Clinical trial NCT02720484
Conditions: Metastatic Carcinoma in the Adrenal Cortex Recurrent Adrenal Cortex Carcinoma Stage III Adrenal Cortex Carcinoma Stage IV Adrenal Cortex Carcinoma
Sponsor: Northwestern University
Start date: 2016-03-30; Completion date: 2018-11-02
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective will be to assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma. Nivolumab was recently approved by U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma, non-small cell lung cancer and renal cell carcinoma. It is considered investigational for the treatment of advanced or refractory adrenocortical carcinoma. "Investigational" means that the drug is not approved by the USFDA or not approved for the indication under investigation. Nivolumab could shrink adrenocortical carcinoma but it could also cause side effects. Researchers hope to learn if the study drug will shrink the cancer and hopefully to relieve symptoms that are related to the cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma (ACC).

SECONDARY OBJECTIVES:

I. To assess the progression free survival defined as time from date of first nivolumab infusion until date of death or evidence of progression of disease as assessed by computed tomography (CT) imaging every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.

II. To assess the overall survival defined as time from date of first nivolumab infusion until death of patients with metastatic or locally advanced ACC.

III. To assess the safety and tolerability profile of nivolumab described by number, frequency, and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3 assessed every 2 weeks while patients are on therapy.

TERTIARY OBJECTIVES:

I. To assess the overall response rate, progression free survival and overall survival according to tumor programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2) expression.

II. To assess the overall response rate, progression free survival and overall survival according to serum interleukin levels and peripheral T cell profile levels.

III. To measure humoral and cellular responses to tumor antigens on serum samples by measuring the levels of cytokines (ie, interleukin \[IL\] -2, IL-6, IL-8, IL-10, IL-18, interferon \[IFN\] gamma and tumor necrosis factor \[TNF\]-alpha) and peripheral blood lymphocyte phenotype.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity, or withdrawal of consent.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Arms: arm 1: Patients receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Nivolumab
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 
Do not disclose or use except as authorized in writing by the study sponsor.
1
Phase II study of nivolumab (anti-PD-1 antibody) for treatment of 
metastatic adrenocortical carcinoma
Principal Investigator: Devalingam Mahalingam, MD,
Northwestern University 
Associate Professor, Division of Hematology and Oncology
645 N. Michigan Avenue Suite 1006
Chicago, IL 60611
Phone: 312.472.1234
Fax: 312.472.0564
mahalingam@northwestern.edu; mahalingam@nm.org
Sub-Investigators:
Northwestern University
Sunandana Chandra, MD
Young Chae, MD
Maria Matsangou, MD
Jason Kaplan, MD
Aparna Kalyan, MD
Joshua Meeks, MD, PhD
Maha Hussain, MD
Bhavana Khondra, MD
Jeffery Russell, MD, PhD
Assistant Professor
Assistant member, Head and Neck/
Division of Medical Oncology
Cutaneous Oncology
Ohio State University
Moffitt Cancer Center
A440 Starling-Loving Hall
12902 USF Magnolia Dr
320 West 10th Avenue
Tampa, FL 33612
Columbus, OH 43210
Tel: 813-745-8118
Tel: 614-293-6401
Email: Jeffery.russell@moffitt.org
Email: bhavana.khondra@osumc.edu 
Douglas Ball, MD
Associate Professor, Medicine
Johns Hopkins Medicine
SOM Office of Research Administration
733 N Broadway, Suite 117
Baltimore, MD 21205
Tel: 410-955-3061
Email: dball@jhmi.edu
Biostatistician:
Alfred Rademaker, PhD
Study Intervention(s):
Nivolumab
IND Number:
IND-exempt
Funding Source: 
Bristol-Myers Squibb 
Version Date:
 7/31/2017 (Amend 3)
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 #: STU00202153 Approved by NU IRB for use on or after 11/20/2018 through 11/19/2019.


CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 
Do not disclose or use except as authorized in writing by the study sponsor.
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................3
STUDY SCHEMA ............................................................................................................................4
STUDY SUMMARY .........................................................................................................................5
1.0 Introduction – Background & Rationale ................................................................................6
2.0 Objectives & Endpoints.........................................................................................................12
3.0 Patient Eligibility ....................................................................................................................13
4.0 Treatment Plan .......................................................................................................................16
5.0 Study Procedures ..................................................................................................................24
6.0 Endpoint Assessment ...........................................................................................................26
7.0 Adverse Events ......................................................................................................................29
8.0 Drug Information....................................................................................................................33
9.0 Correlatives/Special Studies.................................................................................................36
10.0 Statistical Considerations...................................................................................................37
11.0 Study Management ..............................................................................................................38
References....................................................................................................................................42
APPENDICES................................................................................................................................45
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LIST OF ABBREVIATIONS
 ACC                  Adrenocortical Carcinoma
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DMC
DSMB
Data Monitoring Committee
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
H&PE
History & Physical Exam
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
NSCLC
Non-small cell lung cancer
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PI
PO (or p.o.)
Principal Investigator
Per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
RCC
Renal cell carcinoma
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
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 STUDY SCHEMA 
10 patients treated with nivolumab 240mg 
infusion every 2 weeks until disease 
progression, unacceptable toxicity, or 
withdrawal of consent
Patients with metastatic or locally advanced adrenocortical carcinoma (ACC)
Treated with at least one prior therapy for metastatic disease. 
No history of autoimmune disease or syndrome that require immunosuppressive agents
0 responses ≥ Stable Disease (SD)
≥ 1 response ≥ SD
Expand trial to include 19 more patients
Due to inevaluable patients and dropout, target accrual will be 33 patients
The study follow up time will be up to 2 years after discontinuation of 
treatment
Stop trial
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STUDY SUMMARY
Title
Phase II study of nivolumab (anti-PD-1 antibody) for treatment of 
metastatic adrenocortical carcinoma
Short Title
Nivolumab for treatment of metastatic adrenocortical carcinoma
Version
July 5th, 2016
Study Design
Simon two stage optimum Phase II clinical trial
Study Center(s)
Northwestern Medicine Developmental Therapeutics Institute
Robert H. Lurie Comprehensive Cancer Center
Objectives
Primary:
To assess efficacy of nivolumab monotherapy according to objective 
response rate (ORR) as assessed by RECIST 1.1 in patients with 
advanced adrenocortical carcinoma
Secondary:
To assess the efficacy of nivolumab according to progression-free 
survival (PFS), overall survival (OS)
Sample Size
33 study participants 
Diagnosis & Key 
Eligibility Criteria
Patients with metastatic or locally advanced adrenocortical carcinoma   
with disease progression after treatment with at least one line of therapy 
including mitotane and/or chemotherapy.
Treatment Plan
Patients will be treated with nivolumab  240mg as in intravenous infusion 
over 30 minutes every 2 weeks until confirmed disease progression, 
unacceptable toxicity, or withdrawal of consent.
Statistical Methodology
Up to 33 patients will enroll in the two stage phase II clinical trial. In the 
first stage, up to 12 patients will be entered to achieve 10 evaluable. If no 
patients show a response, then the trial will be terminated due to inactivity 
of the treatment.  If 1 or more of 10 show a response, then up to an 
additional 21 patients will be added to achieve 19 evaluable. If 3 or fewer 
of 29 show a response, then the trial will conclude that the response rate 
could be as low as 5%.  If 4 or more respond, then the trial will conclude 
that the response rate is at least 20%.  This design has a 20% chance of 
falsely concluding the rate is 5% (false negative Type II error rate = 20%, 
or power = 80%), and a 5% chance of falsely concluding that the rate is 
20% (false positive Type I error rate = 5%). Taking into account dropout 
and patients not evaluable, target accrual will be up to 33 patients.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
Adrenocortical carcinoma (ACC) is an exceedingly rare malignancy with no 
effective standard treatment options. ACC is responsible for 0.2% of all cancer 
deaths in the United States and has an estimated incidence of 0.7 cases per 
million per year [1, 2]. The disease incidence has a bimodal distribution with 
peaks in first and fourth decades with a female to male ratio 1.5-2.5:1 [3, 4]. 
While a growing number of patients are diagnosed with early stage and indolent 
disease incidentally after having abdominal CT scans, the majority of patients 
(40-60%) present with symptoms related to excessive hormonal production (i.e. 
hypercortisolism or hyperandrogenism)[3, 5]. Surgery is the treatment of choice 
for patients presenting with localized disease and is often followed by adjuvant 
chemotherapy with mitotane to mitigate the risk of disease recurrence in high-risk 
patients [6-8]. The group of approximately 30-70% of patients presenting with 
metastatic disease carry an extremely poor prognosis related to the aggressive 
biological behavior and lack of effective therapeutic options [3, 5]. The 5-year 
survival rate for this patient population is estimated at less than 15% [9]. 
Mitotane, the only FDA-approved drug for ACC, displays single-agent activity 
(10-30% tumor response rates) based on its adrenolytic activity but its broad 
clinical use is challenged by an unfavorable toxicity profile [10-12]. 
Chemotherapy has also limited efficacy in advanced disease with retrospective 
studies showing response rates of 10-20% [13-15]. The only phase 3 randomized 
clinical trial ever conducted in advanced ACC showed that mitotane combined 
with etoposide, doxorubicin and cisplatin (EDPM) provided additional clinical 
benefit compared to mitotane plus streptozocin [16]. In spite of higher tumor 
response rates with EDPM (23% vs. 9%) and prolongation of progression-free 
survival (PFS; 5 vs. 2 months), there was no significant benefit in median overall 
survival (OS; 14 vs. 12 months) and up to 58% of patients receiving EDPM had 
serious adverse events. In fact, as a clear statement to the unmet need for 
effective treatments, the National Comprehensive Cancer Network 
recommendations for first line treatment of metastatic ACC include consideration 
of systemic therapies in clinical trials.
Advances in the molecular understanding of pathogenesis revealed novel 
therapeutics targets but no definitive efficacy with targeted therapies have been 
demonstrated. The role of the insulin growth factor (IGF) pathway in adrenal 
gland development coupled with results showing that overexpression of IGF2 in 
80% of ACC tumors correlates with worse outcome provided the rationale for 
investigating inhibitors of the IGF-1R [17-20]. Nevertheless, a placebo-controlled 
phase III trial evaluating the IGF1-R inhibitor linsitinib among 139 patients with 
recurrent or metastatic ACC following first or second line treatments showed no 
improvement in PFS or OS (10.8 vs. 11.8 months) [21]. Disappointing results 
were also seen with agents blocking the VEGF pathway including bevacizumab, 
sorafenib, and sunitinib despite preclinical data supporting angiogenesis as a 
relevant therapeutic target [6, 22-24]. Even though results of comprehensive 
genetic profiling revealed promising therapeutic targets, strategies beyond 
interfering with disrupted cancer cell signaling are urgently needed [25]. Hence, 
immunotherapy approaches emerge as potential treatment options clinically 
feasible with novel checkpoint inhibitors. We propose to investigate the safety 
and efficacy of the monoclonal antibody against programmed death-1 (PD-1) 
nivolumab for the treatment of metastatic ACC.
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1.2
Intervention Overview & Background
1.2.1
Overview
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). The combination of 
nivolumab and ipilimumab (anticytotoxic T lymphocyte associated 
antigen-4 [anti-CTLA-4]) in phase 1/2 trial showed markedly enhanced 
clinical activity with acceptable safety profile in melanoma patients [26].
The clinical use of monoclonal antibodies to T-cell inhibitory receptors 
has provided transformative information on the nature of the immune 
system and cancer. An emerging picture suggests that endogenous 
immune responses can mediate effective tumor regression and/or 
improved survival even in patients with large volume tumors resistant to 
other forms of therapy. Some of the unique features of this type of 
therapy, based largely on experience in advanced melanoma, include: 
improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be 
delayed or occur after radiographic disease progression; combinations of 
immune modulators with enhanced or novel activities (in the example of 
ipilimumab and nivolumab); and toxicity that is almost exclusively 
immune or inflammatory in nature. It is not yet clear what factors 
determine responses and which components of the immune system are 
needed for this to occur. It seems likely that both memory helper and 
effector cells would be needed to sustain long-term responses. 
Increasing emphasis has been placed on understanding the relationships 
of the tumor, cellular infiltrate, and immunologic milieu surrounding each 
tumor.
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 
family of T-cell co-stimulatory receptors that include Ig super family 
member CD28, CTLA-4, inducible co-stimulator (ICOS), and B and T 
lymphocyte attenuator (BTLA) (Investigator Brochure version 2014). PD-
1 is transiently but highly expressed on activated T cells functioning to 
limit immune effectors at the site of activation. Chronic stimulation may 
prevent the re-methylation of the PD-1 gene leading to continuous 
expression and characterizes a state of “exhausted” T cells that lose 
function and proliferative capacity while enhancing a suppressive tumor 
microenvironment. PD-1 may act together with other T-cell modulating 
molecules, including CTLA-4, TIM-3, lymphocyte-activation gene 3 (LAG-
3) as well as indoleamine-pyrrole 2, 3-dioxygenase 1 (IDO-1), cytokines, 
and transforming growth factor beta (TGF-beta).
Two ligands specific for PD-1 have been identified: PD-ligand 1 (PD-L1, 
also known as B7-H1 or CD274, expressed on tumor, antigen-presenting 
cells [APCs], and dendritic cells [DCs]) and PD-L2 (also known as B7-DC 
or CD273, expressed on endothelial cells). The interaction of PD-1 with 
PD-L1 and PD-L2 results in negative regulatory stimuli that down-
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modulate the activated T-cell immune response through SHP-1 
phosphatase.
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c). In transplantable tumor 
models that expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and 
CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured most 
mice of established tumors that were largely resistant to single antibody 
treatment [27]. Despite minimal immunopathologic sequelae in PD-1 and 
LAG-3 single knockout mice, dual knockout mice abrogated self-
tolerance with resultant autoimmune infiltrates in multiple organs, leading 
to eventual lethality.
PD-L1 expression is found on a number of tumors, and is associated 
with poor prognoses based on OS in many tumors, including melanoma, 
renal, esophageal, gastric, ovarian, pancreatic, lung, and other cancers 
(Investigator Brochure version 2014) [28-34]. No published data is 
available evaluating PD-L1 expression in adrenocortical carcinoma. 
1.2.2
Clinical development of nivolumab
Nivolumab is being evaluated as monotherapy and in combination with 
cytotoxic chemotherapy, other immunotherapy (such as ipilimumab), 
anti-angiogenesis therapy, and targeted therapies in completed and 
ongoing BMS-sponsored clinical trials in NSCLC, melanoma, RCC, 
hepatocellular carcinoma (HCC), gastrointestinal (GI) malignancies 
including colorectal cancer with microsatellite instability (MSI), and triple-
negative breast cancer (TNBC) with an expanding group of indications 
(Investigator Brochure version 2014). Nivolumab is currently FDA 
approved for the treatment of patients with: (i) unresectable or metastatic 
melanoma and disease progression after ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor; (ii) patients with metastatic 
squamous non-small cell lung cancer with progression on or after 
platinum-based chemotherapy.
1.2.3
Clinical efficacy
Nivolumab has demonstrated clinical activity as monotherapy and as 
combination therapy with ipilimumab in several tumor types, including 
RCC, melanoma, NSCLC, and some lymphomas. The majority of 
responses was durable and exceeded 6 months (Investigator Brochure 
version 2014). Nivolumab is being investigated both as monotherapy and 
in combination with chemotherapy, targeted therapies, and other 
immunotherapies. 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation 
study the 3 mg/kg dose was chosen for expanded cohorts. Among 236 
patients, objective responses (ORs) (complete or partial responses [CR 
or PR]) were seen in NSCLC, melanoma, and RCC. ORs were observed 
at all doses. Median OS was 16.8 months across doses and 20.3 months 
at the 3 mg/kg dose. Heavily pretreated patients with NSCLC treated 
with nivolumab (1, 3, or 10mg/kg) achieved median OS across all dose 
cohorts of 9.9 months with response rates of 17% and median duration 
of response 17 months [35]. 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 
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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%) [36]. 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) [37]. Median overall survival was 18, 25, 
and 24 months for the three dose cohorts, respectively. Response rates 
were in average 20% with only 11% incidence of grade 3-4 treatment-
related adverse events. In an advanced melanoma phase 1 study, 
nivolumab and ipilimumab were administered IV every 3 weeks for 4 
doses followed by nivolumab alone every 3 weeks for 4 doses 
(concurrent regimen) [26]. The combined treatment was subsequently 
administered every 12 weeks for up to 8 doses. In a sequenced regimen, 
patients previously treated with ipilimumab received nivolumab every 2 
weeks for up to 48 doses. In the concurrent regimen (53 patients), 53% 
of patients had an OR at doses 1 mg/kg nivolumab and 3 mg/kg 
ipilimumab, with tumor reduction of 80% or more (modified World Health 
Organization criteria). In the sequenced-regimen (33 patients), the 
objective response rate (ORR) was 20%. These results demonstrate 
significant clinical activity of nivolumab across multiple histologies with 
favorable toxicity profile.
1.2.4
Clinical safety
The overall safety experience with nivolumab, as monotherapy or in 
combination with other therapeutics, is based on experience in 
approximately 4,000 subjects treated to date. For monotherapy, the 
safety profile is similar across tumor types. 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. 
In several ongoing clinical trials, the safety of nivolumab in combination 
with other therapeutics such as ipilimumab, cytotoxic chemotherapy, 
anti-angiogenics, and targeted therapies 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 [26]. 
1.2.5
Biomarkers
Significant efforts continue to explore potential tumor cells and 
microenvironment-related biomarkers that could predict response to 
nivolumab and other checkpoint inhibitors. For instance, tumor cell 
expression of PD-L1 was characterized with the use of IHC staining and 
pharmacodynamics changes in the peripheral blood absolute lymphocyte 
count in the study investigating the combination of nivolumab and 
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ipilimumab in melanoma [26]. PD-L1 positivity was defined as expression 
in at least 5% of tumor cells. Among patients treated with the concurrent 
regimen of nivolumab and ipilimumab, ORs were observed in patients 
with either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–
negative tumor samples (9 of 22). In the sequenced regimen cohorts, a 
higher number of overall responses were seen among patients with PD-
L1–positive tumor samples (4 of 8 patients) than among patients with 
PD-L1–negative tumor samples (1 of 13) suggesting the possibility that 
these tumors have higher response rates to the combination. Other 
biomarkers such as tissue expression of PDL-2, interferon-γ (IFN- γ), 
IDO (indoleamine-pyrrole 2,3-dioxygenase), and T cell CD8+ infiltration 
are also being investigated. However, there is no definitive date to 
support the use of any of these biomarkers to select patients for 
treatment at this time.
1.3
Rationale for the Current Study
Studies investigating immunotherapy strategies in ACC provide preliminary 
evidence that anti-tumor immune response can be promoted in this disease. 
Based on the wide expression of the steroidogenic acute regulatory protein 
(StAR) in ACC tumors, a specific immune response against this antigen was 
elicited using an immunization protocol with DNA plasmids and recombinant 
vaccinia virus vector that resulted in an anti-tumor effect in a xenograft model 
utilizing tumor cell line expressing StAR [38, 39]. Another study describing 
vaccination of two patients with metastatic ACC using autologous dendritic cells 
pulsed with autologous tumor lysate showed tumor-specific immune response in 
spite of tumor excess production of glucocorticoids [40]. Furthermore, results 
from molecular studies show that ACC is a heterogeneous disease defined by a 
wide array of somatic alterations and differential transcriptional patterns. The 
characteristic genetic instability of ACC with high rate of chromosomal alterations 
and somatic mutations certainly results in a significant number of neoepitope 
peptides derived from these altered genes [25]. These neoepitopes can elicit the 
generation of specific CD4+ T cells capable of killing cancer cells directly [41, 
42]. 
Hence, the proposed association between mutational burden of tumors and 
clinical benefit from immunotherapy strategies (i.e. checkpoint inhibitors anti-
CTLA-4 and anti-PD-1 antibodies), with remarkable anti-tumor effects seen with 
tumors displaying the highest rates of mutations such as melanoma [43, 44]. This 
is also illustrated by the anti-tumoral immunologic response to anti-PD-1 antibody 
in patients with colorectal cancer with increased mutational burden secondary to 
mismatch repair deficiency [45]. Building upon this scientific rationale supporting 
the potential for immunotherapies in ACC and the immeasurable clinical need for 
novel treatments, we propose to investigate the safety and efficacy of nivolumab 
for the treatment of metastatic ACC. In light of the afore mentioned antitumor 
activity in solid tumors, well studied pharmacokinetics and toxicity profile a phase 
II trial is appropriate at this juncture to assess the antitumor activity of nivolumab 
in these patients at current standard approved dose of  240mg intravenously 
every 2 weeks.
1.3.1
Rationale for nivolumab dose and schedule 
The dose and schedule of nivolumab in this study will be 240mg every 2 
weeks, based upon safety, efficacy, and exposure-response data from 
ongoing BMS studies. The Phase 1 study, CA209003. Anti-tumor activity 
was observed in study CA209003 at dose levels ranging from 1 to 10 
mg/kg in RCC. The antitumor activity of nivolumab tended to increase 
with dose, as did the incidence of SAEs. The anti-tumor activity of 
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nivolumab in RCC was investigated at dose levels 1 and 10 mg/kg, with 
the higher activity observed at 10 mg/kg. The observed anti-tumor 
activity in melanoma, and NSCLC was highest at 3 mg/kg, suggesting 
that anti-tumor activity approaches a plateau at dose levels of 3 mg/kg 
and above. Consistent with these observations, the results of the 
exposure-response analyses for these tumor types, show that the 
probability of a tumor response tended to approach a plateau for trough 
concentrations produced by 3 and 10 mg/kg every 2 week dosing. 
Nivolumab was adequately tolerated up to 10 mg/kg, the highest dose 
level tested, and no maximum tolerated dose (MTD) was identified. 
Although the spectrum, frequency, and severity of nivolumab-related AEs 
were generally similar across the dose levels tested, the 10 mg/kg doses 
level had numerically higher Grade 3/4 drug-related SAEs and AEs 
leading to discontinuation. Based on the totality of the safety, efficacy, 
and exposure-response data, a dose of 3 mg/kg every two weeks was 
selected as the dose anticipated achieving an appropriate balance of 
benefit and risk. 
1.3.2
Flat Dose Regimen
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is 
expected to be similar to 3 mg/kg Q2W dosing regimen. Using the PPK 
model, exposure of nivolumab at 240 mg flat dose is identical to a dose 
of 3 mg/kg for subjects weighing 80 kg, which is the approximate median 
body weight in nivolumab clinical trials. Across the various tumor types 
in the clinical program, nivolumab has been shown to be safe and well 
tolerated up to a dose level of 10 mg/kg, and the relationship between 
nivolumab exposure produced by 3 mg/kg and efficacy and safety has 
been found to be relatively flat. Given the similarity of nivolumab PK 
across tumor types and the similar exposures predicted following 
administration of 240 mg flat dose compared to 3 mg/kg, it is expected 
that the safety and efficacy profile of 240 mg nivolumab will be similar 
to that of 3 mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is 
under investigation.
1.4
Exploratory Studies
To explore the correlation between PD-1, PD-L1 and PD-L2 expression and 
CD4+ and CD8+ tumor infiltrating lymphocytes and PFS, OS and response 
to treatment. 
PD-1 is a key immune checkpoint receptor expressed by activated T cells and 
mediates immunosuppression. PD-1 functions primarily in peripheral tissues, 
where T cells may encounter the immunosuppressive PD-1 ligands PD-L1 and 
PDL-2, which are expressed by tumor cells, stromal cells or both [46-48]. PD-L1 
and PD-L2 are overexpressed in a variety of solid tumors however no data exists 
in ACC [46].  
There are conflicting data on the predictive value of PD-L1 expression on PD-1 
directed therapy in solid tumors [36, 46]. 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 [49]. The same correlation was 
not observed on stratified analysis according to tumor cell membrane PD-L1 
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expression of non-small cell lung cancer patients treated with nivolumab therapy 
in the second line setting [36].
Pathological slides from tumor archival tissue will be stained using a monoclonal 
antibody against PD-L1 and defined as PD-L1 positive if equal of greater than 
5% of the tumor cells membrane analyzed. We hypothesize that tumor cell 
membrane expression of PD-L1 or PD-L2 can have an impact on treatment 
responses. 
Peripheral blood lymphocyte phenotypes
Lymphocyte subsets (CD3, CD4, CD8, CD19, and CD56) will be analyzed 
according to absolute cell numbers per microliter of whole blood, percent 
representation among all lymphocytes, and coexpression of the activation 
markers CD25, HLA-DR, and CD45RO using automated flow cytometric 
techniques at the Flow Cytometry Core Laboratory, Robert H Lurie Cancer 
Center of Northwestern University under the supervision of Suchitra 
Swaminathan, PhD. 
To measure humoral and cellular responses to tumor antigens on serum 
samples by measuring the levels of cytokines (ie, IL-2, IL-6, IL-8, IL-10, IL-
18, IFN and TNF-) and peripheral blood lymphocyte phenotype. Measures 
of immunologic response correlate with lack or presence of response to 
treatment with nivolumab.
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
The primary objective will be to assess overall response rate of 
nivolumab in patients with metastatic or locally advanced adrenocortical 
carcinoma. Overall response rate will be measured according to RECIST 
criteria 1.1 at every 8 weeks interval by using CT scans.
2.2
Secondary Objectives & Endpoints
2.2.1
To assess the progression free survival defined as time from date of first 
nivolumab infusion until date of death or evidence of progression of 
disease as assessed by CT imaging every 8 weeks according to RECIST 
criteria 1.1. 
2.2.2
To assess the overall survival defined as time from date of first 
nivolumab infusion until death of patients with metastatic or locally 
advanced ACC. The patients will be assessed for survival (either by 
routine clinic visit our by phone) every 2 weeks while on treatment and 
every 3 months for up to 2 years after completion of trial to document 
survival and disease progression,
2.2.3
To assess the safety and tolerability profile of nivolumab described by 
number, frequency, and severity of adverse events according to the 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.3 assessed every 2 weeks while patients 
are on therapy.
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2.3
Exploratory Objectives & Endpoints
2.3.1
To assess the overall response rate, progression free survival and 
overall survival according to tumor PD-L1 and PD-L2 expression,
2.3.2
To assess the overall response rate, progression free survival and 
overall survival according to serum interleukin levels and peripheral T 
cell profile levels,
2.3.3
To measure humoral and cellular responses to tumor antigens on serum 
samples by measuring the levels of cytokines (ie, IL-2, IL-6, IL-8, IL-10, 
IL-18, IFN and TNF-) and peripheral blood lymphocyte phenotype. We 
wil explore potential correlations between differential measures of 
response and the toxicity and efficacy of nivolumab,
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with metastatic or locally advanced ACC 
who have been treated with mitotane and/or one line of chemotherapy. This will be a 
multicenter trial conducted at Northwestern University. Northwestern University will serve 
as the lead site and coordinating center for this study. Participating sites will include Ohio 
State University, Moffitt Cancer Center, and Johns Hopkins University. 
A total of up to 33 subjects will be needed for this trial. Given that this is an NIH rare 
disease, approximately 5 patients can be enrolled per year. Potential patients may be 
referred to the Principal Investigator (PI) at Northwestern University, Dr. Devalingam 
Mahalingam at (312) 472-1234.
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. 
3.1
Inclusion Criteria
3.1.1
Patients must have a histologically confirmed stage IV or unresectable 
locally advanced adrenocortical carcinoma,
 
3.1.2
Patients must have disease progressing after treatment with at least one 
line of therapy including mitotane and/or chemotherapy. 
Note: Patients who are deemed ineligible to receive first line treatment 
with mitotane and/or chemotherapy or who decline first line treatment 
may be eligible for this study after discussion with the PI.
3.1.3
Patients must have measurable disease according to the standard 
RECIST version 1.1. CT scans or MRIs used to assess the measurable 
disease must have been completed within 28 days prior to registration.
3.1.4
Patients must be of age ≥18 years at the time of study registration.
3.1.5
Patients must exhibit an ECOG performance status of 0-3.
3.1.6
Patients must have adequate organ and bone marrow functions:

leukocytes ≥ 2,000/mcL 
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14

absolute neutrophil count ≥ 1,500/mcL 

hemoglobin ≥ 9 g/dL 

platelets ≥ 75,000/mcL 

total bilirubin ≤1.5× institutional upper limit of normal (ULN) 
(except patients with Gilbert Syndrome, who can have total bilirubin  
<3.0 mg/dL) 

AST(SGOT)/ALT(SGPT) ≤ 3 x ULN
NOTE: If liver metastases are present, AST/ALT ≤ 5 x ULN is 
permitted

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
3.1.7
Patients with history of central nervous system (CNS) metastases are 
eligible if CNS disease has been radiographically and neurologically 
stable for at least 6 weeks prior to study registrations and do not require 
corticosteroids (of any dose) for symptomatic management
3.1.8
Females of childbearing potential (FOCBP) must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG) within 24 hours prior to the start of study drug. 
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)
3.1.9
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 B for 
details on appropriate contraception methods) 
3.1.10
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 who have had chemotherapy or radiotherapy within 4 weeks 
prior to entering the study are not eligible.
3.2.2.
Patients  who have not recovered to  ≤ Grade 1 from adverse events due 
to agents administered more than 4 weeks earlier are not eligible.
3.2.3.
Patients may not be receiving any other investigational agents.
3.2.4.
Patients who have a history of allergic reactions attributed to compounds 
of similar chemical or biologic composition to nivolumab are not eligible.
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3.2.5.
Patients should be excluded if they have had prior treatment with an anti-
PD1 or anti-PD-L1. Please contact principal investigator, Devalingam 
Mahalingam, for specific questions on potential interactions.
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 are ineligible who 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 steroids and adrenal replacement steroid doses >10mg 
daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment 
of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by a contact allergen) is permitted. 
3.2.8.
Patients who have an uncontrolled intercurrent illness including, but not 
limited to any of the following, are not eligible: 

Uncontrolled hypertension – blood pressure ≥ 150/90 mmHg despite 
medical therapy

Ongoing or active infection requiring systemic treatment

Symptomatic congestive heart failure

Unstable angina pectoris

Cardiac arrhythmia

Psychiatric illness/social situations that would limit compliance with study 
requirements
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
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety 
or study endpoints
3.2.9.
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, 
adequately treated Stage I or II cancer from which the patient is currently 
in complete remission, 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 or chronic infection is not permitted.
4.0
TREATMENT PLAN
This will be a single-center phase II trial with patients with metastatic or locally advanced 
ACC who have been treated with at least one line of therapy including mitotane and/or 
chemotherapy. Patients will be treated with nivolumab 240mg as an intravenous infusion 
over 30 minutes every 2 weeks until confirmed disease progression, unacceptable 
toxicity, or withdrawal of consent. Note: Please refer to section 4.2.3 for patients who may 
continue treatment after initial progression.
4.1
Treatment Administration
Treatment will be administered on an outpatient basis. Reported adverse events 
and potential risks are described below. No investigational or commercial agents 
or therapies other than those described below may be administered with the 
intent to treat the patient’s malignancy.
Nivolumab will be administered at a dose of 240mg as an intravenous infusion 
over 30 minutes every 2 weeks until disease progression, unacceptable toxicity, 
or withdrawal of consent. 
There will be no dose escalations or reductions of nivolumab allowed. Subjects 
may be dosed no less than 12 days from the previous dose. There are no pre-
medications recommended for nivolumab on the first cycle. If an acute infusion 
reaction is notes, subjects should be managed according to Section 4.2.4. 
Nivolumab is to be administered as a 30-minute IV infusion (a window of +/- 5 
minutes is allowed), using a volumetric pump with a 0.2/1.2 micron in-line filter at 
the protocol-specified dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration of the solution cannot be below 1 
mg/mL. It is not to be administered as an IV push or bolus injection. At the end of 
the infusion, flush the line with a sufficient quantity of normal saline. 
Subjects will be monitored continuously for AEs while on study. Treatment 
modifications (e.g., dose delay or discontinuation) will be based on specific 
laboratory and adverse event criteria. 
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Early recognition and management may mitigate severe toxicity. Evaluation and 
Management Guidelines were developed to assist investigators and can be 
found in the Investigator Brochure: 

Suspected Pulmonary Toxicity  

Diarrhea and Colitis  

Suspected Hepatotoxicity (including asymptomatic    liver function tests 
[LFT] elevations)  

Suspected Endocrinopathy  

Nephrotoxicity  
4.2
Dosing delays, support care, and discontinuation of therapy
There will be no dose modifications allowed for management of toxicities.
Nivolumab administration should be delayed for the following until resolution to ≤ 
Grade 1: 

Any Grade ≥ 2 non-skin, drug-related adverse event, with the following 
exceptions: 
o
Grade 2 drug-related fatigue or laboratory abnormalities do not 
require a treatment delay 
o
Any Grade 3 skin, drug-related adverse event
o
Any Grade3 drug-related laboratory abnormality, with the following 
exceptions for  lymphopenia, leukopenia, AST, ALT, or total bilirubin:

Grade 3 lymphopenia or leukopenia does not require dose delay

If a subject has a baseline AST, ALT or total bilirubin that is 
within normal limits, delay dosing for drug-related Grade ≥ 2 
toxicity 

If a subject has baseline AST, ALT, or total bilirubin within the 
Grade 1 toxicity range, delay dosing for drug-related Grade ≥ 3 
toxicity

Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the investigator, warrants delaying the dose of study 
medication.  
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity 
and duration than AEs caused by other therapeutic classes. Nivolumab is 
considered an immuno-oncology agent in this protocol. Early recognition and 
management of AEs associated with immuno oncology agents may mitigate 
severe toxicity. Management Algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in the nivolumab Investigator Brochure and 
appendix D of this protocol.
4.2.1
Treatment discontinuation criteria
Nivolumab treatment should be permanently discontinued for the 
following: 
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
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 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 
days 

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation 

Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except: 
o
Grade 3 drug-related thrombocytopenia > 7 days or 
associated with bleeding requires discontinuation  
o
Any drug-related liver function test (LFT) abnormality 
that meets the following criteria requires discontinuation:  

AST or ALT > 5-10x ULN for > 2 weeks

AST or ALT > 10x ULN

Total bilirubin > 5x ULN

Concurrent AST or ALT > 3x ULN and total 
bilirubin > 2x ULN

Any Grade 4 drug-related adverse event or laboratory 
abnormality, except for the following events: 
o
Grade 4 neutropenia ≤ 7 days does not require 
discontinuation 
o
Grade 4 lymphopenia or leukopenia does not require 
discontinuation 
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 do not 
require discontinuation 
o
Isolated Grade 4 amylase or lipase abnormalities not 
associated with symptoms or clinical manifestations of 
pancreatitis. The PI and Data Monitoring Committee 
(DMC) should be notified of  Grade 4 amylase or lipase 
abnormalities (please do so by sending an email to 
croqualityassurance@northwestern.edu)

Any dosing interruption lasting > 6 weeks with the following 
exceptions: 
o
Dosing interruptions to manage drug-related adverse 
events, such as prolonged steroid tapers, are allowed. 
Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the PI and DMC should 
be consulted (by emailing 
croqualityassurance@northwestern.edu). Tumor 
assessments should continue as per protocol even if 
dosing is interrupted.  
o
Dosing interruptions > 6 weeks that occur for non-drug-
related reasons may be allowed if approved by thePI 
and DMC. Prior to re- initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the PI and 
DMC designee must be consulted. Tumor assessments 
should continue as per protocol even if dosing is 
interrupted.  
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
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.  
4.2.2
Treatment of nivolumab-related infusion reactions
Since nivolumab contains only human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions. However, if such a reaction were to occur, it 
might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-
like reactions. All grade 3 or 4 infusion reactions should be reported 
within 24 hours to the study QAM and reported as an SAE if it meets the 
criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0.3) guidelines. 
Treatment recommendations are provided below and may be modified 
based on local treatment standards and guidelines, as appropriate: 
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Remain at bedside and monitor 
subject until recovery from 
symptoms. 
The following prophylactic pre-
medications are recommended for 
future infusions: 

Diphenhydramine 50 mg (or 
equivalent) and/or

Acetaminophen/paracetamol 
325 to 1000 mg at least 30 
minutes before additional 
nivolumab 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 infusion, 
begin an IV infusion of normal 
saline, and treat the subject 
with diphenhydramine 50 mg IV 
(or equivalent) and/or 
acetaminophen/paracetamol 
325 to 1000 mg; 
 
Remain at bedside and monitor 
subject until resolution of 
symptoms. 
Corticosteroid and/or 
bronchodilator therapy may 
also be administered as 
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. 
For future infusions, the following 
prophylactic pre-medications are 
recommended: 

Diphenhydramine 50 mg (or 
equivalent) and/or

Acetaminophen/paracetamol 325 
to 1000 mg should be 
administered at least 30 minutes 
before nivolumab infusions. If 
necessary, corticosteroids (up to 
25 mg of SoluCortef or equivalent) 
may be used.
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4.2.3
Treatment with nivolumab beyond progression
A minority of subjects treated with immunotherapy may derive clinical 
benefit (either delayed responses, stable disease, or increased overall 
survival) despite initial evidence of progressive disease (PD) with 
nivolumab. 
Patients may be permitted to continue treatment beyond initial RECIST 
1.1-defined PD occurring during the initial treatment period (up to 12 
weeks) as long as they meet the following criteria: 

No more than 4 new lesions, total sum of the longest diameter 
(SHORT diameter for LN) cannot exceed 40% of the initial sum 
including new lesions 

Patients must be clinically stable with no change in performance 
status due to disease progression 
Monitor subject closely. If 
symptoms recur, then no 
further nivolumab will be 
administered at that visit.
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. Begin an 
IV infusion of normal saline and 
treat the subject as follows: 
Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 
1:1000 solution for 
subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV 
administration, and/or 
diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV 
(or equivalent), as needed. 
Subject should be monitored 
until the Investigator is 
comfortable that the symptoms 
will not recur. Nivolumab 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
No subsequent dosing
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
No indication for immediate alternative treatment 

Patient [assessed by the investigator] is showing clinical benefit 
and tolerates study drug. The assessment of clinical benefit 
should take into account whether the subject is clinically stable 
or deteriorating and likely or unlikely to receive further benefit 
from continued treatment. 

The time of progression is noted from the first assessment that 
exceeds standard criteria
New lesions are considered measurable at the time of initial progression 
if the longest diameter is at least 10 mm (except for pathological lymph 
nodes, which must have a short axis of at least 15 mm). Any new lesion 
considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except 
for pathological lymph nodes, which must have an increase in short axis 
to at least 15 mm). 
Patients are allowed to continue treatment after initial disease 
progression for 2-3 additional doses (4-6 weeks) only after consulting 
with the study PI. These patients must be reassessed for response within 
8 weeks; the scan initially confirming PD should be used as a new 
baseline. If two consecutive scans confirm PD, the patient should come 
off treatment. However, as long as subsequent scans show a response 
equal to or better than Stable Disease (SD), the patient may continue 
receiving treatment every 2 weeks, and must have scans every 8 weeks. 
Treatment may continue up to an additional 30% total single diameter 
increased over baseline. New measureable lesions are not permitted 
with this schema 
4.3
Concomitant Medications/Treatments
4.3.1
Permitted Medications
All treatments that the investigator considers necessary for a subject’s 
welfare may be administered at the discretion of the investigator in 
keeping with the community standards of medical care. All concomitant 
medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids. If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 28 days before the first dose 
of trial treatment and 30 days after the last dose of trial treatment should 
be recorded.  Concomitant medications administered after 30 days after 
the last dose of trial treatment should be recorded for SAEs.
In general, corticosteroids (>10mg prednisone or equivalent) and other 
immunosuppressive medications are not permitted. However, subjects 
are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). A brief 
(less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast 
dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 
mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
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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. 
4.3.2 
Prohibited Medications
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial:

Anti-cancer systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than nivolumab

Radiation therapy 

Systemic corticosteroids (>10mg prednisone or equivalent) or 
other immunosuppressive medications are not permitted unless 
they fall under the criteria listed in 4.3.1. 
4.4
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 4.2.3 for guidance regarding 
treatment beyond progression),
o
Intercurrent illness that prevents further administration of treatment,
o
Unacceptable adverse event(s) as already described in session.
4.5
Duration of Follow Up
All patients will be followed for adverse events for 12 weeks after last dose of 
nivolumab, 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 8 weeks until the time of progression radiographically 
according to RECIST 1.1 criteria. In the event that a radiographic response is 
detected, then this event will be included as a response in the final analysis, and 
the time of progression used in calculation of the survival analysis. Patients will 
be followed for survival status every 3 months for 2 years after treatment 
discontinuation or until death, whichever occurs first.
4.6
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

Patient demonstrates disease progression (per parameters above)

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in 
the patient’s best interest

Patient becomes pregnant 
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
Patient develops a second malignancy that requires treatment which would 
interfere with this study

Patient becomes lost to follow-up (LTF) 
4.7
Patient Replacement 
Any patient who signs consent but does not receive study treatment may be 
replaced.
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24
5.0
STUDY PROCEDURES
Screening1
On Treatment9  
(1 cycle = 28 days)
Off Treatment
Cycle 1 
Cycle 2
Cycle 3+
Time Period
Baseline
D1 
(±3 days)
D15 
(±3 days)
D1 
(±3 days)
D15
(±3 days)
D1 
(±3 days)
D15
(±3 days)
End of 
Treatment10
Follow-
up11
Assessment or Activity
Informed Consent
X
Medical history 
X
X
Physical exam2
X
X
X
X
X
X
ECOG status
X
X
X
X
X
X
Adverse 
Events 
& 
ConMeds
X
X
X
X
X
X
X
X
Toxicity assessment
X
X
X
X
X
X
X
X
Tumor Assessments 3
X
X3
X
CBC with diff 1
X
X
X
X
X
X
X
X
Chemistry panel 1
X
X
X
X
X
X
X
X
TSH  4
X
Pregnancy test5
X
X5
Nivolumab administration6
X
X
X
X
X
X
Correlative blood samples
X7
X7
Archival tissue collection8
X
Survival status
X
1 CBC with diff and Chemistry panel should be within 14 days of registration; all other screening
procedures should take place within 28 days of registration. CBC should include WBC, Hemoglobin, Platelets, ANC, ALC. Chemistry panel 
should include glucose, calcium, albumin, ALT, AST, sodium, potassium, total bilirubin, alk phose, and creatinine. 
2 Includes vital signs (pulse, respirations, blood pressure) and height (baseline only) and weight.
3 CT or MRI (per treating investigator’s discretion) will take place within 28 days of registration; the same modality used at baseline should be used 
throughout. Tumor assessment will be performed at Cycle 3 Day 1 (- 7 days)and every 2 cycles (- 7 days) thereafter, regardless of dosing 
schedule for the first 13 months then every 3 cycles (-7 days) until progression or treatment discontinuation whichever occurs later. Tumor 
assessments will incorporate both RECIST and clinical criteria. Brain MRI is the preferred imaging method for evaluating CNS metastasis, 
and assessment is required during screening in all eligible subjects with history of CNS involvement. 
If PD is confirmed at any time, see section 4.2.3 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.


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4 If TSH is abnormal, free T4 should be tested
5 Serum or urine test for females of child-bearing potential must be completed at screening and within 24 hours of treatment.
6 Nivolumab will be administered IV at 240mg over 30 minutes every two weeks. 
7 A correlative blood sample will be drawn pre-dose at C1D1 and C2D15. Please see separate lab manual for details. 
8 Archival tissue will be collected at baseline if available. Please see separate lab manual for details.
9 Treatment will continue until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Study assessments may take place 
within 24 hours of scheduled treatment if needed.
10 End of Treatment visit will occur approximately 12 weeks after stopping nivolumab treatment,
or until the patient starts new treatment, whichever occurs first.
11 Patients will be followed (either by routine clinic visit or by phone) every 2 weeks while on treatment and every 3 months for up to 2 years while 
off treatment to document survival and disease progression. Adverse events will be followed for the first 12 weeks after stopping 
treatment.


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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 8 weeks. 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).
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) [50]. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria.
High resolution CT with oral/intravenous contrast or contrast-enhanced MRI is 
the preferred imaging modalities for assessing radiographic tumor response. If a 
subject has a known allergy to contrast material, please use local prophylaxis 
standards to obtain the assessment with contrast if at all possible, or use the 
alternate modality. In cases where contrast is strictly contraindicated, a non-
contrast scan will suffice. Screening assessments should be performed within 28 
days of registration. Brain MRI is the preferred imaging method for evaluating 
CNS metastasis, and assessment is required during screening in all eligible 
subjects. All known or suspected sites of disease (including CNS if history of 
CNS metastases) should be assessed at screening and at subsequent 
assessments using the same imaging method and technique. If more than one 
method is used at screening, then the most accurate method according to 
RECIST 1.1 should be used when recording data, and should again be used for 
all subsequent assessments. Previously treated CNS metastases are not 
considered measurable lesions for purposes of RECIST determined response. 
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated. 
Radiographic tumor assessments will be conducted at week 8 (± 1 week) and 
every 8 weeks (± 1 week) for the first 13 months and then every 12 weeks (±1 
week) until disease progression or treatment discontinuation whichever occurs 
later. Tumor assessments for all subjects should continue as per protocol even if 
dosing is interrupted. Tumor measurements should be made by the same 
investigator or radiologist for each assessment whenever possible. Changes in 
tumor measurements and tumor responses to guide ongoing study treatment 
decisions will be assessed by the investigator using RECIST. 
6.2
Primary Endpoint
The primary endpoint of this study is overall response rate to treatment and all 
patients who received at least one dose of nivolumab will be considered for 
evaluation of response to therapy. For the purposes of this study, patients should 
be re-evaluated for response every 8 weeks. Overall response will be calculated 
by sum of the complete and partial response rates according to measurement of 
target and non-target lesions as described below. 
6.2.1
Definitions:
Evaluable for toxicity. All patients will be evaluable for toxicity from the 
time of their first treatment with nivolumab. 
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Evaluable for objective response. Only those patients who have 
measurable disease present at baseline, have received at least one dose 
of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified 
according to the definitions stated below. 
Evaluable non-target disease response. Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one dose of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
6.2.2
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can 
be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) 
with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm (≥1.5 cm) in short axis when 
assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short 
axis will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including 
small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 
to <15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non- cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
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 
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axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up. 
6.2.3
Response criteria
6.2.3.1 Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <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.
6.2.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target 
lesions and normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10 mm [<1 cm] short axis). 
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 
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confirmed at a later time by the review panel (or Principal 
Investigator). 
6.2.3.3 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 4.2.5)
6.2.3.4 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 
category when no lesions can be measured is not advised 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. 
6.3
Secondary Endpoints
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. Progression assessment will be 
performed by investigator each time the patients has a radiologic evaluation after 
8 weeks of treatment. OS is defined as the duration of time from start of 
treatment to time of death.
Safety and tolerability will be measured by the incidence of all adverse events, 
serious adverse events, deaths and laboratory abnormalities. Adverse event 
assessments and laboratory tests will be performed at baseline, and continuously 
throughout the study at the beginning of each subsequent cycle. 
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 
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refer to Appendices for additional information). The level of risk attributed to this study 
requires High Intensity Monitoring, as outlined in the DSMP. In addition, the study will 
abide by all safety reporting regulations, as set forth in the Code of Federal Regulations.  
7.1
Definition of Adverse Event 
An adverse event is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have to have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, 
whether or not considered related to the medicinal product or protocol-specified 
procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally 
associated with the use of the BMS’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary 
significantly in frequency or severity from expected levels are not to be 
considered adverse events. Examples of this may include, but are not limited to, 
teething, typical crying in infants and children and onset of menses or 
menopause occurring at a physiologically appropriate time.
BMS product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational 
(including placebo or active comparator medication) or marketed, manufactured 
by, licensed by, provided by or distributed by BMS for human use.
Adverse events may occur during the course of the use of BMS product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in 
clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation 
baseline period as a result of a protocol-specified intervention, including washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure.
All adverse events will be recorded from the time the consent form is signed 
through 30 days following cessation of treatment and at each examination on the 
Adverse Event case report forms/worksheets. The reporting timeframe for 
adverse events meeting any serious criteria is described in section 6.3.
Adverse events will not be collected for subjects during the pre-screening period 
(for determination of archival tissue status) as long as that subject has not 
undergone any protocol-specified procedure or intervention. If the subject 
requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.
7.2
Severity of Adverse Events
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.3. The CTCAE v4.0.3 is 
available at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
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
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.
7.3
Serious Adverse Events
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 12 weeks after the last administration of study drug, must be 
reported upon discovery or occurrence and within 2 working days to BMS Global 
Safety. 
 .
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 by 20% over the prescribed dose. No 
specific information is available on the treatment of overdose of nivolumab. 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“. 
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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.
7.4
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.   
7.5
Reporting of Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them), including the pregnancy 
of a male subject's female partner that occurs during the trial or within 120 days 
of completing the trial, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  All subjects and female 
partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
7.6
Reporting Requirements for Adverse Events
7.7.1
Routine Reporting
All routine adverse events, such as those that are expected, or are 
unlikely or definitely not related to study participation, are to be reported 
on the appropriate eCRF according to the time intervals noted in the 
appendices. Routine AEs will be reviewed by the Data Monitoring 
Committee (DMC) according to the study’s phase and risk level, as 
outlined in the DSMP. 
7.7.2
Expedited Reporting to the NU QA/DMC
All SAEs must be reported to the assigned QAM (as well as BMS – see 
section 7.7.4) within 24 hours of becoming aware of the event.  
Completion of the NU CRO SAE Form is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
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7.7.3
Expedited Reporting to the Northwestern IRB

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment) will be promptly reported to the NU IRB within 24 hours of 
notification, per Lurie Cancer Center policy.

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.7.4
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-
612).The assigned study coordinator will facilitate all reporting to BMS 
Global Safety and email QA a copy of the report upon completion. BMS 
Global Safety can be notified at:
Email Address: Worldwide.Safety@BMS.com
Facsimile Number: 609-818-3804
 
8.0
DRUG INFORMATION
8.1
Drug name: Nivolumab
8.1.1
Other names for the drug(s): 
ONO-4538, BMS-936558, or MDX1106, Opdivo
8.1.2
Classification - type of agent: 
Human IgG4 anti-PD-1 monoclonal antibody
8.1.3
Mode of action: 
Nivolumab acts as an immunomodulator by blocking ligand activation of 
the programmed cell death 1 (PD-1) receptor on activated T cells anti-
PD1.
8.1.4
Storage and stability: 
Nivolumab solution for infusion (100mg/vial) is a sterile, non-pyrogenic 
single-use, isotonic aqueous solution formulated at 10mg/mL. Vials must 
be stored in a secure, limited-access location at 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 DP can be further diluted with normal saline in IV 
containers made of polyvinyl chloride (PVC) or non-PVC material. 
Opened or accessed vials should be immediately used to prepare the 
infusion solution in the IV bag and the infusion solution should be 
immediately administered. If refrigerated, the vials and/or IV bags should 
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be allowed to equilibrate to room temperature prior to subsequent use. 
Nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored up to 20 hours 
under refrigeration conditions (2º-8º) and used within 4 hours for up to 24 
hours. Nivolumab solutions may be stored at room temperature for a 
cumulative time of up to 4 hours. This includes room temperature 
storage of solution in vials, room temperature storage of prepared 
solution in the syringe and the duration of drug administration.
8.1.5
Protocol dose: 
 240mg
8.1.6
Preparation: 
Nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents 
applying aseptic technique.
Visually inspect the drug product solution for particulate matter and 
discoloration prior to administration.  Discard if solution is cloudy, if there 
is pronounced discoloration (solution may have a pale-yellow color), or if 
there is foreign paticulate matter other than a few translucent-to-white, 
amorphous particles.
Note: Mix by gently inverting several times.  Do not shake.
Aseptically withdraw the required volume of nivolumab solution into a 
syringe, and dispense into an IV bag.  If multiple vials are needed for a 
subject, it is important to use a separate sterile syringe and needle for 
each vial to prevent problems such as dulling of needle tip, stopper 
coring, repeated friction of plunger against syringe barrel wall. Do not 
enter into each vial more than once.  Do not administer study drug as an 
IV push or bolus injection
Add the appropriate volume of 0.9% Sodium Chloride Injection solution 
or 5% Dextrose Injection solution. It is acceptable to add nivolumab 
solution from the vials into an appropriate pre-filled bag of diluent.
Nivolumab infusion concentration must be at or above the minimum 
allowable concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2]
 “Channel” or tube systems should not be used to transport prepared 
infusions of nivolumab.
8.1.7
Route of administration for this study: 
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer through a 0.2 micron to 1.2 micron pore size, low-protein 
binding polyethersulfone membrane in-line filter.
At the end of the infusion period, flush the line with a sufficient quantity of 
approved diluents.
8.1.8
Potential Drug Interactions: 
No incompatibilities between nivolumab injection and polyvinyl chloride 
(PVC), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) IV components, 
or glass bottles have been observed. 
8.1.9
Availability: 
The supply for this study will be investigational – not commercially 
available. Supply will be provided by BMS free of charge. Nivolumab will 
be supplied as 100 mg/vial (10mg/mL) packaged in cartons of 5 or 10 
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vials. Drug is protocol specific, but not patient specific.
Drug can be ordered using the Drug Request Form provided by BMS. 
The form is provided as a separate document and should be submitted 
electronically at least 7 business days for initial order and at least 14 
days for re-supply before the expected delivery date. The initial order 
should be limited to 20 vials. Contact and submission details can be 
found directly on the Drug Request Form. Deliveries will be made 
Tuesday through Friday.
8.1.12
Return and Retention of Study Drug
The clinical study team will be responsible for keeping accurate 
records of the clinical supplies received from BMS or designee, the 
amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.
Upon completion or termination of the study, all unused and/or 
partially used investigational product will be destroyed at the site per 
institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper 
disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept.
8.1.13
Side effects
Local bladder toxicities including but not limited to dysuria, urinary 
urgency, frequency and hematuria. Immune-related adverse events have 
been associated with Nivolumab is administered intravenously. 
Below are safety data from 268 subjects with unresectable or metastatic 
melanoma and 117 patients with metastatic squamous NSCLC who 
received nivolumab alone. Related side effects reported in subjects 
receiving nivolumab alone were:
Very Frequent – Expected to occur in more than 20% of people (more 
than 20 out of 100 people): Fatigue (50%), Dyspnea (38%), 
Musculoskeletal pain (36%), Rash (21%), Increased AST (28%), 
Increase alkaline phosphatase (22%), Hyponatremia (25-38%)
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 
100 people): Pruritus (19%), Cough (17%), URI (11%), Peripheral edema 
(10%), Increased ALT (16%), Hyperkalemia (15%)
Not Frequent – Expected to occur in less than 10% of people (less than 
10 out of 100 people): ventricular arrhythmia, iridocyclitis, infusion-
related reactions, increased amylase, increased lipase, dizziness, 
peripheral and sensory neuropathy, exfoliative dermatitis, erythema 
multiforme, vitiligo, psoriasis
Deaths thought to be related to nivolumab when given alone were 
reported in approximately 0.5% of subjects treated (approximately 1 out 
200 people).
For the most recent safety update, please refer to the current 
Investigator’s Brochure or Study Agent Prescribing Information.
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8.2
Safety Monitoring Plan 
All participants will be carefully followed for safety. Participants are seen by their 
study doctor and research nurse before each dose of nivolumab (every 2 weeks). 
Safety evaluations at this time include a physical exam, vital signs, performance 
status assessment, and safety laboratory tests. The study team will continuously 
monitor participants for treatment side effects. Participants are instructed to 
inform their study doctor right away if they notice or feel anything different so the 
study doctor can check for side effects. The study doctor may be able to provide 
treatment for side effects. The study doctor may temporarily hold the study drug 
to reduce side effects. The study doctor will permanently stop the study drug if 
side effects are too severe and/or long lasting. All participants will be followed for 
side effects for 12 weeks from their last dose of nivolumab. Participants with 
ongoing side effects will continue to be followed until resolution or stabilization of 
the side effects. Because it is not known if nivolumab will be effective against 
anal cancer, to enrollment will stop after 12 participants are treated with 
nivolumab if none of them have their tumors shrink. Study team conferences will 
be held monthly or more frequently if needed. 
9.0
CORRELATIVES/SPECIAL STUDIES
9.1
Tumor biopsy immunohistochemical (IHC) staining and analysis for PD-L1, 
PD-1, CD8+ and CD4+ tumor infiltrating lymphocytes
Detection of the selected markers for this study will be performed using 
immunohistochemistry. After the staining, the slides will be digitally scanned in an 
Aperio AT system (AperioTM, Leica BiosystemsTM) to convert the IHC slides 
into digital pathology files for posterior analysis. IHC expression analyses of 
markers consider a thorough staining pattern evaluation including distribution 
(percentage of positive cells) and intensity in the form of H-score, and evaluating 
the IHC expression in the proper subcellular location (i.e. membrane, cytoplasm 
or nucleus). IHC analysis and scoring will be performed by a certified pathologist 
using an image analysis software (Image Toolbox, AperioTM). 
Outcome from the analysis will be calculated according to the H-score. The H-
score ranges from 0 to 300, and it considers both intensity of the IHC (from 0 to 
3) and distribution (percentage of the target cells positive, from 0 to 100). The 
scoring is the addition of the percentages of cells with intensity 0 + intensity 2 + 
intensity 3, thus the addition of the final percentage is 100% and the scoring will 
range from 0 to 300. Hence, the H score will incorporate both percentage of 
positive cells and intensity of marker expression. Hematoxylin/eosin and PD-1, 
PD-L1 and PD-L2-stained sections will be reviewed by apathologist. Criteria to 
be evaluated include histologic subtype and grade, TNM 2002 pathologic tumor 
stage, the presence and type of intratumoral lymphocytic infiltration, and the 
quantity and location of PD-L1 staining. The tumor will be considered positive for 
PD-1, PD- L1, PD-L2 if >5% of tumor cells had histologic evidence of plasma 
membrane staining.
9.2
Peripheral blood lymphocyte phenotypes
Lymphocyte subsets (CD3, CD4, CD8, CD19, and CD56) will be analyzed at 
baseline and after 2 doses according to absolute cell numbers per microliter of 
whole blood, percent representation among all lymphocytes, and coexpression of 
the activation markers CD25, HLA-DR, and CD45RO using automated flow 
cytometric techniques at the Flow Cytometry Core Laboratory, Robert H Lurie 
Cancer Center of Northwestern University under the supervision of Suchitra 
Swaminathan, PhD. 
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9.3
Specimen Banking
Patient samples collected for this study will be retained at Robert H Lurie Cancer 
Center of Northwestern University Pathology Core Facility. Specimens will be 
stored indefinitely or until they are used up. If future use is denied or withdrawn 
by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens.
Dr. Devalingam Mahalingam 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
A Simon two-stage optimum Phase II design will be used. Up to 33 patients will 
be entered into the trial.  In the first stage, up to 12 patients will be entered to 
achieve 10 evaluable.  If no patients show a response, then the trial will be 
terminated due to inactivity of the treatment.  If 1 or more of 10 show a response, 
then up to an additional 22 patients will be added to achieve 19 evaluable.  If 3 or 
fewer of 29 show a response, then the trial will conclude that the response rate 
could be as low as 5%.  If 4 or more respond, then the trial will conclude that the 
response rate is greater than 5%.  This design has a 20% chance of falsely 
concluding the rate is 5% (false negative Type II error rate = 20%, or power = 
80%), and a 5% chance of falsely concluding that the rate is 20% (false positive 
Type I error rate = 5%). There is a 60% probability of early termination of the trial 
when the true response rate is 5%. Due to inevaluable patients and dropout, 
target accrual will be up to 33 patients.  It is anticipated that 8 patients will be 
accrued per year so that accrual to this study will take 4 years.
10.2
Statistical Analysis
Response rates and 95% confidence intervals will be calculated using exact 
binomial probability distributions.  Progression-free survival and overall survival 
will be analyzed using Kaplan-Meier curves.  Adverse events will be summarized 
descriptively using frequencies and percentages.  Statistics will be given on type, 
severity, frequency and attribution of adverse events.  Sample size 
considerations are described above.
An intention to treat analysis will be done.  In a single group Phase II study, 
intention to treat means that all patients who are evaluated and registered for the 
study are followed and analyzed regardless of (a) whether they were 
subsequently found to be protocol ineligible and (b) the amount of study 
treatment (nivolumab) they received. This definition parallels the definition of 
intention to treat in randomized clinical trials. For response rates, patients will be 
considered evaluable for response if they meet the criteria in the second 
paragraph of Section 6.2.1. Otherwise, they are unevaluable for response. The 
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ITT analysis of response will specify the number of patients unevaluable for 
response and will determine the response rate in those evaluable for response. 
For progression-free and overall survival, all registered patients will be included 
in the analysis, making this ITT. For patients who receive no nivolumab, survival 
times will be taken from the time of study registration. For toxicity, patients will be 
considered evaluable for toxicity if they meet the criteria in the first paragraph of 
Section 6.2.1. Otherwise, they are unevaluable for toxicity. The ITT analysis of 
toxicity will specify the number of patients unevaluable for toxicity and will 
perform the toxicity statistical analysis in those evaluable for toxicity. 
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB 
approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol 
and/or informed consent. All amendments will be subject to the review and 
approval of the appropriate local, institutional, and governmental regulatory 
bodies, as well as by BMS. 
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. 
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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 Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to Appendices for additional information). The level of 
risk attributed to this study 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 Appendices 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).  
11.5
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. 
11.5.1
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. 
11.5.2
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.
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
Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Promptly 
Reportable Non-Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the 
study.

Results from willful or knowing misconduct on the part of the 
investigator(s).

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
11.6
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. 
11.7
Publication Policy
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. The assigned QAM will 
prepare a preliminary data summary (to be approved by the DMC) no later than 3 
months after the study reaches its primary completion date (the date that the final 
subject is examined or receives an intervention for the purposes of final data 
collection for the primary endpoint). If the investigator’s wish to obtain DMC-
approved data prior to this point (or prior to the point dictated by study design), 
the PI must send a written request for data to the QAM which includes 
justification. If the request is approved, data will be provided no later than 4 
weeks after this request approval. The data will be presented to the DMC at their 
next available meeting, and a final, DMC-approved dataset will be released along 
with any DMC decisions regarding publication. The investigators are expected to 
use only DMC-approved data in future publications. The investigators should 
submit a copy of the manuscript to the biostatistician to confirm that the DMC-
approved data are used appropriately.  Once the biostatistician gives final 
approval, the manuscript may be submitted to external publishers.
NU shall provide BMS with a copy of each Publication at the earliest practicable 
time, but in any event not less than thirty (30) days prior to its submission to a 
journal, publisher or meeting or fifteen (15) days prior to any public disclosure of 
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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.
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IRB #: STU00202153 Approved by NU IRB for use on or after 11/20/2018 through 11/19/2019.


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Amendment 3:  July 31, 2017
45
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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46
Appendix B – Contraception Requirements
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
a) 
Male condoms with spermicide
b)
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by WOCBP 
subject or male subject’s WOCBP 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 WOCBP subject or male subject’s WOCBP partner
f)
Female Condom*
*A male and female condom must not be used together
Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements. However they must still undergo pregnancy
testing as described in this sections.
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Amendment 3:  July 31, 2017
47
Appendix C
ECOG Performance Status
Grade
Description
0
Normal  activity.  Fully  active,  able  to  carry  on  all  pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self- 
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
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Amendment 3:  July 31, 2017
48
Appendix D – Adverse Events Algorithm
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, neurologic 
toxicity, pulmonary toxicity, renal toxicity and skin toxicity
. 


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Amendment 2:  July 5, 2016
Amendment 3:  July 31, 2017
50
e


Amendment 2:  July 5, 2016
Amendment 3:  July 31, 2017
51
Appendix E
Protocol History of Changes by Amendment
Original Version Approved by the Northwestern University IRB – 2/4/2016
Updated Version Approved by the Northwestern University IRB – 
Amendment 1 – March 16, 2016 
Approved by Scientific Review Committee – 3-17-2016
Section(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
Header
n/a
Adds BMS Study Number (CA 
209-612)
Administrative – 
study number 
now available
3.1.2 (Inclusion 
Criteria)
An exception to patients having 
received one line of therapy 
read: “Patients declining first 
line treatment…based on 
limited efficacy are also eligible 
for this study”
Now reads: “Patients who are 
deemed ineligible to receive first 
line treatment… or who decline 
first line treatment may be 
eligible for this study after 
discussion with the PI.” 
PI decision to 
expand eligibility. 
PI thinks it is 
reasonable to 
include patients 
who are ineligible 
as well as those 
who decline
3.1.8 (Inclusion 
Criteria), 
5.0 (Study 
Procedures)
FOCBP must have a negative 
pregnancy test within 72 hours 
of drug
FOCBP must have a negative 
pregnancy test within 24 hours of 
drug
New language 
provided by 
sponsor
3.1.9 (Inclusion 
Criteria), 
Appendix B
Listed contraception 
requirements separately for 
men and women, including 
specifics on contraception 
methods and timing
Adds Appendix B with specific 
contraception language from 
BMS.
Combines two inclusion criteria 
(3.1.9 and 3.1.10) into one, 
referencing contraception for 
both men and women with 
specific instructions listed in 
Appendix B
Additional 
language 
provided by 
sponsor
Simplifies 
inclusion 
criteria
3.2.7 
(Exclusion 
Criteria)
Incomplete sentence
Rewords to make complete 
phrase
Grammatical 
clarification
4.2.1 
(Treatment 
Discontinuation 
Criteria)
Referred to sponsor Medical 
Monitor for non-drug related 
dose delays >6 weeks
Removes Medical Monitor 
references and replaces with PI 
& DMC
Administrative – 
PI and DMC will 
serve as 
“medical monitor” 
for NU IIT
5.0 (Study 
Procedures)
#1: n/a
#5: Pregnancy test only 
required at screening
#1: Adds specific labs required 
for CBC and Chem panel
#5: Pregnancy test required 
within 24 hours of study drug
#1: Clarification
#5: Sponsor 
requirement
6.1 (Definitions)
Non-descript symbol included 
inadvertently
Replaces non-descript symbol 
with ± symbol
Administrative
7.3 (Serious 
Adverse 
Events)
SAE’s to be collected through 
30 days after last study drug
Changes to SAE’s being 
collected 12 weeks after last 
study drug
Clarification to 
align with 
procedures table
7.7.4 
(Reporting to 
the FDA)
Includes a section on FDA 
Reporting
Removes FDA Reporting 
instructions
FDA reporting is 
not required 
since the study is 
IND-exempt
8.2 (Safety 
Patients were to be followed for 
Patients will be followed for side 
Clarification to 
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Amendment 2:  July 5, 2016
Amendment 3:  July 31, 2017
52
Monitoring 
Plan)
side effects for 100 days
effects for 12 weeks
align with Study 
Procedures 
Table
9.1 (Correlative 
Studies)
IHC was to be analyzed using 
Dako kits provided by BMS
IHC is now being analyzed at NU 
PCF-CTU using a different assay 
methodology. Language referring 
to Dako kits and analysis at MD 
Anderson has been removed
Dako kits were 
not available, 
and a different 
analysis method 
will be utilized. 
Amendment 2 – July 5, 2016 
Approved by Scientific Review Committee – 7-27-2016
Cover Page
Listed Benedito Carneiro under 
the Northwestern Medicine 
Developmental Therapeutics 
Institute
Changes to Northwestern 
University, Developmental 
Therapeutics Program of the 
Division of Hematology 
Oncology
Removes Timothy Kuzel as 
sub-investigator
Administrative
Cover Page; 
3.0 (Eligibility 
Criteria)
Study listed as a single-center 
trial 
Adds the following sub-sites:
-Ohio State University
-Moffitt Cancer Center
-Johns Hopkins University
Removes specific locations at 
Northwestern where research 
will take place
Administrative – 
sub-sites have 
been confirmed 
and specific 
treatment 
locations at 
Northwestern are 
not needed.
3.1.6 (Inclusion 
Criteria)
Platelets were required to be 
100,000/mcL
Hemoglobin was required to 
be 9 g/dL
Requirement for 
AST(SGOT) / ALT (SGPT) 
was ≤ 2.5 x ULN

Platelets must now be 
75,000/mcL

Hemoglobin must now be 8 
g/dL

Increases AST(SGOT)/ 
ALT(SGPT) requirement to ≤ 
3 x ULN. Also notes that if 
liver metastases are present, 
AST/ALT ≤ 5 x ULN is 
permitted
PI determined 
that the new 
eligibility values 
will allow for 
easier accrual 
and are clinically 
appropriate.
3.2.8 
(Exclusion 
Criteria)
Patients cannot have 
“Hypertension that is not 
controlled on medication(Note: 
Hypertension is defined as 
blood pressure ≥ 140/90)”
Changes exclusion to 
“Uncontrolled hypertension – 
blood pressure ≥ 150/90 mmHg 
despite medical therapy”
Clarification; PI 
does not feel that 
a cut-off of 
140/90 for blood 
pressure is 
appropriate
4.2 (Dosing 
delays, support 
care, and 
discontinuation 
of therapy); 
Appendix D
n/a
Adds specific algorithms, and a 
reference to such algorithms, 
for AE’s related to Immuno-
Oncology agents:
Gastrointestinal
• Renal
• Pulmonary
• Hepatic
• Endocrinopathy
• Skin
• Neurological
BMS provided 
algorithms to 
align with most 
current guidelines 
for Immuno-
Oncology agents, 
including 
nivolumab
4.2.1 
(Treatment 
Discontinuation
Included statement: “Tumor 
assessments for all subjects 
should continue as per 
Removes statement
Patients do not 
need to have 
scans after the 
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Amendment 2:  July 5, 2016
Amendment 3:  July 31, 2017
53
protocol even if dosing is 
discontinued.”
“treatment 
discontinuation” 
4.3 
(Concomitant 
Medications/ 
Treatments)
n/a
Splits section into “4.3.1 
Permitted Medications” and 
“4.3.2 Prohibited Medications”
Adds more specific language 
about permitted 
corticosteroids. In general, 
corticosteroids >10mg 
prednisone are not permitted 
unless they meet specific 
criteria 
Clarifications 
5.0 (Study 
Procedures 
Table)
Listed visits by weeks (“every 
2 weeks” and a column for 
scans “every 8 weeks”) with 
a ± 2 day window for visits 
and ± 7 days for scans
Unclear if physical exam 
should take place at every 
treatment visit
#7: “A correlative blood 
sample will be drawn at 
baseline and after 2 doses of 
nivolumab”
#9: n/a

Changes visits to cycles 
where 1 cycle = 28 days, and 
visits have a ± 3 day window. 
Scans take place every 2 
cycles (rather than 8 weeks) 
for consistency, and the 
window has been changed to 
-7 days

Physical exam is only 
required at Day 1 of each 
cycle

#7: “A correlative blood 
sample will be drawn pre-
dose at C1D1 and C2D15”

#9: Study procedures can 
take place within 24 hours of 
planned study treatment
Clarification to 
simplify table; 
longer visit 
window 
accounts more 
inclusively for 
unexpected 
dose delays. 
+7-day scan 
window has 
been removed 
so that scans 
take place 
before dosing
Clarification
#7: 
Clarification
#9: To allow 
flexibility if a 
patient comes 
from out of 
town
7.7.2 
(Expedited 
Reporting to 
the NU 
QAM/DMC; 
7.7.4 
(Reporting to 
BMS)
7.7.4 stated “SAE reports will 
be reported within 24 hours to 
BMS Global Safety (using the 
NU CRO SAE Form)” 
Email was listed incorrectly: 
wolrdwidesafety@BMS.com; 

Added language: “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 209-612).”

7.7.2 references BMS 
reporting instructions in 7.7.4 

Corrects email typo: 
worldwidesafety@BMS.com
Clarification for 
SAE reporting 
to avoid 
oversight or   
deviations
Administrative 
update with 
correct email
10.1 (Study 
Design / Study 
Endpoints)
Statistical conclusion stated 
that “If 4 or more respond then 
the trial will conclude that the 
response rate is at least 20%.”
Changes conclusion to: “If 4 or 
more response then the trial will 
conclude that the response rate 
is greater than 5%”
Correction for 
statistical 
accuracy
10.2 (Statistical 
Analysis)
n/a
Adds information on evaluable 
patients and the intention to treat 
(ITT) plan
Statistical 
clarifications for 
accuracy
11.7 
n/a
Adds language relating to the 
To align with 
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Amendment 2:  July 5, 2016
Amendment 3:  July 31, 2017
54
(Publication 
Policy)
BMS agreement for publications 
with NU
contract 
language
Amendment 3 – July 31, 2017
Cover Page

Listed Benedito Carneiro as 
the PI

Listed Manisha Shah as the 
participating site PI at Ohio 
State University
Changed to Devalingam 
Mahalingam as the PI
Removed Sub-Is - Ricardo 
Costa, Sachin Pai, Cord 
Sturgeon, Dina Elaraj, Anthony 
Yang, Peter Kopp
Added Sub-I -  Maha Hussain
Changed Ohio State University 
participating PI to Bhavana 
Khondra
Administrative
IRB #: STU00202153 Approved by NU IRB for use on or after 11/20/2018 through 11/19/2019.