 mg administered once every 4 weeks (Q4W) is 
currently under investigation. The less frequent dosing regimen is designed to 
afford more convenience to the target patient populations. The nivolumab dose of 
480 mg Q4W was selected based on clinical data and modeling and simulation 
approaches using PPK and exposure-response analyses of data from studies in 
multiple tumor types (melanoma, NSCLC, and RCC) to provide an approximately 
equivalent dose of nivolumab 3 mg/kg Q2W. Exposures following nivolumab
480 mg Q4W regimen are predicted to be within the exposure ranges observed 
at doses up to 10 mg/kg Q2W used in the nivolumab clinical program, and are
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not considered to put participants at increased risk. Hence, the flat doses of 
240mg and 480mg nivolumab are 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 patients with advanced lung cancer.23
1.4
Exploratory Studies
In the era of personalized therapy appropriate patient selection to immune-check point 
inhibitors remains an elusive goal. There are conflicting data on the predictive value of 
PD-L1 expression on PD-1 directed therapy in solid tumors.30,42 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 43. 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
All subjects will be asked to provide consent to supply a sample of their archival tumor 
blocks if a sample is available. Archival tumor samples, when available, may be 
evaluated for the immunosuppressive biomarker PD-L1 protein on tumor cells and the 
expression level and localization of other markers of inflammatory/immune signature that 
may include but not be limited to PD-1, OX40, CD73, CD39, T cell immunoglobulin and 
mucin domain containing protein 3 (TIM3), GITRL, CTLA-4, CD3, CD4, CD8, protein 
tyrosine phosphatase receptor type C (CD45RO), forkhead box P3 (FOXP3), and 
granzyme by immunohistochemistry analysis and/or flow cytometry and comprehensive 
genomic profiling.
The association between treatment response and the above biomarker status will be 
investigated.
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2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
To assess median progression-free survival (PFS) as well as PFS at 6 and 12 months in 
patients with recurrent or metastatic adenoid cystic carcinoma (ACC) treated with a 
combination of nivolumab and ipilimumab.44 Patients will have scans every 12 weeks.
Efficacy will be evaluated in all patients who receive at least one dose of study treatment 
and have had their disease re-evaluated.
2.2
Secondary Objectives & Endpoints
2.2.1
To assess the efficacy of nivolumab and ipilimumab according to response rate 
(RR), disease control rate (DCR; CR, PR, and SD at 6 and 12 months), overall 
survival (OS) and progression free survival (PFS) using RECIST criteria in 
patients with recurrent or metastatic ACC. 44
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. Efficacy will be evaluated 
in all patients who receive at least one cycle of study treatment.
2.2.2
To assess the efficacy of nivolumab and ipilimumab according to ORR, DCR, 
PFS, and OS in patients with recurrent or metastatic ACC using irRECIST 
criteria.45. Efficacy will be evaluated in all patients who receive at least one dose 
of study treatment and have had their disease re-evaluated.
2.2.3
To assess the safety and tolerability profile of nivolumab and ipilimumab therapy 
in patients with recurrent or metastatic ACC using CTCAE version 4.03. The 
number, frequency, and severity of adverse events will be collected from time of 
consent until 30 days after study treatment for all patients who receive at least one 
dose of study drug.
2.3
Exploratory Objectives & Endpoints
2.3.1
Assess safety, tolerability and activity of nivolumab and ipilimumab in non-ACC 
malignant salivary gland tumors (MSGT’s) using CBR, ORR, PFS, OS.
2.3.2
To assess the predictive value of genomic aberrations observed upon 
comprehensive genomic profiling of the tumor DNA derived from archival tumor 
tissue, if available, or blood from patients with recurrent or metastatic ACC and 
non-ACC MSGTs.
2.3.3
Correlation between expression of PD-L1 and response to treatment will be 
explored in all patients enrolled in the study.
2.3.4
Correlations between other markers of inflammatory/immune signature will be 
performed that may include but not be limited to PD-1, OX40, CD73, CD39, T cell 
immunoglobulin and mucin domain containing protein 3 (TIM3), GITRL, CTLA-4, 
CD3, CD4, CD8, protein tyrosine phosphatase receptor type C (CD45RO), 
forkhead box P3 (FOXP3), and granzyme by immunohistochemistry analysis 
and/or flow cytometry.
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with metastatic/recurrent adenoid cystic carcinoma 
(ACC) and non-adenoid cystic carcinomas (non-ACC) of major or minor salivary glands who are 
not surgical or radiation candidates with evidence of disease progression. This study will be led by 
Northwestern University. At Northwestern University, there is no competing trial.
A total of 63 [43 patients with ACC plus 20 patients with non-ACC MSGT (exploratory group)] 
subjects will be needed for this trial. Approximately 2 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.
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 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have histologically or cytologically confirmed metastatic/recurrent 
adenoid cystic carcinoma (ACC) of any anatomic site of origin or non-adenoid 
cystic carcinomas (non-ACC) of major or minor salivary glands
3.1.2
Patients must have evidence of disease progression and cannot be a candidate 
for curative surgical or radiation therapy.
NOTE: Disease progression is defined as one of the following occurring at least 6 
months prior to study entry:

At least a 20% increase in radiologically or clinically measurable lesions

Appearance of any new lesions or

Symptomatic and/or deterioration in clinical status 
NOTE: Palliative radiotherapy is permitted.
3.1.3
Patients may or may not have received prior therapy for their recurrent/metastatic 
disease.
NOTE: There is no limit to the number of prior systemic therapies for stage IV 
disease.
NOTE: Patients should not be a candidate for curative surgical or radiation 
therapy (palliative radiotherapy is permitted).
3.1.4
Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension in accordance with RECIST 
criteria v1.1.
NOTE: Scans must be ≤28 days prior to study treatment.
3.1.5
Patients must be ≥ 18 years old.
3.1.6
Patients must exhibit an ECOG status of 0-2.
NOTE: ECOG performance status 3 will be allowed only if thought to be directly 
secondary to adenoid cystic carcinoma disease by treating physician.
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3.1.7
Patients must have adequate organ and bone marrow function within 14days 
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) or creatinine clearance ≥ 30 mL/minute 
(using Cockcroft/Gault formula below):
Female CrCl = (140 – age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL
Male CrCl =
(140 – age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/dL
3.1.8
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 does not require corticosteroids (of any dose) 
for symptomatic management.
NOTE: Only patients with a known history or indication of CNS disease are 
required to have CNS imaging prior to study entry.
3.1.9
Females of childbearing potential (FOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) ≤14 
days prior to 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)
3.1.10
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)
3.1.11
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 ≤ 28 days or radiotherapy ≤ 7 days 
prior to study treatment.
NOTE: See section 4.6.1 for further clarification on palliative radiotherapy.
3.2.2
Patients who have not recovered to ≤ Grade 1 or tolerable Grade 2 from adverse 
events due to agents administered ≥ 28 days earlier are not eligible.
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3.2.3
Patient must not be a candidate for curative surgical or radiation therapy. 
NOTE: Palliative radiotherapy is permitted.
3.2.4
Patients may not be receiving any other investigational agents ≤ 28 days prior to 
study treatment.
3.2.5
Patients who have had prior exposure to immune checkpoint inhibitors are not 
eligible. Please contact principal investigator, for specific questions on potential 
interactions.
NOTE: Immune checkpoint inhibitors working through OX40 are an exception (for 
example, MEDI6383, MEDI6469, MEDI0562, oxelumab, and PF-04518600) and 
are permitted ≥ 28 days prior to study registration.
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
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 class 3 or 4 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
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3.2.8
Patients should not have any condition requiring systemic treatment with 
corticosteroids (>10mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days prior to first dose of study drug.
NOTE: Inhaled or topical steroids and adrenal replacement steroids at any dose 
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 (e.g., delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted.
3.2.9
Female patients who are pregnant or nursing are not eligible.
3.2.10. No other prior malignancy is allowed except for the following:

adequately treated basal cell or squamous cell skin cancer,

in situ cervical cancer,

or any other cancer from which the patient has been disease free for at 
least three years.
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 
infection is not permitted.
3.2.13. Patients who received a live, attenuated vaccine ≤ 30 days before study 
treatment or are anticipated to require such a live attenuated vaccine are not 
eligible.
NOTE: Influenza vaccination should be given during influenza season only 
(approximately October to March). Patients must not receive live, attenuated 
influenza vaccine (e.g., FluMist) ≤ 30 days prior to study registration or at any 
time during the study.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
23
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 over 30 minutes (-5 /
+15 minutes) every 2 weeks starting with Cycle 1 Day 1 for the first 16 weeks (1 cycle = 
12 weeks). Starting with Cycle 2 Day 29, nivolumab will be given at 480mg IV over 60 
minutes (-10 / +15 minutes) every 4 weeks. Ipilimumab will be given at 1mg/Kg every 6 
weeks starting with Cycle 1 Day 1 over approximately 90 minutes (-5 / +15 minutes). On 
days when both nivolumab and ipilimumab are administered, nivolumab should be given 
first, followed by ipilimumab about 30 minutes after completion of nivolumab. Patients will 
be assessed for response every 12 weeks (±7 days). Note: Please refer to section 4.4 for 
patients who may continue treatment after initial progression.
4.2
Treatment Administration
Table 1 - Treatment Administration Summary
Agent
Pre- 
meds
Dose
Route
Schedule**
Cycle 
Length
Supportive 
Therapies
Nivolumab
None
240mg
IV infusion over
~30 minutes (-5 /
+15 minutes,
before ipilimumab)
C1: q2weeks 
C2D1 & C2D15
Nivolumab
None
480mg
IV infusion over 
60minutes (-10 /
+15 minutes, 
before ipilimumab)
C2D29 & C2D57 
C3+: D1, 29, 57
Ipilimumab
None
1mg/Kg
IV infusion over
~90 minutes (-5 /
+15 minutes)
(30 min after
completion of 
nivolumab)
Day1 & 43 of 
each cycle
12 weeks
(84 days)
As needed
**See Table 2 for a simplified summary of the treatment schedule
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.
For the first 8 doses (Cycle 1 + C2D1 + C2D15) nivolumab will be administered 
at a dose 240mg as an intravenous infusion over 30 minutes (-5 / + 15 minutes)
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
24
every 14 days. Starting with C2D29, nivolumab will be administered at 480mg IV 
over 60 minutes (-10 / +15 minutes) every 28 days until disease progression, 
unacceptable toxicity, or withdrawal of consent.
There will be no dose escalations or reductions of nivolumab allowed. Patients 
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 doses 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.
4.2.2
Ipilimumab
Ipilimumab will be administered at a dose of 1mg/Kg as an intravenous infusion 
over approximately 90 minutes every 6 weeks until disease progression or 
unacceptable toxicity. Dosing will be based on weight at baseline, however if 
there is a weight change ≥10%, the dose should be adjusted accordingly. It 
should be administered approximately 30 minutes after nivolumab infusion.
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 must be 1-2 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.
4.3
Toxicity Management & Dose Delays/Modifications
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.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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4.3.1
Dose delays: Ipilimumab and/or nivolumab
Ipilimumab and/or nivolumab administration should be delayed for the following 
until resolution to ≤ Grade 1 or baseline:

Any Grade 2 non-skin, drug-related adverse event, except for fatigue 
and laboratory abnormalities

Any Grade ≥ 3 skin drug-related AE

Any Grade ≥ 3 drug-related laboratory abnormality with the 
following exceptions for lymphopenia, AST, ALT, or total 
bilirubin or asymptomatic amylase or lipase:
•
Grade 3 lymphopenia does not require a dose delay
•
If a participant has a baseline AST, ALT, or total bilirubin that is 
within normal limits, delay dosing for drug-related Grade 2 toxicity
•
If a participant has baseline AST, ALT, or total bilirubin within 
the Grade 1 toxicity range, delay dosing for drug-related Grade ≥ 
3 toxicity
•
Any Grade ≥ 3 drug-related amylase or lipase abnormality that is 
not associated with symptoms or clinical manifestations of 
pancreatitis does not require dose delay.

Any AE, laboratory abnormality or inter-current illness which, in the judgment 
of the investigator, warrants delaying the dose of study medication.
Participants that have drug-related toxicities that meet the criteria for dose 
delay, should have both drugs (ipilimumab and nivolumab) delayed until 
retreatment criteria are met. (Exceptions apply to the retreatment criteria 
after dose delay of ipilimumab and nivolumab for Grade ≥ 3 amylase and 
lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis and that are attributed to ipilimumab alone.)
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 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 a 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 (can 
be < 7 days) 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
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
26
 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 
Safety and Monitoring Committee (DSMC) 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
o
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.

Any event that leads to interruption in dosing lasting > 6 weeks (42 days) 
from the previously required dose requires discontinuation, with the following 
exceptions:
o
Dosing interruptions to allow for prolonged steroid tapers to manage
drug-related adverse events are allowed. Prior to re-initiating treatment in 
a subject with a dosing interruptions lasting > 6 weeks from the previous 
dose, the PI and DSMC must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. Periodic study 
visits to assess safety and laboratory studies should also continue every 
4 weeks or more frequently if clinically indicated during such dosing 
interruptions.
o
Dosing interruptions lasting > 6 weeks from the previous dose that occur 
for non-drug- related reasons may be allowed if approved by the PI and 
DSMC. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the PI and DSMC must be consulted. 
Tumor assessments should continue as per protocol even if dosing is 
interrupted. Periodic study visits to assess safety and laboratory studies 
should also continue every 4 weeks or more frequently if clinically 
indicated during such dosing interrupted.
o
Any adverse event, laboratory abnormality, or intercurrent illness, which 
in the judgment of the Investigator, presents a substantial clinical risk to 
the subject with continued nivolumab dosing.
o
If the patient is still receiving clinical benefit, he or she can hold drug for 
a maximum of 42 days (6 weeks), or 60 days with approval from the 
DSMC, and subsequently continue therapy following the original 
treatment schedule.
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.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
27
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
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
Immediately discontinue infusion of 
nivolumab/ipilimumab infusion.
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.
No subsequent dosing
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
28
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Subject should be monitored until 
the Investigator is comfortable that 
the symptoms will not recur.
Nivolumab or ipilimumab will be 
permanently discontinued.
Investigators should follow their 
institutional guidelines for the 
treatment of anaphylaxis. Remain 
at bedside and monitor subject 
until recovery of the symptoms
In case of late-occurring 
hypersensitivity symptoms (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.
a. Confirmed PD: a subsequent scan obtained no sooner than 4 weeks from prior scan is 
suggestive of PD by RECIST 1.1 (see section 6.6), and the patient has clinical decline. 
NOTE: If PD is confirmed but the patient continues to have clinical benefit (e.g. 
improvement of symptoms and is tolerating treatment), the patient can continue 
treatment beyond PD per clinician’s discretion.
b. Meets any of the other investigational product discontinuation criteria (Section 4.3.2)
c. Clinical symptoms or signs indicating significant PD, for example the benefit-risk ratio 
of continuing therapy is no longer justified.
d. Decline in ECOG performance status.
e. Threat to vital organs/critical anatomical sites (e.g., 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.
4.5
Interim Safety Analyses
Enrollment will be paused for a safety analysis after the first 15 evaluable ACC patients 
have been enrolled and treated. If ≥ 7 patients have been discontinued after <24 weeks 
of treatment for any reason (including toxicity, progression, intolerance etc.) accrual of 
ACC patients will be terminated. Otherwise, the study may continue enrollment until a 
total of up to 43 ACC subjects are treated.
An additional 20 patients with non-ACC MSGT’s will be treated as an exploratory cohort. 
They can be enrolled at any point throughout the study and will not count toward the 15- 
patient safety analysis. A separate safety analysis will take place to analyze the first 10 
non-ACC patients who are enrolled and treated. If >2 patients discontinue treatment prior
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
29
to 24 weeks (for reasons other than withdrawal of consent), accrual of non-ACC patients 
will discontinue.
4.6
Concomitant Medications/Treatments
4.6.1
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 and the protocol’s prohibited medications 
in 4.5.2. 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 (e.g., contrast dye allergy) or 
for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted.
Inhaled or topical steroids are permitted at any dose in the absence of active 
autoimmune disease. Adrenal replacement steroid doses are permitted as long 
as < 10mg prednisone (or equivalent) per day.
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.
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 past 30 days of treatment should be 
recorded if associated with an SAE.
4.6.1.1
Palliative Radiation Therapy or Surgery
Non-target Lesion
During study treatment, palliative radiation therapy or surgery to non- 
target lesions is permitted for symptom control. Study treatment must 
be held for the duration of the palliative treatment.
Target Lesion
If radiotherapy or surgery is needed for a target lesion, the patient is 
permitted to continue study treatment if another target lesion can be 
identified. Study treatment must be held for the duration of the 
palliative treatment. The newly selected target lesion will then be 
included for future scan assessments. In addition, previous scan 
assessments will be reevaluated to include the newly selected target 
lesion. If another target lesion cannot be identified, it will be per 
physician’s discretion if treatment may continue after discussion with 
the PI and study QAM.
4.6.2
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 ≤ 28 days prior 
to starting study treatment

Immunotherapy not specified in this protocol ≤ 28 days prior to starting 
study treatment
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
30

Chemotherapy not specified in this protocol ≤ 28 days prior to starting 
study treatment

Investigational agents other than nivolumab or ipilimumab ≤ 28 days prior 
to starting study treatment

Radiation therapy

NOTE: Palliative radiation on study is permitted. Refer to Section 4.6.1.1 
for details.

Live attenuated vaccines ≤ 30 days prior to starting study treatment 
NOTE: Influenza vaccination should be given during influenza season 
only (approximately October to March). Patients must not receive live, 
attenuated influenza vaccine (e.g., FluMist) ≤ 30 days prior to study 
treatment or at any time during the study.

Corticosteroids are not permitted ≤ 14 days prior to study treatment 
unless they fall under the criteria listed in 4.6.1
4.7
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.
o
Patient holds drug for ≥6 weeks (42 days) for reasons of toxicity (or 60 days with 
approval from the DSMC)
4.8
Duration of Follow Up
All patients will be followed for adverse events for 30 days after last dose of nivolumab 
and or ipilimumab (100 days for SAEs), 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 disease progression, then the patient will be followed with 
imaging studies every 12 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 seen in clinic every 4 weeks 
for the first 12 weeks after treatment discontinuation. Thereafter, patients will be followed 
for survival (by clinic visit or phone call) every 12 weeks for 2 years from treatment 
discontinuation or until death, whichever occurs first.
4.9
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
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
31

Patient becomes pregnant

Patient develops a second malignancy that requires treatment which would 
interfere with this study

Patient becomes lost to follow-up (LTF)
4.10
Patient Replacement
Any patient who signs consent but does not receive study treatment may be replaced.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016
 Amendment 8: 10/6/2022
32
5.0
STUDY PROCEDURES
On Treatment15,16
(1 cycle = 12 weeks / 84 days)
Off Treatment
Screening1
Cycle 1
(Each visit -2/+4 days)
Cycle 2
(Each visit -2/+4 days)
Cycle 3+
(Each visit -2/+4 days)
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+
End of 
Treatment17 
(±7 days)
Follow- 
Up
Informed Consent
X
Medical history
X
Physical exam2
X
X
X
X
X
X
X
X
ECOG status
X
X
X
X
X
X
X
X
Adverse Events & 
ConMeds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
Scans (C/A/P/N) 3,4,5
X3
X4,5
X4.5
X5
CBC with diff 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Amylase/Lipase8
X
X
X
X
X
X
X
X
TSH with reflex9
X
X
X
X
X
X
X
X
Echo/ECG19
X19
Tissue for NGS20
X20
X20
Liquid biopsy21
X21
X21
X21
X21
X21
Pregnancy test10
X
X
Nivolumab 
administration11
T
T
T
T
T
T
T
T
F
F
F
F
F
Ipilimumab 
administration12
X
X
X
X
X
X
Study Labs13
X
X13
X
Tissue collection14
X
X14
Survival status
X18
T = 240mg nivolumab 
F = 480mg nivolumab
1 Screening procedures must take place within 28 days of registration unless otherwise specified (CBC with diff and Chemistry panel should be within 14 days 
of registration; scans should be within 28 days prior to starting treatment);
2 Includes vital signs (pulse, blood pressure) and height (baseline only) and weight.
3 Imaging scans must include recurrent and/or metastatic disease, and must be within 28 days prior to starting study treatment. If a patient is scheduled to 
start treatment >28 days after the last scan, imaging must be repeated. Per treating investigator’s discretion, images may include Neck, Chest, 
Abdomen, and Pelvis (or any combination to perform tumor assessment). Scans may be by CT, PET/CT or MRI (per treating investigator’s

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016
 Amendment 8: 10/6/2022
33
discretion) with contrast unless strictly contraindicated; the same modality used at baseline should be used throughout. Brain MRI should be 
performed at baseline if clinically indicated, ≤ 6 weeks prior to registration. Tumor assessment (incorporating both RECIST and clinical criteria) 
should be done Day 1 of every cycle, i.e. every 12 weeks (± 7 days) starting with Cycle 2, until progression or treatment discontinuation whichever 
occurs first.
4 Earlier scans may be performed at the discretion of the treating physician.
5 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 8 weeks until PD is confirmed by 2 consecutive scans.
6 CBC with differential will be collected within 14 days of registration and at each treatment visit, pre-treatment. It will include WBC, ANC, ALC, Platelets, and 
Hemoglobin.
7 Chemistry panel will be collected within 14 days of registration and at each treatment visit, pre-treatment. It will include glucose, calcium, albumin, ALT, 
AST, sodium, potassium, total bilirubin, alk phos, and creatinine.
8 Amylase and lipase will be assessed at screening and every 6 weeks (Day 1 and 43 of each cycle) pre-treatment.
9 TSH will be tested at screening and every 6 weeks (Day 1 and 43 of each cycle), pre-treatment. If TSH is abnormal, free T4 should be tested
10 Serum or urine test for females of child-bearing potential (FOCBP) ≤14 days prior to registration. FOCBP are also required to have a negative pregnancy 
test within 24 hours of starting nivolumab.
11 Nivolumab will be administered in combination with ipilimumab as follows: 
First 8 doses (Cycle 1, C2D1, & C2D15): 240mg IV q2weeks
Starting with C2D29: 480mg IV q4weeks until disease progression, intolerable toxicity or withdrawal of consent.
12 Ipilimumab will be administered IV at 1mg/kg over 90 minutes every six weeks in combination with nivolumab. Dosing will be based on weight at baseline 
unless there is a change ≥10%. Nivolumab will be given before ipilimumab.
13 A correlative blood sample (3x 8mL heparin tubes) will be drawn at baseline (C1D1, pre-dose), at the first scheduled study visit after response is 
confirmed (PR or CR), and at the end of treatment visit. Please see separate lab manual for details.
14 Archival tissue will be collected at baseline for all patients (if available).Additional tissue may be collected (if feasible) during biopsies performed as 
standard of care during study participation. Please see separate lab manual for details.
15Treatment will start within 7 days after registration, and continue until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. See 
section 4.4 for conditions to continue treatment beyond initial progression.
16 Study procedures may take place within 24 hours prior to study treatment.
17 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 30 days after stopping treatment (SAE’s for 100 days).
18 Patients will be followed 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 to document survival and disease progression. SAE’s will be recorded for the first 
100 days after treatment discontinuation.
19 Echocardiogram and/or ECG should be performed at screening as clinically indicated for patients with a history of congestive heart failure or at risk 
because of underlying cardiovascular disease or exposure to cardiotoxic drugs. Cardiac toxicities should be closely monitored throughout treatment.
20 Tissue will be collected for Next Generation Sequencing any time prior to study treatment (we will accept archival tissue from the lesion demonstrating 
progression of recurrent/metastatic disease, as long as the patient has not received other treatment since that biopsy). Tissue will also be collected 
with any SOC biopsies throughout study treatment. If a patient has not had NGS performed from the lesion demonstrating PD, and the lesion is 
amenable to biopsy, the patient may agree to provide a fresh biopsy for standard-of-care NGS. If a biopsy is not feasible, is a high-risk procedure for 
patient, or the patient is not willing, he or she will be required to provide blood for ct DNA and will not be excluded from the study.

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21 A liquid biopsy (blood sample for ctDNA) will be collected at baseline (any time prior to study treatment). If a patient already had this test, we will accept 
that, as long as the patient has not received other treatment since that liquid biopsy was obtained. During the course of treatment, patients will be 
asked to have repeat ctDNA testing, as per standard of care procedures, progression of disease, and as clinically indicated.

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6.0
ENDPOINT ASSESSMENT
6.1
Definitions
For the purposes of this study, patients should be re-evaluated for response every 12 
weeks (±7 days). 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.
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) 44. 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 only 
required during screening for patients who have a known history of CNS disease. 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
Median progression-free survival (PFS) as well as PFS at 6 and 12 months [defined the 
absence of death and of progression of disease. The Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) criteria will be used for objective tumor response 
assessment.44
 Clinical and radiological assessments will be performed every 12 weeks (+/- 7 days) 
while on treatment. All patients who receive at least one dose of nivolumab and have 
had their disease re-evaluated will be included in the primary analysis of PFS.
6.3
Secondary Endpoints
 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. Overall survival (OS) is defined as time in months from the date of first 
study treatment to the date of death. All patients who receive at least one dose of 
nivolumab and have had their disease re-evaluated will be included in the secondary 
analyses of PFS and OS.
 Clinical Benefit Rate at 6 and 12 months (CBR, defined as CR + PR + Stable 
Disease (SD)) in patients with advanced progressive adenoid cystic carcinoma 
treated with nivolumab and ipilimumab using RECIST v1.1.
 To assess the efficacy of the regimen according to ORR, CBR, PFS, and in the 
above population using immune-related response criteria (irRECIST) criteria.45
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 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 
in patients with advanced progressive adenoid cystic carcinoma. Adverse events will 
follow National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03
 Overall survival defined as time in months from the date of first study treatment to the 
date of death.
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 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.
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/pneumonitis, 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.
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
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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 – RECIST v1.1
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).
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).
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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
Immune-related RECIST (irRECIST)
Immune-related complete Response (irCR): complete disappearance of all lesions 
(whether measurable or not, and no new lesions)
Immune-related partial Response (irPR): decrease in tumor burden ≥30% relative to 
baseline.
Immune-related progressive Disease (irPD): increase in tumor burden ≥20% relative to 
nadir (minimum recorded tumor burden)
Confirmation by a repeat, consecutive assessment no less than 4 weeks from the date 
first documented
Immune-related stable Disease (irSD): not meeting criteria for irCR or irPR, in absence of 
irPD
6.8
Evaluable patients
All patients who receive at least one dose of nivolumab will be considered evaluable for 
the toxicity endpoints.
All patients who receive at least one dose of nivolumab and have a radiologic evaluation 
of disease are evaluable for efficacy endpoints.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
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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 NOTIS 
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 
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:
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NU Study Number: NU 16N03
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
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 100 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
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.

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“.
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.
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NU Study Number: NU 16N03
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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 5 months after the last dose of study 
drug for FOCBP or 7 months for males with FOCBP partners. 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 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 Safety Monitoring Committee (DSMC) 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
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
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/DSMC
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 DSMC at their next 
meeting.
7.4.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

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 BMS
All 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 209-802). 
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
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
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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 is a sterile, non-pyrogenic single-use, isotonic 
aqueous solution. Vials must be stored in a secure, limited-access location at 2 
to 8 degrees C (36 to 46 degrees F) 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 product 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.
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 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation.

Do not freeze.
8.1.5
Protocol dose specifics
240mg q2weeks and 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 
particulate 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.
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted so as not to 
exceed a total infusion volume of 120mL.
8.1.7
Route of administration for this study
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer nivolumab 240 mg as an intravenous infusion over 30 (-5/+15)
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
44
minutes and 480mg as an intravenous infusion over 60 (-10/+15) minutes 
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. Nivolumab should not be infused concomitantly in the same 
intravenous line with other medicinal products.
8.1.9
Availability & Supply
Nivolumab will be supplied by the study as 100 mg/Vial (10 mg/mL) clear to 
opalescent, colorless to pale yellow liquid in 10-cc Type 1 flint glass vials 
stoppered with butyl stoppers and sealed with aluminum seals. May contain 
particles.
A supply of nivolumab may be ordered from by completing a Drug Request Form 
provided by BMS. The first request may take place upon screening of the first 
patient. The initial order should be limited to 20 vials. Allow 5 business days for 
shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug product will be shipped by courier in a 
temperature-controlled container. It is imperative that only drug product 
designated for this protocol number be used for this study.
Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date. Deliveries will be made Tuesday through 
Friday. When assessing need for resupply, keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from 
receipt of request. Drug is not patient-specific.
8.1.10
Side effects
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.
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
45
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 or 4 
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 30 days from their last dose of nivolumab.
Participants with ongoing side effects will continue to be followed until resolution 
or stabilization of the side effects. Because it is not known if nivolumab will be 
effective against this type of cancer, enrollment will stop after 12 participants are 
treated with nivolumab if none of them have their tumors shrink..
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 
not used 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 arr ange f or 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. Inform BMS on all drug 
destructions pertaining to both nivolumab and ipilimumab.
Table 8.1 – Nivolumab Product Information
Product
Potency
Primary
Secondary
Appearance
Storage
Description
Packaging
Packaging
Conditions
and Dosage
(Volume)/
(Qty) /Label
(per label)
Form
Label Type
Type
Nivolumab
100 mg
10 mL vial
5 vials per
Clear to opalescent
2 to 8ºC.
BMS-936558-01
(10
carton/
colorless to pale
Protect form
Solution for
mg/mL)
Open-label
yellow liquid. May
light and
Injection
contain particles
freezing
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 injection is a sterile, nonpyrogenic, clear to slightly opalescent, colorless to pale 
yellow solution, single-use, preservative-free, isotonic aqueous solution that may contain 
particles. It is formulated at a concentration of 5 mg/mL ipilimumab in TRIS hydrochloride 
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
46
(also known as 2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride), sodium chloride, 
mannitol, pentetic acid (also known as diethylenetriaminepentaacetic acid or DTPA), 
polysorbate 80, and water at pH 7.0. Sodium hydroxide and/or hydrochloric acid may be 
used to adjust the pH of the solution.
Ipilimumab Injection 50 mg/10 mL (5 mg/mL) is packaged in a 10-cc Type I flint tubing 
glass vials, stoppered with 20-mm gray butyl rubber stoppers, and sealed with 20-mm 
aluminum flip-off seals. Each vial includes a 0.7-mL overfill for vial, needle, and syringe 
(VNS) holdup
Ipilimumab injection, 50 mg/10 mL (5 mg/mL), must be stored refrigerated (2°C to 8°C) 
and protected from light. Ipilimumab injection must not be frozen. Partially used vials or 
empty vials of ipilimumab injection should be discarded at the site according to appropriate 
drug disposal procedures. 
Ipilimumab injection may be stored undiluted (5 mg/mL) or following dilution in 0.9% 
sodium chloride injection or 5% dextrose injection in PVC, non-PVC/non-DEHP, or glass 
containers for up to 24 hours at 2°C to 8°C or room temperature/room light. 
Recommended safety measures for preparation and handling include protective clothing, 
gloves, and safety cabinets.
8.2.5
Protocol dose specifics
1mg/Kg
8.2.6
Preparation
Ipilimumab injection, 50 mg/10 mL (5 mg/mL), can be used for intravenous (IV) 
administration without dilution after transferring to a polyvinyl chloride (PVC), 
non-PVC/non-di(2-ethylhexyl)phthalate (DEHP), or glass container and is stable 
for 24 hours at 2°C to 8°C or room temperature/room light. Ipilimumab injection 
may be diluted in 0.9% sodium chloride injection or 5% dextrose injection to 
concentrations between 1 mg/mL and 4 mg/mL and stored in PVC, non-
PVC/non-DEHP, or glass containers for up to 24 hours at 2°C to 8°C or room 
temperature/room light. The product may be infused using a volumetric pump at 
the protocol-specific dose(s) and rate(s) through a PVC IV solution infusion set 
with an in-line, sterile, nonpyrogenic, low protein binding filter (pore size of 0.2 
m to 1.2 m). Ipilimumab injection must not be administered as an IV push or 
bolus injection. Care must be taken to assure sterility of the prepared solutions 
since the drug product does not contain any antimicrobial preservatives or 
bacteriostatic agents.
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 /vial (5mg/mL) packaged in cartons of 6 vials. Drug is protocol specific, but 
not patient specific.
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
47
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. Contact and submission details can be found directly 
on the Drug Request Form.
Deliveries will be made Tuesday through Friday.
Starting January 2023, Ipilimumab will be supplied in 50mg vials. Each carton will contain 
6 x 50mg vials.
Ipilimumab product supply
Container 
description
Type: Single-use vials of 50 
mg/10 mL
Material:
clear glass
Size:
10 mL vials
Active ingredient 
content
Mass/Weight:
50 mg
Volume:
10 mL
 
Concentration:
5 mg/mL
 
Table 8.2 – Ipilimumab Product Information
Product
Potency
Primary
Secondary
Appearance
Storage
Description
Packaging
Packaging
Conditions
and Dosage
(Volume)/
(Qty) /Label
(per label)
Form
Label Type
Type
Ipilimumab
50 mg
10 mL vial
6 vials per
Clear, colorless
2 to 8°C.
Solution for
(5
carton/Open-
to pale yellow
Protect from
Injection
mg/mL)
label
liquid. May
light and
contain particles
freezing.
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
48
8.2.10
Side effects
Immune-related adverse events have been associated with ipilimumab is 
administered intravenously.
Since its first approval for advanced melanoma in the US on 25-Mar-2011, 
followed by European Medicines Agency approval in the EU on 13-Jul-2011, 
ipilimumab has been approved for market use in 47 countries worldwide.
Based on information published in the ipilimumab Periodic Benefit-risk Evaluation 
Report (PBRER) #5, cumulatively through 24-Mar-2015 (the cutoff date for the 
last PBRER), approximately 30,540 patients have been exposed to ipilimumab 
through marketed drug worldwide (excluding investigator-sponsored 
trials/research exposure). In addition, 5,877 subjects have been cumulatively 
exposed to ipilimumab through clinical trials, and 10,486 patients have been 
exposed to ipilimumab through EAPs. During the reporting period of PBRER #5, 
13 clinical trials (including EAPs, CA184045 and CA184089) met the inclusion 
criteria as ongoing studies, and 1 clinical trial (Study CA184202, Phase 1 to 3) in 
melanoma was completed. During that reporting period, the Company Core Data 
Sheet was updated once, on 21-Jan-2015. One new safety signal was identified: 
drug reaction with eosinophilia and systemic symptoms. For toxic epidermal 
necrolysis, a known, labeled AE, a cautionary note was added for the specific 
context when ipilimumab treatment is considered for a patient who has previously 
experienced a severe or life-threatening skin adverse reaction on a prior cancer 
immune-stimulatory therapy.
Based on package insert 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)
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
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
49
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 
30 days 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 
not used 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 arr ange f or 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. Inform BMS on all drug 
destructions pertaining to both nivolumab and ipilimumab.
                                               
Container 
description
Type: Single-use vials of 50 
mg/10 mL
Material:
clear glass
Size:
10 mL vials
Active ingredient 
content
Mass/Weight:
50 mg
Volume:
10 mL
 
Concentration:
5 mg/mL
 
9.0
CORRELATIVES/SPECIAL  STUDIES
Archival tumor samples, when available, and any tissue that may feasibly be collected from SOC 
biopsies throughout the study, may be evaluated for the immunosuppressive biomarker PD-L1 
protein on tumor cells and the expression level and localization of other markers of 
inflammatory/immune signature that may include but not be limited to PD-1, OX40, CD73, CD39, 
T cell immunoglobulin and mucin domain containing protein 3 (TIM3), GITRL, CTLA-4, CD3, 
CD4, CD8, protein tyrosine phosphatase receptor type C (CD45RO), forkhead box P3 (FOXP3), 
and granzyme by immunohistochemistry analysis and/or flow cytometry. Comprehensive genomic 
profiling of the tumor samples will also be performed.
A baseline whole blood sample and serum sample will also be collected for future biomarker 
analysis that may include tumor and immune cell, poreosome, and exosome analysis at 
partnering laboratories. Collection and processing instructions are available in a separate lab 
manual, available on the NOTIS protocol page.
Repeated blood samples will be collected at the time of disease progression and partial or 
complete response (± 2 weeks of confirmation). Details on sample collection, shipping, and 
processing are available in a separate lab manual.
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
50
9.1
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.
The PI 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 arm open label phase II clinical trial which will assess the anti-tumor 
efficacy of nivolumab in combination with ipilimumab in ACC. As these two monoclonal 
anti-bodies already have been studied and approved as monotherapy or combination in 
other histological tumor types we believe that a phase II study is appropriate for 
development of these drugs in metastatic/recurrent adenoid cystic carcinoma (ACC). The 
non-adenoid cystic carcinomas (non-ACC) of major or minor salivary glands are for 
exploratory purposes for signal finding and will not be included in our statistical plan.
10.1.1
Primary:
To assess the median progression-free survival (PFS) as well as PFS at 6 and 
12 months [defined as the absence of death and of progression of disease] in 
patients with metastatic/recurrent and progressive ACC. The Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for 
objective tumor response assessment
10.1.2
Secondary:
(1) To assess the efficacy of nivolumab and ipilimumab according to response rate 
(RR), disease control rate (DCR; CR, PR, and SD at 24 weeks), overall survival 
(OS) and progression free survival (PFS) in the above population using RECIST 
criteria.
(2) To assess the efficacy of nivolumab and ipilimumab according to ORR, DCR, 
PFS, and OS in the above population using irRECIST criteria.
(3) To assess the safety and tolerability profile of nivolumab and ipilimumab 
therapy in the above population using CTCAE version 4.03
(4) To assess the immune-related biomarkers and their association with treatment 
response
(5) Assess activity of nivolumab and ipilimumab in non-ACC malignant salivary 
gland tumors (MSGTs)
10.1.3
Exploratory endpoints:

To assess the predictive value of baseline immunosuppressive biomarker 
PD-L1 protein on tumor cells and the expression level and localization of
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
51
other markers of inflammatory/immune signature. Correlations between cell 
free tumor DNA and tumor tissue genomic aberrations with anti-tumor 
efficacy of nivolumab/ipilimumab combination will be explored.
10.2
Sample Size and Accrual
A Simon two stage optimum Phase II design will be used 46. The main outcome is median 
Progression Free Survival (PFS) as well as PFS at 6 and 12 months. The optimal two- 
stage design to test the null hypothesis that P<=0.450 versus the alternative that P>=0.650 
has an expected sample size of 24.70 and a probability of early termination of 0.654. If the 
drug is actually not effective, there is a 0.048 probability of concluding that it is (the target 
for this value was 0.050). If the drug is actually effective, there is a 0.196 probability of 
concluding that it is not (the target for this value was 0.200). After testing the drug on 15 
patients in the first stage, ACC accrual will be terminated if 7 or more patients are withdrawn 
from the study after <24 weeks of treatment for any reason other than withdrawal of 
consent (this includes toxicity, PD, intolerance etc.) If the trial goes on to the second stage, 
a total of 43 patients will be studied. If the total number responding (defined as stable 
disease or better) is less than or equal to 24, the drug is rejected. An exploratory group of 
20 patients with MSGTs will be included in the study, in addition to the 43 patients 
mentioned above. They can be enrolled in any order within the total accrual of 63 patients 
and will not participate in statistical analysis. A separate safety analysis will take place; if
>2 of the first 10 non-ACC patients are withdrawn after <24 weeks of treatment, non-ACC 
accrual will discontinue.
.
10.3
Data Analyses Plans
Response rates and 95% confidence intervals will be calculated using exact binomial 
probability distributions for discrete outcomes. Progression-free survival and overall 
survival will be graphically depicted 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 REFERENCES
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.
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
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
52
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
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission to the 
local IRB

A copy of the official IRB approval letter for the protocol and informed consent.
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
53

CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, study- 
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation.
11.6
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 NOTIS for additional information). The level of risk attributed to this study 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).
11.7
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 Reportable New 
Information (RNI) if it:
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
54

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.
11.8
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 
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.
11.9
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, diagrams, abstracts, posters, charts, slides, pictures, 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 DSMC) 
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 DSMC-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 DSMC at their next available meeting, and a final, DSMC- 
approved dataset will be released along with any DSMC decisions regarding publication. 
The investigators are expected to use only DSMC-approved data in future publications. 
The investigators should submit a copy of the manuscript to the biostatistician to confirm 
that the DSMC-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 #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
55
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IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
56
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September 6-0,2015. Denver Colorado USA, 2015
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Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123-35, 2015
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Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin 
Oncol 33:2013-20, 2015
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van Elsas A, Sutmuller RP, Hurwitz AA, et al: Elucidating the autoimmune and antitumor 
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with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J Exp Med 194:481-9, 2001
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Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 363:711-23, 2010
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Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 364:2517-26, 2011
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Curran MA, Montalvo W, Yagita H, et al: PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc 
Natl Acad Sci U S A 107:4275-80, 2010
38.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med 373:23-34, 2015
39.
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 33:2004-12, 2015
40.
Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for Metastatic Renal Cell Carcinoma: 
Results of a Randomized Phase II Trial. J Clin Oncol 33:1430-7, 2015
41.
Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus Everolimus in Advanced 
Renal-Cell Carcinoma. N Engl J Med 373:1803-13, 2015
42.
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti- 
PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012
43.
Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD- 
L1 antibody MPDL3280A in cancer patients. Nature 515:563-7, 2014
44.
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009
45.
Wolchok JD, Hoos A, O'Day S, et al: Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412-20, 2009
46.
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10,
1989
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
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Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
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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)
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
58
Appendix B – ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status scale
Grade
Description
0
Normal activity. Fully active, a b l e 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.
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NU Study Number: NU 16N03
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Initial Version: 11/23/2016 
Amendment 8: 10/06/2022
59
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 from the time of treatment initiation to 5 months 
(for FOCBP) or 7 months (for males with FOCBP partners) after the last dose of nivolumab.
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 #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
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Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
60
Appendix D– Adverse Event Algorithms
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, neurologic 
toxicity, pulmonary toxicity, renal toxicity and skin toxicity

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
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NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: 10/6/2022
66

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: // 10/6/2022
67
Appendix D – Protocol Summary of Changes
Amendment 1 – February 16, 2017
Approved by Scientific Review Committee: March 1, 2017
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover Page; Study 
Summary
Title referred to treatment 
of “advanced” ACC and 
non ACC
Changes title to refer to 
treatment of 
“metastatic/recurrent” ACC 
and non ACC
Revised for consistency 
with population and 
eligibility criteria
Study Schema; Study 
Summary; 3.0 (Patient
Eligibility); 3.1.2, 3.1.3 
(Inclusion Criteria)
Patients “cannot be a 
candidate for surgical 
treatment”
Patients “cannot be a 
candidate for surgical or 
radiation treatment”
Revised for consistency 
with 3.2.3
Study Summary; 2.1
(Primary Objective); 6.2 
(Primary Endpoint);
10.1.1 (Primary);
10.2 (Sample Size and 
Accrual)
“To assess progression- 
free survival rate (PFSR) 
at 6 months” or
“To assess median 
progression-free survival 
rate (PFSR) as well as 
PFSR at 6 and 12 months”
To assess median 
progression-free survival 
(PFS) as well as PFS at 6 
and 12 months
Progression-free survival 
does not need to be 
measured as a rate.
To correct discrepancies – 
we will look at median and 
12-month PFS as well as 
6-month.
3.1.3 (Inclusion 
Criteria)
“Patients must have 
received at least one prior 
line of systemic therapy”
“Patients may or may not 
have received prior therapy 
for their 
recurrent/metastatic 
disease”
Disease team requested to 
expand eligibility to patients 
who have not received 
treatment for
metastatic/recurrent 
disease.
4.1 (Overview);
4.2 (Treatment 
Administration);
4.2.1 (Nivolumab);
4.2.2 (Ipilimumab)
Treatment windows were 
as follows:
Nivolumab over 30 mins 
(±5 mins) / 60 mins (±10 
mins)
Ipilimumab over 90 mins
(±5 mins)
Changes treatment windows: 
Nivolumab over 30 mins (-5 /
+15 mins) / 60 mins (-10 /
+15 mins)
Ipilimumab over 90 mins (-5 /
+15 mins)
Allows for flexibility of a 
longer infusion if needed, 
without compromising 
safety
11.6.2 (Other Protocol 
Deviations)
Refers to “Promptly 
Reportable Non-
Compliance (PRNC)”
Changes to “Reportable New 
Information (RNI)”
Administrative – to align 
with current internal
policies
Amendment 2 – March 13, 2017
Approved by Scientific Review Committee: March 27, 2017
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
1.4 (Exploratory 
Studies);
2.3.3 (Exploratory 
Objectives & 
Endpoints); 5.0 (Study 
Procedures);
9.0 (Correlatives / 
Special Studies)
Included cfDNA 
exploratory objective and 
correlative samples, to be 
performed at Guardant
Removes cfDNA samples 
and any reference to such 
analysis at Guardant. Such 
samples will be collected and 
sent as part of SOC, and 
have been added as a 
separate procedure in 5.0.
Administrative decision to 
remove samples due to 
logistical issues with 
Guardant
5.0 (Study Procedures)
n/a
Adds optional Echo/ECG at 
baseline for patients with a 
history of congestive heart 
failure or at risk because of
Response to CTEP action 
letter advising for cardiac 
monitoring as a result of 
recent myocarditis
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Amendment 8: // 10/6/2022
68
underlying cardiovascular 
disease
5.0 (Study Procedures,
#12); 9.0 (Correlative/ 
Special Studies)
Tissue was to be collected 
from SOC biopsies 
throughout the study “If 
the patient agrees”, and
were not mentioned in 9.0
Removes “If the patient 
agrees” and adds “if feasible”
Tissue collection from SOC 
biopsies will be mandatory 
if feasible, and the patient’s 
overall consent will account
for this
5.0 (Study 
Procedures);
9.0 (Correlative/ 
Special Studies)
NGS was listed as a 
correlative sample
Adds NGS as a separate 
study procedure, which will 
be performed as part of 
standard of care (rather than
a correlative sample)
Clarification – NGS is 
performed SOC and is not 
meant to be processed 
through Pathcore or as a
research charge.
5.0 (Study Procedures,
#11)
n/a
Adds blood volume and tube 
types for correlative samples.
Clarification
Amendment 3 – May 17, 2017
Approved by Scientific Review Committee: June 2, 2017
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Cover Page
Includes Ricardo Costa as 
Sub-Investigator
Removes Ricardo Costa as 
Sub-Investigator
Administrative; Dr. Costa 
has left the university
Study Summary;
6.3 (Secondary 
Endpoints)
Secondary objective to 
look at clinical benefit rate 
(CBR) at 24 weeks
Changes secondary objective 
to clinical benefit rate (CBR) 
and 6 and 12 months
Revision of discrepancy
Study Summary; 2.2.2 
(Secondary Objectives 
& Endpoints);
6.7 (Immune-related 
RECIST);
10.1.2 (Secondary)
Secondary objective of 
efficacy using immune- 
related response criteria 
(irRC)
Changes secondary objective 
to efficacy using immune- 
related RECIST (irRECIST). 
Updates criteria in 6.7 to
align with current definitions 
of irRECIST
Revision of discrepancy; 
irRECIST is most current 
immune-related response 
criteria
3.1.9 (Inclusion
Criteria); 5.0 (Study
Procedures, #8)
Pregnancy test was 
required within 72 hours of
Registration
Pregnancy test required ≤14 
days prior to registration
Clarification to allow for 
greater flexibility in
screening
3.2.1, 3.2.4, 3.2.13
(Exclusion Criteria);
4.6.2 (Prohibited 
Medications)
Windows for prohibited 
medications were from 
study registration
Windows for prohibited 
medications are changed to 
be measured from start of 
study treatment
A window from study 
treatment rather than 
registration allows for 
greater flexibility at 
screening, and is more 
clinically appropriate, per
PI
4.2.2. (Ipilimumab); 5.0 
(Study Procedures, 
#10)
n/a
Adds: “Dosing will be based 
on weight at baseline, 
however if there is a weight 
change ≥10%, the dose 
should be adjusted
accordingly”
Clarification
TSH
TSH with reflex
Clarification
#2: Vital signs included 
pulse, respirations, and 
blood pressure
#2: Removes respirations 
from vital signs
Missing respirations are a 
common source for 
protocol deviations; they 
are not clinically necessary
5.0 (Study Procedures)
#11: Correlative blood 
samples were to be
collected in 10mL heparin 
tubes
#11: Changes correlative 
tubes to 8mL heparin tubes
Correction
Amendment 4 – August 14, 2017
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NU Study Number: NU 16N03
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Initial Version: 11/23/2016 
Amendment 8: // 10/6/2022
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Approved by Scientific Review Committee:
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page; Study 
Summary
Title: Phase II study of 
nivolumab and ipilimumab 
for treatment of 
metastatic/recurrent 
adenoid cystic carcinoma 
and non-adenoid cystic 
carcinoma
Title: Phase II study of 
nivolumab and ipilimumab for 
treatment of 
metastatic/recurrent adenoid 
cystic carcinoma of all 
anatomic sites of origin and 
non-adenoid cystic 
carcinoma malignant 
tumors of the salivary
gland
Clarification to address 
discrepancies in study 
population
Study Schema; 3.1.1 
(Inclusion Criteria);
Study population was to 
include ACC patients with 
evidence of disease 
progression.
Clarifies that ACC can be of 
any anatomic site of origin
Clarification of study 
population to ensure it is 
inclusive
Study Schema; 3.1.2,
3.1.3 (Inclusion
Criteria); 3.2.3 
(Exclusion Criteria)
Study population was to 
include ACC patients who 
are not surgical or 
radiation candidates
Clarifies that patients cannot 
be a candidate for curative 
surgical or radiation therapy
Clarification; distinguishes 
between surgical/radiation 
therapy which is palliative 
or otherwise non-curative, 
which is permitted
3.1.3 (Inclusion 
Criteria)
NOTE: There is no limit to 
the number of prior 
therapies for stage IV
Disease
NOTE: There is no limit to the 
number of prior systemic 
therapies
Clarification
3.1.4 (Inclusion 
Criteria)
n/a
Adds note that scans must be
≤28 days prior to study 
treatment
Clarification
3.1.7 (Inclusion 
Criteria)
Requirements for bilirubin 
and creatinine were listed 
as <3.0 x ULN and > 30 
mL/minute
Updates to ≤ and ≥ 
respectively
Clarification; criteria are 
meant to be inclusive of the 
borderline value
3.2.1 (Exclusion 
Criteria)
Chemotherapy and 
radiotherapy were not 
permitted ≤28 days prior 
to study treatment
Shortens window for 
radiotherapy; now permitted
>7 days prior to study 
treatment
Allows greater flexibility in 
the allowance for 
radiotherapy since it might 
be clinically indicated to
have radiotherapy close to 
treatment and is lower risk
3.2.5 (Exclusion 
Criteria)
Included a reference to 
specific PD-1, PD-L1, and 
CTLA4 monoclonal 
antibodies
Removes reference and list 
of specific monoclonal 
antibodies
The list is incomplete and 
potentially misleading. The 
PI can be contacted for any 
questions on specific 
immune checkpoint
inhibitors
3.2.12 (Exclusion 
Criteria)
Patients were excluded 
with any known positive 
test for Hepatitis B or C 
indicating acute or chronic 
infection
Only acute, and not chronic, 
Hepatitis B or C infection is 
considered exclusionary
A controlled chronic 
condition does not indicate 
the need to exclusion
4.3.2 (Treatment 
Discontinuation);
4.7 (Duration of
Therapy); 7.4.1
Referred to NU’s internal 
Data Monitoring 
Committee (DMC)
Changes to Data Safety 
Monitoring Committee 
(DSMC)
To align with updated 
policies
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: // 10/6/2022
70
(Routine Reporting);
7.4.3.1 (Reporting to
NU QAM/DSMC); 11.9
(Publication Policy)
5.0 (Study Procedures)
Window for treatment and 
procedures was ±4 days
Changes treatment and 
procedure window to -2/+4 
days
Changes EOT window to ±7 
days
Nivolumab cannot be given
<12 or 24 days after the 
previous dose; smaller 
window prevents overlap 
Larger EOT window allows 
flexibility
5.0 (Study Procedures
#1,3)
Baseline imaging was to 
include CT of Neck, 
Chest, Abdomen and 
Pelvis within 28 days prior 
to registration.
Baseline imaging must be 
within 28 days prior to 
starting treatment and may 
include Neck, Chest, 
Abdomen and Pelvis (or any 
combination) at investigator 
discretion.
Allows more flexibility for 
investigator to use 
discretion as to which 
scans are clinically 
relevant. The timing of 
scans from treatment is 
more important to get the 
most accurate picture of 
disease burden.
5.0 (Study Procedures
#3,4,5)
One footnote was included 
with all instructions related 
to scans on study
Separates into 3 footnotes to 
clearly delineate instructions 
for scans at baseline, prior to 
each cycle, and in the case of 
PD. Re-numbers subsequent
footnotes appropriately.
Simplified for clarity
5.0 (Study Procedures,
#20)
NGS was to be performed 
using Foundation One, 
“any time prior to study 
treatment, preferably 
within 6 weeks”
Removes Foundation One
NGS can be performed any 
time prior to study treatment 
as long as the patient has 
not received other treatment 
since the biopsy.
Clarifies that tissue should 
be taken from the lesion 
demonstrating progression 
and that patients may agree 
to provide a fresh biopsy if
not available
Allows greater flexibility in 
using different companies 
for NGS testing
Clarification; it is more 
important that the biopsy 
not be intervened by 
treatment rather than the 
actual timing
Clarification
5.0 (Study Procedures,
#21)
A liquid biopsy was to be 
performed prior to study 
treatment, “preferably 
within 6 weeks, per 
clinician’s discretion”
Liquid biopsy can be 
performed any time prior to 
study treatment “as long as 
the patient has not received 
other treatment since the 
biopsy, per standard of care
procedures”
Clarification; it is more 
important that the sample 
not be intervened by 
treatment rather than the 
actual timing
8.1 (Nivolumab)
Contained outdated 
language on nivolumab 
details. Specifically:
8.1.4: Nivolumab could be 
stored up to 4 hours at 
room temperature
8.1.6: Listed details on 
minimum concentration 
with weight-based dosing
Updates nivolumab details to 
align with new Investigator’s 
Brochure and internal 
template language for 
nivolumab protocols.
Specifically:
8.1.4: Nivolumab can be 
stored up to 8 hours at room 
temperature
Updated for simplicity to 
align with other internal 
nivolumab protocols
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: // 10/6/2022
71
8.1.6: Removes reference to 
weight-based dosing 
preparation
Amendment 4 continued – September 8th, 2017
Approved by Scientific Review Committee:
Section(s) Affected
Prior Version
Amendment 4 Changes 
cont.
Rationale
7.3 (Reporting of 
pregnancy and 
lactation); Appendix A
Contraception timing post- 
treatment was not 
specified; pregnancy was 
to be monitored up to at 
least 6 half-lives after 
product administration
WOCBP will be instructed to 
adhere to contraception for a 
period of 5 months after the 
last dose of nivolumab. Men 
receiving nivolumab will be 
instructed to adhere to 
contraception for a period of 
7 months after the last dose
of nivolumab.
Updated per BMS to align 
with new nivolumab IB v16 
requirements for pregnancy 
and contraception.
8.1.9 (Availability and 
Supply)
Did not specify timing for 
drug re-supply requests
Drug re-supply should be 
submitted 10 business days 
before the delivery date
Updated for accuracy per 
BMS
8.1.12, 8.2.12 (Return
& Retention of Study 
Drug)
n/a
Adds statement: “Inform 
BMS on all drug destructions 
pertaining to both nivolumab 
and ipilimumab.”
BMS request.
Tale 8.1 (Nivolumab 
Product Description)
5-10 vials per carton were 
supplied
5 vials per carton are 
supplied
Updated for accuracy per 
BMS
8.2.4 (Storage and 
stability)
n/a
Replaces language with 
internal ipilimumab template
For consistency among 
internal IIT protocols using 
ipilimumab
Table 8.2 (Ipilimumab 
Product Description)
4 vials per carton were 
supplied
5 vials per carton are 
supplied
Updated for accuracy per 
BMS
Appendix B
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,
Updated per BMS for 
consistency with new 
nivolumab IB v16 and 
additional or clarified safety 
measures.
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.

NU Study Number: NU 16N03
BMS Study Number: CA 209-802
Initial Version: 11/23/2016 
Amendment 8: // 10/6/2022
72
permanently discontinue 
I-O therapy.”
Amendment 5 – September 11th 2019
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Coverpage
3.0 (Subject Eligibility)
Lists Maria Matsangou as 
the PI for the study
Changes to list Mark Agulnik 
as the PI
Change due to original PI 
leaving Northwestern
Amendment 6 – October 11th 2019
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
4.6.1 (Permitted 
Medications)
4.6.2 (Prohibited 
Medications)
n/a
Adds guidelines of permitted 
palliative radiation or surgery 
on study
To allow patients to have 
palliative radiation or 
surgery when on treatment
Amendment 7– June 26th 2020
Section(s) Affected
Prior Version
Amendment 7 Changes
Rationale
Lists Mark Agulnik as the 
PI for the study
Changes to list Young Chae 
as the PI
Change due to PI leaving 
Northwestern
Coverpage
Lists Sub-investigators for 
the study
Removes Sub-investigators 
from the coverpage
Per new policies, sub- 
investigator lists will be 
maintained in DOA and
APL only and not on the 
protocol coverpage
3.0 (Subject Eligibility)
9.1 (Specimen 
Banking)
Lists the PIs by name and 
in some places provides 
contact information
Removed or replaced with 
“PI”
Removed as PI is leaving 
Northwestern and to 
provide consistency
throughout the protocol
Amendment 8 
Section(s) Affected
Prior Version
Amendment 8 Changes 
Rationale
8.2.5 
Ipilimumab storage and 
stability
Previous information 
Updated with current 
information 
As mandated by BMS,
based on current IB
8.2.6 
Preparation of 
ipilimumab 
Previous information
Updated with current 
information
As mandated by BMS,
based on current IB
8.2.9 
Availability and supply of 
Ipilimumab 
And 8.2.12 
Return and retention of 
drug 
Previous information
Updated to state,
“Starting January 2023, 
Ipilimumab will be supplied in 
50mg vials. Each carton will 
contain 6 x 50mg vials.”
Other associated information 
updated
As mandated by BMS,
based on current IB
IRB #: STU00204579-CR0006 Approved by NU IRB for use on or after 9/20/2023 through 9/19/2024.