Phase I/Ib Study of Nivolumab in Combination With Therasphere (Yttrium-90) in Patients With Advanced Hepatocellular Carcinoma
Phase: PHASE1
Conditions: Stage IIIA Hepatocellular Carcinoma, Stage IIIB Hepatocellular Carcinoma, Stage IIIC Hepatocellular Carcinoma, Stage IVA Hepatocellular Carcinoma, Stage IVB Hepatocellular Carcinoma
Sponsor: Northwestern University

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
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.
Phase I/Ib study of nivolumab in combination with Therasphere® 
(yttrium-90) in patients with advanced hepatocellular carcinoma 
Principal Investigator:
Aparna Kalyan, MBBS, FRACP
Assistant Professor
Northwestern Medicine Developmental Therapeutics Program (NMDTP)
Division of Hematology and Oncology
Robert H. Lurie Comprehensive Cancer Center of Northwestern University 
(RHLCCC)
645 N. Michigan Ave, Suite 1006
Chicago, IL 60611
Aparna.kalyan@northwestern.edu
Sub-Investigator(s):
Mary Mulcahy, MD
Al Benson, MD
Halla Nimeiri, MD
Sheetal Kircher, MD
Laura Kulik, MD
Robert Lewandowski, MD
Riad Salem, MD
Valerie Nelson, MD
Biostatistician:
Hui Zhang, PhD
Northwestern University
hzhang@northwestern.edu
Study Intervention(s):
Nivolumab and Theraspheres
IND Number:
Exempt
IND Holder:
Exempt
Funding Source: 
Bristol-Myers Squibb (BMS)
Version Date:
July 16, 2020 (Amendment 7)
Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/CRO/index.cfm
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NU Study Number: NU 16I01
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................5
STUDY SCHEMA ............................................................................................................................6
STUDY SUMMARY .........................................................................................................................6
1.0 INTRODUCTION – BACKGROUND & RATIONALE................................................................8
1.1
Disease Background .......................................................................................................8
1.2
Intervention Background & Overview ..............................................................................9
1.3
Rationale for combining y-90 with nivolumab:...............................................................12
1.4
Hypothesis.....................................................................................................................13
1.5
Exploratory Studies .......................................................................................................13
2.0 OBJECTIVES & ENDPOINTS.................................................................................................14
2.1
Primary Objectives & Endpoints....................................................................................14
2.2
Secondary Objectives & Endpoints ...............................................................................14
2.3
Exploratory Objectives & Endpoints ..............................................................................14
3.0 PATIENT ELIGIBILITY............................................................................................................15
3.1
Inclusion Criteria............................................................................................................15
3.2
Exclusion Criteria...........................................................................................................17
4.0 TREATMENT PLAN ................................................................................................................19
4.1
Overview........................................................................................................................19
4.2
Treatment Administration ..............................................................................................19
4.3
Phase I Dose Escalation Scheme .................................................................................20
4.4
Toxicity Management: Dose Delays and Discontinuation .............................................22
4.5
Concomitant Medications/Treatments ...........................................................................26
4.6
Other Modalities or Procedures.....................................................................................27
4.7
Duration of Therapy.......................................................................................................27
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4.8
Duration of Follow Up....................................................................................................28
4.9
Removal of Subjects from Study Treatment and/or Study as a Whole .........................28
4.10
Patient Replacement .....................................................................................................28
5.0 STUDY PROCEDURES...........................................................................................................29
6.0 ENDPOINT ASSESSMENT.....................................................................................................31
6.1
Definitions......................................................................................................................31
6.2
Primary Endpoint ...........................................................................................................31
6.3
Secondary Endpoints ....................................................................................................31
7.0 ADVERSE EVENTS ................................................................................................................34
7.1
Adverse Event Monitoring .............................................................................................34
7.2
Definitions & Descriptions..............................................................................................35
7.3
Adverse Event Reporting...............................................................................................38
8.0 DRUG INFORMATION ............................................................................................................40
8.1
Yttrium-90 (Theraspheres) ............................................................................................40
8.2
Nivolumab......................................................................................................................44
9.0 CORRELATIVES/SPECIAL STUDIES....................................................................................46
9.1
Sample Collection Guidelines........................................................................................46
9.2
Sample Processing, Storage, and Shipment.................................................................47
9.3
Assay Methodology .......................................................................................................47
9.4
Specimen Banking.........................................................................................................47
10.0 STATISTICAL CONSIDERATIONS ......................................................................................48
10.1
Study Design/Study Endpoints......................................................................................48
10.2
Data Analyses Plans .....................................................................................................48
11.0 STUDY MANAGEMENT........................................................................................................49
11.1
Institutional Review Board (IRB) Approval and Consent...............................................49
11.2
Subject Recruitment and Screening..............................................................................49
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11.3
Amendments .................................................................................................................49
11.4
Registration Procedures................................................................................................49
11.6
Instructions for Participating Sites .................................................................................50
11.7
Data Management and Monitoring/Auditing ..................................................................50
11.8
Adherence to the Protocol.............................................................................................50
11.9
Investigator Obligations.................................................................................................51
11.10
Publication Policy ..........................................................................................................51
REFERENCES ..............................................................................................................................53
Appendices...................................................................................................................................55
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NU Study Number: NU 16I01
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Amendment 7: 07/16/2020
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LIST OF ABBREVIATIONS
AASLD
AE
American Association for the Study of Liver Diseases
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
CNS
Comprehensive Metabolic Panel
Central Nervous System
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
HCC
Eastern Cooperative Oncology Group
Hepatocellular carcinoma
H&PE
History & Physical Exam
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
NCI
NSCLC
OLT
National Cancer Institute
Non-Small Cell Lung Cancer
Orthotopic liver transplant
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
RECIST
Partial Response
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
VEGF
Serum Glutamic Pyruvic Transaminase
Vascular Endothelial Growth Factor
WBC
White Blood Cells
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NU Study Number: NU 16I01
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STUDY SCHEMA
Patients with CR/PR/SD will 
continue treatment with nivolumab 
until progression, unacceptable 
toxicity or withdrawal of consent
Once off treatment continue survival follow-up q 6 months up to 2 
years
Patients with advanced Hepatocellular carcinoma (HCC) 
defined as those who are not transplant or resection candidates.
Patients will be treated with Y-90 (Theraspheres®) followed 7-14 days later by 
nivolumab. The first 3 patients in Phase I are treated at 80mg IV every 2 weeks. 
Remaining patients will then follow the standard regimen of 240mg every 2 weeks 
until progression, unacceptable toxicity or withdrawal of consent (see section 4.3 
for dose escalation). Patients will have imaging 21-28 days after Y-90 treatment, 
every 8 weeks (2 cycles) for the first 13 cycles, and every 12 weeks (3 cycles) 
thereafter to assess response. 
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NU Study Number: NU 16I01
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Amendment 7: 07/16/2020
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STUDY SUMMARY
Title
Phase I/Ib study of nivolumab in combination with yttrium-90 
(Therasphere ®) in patients with advanced hepatocellular carcinoma
Version
04/10/2019 (Amendment 6)
Study Design
Phase 1/1b
Study Center(s)
Single-center, Northwestern: (Northwestern University, Northwestern 
Memorial Hospital and Northwestern Memorial Faculty Foundation)
Objectives
Primary Objective(s): 

Phase I:
To identify maximum tolerated dose (MTD) of nivolumab for 
combination treatment of nivolumab and Y-90 in patients with 
advanced hepatocellular carcinoma.

Phase Ib:
To evaluate the proportion of patients with objective response 
rate (ORR) to the combination treatment of nivolumab with Y-90.
Secondary Objective(s):

To evaluate the toxicities (according to the NCCN CTCAE v4.03)  
and tolerability of nivolumab and y-90 in patients with advanced 
hepatocellular carcinoma 

To evaluate the proportion of patients alive and progression free 
at 24 weeks in the described population.

To evaluate the disease control rate for the combination of Y-90 
and nivolumab at 24 weeks from starting nivolumab treatment. 
Exploratory Objective(s):

Intratumoral Assessment: Fresh biopsy or archived tissue will be 
used if available. PD-L1 protein on tumor cells and the 
expression levels of other markers of inflammatory/immune 
signature that may include but not be limited to PD-1, OX40, 
CD73, CD39, T cell immunoglobulin and TIM3, GITRL, CTLA-4, 
CD3, CD4, CD8, CD45RO, FOXP3, and granzyme by IHC and/or 
flow cytometry will be evaluated. Whole exome sequencing and 
computational analyses will be performed to assess mutanome 
and immunome (subpopulations of immune cells).

Circulating free DNA (cfDNA) mutation analyses: Blood will be 
drawn before treatment and every 8 weeks with imaging for the 
first 24 weeks then every 16 weeks until disease progression. 
Change in clonal burden landscape of various mutanome and 
immunome will be analyzed to investigate its correlation with 
treatment response or development of resistance to treatment. 
Sample Size
Phase 1: 9-15 patients, Phase 1b requires 29 patients in a two-stage 
optimum Simon design.  The 6 at the MTD in Phase 1 are counted as 
part of the 29.  This would require up to 15 in Phase 1, 23 new patients 
in Phase 1b for a total of 38 patients.  Target accrual is 40 patients to 
account for potentially unevaluable patients. 
Diagnosis & Key 
Eligibility Criteria
Subjects with advanced hepatocellular carcinoma who are non-
transplant candidates. 
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Treatment Plan
Y-90 will be administered once at a calculated dose based on the 
volume of liver tissue supplied by the artery to be infused (lobar, 
segmental, subsegmental) and the estimated lung shunt fraction. 
TheraSphere dosimetry is independent of the tumor burden.
Nivolumab will be administered as an IV infusion 7-14 days after Y-90 
administration. The first 3 patients in Phase I are treated at 80mg IV 
every 2 weeks until disease progression, intolerable toxicity, or 
withdrawal of consent. Remaining patients will then follow the standard 
regimen of 240mg every 2 weeks until disease progression, intolerable 
toxicity, or withdrawal of consent. See section 4.3 for dose escalation 
details.  
Statistical Methodology
This is a Phase I/Ib study with dose identification in the initial phase and 
safety/tolerability in the phase Ib section. The expected number of 
patients on dose escalation will be in the range of 9-15 based on the 
3+3 design. Six patients will be treated at the MTD in the dose 
escalation phase.  The dose calculation for Yttrium-90 Therasphere will 
be done according to standard protocol at Northwestern Memorial 
Hospital. Please note - details of this are located in section 8.1. The 
Phase 1b expansion cohort will be a two-stage optimum Simon design 
with 29 patients.  See Section 10.0 for details.
 
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
The incidence of hepatocellular carcinoma (HCC) has risen over the last 3 decades.(1,2) 
Therapeutic options for HCC are complex. Treatment with ablative liver directed therapies 
or resection are often suboptimal due to cumulative local or de novo recurrence rates of 60 
to 100% at 5 years.(3-5) Orthotopic liver transplant (OLT) offers the best chance for long 
term survival after the detection of early hepatocellular carcinoma (HCC) by removing the 
entire pre-neoplastic cirrhotic liver. However, with the growing number of patients who 
require OLT, prolonged waiting times can often lead to drop out from the transplant list due 
to tumor progression.(6) Patients with HCC within Milan criteria (a single lesion ≤ 5 cm or 3 
lesions ≤ 3 cm, without gross vascular invasion) are granted an upgrade in order to 
expedite the access of patients with early HCC to transplantation before tumor 
progression.(7-9) With increasing Hepatitis C virus infection, HCC incidence and cancer 
death owing to this is becoming the third leading cause of cancer death worldwide. 
Furthermore, HCC arises on a background of chronic inflammation due to underlying viral 
infection, which in turn creates an ideal environment for tumor cells to accumulate 
mutations. These mutations have made HCC resistant to traditional chemotherapy and 
treatment with chemotherapies is further limited by impaired hepatic function (10). The only 
current systemic therapy approved for HCC is Sorafenib, based on the results of the 
SHARP trial (11). While, many agents have looked promising they have failed to 
demonstrate sufficient improvement for this difficult population. 
HCC is a highly vascular tumor. Angiogenesis plays a pivotal role in the early stages of 
carcinogenesis, progression and development of metastasis in HCC. Vascular endothelial 
growth factor (VEGF) expression has been found to correlate with important 
clinicopathological factors and risk of recurrence post resection.(10) Environmental factors 
such as hypoxemia are known to upregulate the expression of VEGF via hypoxia induced 
factor -1α (HIF). 
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1.2
Intervention Background & Overview
1.2.1
Preclinical Evidence for the PD-1 pathway in HCC:
The role of immune surveillance in controlling growth and the oncogenic properties 
have been well established for several decades. There is now a plethora of 
evidence that describes the correlation between tumor-infiltrating lymphocytes 
(TILs) within tumor cells and favorable prognosis overall. 
The PD-1 pathway is a major component of tumorigenesis by suppressing the 
immune system. The innate function of the PD-1, when expressed on activated T-
cells is to down regulate unwanted / excessive immune responses thus controlling 
autoimmune conditions. 
PD-1 is a T-cell co-inhibitory receptor with two well-recognized ligand PD-L1 (B7-
H1) and PD-L2 (B7-DC)12. The binding of PD-1 to PD-L1 leads to T-cell 
activation and ultimately several immunosuppressive effects, which includes 
inhibition of cell survival factor Bcl-xL (13,14). Within the HCC, a significant 
proportion of PD-L1 is expressed by Kupffer cells (15) and in turn this expression 
is driven by IL-10 in HCC. The expression of PD-1 is markedly higher in the 
tumor and peripheral blood of patients with HCC compared to controls with 
cirrhosis alone (16). 
A study of 54 patients with HCC and HBV co-infection who underwent surgical 
resection, the levels of Pd-1 expression was evaluated. This study demonstrated 
that higher versus lower expression of intrahepatic PD-1 on T-cells was 
associated with lower disease free survival (13.6 mths vs. 28.7 mths; p < 0.001) 
(17). Similar results were mirrored when the expression of PD-1 in peripheral 
blood was measured. In addition, the levels of circulating PD-1 correlated directly 
with the stage of HCC. This small study clearly demonstrated that higher levels of 
PD-1 expression in the tumor microenvironment are associated with worse 
overall survival & prognosis. (17)
Chronic Inflammation is a key feature of hepatitis associated HCC. High rates of 
HCC recurrence after surgical resection is associated with chronic viral infection 
as well as its concomitant inflammatory features which lends itself to set up 
further de-novo mutations and tumor regrowth. Urbani and colleagues (27) have 
shown recently that the PD-1/PD-L1 pathway is a key contributor to viral 
persistence in HBV /HCV infections. Many studies have demonstrated that HBV 
circulating CD8+ t-cells in chronic HBV infection are in fact PD-1 positive – 
lending to thought that this is due to chronic antigenic stimulation (5). There is 
also up-regulation of the PD-1 system in chronic antigenic stimulation, which may 
be a mechanism of immune tolerance. Furthermore, in-vitro studies have shown 
that blockade of PD-1/PD-L1 increases HBV specific CD8+ T-cells, higher IL-2 
and IFNγ by these cells, suggesting more potent effector activity.
1.2.2
Nivolumab as a PD-1 inhibitor
Nivolumab (also known by BMS-936558 or MDX1106) is a fully humanized 
monoclonal antibody of the IgG4/kappa isotype that binds to PD-1 and blocks the 
interaction between PD-1 and PD-L1 and PD-L2. Both PD-1 and PD-1 ligands are 
upregulated following initiation of an immune response and help to limit that 
response to avoid tissue damage. Upregulation of PD-1 ligands also occurs in 
some tumors and is thought to contribute to inhibition of active T-cell immune 
surveillance of tumors. 
Nivolumab has been extensively investigated in several large clinical trials thus 
establishing the safety, PK, and clinical activity of nivolumab. To date there are 
approximately 32 clinical trials in various phases (11 phase 1 studies, 13 phase 2 
studies and 8 phase 3 studies) across several histologies (including NSCLC, 
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melanoma, RCC, mCRPC and hematologic malignancies) evaluating nivolumab 
either as monotherapy or in combination with cytotoxic chemotherapy or targeted 
therapies.  Clinical activity has been shown both as monotherapy as well as in 
combination with other immunotherapy agents such as an anti-CTLA4 antibody 
(ipilimumab) with durable responses exceeding 6 months. 
Currently, nivolumab is approved for treatment of unresectable or metastatic 
melanoma and disease progression on ipilimumab regardless of BRAF mutational 
status. It is also indicated for the treatment of patients with metastatic non-small 
cell lung cancer (NSCLC) with progression on or after platinum-based 
chemotherapy. It is currently approved at a dose of 3mg/kg every 2 weeks and for 
both melanoma and NSCLC. The side effect and safety profile seen to date are 
consistent across all histologies tested. There has been no maximum tolerated 
dose (MTD) reached at the monotherapy doses tested up to 10mg/kg. Additionally, 
there was no pattern in the incidence, severity or causality of AEs to nivolumab 
dose levels. 
To-date the primary treatment-related AEs with nivolumab have included 
pulmonary toxicity, renal toxicity, endocrine abnormalities, GI toxicity, dermatologic 
toxicity and hepatotoxicity.  The majority of the AEs encountered have been 
managed with supportive care and in severe cases a combination of dose delay, 
permanent cessation of the drug and/or addition of systemic corticosteroids. 
There are now several more studies in the pipeline evaluating the combination of 
nivolumab with other agents. Recently, results from the phase II study of nivolumab 
for patients with advanced HCC were presented. Of 42 evaluable patients, 28 
patients had a response (2 CR, 6 PR, 20 SD) corresponding to an objective 
response rate of 67% (28/42). Further, of the 8 patients with a response, 7 patients 
responded within 3 months of therapy and ongoing response was seen in 6/8 
patients. This further provides evidence to the active role of PD-1 inhibitors in 
advanced HCC regardless of hepatitis status 1. 
1.2.3
Role for Therasphere (yttrium-90) in HCC:
Treatments, such as TACE, attempt to take advantage of the vascular nature of 
HCC by impairing the blood supply of the tumor and inducing a hypoxic state. 
Higher baseline serum levels of VEGF have been demonstrated to predict a poor 
response to TACE.(19) Therasphere, a novel therapeutic approach, are composed 
of non-biodegradable glass microspheres coated with yttrium-90.(20) They are 
injected into the hepatic artery and are preferentially trapped in the tumor capillary 
bed relative to surrounding non-tumor parenchyma. The ability to concentrate 
radioactive microspheres within the tumor leads to an "inside-out" radiation, which 
in turn exerts a local tumoricidal effect. Unlike TACE, Therasphere do not induce 
hypoxemia, but rather, requires oxygen for the maximal radiation effect20. 
The mechanistic differences in TACE and Therasphere theoretically may have an 
impact on angiogenesis and therefore an effect on tumor progression as a patient 
awaits transplantation. Radioembolization of the hepatic artery with microspheres 
coated with yttrium-90, a source of beta energy, capitalizes on the hypervascular 
nature of HCC. The distribution of blood flow is three to seven times greater within 
the tumor than the surrounding noncancerous tissue (1). The preferential delivery 
of microspheres to the tumor capillary bed allows for higher doses of radiation to 
be delivered to the tumor relative to surrounding non-tumor parenchyma. The 
ability to concentrate radioactive microspheres within the tumor leads to an “inside-
out” radiation, which in turn exerts a local tumoricidal effect. In 1999, the FDA 
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granted a humanitarian device exemption for the use of TheraSphere® (MDS 
Nordion, Ottawa, Ontario, Canada) for the treatment of unresectable HCC. 
Phase 1 and 2 trials have demonstrated a positive safety profile for TheraSphere 
therapy in patients with a bilirubin < 2 rends in improved survival have been 
reported in patients who received > 104 Gy. Several additional publications have 
testified Y-90 to be a safe and efficacious therapy for unresectable HCC. While 1 
year 
survival 
rates 
are 
comparable 
to 
the 
RCTs 
of 
trans-arterial 
chemoembolization (TACE) versus supportive care, no RCTs comparing Thera-
Spheres to TACE have been performed.(30-35)
Radioembolization therapy is performed in a two-step process: a “trial run” followed 
by the treatment session which is generally performed a few days afterwards. Prior 
to the administration of Y-90, a mesenteric angiogram is performed to determine 
the tumor’s blood supply, aberrant anatomy and to ensure proper catheter position. 
Coiling of extrahepatic arteries may be required to avoid inadvertent delivery of 
microspheres to surrounding organs (stomach, diaphragm and gallbladder). At the 
same time, Technetium-99 macroaggregated albumin (The99Tc-MAA) is injected 
into the hepatic artery to estimate the degree of intratumoral arteriovenous 
shunting. The99Tc-MAA particles are similar in size to the Y-90 microspheres (20-
40 microns) and therefore will simulate the distribution of Y-90.   A single photon 
emission CT is then used to calculate the dose of radiation that will be distributed 
to the lungs and/or viscera. A hepatopulmonary shunt greater than 20% of the 
injected dose, failure to prevent blood flow into the gastrointestinal organs by 
embolization or proper catheter placement will preclude therapy with Y-90. The 
dose of radiation delivered to the lungs is cumulative and should not exceed 50 
Gy. A mesenteric angiogram and 99 Tc-MAA will be repeated before every 
treatment session with Y-90 to evaluate for the degree of shunting. 
The calculated radiation dose for TheraSphere therapy is based on the volume of 
liver tissue supplied by the artery to be infused (lobar, segmental, subsegmental) 
and the estimated lung shunt fraction. TheraSphere dosimetry is independent of 
the tumor burden. 
Side effects following Y-90 therapy are usually mild and temporary. Fatigue is the 
most common side effect. Fever, chills, and flu-like symptoms may also occur and 
generally require no specific intervention. More serious side effects relate to 
inadvertent migration of a microsphere(s) with radiation exposure to non-targets 
(cholecystitis, gastritis/ulceration, pancreatitis or pneumonitis). Lymphopenia 
presumed secondary to bone marrow suppression has been reported in patients 
treated with Y-90, however there have been no reports of opportunistic infections 
or clinical complication relating to Y-90 therapy. Cases of lymphopenia have been 
extremely rare and asymptomatic. Peak incidence while theoretically can occur up 
to 3 months after therapy, to date no clinical infections or clinical complications 
have been reported in the literature. Patients will have a 4 week break between 
receiving Y90 treatment and starting nivolumab to allow for recovery and to obtain 
repeat scans. A long-term complication of hepatic fibrosis and portal hypertension 
has been reported. All patients undergo esophagogastroduodenoscopy (EGD) as 
standard of care with banding of large esophageal varices. While pneumonitis has 
been reported, the number of cases from this remains very few and overall 
incidence is extremely rare; as such current standard of care does not require 
additional pulmonary testing prior to Y-90. All patients will undergo an angiogram 
prior to Y-90 administration to calculate the appropriate Y-90 dose, and presence 
of lung shunt will be ruled out at that time.
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1.2.4
Measurement of disease response
Insight into the biological behavior of a tumor may be gained by the response to 
liver directed therapy. A lack of progression with liver directed therapy might lead 
to improved overall survival (OS). A recent study supported that radiographic 
response to TACE could serve as a biological marker of tumor behavior.(21) The 
ability to measure the effectiveness of therapy and/or need for additional treatment 
is restricted by reliance upon radiographic endpoints of tumor size and 
enhancement as opposed to a measurable biological response at the cellular level. 
The shortcomings of conventional imaging to assess treatment response are 
highlighted in studies demonstrating a discrepancy between radiographic 
response and explant pathology.(22,23) Ability to accurately determine efficacy of a 
therapy (radiographically) is vital to obtain the maximal benefit of locoregional 
therapy. The degree of necrosis on explant associated with liver directed therapy 
has shown conflicting results in terms of HCC recurrence post-transplant.(21,22,24) 
Diffusion-weighted magnetic resonance imaging (MRI) operates on the premise 
that the diffusion of water within a cell is dependent upon the integrity of the cellular 
membrane. Within viable cells, water movement is restricted by the boundaries of 
an intact cellular membrane, whereas in necrotic cells, water is able to freely 
diffuse. The distribution of water within a given area can be calculated as an 
apparent diffusion coefficient (ADC) and provide functional information for a given 
lesion. Increased diffusion of water within a targeted lesion has been shown to be 
a reliable early marker of treatment response to radiation and chemotherapy in 
brain and breast cancer.(25,26) More recently, diffusion weighted MRI has been 
reported to detect treatment response in HCC after chemoembolization and 90Y 
radioembolization.(27-29) Detection of early treatment response with necrosis of the 
targeted tumor may act as a surrogate marker for selection of patients most likely 
to benefit from transplant. Such a tool could also prevent unnecessary repeated 
therapeutic sessions and the associated potential complications including 
treatment induced liver failure. Necrosis induced by systemic therapies such as 
nivolumab would also be expected to be detected with diffusion-weighted imaging.
1.3
Rationale for combining Y-90 with nivolumab:
As described above, there is evidence that manipulating the PD-1 pathway in HCC affects 
the balance between anti-tumor active and immune tolerance in advanced HCC. 
Nivolumab has recently been approved for the treatment of squamous non-small cell lung 
cancer and melanoma. The paucity of good treatment options in advanced HCC (apart 
from Sorafenib) creates an ideal environment to pursue immune-modulation in this 
population. Due to the complexity of hepato-carcinogenesis, including the heterozygosity 
of genetic alterations involved in the development and progression of HCC, it is likely that 
a combination approach with systemic immune therapy and liver directed therapy will be 
needed to obtain the most efficacious "kill" of tumor cells.  A decrease in angiogenesis both 
locally within the treated tumor as well as in any clinically undetectable tumor cells would 
hopefully decrease the incidence of progression of HCC and might even allow for some 
patients to become transplant eligible. 
It is for these reasons; we wish to proceed with this early phase study to evaluate the 
combination of Y-90 and nivolumab for treatment of advanced HCC. There is no data 
available that currently combines these two modalities in HCC.
1.3.1
Rationale for Nivolumab Dosing 
The safety and efficacy of 240 mg (monotherapy) Q2W flat dose of nivolumab 
has recently received IRB approval and is expected to be similar to the 3 mg/kg 
Q2W dosing regimen. Using the population PK (PPK) model, exposure of 
nivolumab at 240 mg flat doses is identical to a dose of 3 mg/kg for subjects 
weighing 80 kg, which is the approximate median body weight in nivolumab 
clinical trials. Across the various tumor types in the clinical program, nivolumab 
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has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and 
the relationship between nivolumab exposure produced by 3 mg/kg and efficacy 
and safety has been found to be relatively flat. Given the similarity of nivolumab 
PK across tumor types and the similar exposures predicted following 
administration of 240 mg flat doses compared to 1mg/kg and 3 mg/kg, it is 
expected that the safety and efficacy profile of 240 mg nivolumab will be similar 
to that of 3 mg/kg nivolumab. 
A phase I dose escalation of nivolumab starting at 80mg is included in this study 
given the lack of data combining nivolumab with Y-90.
1.4
Hypothesis 
Subjects treated with nivolumab will have an overall improved response to liver directed 
therapy with Y-90 (Therasphere) as evidenced by markers of angiogenesis, radiographic 
response defined by RECIST criteria, immunological markers; leading to improved clinical 
outcome measurements, less recurrence and potentially meet criteria for liver 
transplantation. 
1.5
Exploratory Studies
It has been shown in animal models, control human subjects as well as in oncology 
patients that, administration of nivolumab modifies the cytokine levels in plasma.
1.5.1
Exploration of 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 [1-3]. PD-L1 
and PD-L2 are overexpressed in a variety of solid tumors however no data exists 
in ACC [1].  
There are conflicting data on the predictive value of PD-L1 expression on PD-1 
directed therapy in solid tumors [1, 4]. 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 [5]. The same correlation was not observed on 
stratified analysis according to tumor cell membrane PD-L1 expression of non-
small cell lung cancer patients treated with nivolumab therapy in the second line 
setting [4].
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. 
1.5.2
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 co-expression 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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1.5.3
Measurement of humoral and cellular responses to tumor antigens on 
serum samples by measuring the levels of cytokines (i.e., 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 Objectives & Endpoints
2.1.1
Phase I: To identify maximum tolerated dose (MTD) of nivolumab for 
combination treatment of nivolumab and Y-90 in patients with advanced 
hepatocellular carcinoma. The MTD will be defined as the highest dose that 
causes dose limiting toxicities (DLTs) in <2 of 6 patients.
2.1.2
Phase Ib: To evaluate the proportion of patients with objective response rate 
(ORR, according to RECIST criteria version 1.1) to the combination treatment of 
nivolumab with Y-90.
2.2
Secondary Objectives & Endpoints
2.2.1
To evaluate the proportion of patients alive and progression free at 24 weeks in 
the described population.
2.2.2
To evaluate the toxicities (according to the NCCN CTCAE v4.03) and tolerability 
of nivolumab and y-90 in patients with advanced hepatocellular carcinoma 
2.2.3
To determine the disease control rate (DCR) to the combination of nivolumab 
and Y-90 at 24 months from the start of nivolumab treatment. DCR is defined as 
the sum of Complete Response, Partial Response, and Stable Disease (DCR = 
CR + PR + SD). 
2.3
Exploratory Objectives & Endpoints
2.3.1
Intratumoral Assessment: 
Fresh biopsy or archived tissue will be used if available. PD-L1 protein on tumor 
cells and the expression levels of other markers of inflammatory/immune 
signature that may include but not be limited to PD-1, OX40, CD73, CD39, T cell 
immunoglobulin and TIM3, GITRL, CTLA-4, CD3, CD4, CD8, CD45RO, FOXP3, 
and granzyme by IHC and/or flow cytometry will be evaluated. Whole exome 
sequencing and computational analyses will be performed to assess mutanome 
and immunome (subpopulations of immune cells). 
2.3.2
Circulating free DNA (cfDNA) mutation analyses: 
Blood will be drawn before treatment and every 8 weeks with imaging for the first 
24 weeks then every 16 weeks until disease progression. Change in clonal 
burden landscape of various mutanome and immunome will be analyzed to 
investigate its correlation with treatment response or development of resistance 
to treatment. 
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with hepatocellular carcinoma. This will be a single-
center trial conducted at Robert H. Lurie Comprehensive Cancer Center (RHLCCC) of 
Northwestern University. 
Up to 40 patients will be enrolled, up to 15 in Phase 1 and up to an additional 25 in Phase 1b. 
Approximately 3 potentially eligible patients are seen per month, and it is anticipated that at least 
2 per month will be accrued. Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Aparna Kalyan, 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. Please refer 
to Section 11.4 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a diagnosis of hepatocellular carcinoma (HCC) confirmed by 
American Association for Study of Liver Diseases (AASLD) guidelines with a 
Childs-Pugh score of A or B (but, ≤ Childs score B8).
NOTE: If the patient does not have histological confirmation of disease by biopsy, 
diagnosis of HCC must be documented with approval by a tumor board or other 
multidisciplinary conference. Please refer to the appropriate source document in 
NOTIS.
3.1.2
Patients must have at least 1 lesion that is measurable using RECIST guidelines.
NOTE: A previously irradiated lesion can be considered a target lesion if the 
lesion is well defined, measurable per RECIST, and has clearly progressed.
NOTE: For patients with infiltrative disease, evaluable disease needs to be 
confirmed by pathology if RECIST measurements cannot be made.
3.1.3
Patients must have advanced disease that is not amenable to transplant or 
resection. 
3.1.4
Patients may be treatment naïve or have received any number of prior therapies.
NOTE:  Prior immunotherapy is contraindicated and not permitted. 
3.1.5
Patients with chronic Hepatitis B are eligible as long as they have evidence of 
ongoing viral replication (detectable HBsAg, HBeAg, or HBV DNA). They must 
have HBV DNA viral load <100 IU/mL at screening. In addition, they must be on 
antiviral therapy per regional standard of care guidelines prior to initiation of 
study therapy. If not on antiviral therapy at screening, then the subject must 
initiate treatment per regional standard of care guidelines at the time of consent. 
Both HBeAg positive and negative patients will be included. 
3.1.6
Patients positive for Hepatitis C are permitted if controlled with medication, in the 
opinion of the investigator.
3.1.7
Adults ≥18 years old of either gender are eligible.
3.1.8
Patients must exhibit an ECOG performance status of 0, 1, or 2.
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3.1.9
Patients must have adequate organ function within 14 days prior to registration 
as determined by:
o
Hematological (without growth factor support)

Hemoglobin ≥ 8.5 g/dL (without the use of growth factors)

ANC ≥1000

Platelet count ≥ 50 x 109/L (without use of growth factors [i.e., IL-11 
{Oprevilekin}])

Prothrombin time (PT)/ International normalized ratio (INR) ≤ 2.3 or PT 
≤ 6 seconds above control.  
NOTE: Abnormal PT/INR may be considered, with documented PI 
approval, if it is due to the use of anticoagulants. For such patients, a 
normal PT/INR must be available from before the start of 
anticoagulation treatment. 
NOTE: Performed at time of screening angiogram; can be outside 14 
days if applicable.
o
Renal 

Calculated creatinine clearance* (CrCl) or 24-hour urine CrCl > 30 
mL/min (*Cockcroft-Gault formula will be used to calculate CrCl)
o
Hepatic

Serum Bilirubin ≤ 3 times the upper limit of normal (ULN) 

AST and ALT ≤ 5 times ULN 
o
Serum Electrolytes

Potassium, sodium, and calcium (corrected for serum albumin) ≤ Grade 
1 or within the institutional ranges of normal. If clinically appropriate, 
electrolytes may be corrected and values re-assessed prior to 
enrollment
3.1.10
Females of childbearing potential (FOCBP), and non-sterilized males who are 
sexually active 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 in Appendix 2. They must also refrain from egg and/or 
sperm cell donation and breastfeeding for 90 days after the final dose of 
investigational product(s) 

Females of childbearing potential are defined as those who are not 
surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy) or postmenopausal (defined as 12 months with 
no menses without an alternative medical cause) 

WOCBP must agree to follow instructions for method(s) of contraception 
for the duration of treatment with nivolumab plus 5 half-lives of nivolumab 
(19 weeks) plus 30 days (duration of ovulatory cycle) for a total of 23 
weeks post-treatment completion.

Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with nivolumab plus 5 half-lives of the study drug (19 weeks) plus 90 
days (duration of sperm turnover) for a total of 31 weeks post-treatment 
completion
3.1.11
FOCBP must have a negative pregnancy test within 7 days prior to registration
Note: FOCBP will have to have repeat pregnancy test within 24 hours of starting 
nivolumab, scheduled for Cycle 1 Day 1.  
3.1.12
Subjects must provide archived tumor specimens for correlative biomarker 
studies if sufficient tissue is available. A fresh biopsy is not required.
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3.1.13
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
3.2
Exclusion Criteria
3.2.1
Patients must not have had prior treatment with nivolumab or any other PDL1 or 
PD-1 antagonists
3.2.2
Patients must not have a history of severe allergic reactions (i.e., Grade 4 allergy, 
anaphylactic reaction from which the subject did not recover within 6 hours of 
institution of supportive care) to any unknown allergens or any components of the 
nivolumab formulations 
3.2.3
Patients diagnosed or treated for malignancy other than HCC are not eligible 
unless they meet one of the following exceptions: 
• Malignancy treated with curative intent and with no known active disease present 
for ≥3 years before registration and felt to be at low risk for recurrence by the 
treating physician. 
• Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease.
• Adequately treated cervical carcinoma in situ without evidence of disease
3.2.4
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.
3.2.5
Patients with renal failure currently requiring dialysis of any kind are not eligible.
3.2.6
Patients with untreated central nervous system (CNS) metastatic disease 
(including spinal cord and leptomeningeal disease) are excluded.
Note: Subjects with previously treated CNS metastases that are radiographically 
and neurologically stable for at least 6 weeks and do not require corticosteroids 
(of any dose) for symptomatic management are permitted to enroll 
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3.2.7
Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study or the follow-up period of an interventional study, is 
excluded. 
3.2.8
Receipt of any investigational therapy is not permitted within 28 days prior to the 
first dose of nivolumab 
3.2.9
Any concurrent chemotherapy, biologic or hormonal therapy for cancer treatment 
is not permitted within 28 days of registration. 
Note: Prior immunotherapy is not permitted.
Note: Concurrent use of hormones for non-cancer-related conditions (e.g., insulin 
for diabetes and hormone replacement therapy) is acceptable. 
3.2.10 Patients with exposure to prior immunotherapy are not eligible. 
3.2.11 Patients are ineligible if they have unresolved toxicities from prior anticancer 
therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1 with 
the exception of alopecia and laboratory values listed per the inclusion criteria. 
Note: Subjects with irreversible toxicity that is not reasonably expected to be 
exacerbated by any of the investigational products may be included (e.g., hearing 
loss) after consultation with the PI and NU QAM. 
3.2.12 Radiation therapy is not permitted within 14 days of registration.
3.2.13 Live vaccines are not permitted within 28 days of study registration.
3.2.14 No systemic glucocorticoids will be permitted within 48 hours prior to study 
registration.
Note: Topical steroids, bronchodilators and local steroid injections are permitted if 
clinically required. 
3.2.15 Patients with cardiac disease defined as one of the following are not eligible: 
Congestive heart failure > class II NYHA.  
Unstable angina (anginal symptoms at rest) or new onset angina (began within 
the last 3 months)
Myocardial infarction within the past 6 months.
3.2.16 Patients with cardiac ventricular arrhythmias requiring anti-arrhythmic therapy are 
not eligible.  
3.2.17 Patients with known human immunodeficiency virus (HIV) infection are not 
eligible.
3.2.18 Patients must not have elevated lung shunting precluding treatment with Y-90. 
3.2.19 Patients who have had major surgery within 4 weeks prior to registration are not 
eligible.
3.2.20 Patients who have active clinically serious infection > CTCAE Grade 2 are not 
eligible.
3.2.21 Patients with a history of gastrointestinal bleeding (GIB) within 6 weeks prior to 
registration are not eligible.
3.2.22 Patients with prior transplant of any kind are not eligible.
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3.2.23 Patients may not be pregnant or lactating at study registration. 
3.2.24 Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible: 
Hypertension that is not controlled on medication
Ongoing or active infection requiring systemic treatment
Psychiatric illness/social situations that would limit compliance with study 
requirements
Any other illness or condition that the treating investigator feels would interfere 
with study compliance or would compromise the patient’s safety or study 
endpoints
Active alcohol use, drug use, or a psychiatric disease that would, in the opinion 
of the PI or a subinvestigator (sub-I), prevent the subject from complying with 
the study protocol and/or endanger the subject during their participation in the 
study
4.0
TREATMENT PLAN
4.1
Overview
Treatment will be administered on an outpatient basis. Patients will first be treated one 
time with liver directed therapy, Therasphere® (Y-90), following institutional procedures**. 
During screening, each patient will undergo an angiogram in interventional radiology to 
determine the appropriate Y-90 dose. Within 7-14 days, patients will begin treatment with 
intravenous nivolumab as maintenance either at 80mg (first 3 patients in Phase I) or 
240mg (Phase Ib if MTD) over 30 minutes (-5 minutes / +15 minutes) every 2 weeks (Day 
1 & 15 of each cycle; 1 cycle = 28 days).
 
After study registration, the patient will proceed to receiving Y-90 per the standard of care 
procedures listed in section 8.1. Y-90 administration is normally planned around 7 days 
from the angiogram, so registration should be planned accordingly. After completion of Y-
90, patients will have 1-2 weeks recovery time prior to proceeding with nivolumab 
administration (4 weeks if necessary). This window allows for recovery from generalized 
fatigue. Study drug nivolumab will continue until disease progression or withdrawal of 
treatment by patient. 
** Repeat therapy to the treated lesion or additional untreated lesions may be warranted. 
If a patient requires additional Y-90 after starting nivolumab treatment, it may be given 
once approval from the interventional radiologist and treating physician has been 
confirmed. In such cases, nivolumab should be held for ≥7 days prior to administering Y-
90. Nivolumab can be resumed at least 7 days after receiving additional Y-90, but can be 
delayed for up to 4 weeks if needed. 
4.2
Treatment Administration
4.2.1
Theraspheres® (Yttrium-90) 
Institutional Standard of Care TheraSphere Treatment Procedure:
The calculated dose of radiation to be delivered to the targeted lesion will be 
calculated by a medical nuclear physicist in Interventional Radiology (Venessa 
Gates MS, DABR, DABSMM) during the screening angiogram. Once the required 
dose of Y-90 is determined, it is ordered from the manufacturer. It is recommended 
the time lapse between work up for Y-90 (angiogram) and the treatment session 
should not exceed 2-3 weeks. 
Please see section 8.1.6 for specific details of Y-90 administration. Patients are 
observed for 2-6 hours post procedure prior to discharge. Patients will be 
evaluated within 14 days after y-90 therapy to assess for side effects, tolerability 
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of therapy and laboratory abnormalities. By 12 days post therapy (4 half-lives of Y-
90), the radioactivity of Y-90 has significantly decayed. Tumor response is 
evaluated radiographically 21-28 days post therapy. Maximal therapeutic effect 
may only become apparent 3 months post therapy.  
Based on follow-up imaging, repeat therapy to the treated lesion or additional 
untreated lesions may be warranted, barring minimal complications with the first 
session. Radiographic evidence of progression of disease following up to 2 
treatments (to the same targeted lesion) of Y-90 may warrant alternative ablative 
or systemic therapies.  These subjects would be considered treatment failures and 
would be terminated from the study. On the other hand, an incomplete response 
or recurrent disease may call for additional therapy.
4.2.2
Nivolumab 
For the first 3 patients in Phase I, nivolumab will be administered at 80mg as an 
intravenous infusion over approximately 30 minutes (-5 minutes / +15 minutes) 
every 2 weeks (Day 1 & 15 of each cycle) until disease progression or intolerable 
toxicity. 
Dose escalation to 240mg will be determined in the standard 3+3 fashion 
(detailed in section 4.3). All patients in Phase Ib will be treated at 240mg IV 
nivolumab if determined to be the MTD. Treatment will begin 7-14 days after Y-
90 administration. Patients should have recovered from any side effects resulting 
from Y-90 treatment (to ≤G1 or baseline). If a patient is still experiencing side 
effects 14 days after Y-90 treatment, the patient’s nivolumab treatment may be 
delayed by up to 14 additional days at the physician’s discretion (maximum 4-
week delay). Scans will need to be performed 21-28 days after Y-90 
administration, and will fall during Cycle 1 of nivolumab. If a patient is not able to 
start nivolumab treatment within 4 weeks (28 days), the patient should come off 
study and be replaced. 
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 noted, subjects should be managed according to Section 
4.2.4. 
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.
4.3
Phase I Dose Escalation Scheme
In this phase 1/1b pilot study, the dose escalation component will be for nivolumab, 
starting at a dose of 80mg. Please see the table in statistical section for dose 
adjustments.
Phase I Dose Escalation Plan based on 3+3 design:
Dose 
Level
Nivolumab
1
80mg IV every 2 weeks
2
240mg IV every 2 weeks
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A standard “3+3” dose escalation design will be utilized. Initially, 3 patients will be enrolled 
at the starting dose (level 1), after which enrollment will be temporarily suspended until all 
3 patients complete the DLT evaluation period (defined as cycle 1 or the first 28 days of 
treatment). Once all 3 patients complete the DLT period and toxicity data has been 
submitted, the Data and Safety Monitoring Committee (DSMC) will review the data and 
confirm the presence or absence of any DLTs (defined below). The following rules will be 
used at each dose level to determine whether or not to proceed to the next dose level:

If 0 of 3 patients at a given dose level experience a DLT (defined below), then 
escalation will proceed to the next dose level.

If 2 or 3 of 3 patients at a given dose level experience a DLT, then one of the 
following must occur:
o
If this happens at level 1, the PI will discuss with DSMC and BMS to 
determine the necessary outcome.
o
If this happens at level 2 or beyond, the previous level will be declared the 
maximum tolerated dose (MTD).

If 1 of 3 patients at a given dose level experiences a DLT, then an additional 3 slots 
will be added (for a total of 6 patients at that level):
o
If 1 of 6 total experiences a DLT, then escalation will proceed to the next 
level.
o
If ≥ 2 of 6 total experience a DLT, the previous level will be declared the 
MTD. 
NOTE: Whichever dose level is declared the MTD must have 6 total patients treated at that 
level. For example, if 3 patients are treated at level 2 and 0 patients experience DLT, 
escalation would then proceed to level 3. However, if ≥ 2 patients at level 3 experience 
DLT, enrollment to level 2 would need to be re-opened to enroll an additional 3 patients at 
that level (with 0 or 1 DLT observed in 6 total patients) in order to declare level 2 the MTD.
4.3.1
Definitions
DLT is defined as a significant adverse events (detailed below) occurring during 
the DLT period (first 28 days of nivolumab treatment) that is related to nivolumab. 
DLT will be evaluated according to CTCAE v 4.03 criteria. Delay in starting 
nivolumab therapy more than 2 weeks due to toxicity regardless of attribution or 
grade, is considered a DLT
4.3.1.1 Grade > 3 non hematological toxicity
Grade >3 non-hematological toxicity felt to be related to study medication 
will be considered dose-limiting with the following clarifications:

Diarrhea Grade 3 will only be considered dose limiting if it is 
refractory to treatment as outlined in the supportive care guidelines 
(section 4.4.3)

Bloody or grade 4 diarrhea will be considered dose limiting

Nausea or vomiting grade 3 will only be considered dose limiting if it 
is refractory to anti-emetic therapy and unable to be corrected to < 
Grade 1 within 24 hours

Rise in serum creatinine to grade 3, not corrected to < grade 1 within 
24hrs with IV fluids will be considered dose limiting

Grade 3 metabolic toxicities unable to be corrected <grade 2 within 
24 hours (like glucose changes, hypokalemia, hypomagnesaemia, 
hypophosphatemia, and hyponatraemia) will be considered dose 
limiting, unless patient had metabolic abnormalities at baseline. 
Grade 4 metabolic toxicities that are symptomatic will be considered 
dose-limiting regardless of duration or ability to correct.

Other Grade 3 lab abnormalities will only be considered a DLT if they 
do not resolve within 2 weeks.

Elevated bilirubin will not be considered a DLT unless >3.5 mg/dL
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4.3.1.2 Hematological Toxicity
The following hematological toxicity will be considered dose-limiting:

Grade 4 thrombocytopenia (<25,000/L)

Grade 4 (<500/L) neutropenia

Grade 3 (<1000/L) neutropenia associated with fever (Febrile 
neutropenia) will be considered dose-limiting
4.4
Toxicity Management: Dose Delays and Discontinuation
Dosing with Yttrium-90 will follow standard of care procedures, and there will be no dose 
modifications. 
Any patient who receives at least one dose of nivolumab will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity by laboratory 
results and physical exam at each study visit, according to CTCAE 4.03. 
Nivolumab may be delayed or discontinued following the instructions detailed in section 
4.4.1. 
In addition, nivolumab should be discontinued for toxicities as outlined in section 4.4.2. 
4.4.1
Dosing delays
There will be no dose modifications allowed for management of toxicities.
Patients will be allowed to delay nivolumab treatment by up to 6 weeks.  
Nivolumab administration should be delayed for the following until resolution to ≤ 
Grade 1 or baseline: 

Any Grade ≥ 2 non-skin, drug-related adverse event, with the following 
exceptions: 
o
Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 

Any Grade 3 skin, drug-related adverse event

Any Grade 3 drug-related laboratory abnormality, with the following 
exceptions for lymphopenia, leukopenia, AST, ALT, or total bilirubin:
o
Grade 3 lymphopenia or leukopenia does not require dose delay
o
If a subject has a baseline AST, ALT or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity 
o
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 or 
2 toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity
o
During Cycle 1, a delay in dosing is not required for Grade 3 total 
bilirubin ≤3.5mg/dL
NOTE: If bilirubin worsens after the first dose of nivolumab, a delay in 
dosing may be warranted per physician discretion.

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 immune-oncology agents may mitigate 
severe toxicity. Management Algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:
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•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in the nivolumab Investigator Brochure and 
appendix 3 of this protocol.
4.4.2
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 4.03) guidelines. 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate: 
NCI CTCAE Grade
Treatment
Premedication at subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Remain at bedside and monitor 
subject until recovery from 
symptoms. 
The following prophylactic pre-
medications are recommended for 
future infusions: 

Diphenhydramine 50 mg (or 
equivalent) and/or

Acetaminophen/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 [e.g., 
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 (please follow 
stability instructions in section 
8.2.4) ; if no further complications 
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 100 mg of 
SoluCortef or equivalent) may be 
used.
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NCI CTCAE Grade
Treatment
Premedication at subsequent dosing
ensue after 30 minutes, the rate 
may be increased to 100% of the 
original infusion rate. 
Monitor subject closely. If 
symptoms recur, then no further 
nivolumab will be administered at 
that visit.
Grades 3 or 4
Severe reaction, 
Grade 3: prolonged 
[i.e., not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion]; recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae [e.g., 
renal impairment, 
pulmonary infiltrates]. 
Grade 4: Life-
threatening; pressor or 
ventilatory support 
indicated
Immediately discontinue infusion of 
nivolumab. 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 (e.g., 
appearance of a localized or 
generalized pruritus within 1 week 
after treatment), symptomatic 
treatment may be given (e.g., oral 
antihistamine or corticosteroids
No subsequent dosing
4.4.3
Treatment Discontinuation Criteria:
Tumor assessments for all subjects should continue every 8 weeks or 12 weeks 
once beyond 13 months of therapy, as per protocol, even if dosing is held or 
delayed. 
Nivolumab treatment should be permanently discontinued for the following: 
•
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the 
re-treatment period OR requires systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions: for laboratory abnormalities, drug-related uveitis, 
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pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, 
and endocrinopathies:
-
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
-
Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation
-
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except:
•
Any Grade 3 drug-related thrombocytopenia > 7 days or associated 
with bleeding requires discontinuation
•
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
-
AST or ALT > 5-10 x ULN for > 2 weeks
-
AST or ALT > 10 xULN
-
Total bilirubin > 5 x ULN
-
Concurrent AST or ALT > 3 xULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation:
-
Grade 4 neutropenia ≤7 days
-
Grade 4 lymphopenia or leukopenia
-
Isolated Grade 4 amylase or lipase abnormalities that are not 
associated with symptoms or clinical manifestations of pancreatitis. The 
PI and DSMC should be consulted for Grade 4 amylase or lipase 
abnormalities.
-
Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae   and   are   corrected   with   
supplementation/appropriate   management   within72 hours of their 
onset
-
Grade  4  drug-related  endocrinopathy  adverse  events,  such  as  
adrenal  insufficiency, ACTH deficiency, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with 
physiologic hormone replacement (corticosteroids, thyroid hormones) or 
glucose-controlling agents, respectively, may not require 
discontinuation.
•
Any event that leads to interruption in dosing lasting > 6 weeks from the 
previous dose requires discontinuation, with the following exceptions:
-
Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruptions lasting > 6 weeks from the previous 
dose, the PI and DSMC must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. Periodic study visits 
to assess safety and laboratory studies should also continue every 6 
weeks or more frequently if clinically indicated during such dosing 
interruptions.
-
Dosing interruptions lasting > 6 weeks from the previous dose that occur 
for non-drug-related reasons may be allowed if approved by the PI and 
DSMC. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the PI and DSMC must be consulted. 
Tumor assessments should continue as per protocol even if dosing is 
interrupted. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing 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.
4.4.4
Treatment with nivolumab beyond progression
In the event of an initial assessment of PD (based on RECIST Version 1.1), a 
subject may continue to receive the assigned study treatment as long as none of 
the criteria listed below are met. Criteria for discontinuation of investigational 
product include:

Confirmed PD without clinical benefit: An initial assessment of PD by RECIST 
Version 1.1 will be confirmed by a repeat evaluation at the next tumor 
assessment time point, but no sooner than 4 weeks later (see Section 6.3.3 
for disease evaluation). Patients with confirmed PD at this time should be 
discontinued. However, if a patient with confirmed PD is still receiving clinical 
benefit in the investigator’s opinion, study drug may be continued after 
discussion and agreement between the treating physician and PI. 

Meets any of the other investigational product discontinuation criteria (Section 
4.4.3) 

Clinical symptoms or signs indicating significant PD such as the benefit-risk 
ratio of continuing therapy is no longer justified. 

Decline in ECOG performance status.

Threat to vital organs/critical anatomical sites (e.g., spinal cord compression) 
requiring urgent alternative medical intervention, and continuation of study 
therapy would prevent institution of such intervention. 
If the lesions included in the tumor burden subsequently regress to the extent 
that the criteria for PD are no longer met, then treatment may continue according 
to the treatment schedule. 
4.5
Concomitant Medications/Treatments
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from the trial may be 
required. The investigator should discuss any questions regarding this with the PI. The final 
decision on any supportive therapy or vaccination rests with the investigator and /or the 
subject’s primary oncologist. However the decision to continue the patient on trial therapy 
or vaccination schedule requires the mutual agreement of the Investigator, the study 
Quality Assurance Monitor (QAM) and the subject. 
4.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare, 
with the exception of those listed in section 4.5.2, 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 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 from the time of informed consent until 30 days 
after the last dose of trial treatment should be recorded. Concomitant medications 
administered past 30 days after the last dose of trial treatment should be recorded 
if given in relation to SAEs. 
Patients who are on treatment for hepatitis B and C will be allowed to continue 
their medications while on study with close monitoring from their treating 
hepatologists. 
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4.5.2
Prohibited Concomitant 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 within 28 days 
of registration.  

Investigational agents within 28 days of study registration.

Radiation therapy within 14 days of registration

Live vaccines within 28 days prior to study registration and while 
participating in the trial.  Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; 
however intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed at any time during the study. 

Glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. However, 
patients are allowed to use bronchodilators or local steroid injections if 
clinically necessary. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary.
The Exclusion Criteria describes other medications, which are prohibited in this 
trial. There are no prohibited therapies during the follow-up phase
4.6
Other Modalities or Procedures
Radioembolization therapy is performed in a two-step process: a diagnostic angiogram and 
Technetium-99 macroaggregated albumin (99Tc-MAA) scan, followed by the treatment 
session. Y90-specific informed consent will be obtained. Prior to the administration of Y90, 
a mesenteric angiogram is performed to determine the tumor’s blood supply, aberrant 
anatomy and to ensure proper catheter position. Using a unilateral femoral approach, 
selective catheterization of the hepatic artery will be performed. Vascular access is 
obtained via the common femoral artery and a guidewire advanced under fluoroscopic 
guidance. A 5-F sheath is then inserted over the guidewire. The superior mesenteric artery 
is selected and an angiogram performed. 
4.7
Duration of Therapy
Y-90 will be administered at the start of the study. A single Y-90 treatment will be 
performed, and nivolumab treatment will start 7-14 days later to allow for full recovery. 
Additional Y-90 treatments may be allowed after discussion with the principal 
investigator**. 
Subjects will receive study treatment (nivolumab) until disease progression (see section 
4.4.3 for details on treatment beyond initial progression), intolerance due to toxicity or 
withdrawal from the study either by the patient or at the recommendation of the treating 
oncologist. The study may be stopped sooner, for, toxicity, IRB stopping the study, FDA 
stopping the study, sponsor stopping the study, principal investigator stopping the study, 
subject has a positive pregnancy test, use of illicit drugs, non-compliance, deterioration to 
ECOG level 4, progression of HCC, withdrawal of consent (regardless of reason), 
variceal bleeding, or death. Patients will be assessed for response by CT scan or MRI 
every 8 weeks (2 cycles) for the first 13 months, and every 12 weeks (3 cycles) 
thereafter.
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**Repeat therapy to the treated lesion or additional untreated lesions may be warranted. 
If a patient requires additional Y-90 after starting nivolumab treatment, it may be given 
once approval from the interventional radiologist and treating physician has been 
confirmed. In such cases, nivolumab should be held for ≥7 days prior to administering Y-
90. Nivolumab can be resumed at least 7 days after receiving additional Y-90, and can be 
delayed for up to 4 weeks if needed.
4.8
Duration of Follow Up
Once a patient comes off study treatment for any reason other than death, an End of 
Treatment visit should occur 30 days (+/- 7 days) after the last dose of nivolumab.
Patients will be followed for survival for up to 2 years after treatment discontinuation. If a 
patient discontinues treatment prior to 24 weeks (6 cycles), they should undergo follow-
up (either by routine clinic visit or by phone call) every 2 weeks until the end of the 24-
week period from start of study treatment to document survival and disease progression. 
After this period, patients should be followed for survival every 6 months for 2 years (by 
routine clinic visit or phone call). Patients should also be followed for SAE’s for 100 days 
after discontinuing study drug.
4.9
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study 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 will be 
documented and may include:

Any event which, in the opinion of the investigator/sub-I’s opinion, requires 
termination of the study/study medications (including non-compliance)

At the request of the subject (Withdrawal of consent)

At the request of a regulatory body (FDA, NU IRB)

Patients with a positive beta-HCG test (consistent with pregnancy)

Use of illicit drugs or other substances that may contribute to toxicity

Deterioration of PS to ECOG 4

Progression of disease, as evidenced by radiologic progression and/or clinical 
status is worsening, subject not benefiting from the study drug.

Development of a second cancer

Subject is lost to follow-up

More than two Y-90 treatments

Grade 4 hyperbilirubinemia (high bilirubin) defined by the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 of bilirubin more than 10 times 
the upper limit of normal, 

The Northwestern University Institutional Review Board/Office for the Protection 
of Research Subjects (offices at Northwestern that protects study patients) stops 
the study. 

Death
The study will be stopped if 2 of the first 5 patients receiving (Y-90 + nivolumab) 
develop grade 4 hyperbilirubememia (>10) OR a death occurs believed to be 
related to therapy and not due to the natural progression of liver disease and liver 
cancer.
4.10
Patient Replacement
Any patient who signs consent but does not receive study treatment may be replaced. In 
addition, any study patient who receives Y-90 but discontinues prior to treatment with 
nivolumab can be replaced. This includes patients who cannot start nivolumab within 4 
weeks of Y-90 treatment, who must come off study.
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5.0
STUDY PROCEDURES
Screening1
On Treatment
(1 cycle = 28 days)
Off Treatment
Time Period
Baseline
Induction 
Treatment9
Cycle 110 
(± 3 days)
Cycle 2+
(± 3 days)
End of 
Treatment13
Follow-
up14
D1 
D15
D1
D15
Assessment or 
Activity
Informed Consent
X
Medical history 
X
Physical exam2
X
X
X
ECOG status
X
X
X
Adverse Events & 
ConMeds
X
X
X
X
X
X
Tumor Measurement 3 
X
X3
X3
Coagulation studies 
(INR, PT, PTT)4
X4
Child-Pugh Class
X
X
CBC with diff5 
X5
X
X
X
X
X
Chemistry panel6 
X6
X
X
X
X
X
AFP
X
X
X
TSH with reflex T3, T4
X
X
Hepatitis Panel7
X
X
Urinalysis
X
X
Pregnancy Test8
X
X
X
X
ECG
X
Angiogram9
X
Y-90 9
X
Nivolumab 10
X
X
X
X
Correlative studies11
X
X
X11
Archival tissue 
collection12
X
Survival status14
X
1 All screening procedures should take place within 28 days of registration unless noted otherwise.
2 Includes vital signs (pulse, respirations, blood pressure), height (baseline only) and weight.

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3 Imaging will be performed at screening, 21-28 days after Y-90 administration (during Cycle 1), and every 2 cycles (starting with Cycle 3 Day 1, ±7 
days) for the first 13 months. Imaging will then occur every 3 cycles (±7 days) until disease progression or treatment discontinuation. Imaging 
will include either CT of Chest/Abdomen/Pelvis or MRI as indicated. Contrast should be used to the greatest extent possible (see section 
6.1 for details).
4 Coagulation studies will be performed at the time of the screening angiogram. Patients who are on Coumadin will require their INR to be checked 
every cycle or according to the treating oncologist. If patient is on low molecular weight heparin, an Anti-Xa level should be tested to ensure 
it is within therapeutic range
5 CBC with differential will include WBC, ANC, ALC, Platelets, and Hemoglobin. CBC should be collected within 14 days prior to registration and 
reviewed prior to each nivolumab treatment.
6 Chemistry panel will be drawn at screening (within 14 days prior to registration) and pre-dose at all treatment visits. Chemistry panel will include 
glucose, calcium, albumin, ALT, AST, sodium, potassium, total bilirubin, alk phos, and creatinine. 
7 Full hepatitis panel at screening including HBsAg, HBeAg, and HBV DNA. If active hepatitis will need to see hepatologist and begin treatment 
prior to starting on study. Patient should have viral load < 100 IU/mLprior to nivolumab infusion. See inclusion criteria 3.1.5 for hepatitis B 
requirements for eligibility. 
8 FOCBP can have either a serum or urine pregnancy test within 7 days prior to registration (note: this may be completed as part of the 
angiogram), prior to Y-90 treatment (pregnancy testing is a standard procedure before Y-90), and within 24 hours prior to starting 
nivolumab treatment (scheduled for C1D1). 
9 Prior to registration, patients will undergo a planning angiogram in IR to determine doses of Y-90. Since Y-90 administration is usually planned 
around 7 days from the angiogram, screening procedures and registration should be planned accordingly.
10 Patients will receive IV nivolumab starting with Cycle 1 Day 1, which is planned 7-14 days after the induction Y-90 procedure to allow for count 
recovery (Note: Patients can be treated with nivolumab up to 4 weeks after Y-90 in the case of TB or continuing side effects). During this 
break, patient will be evaluated by a medical oncologist as part of standard procedures. Starting with Cycle 1 Day 1, patients will begin 
treatment with intravenous nivolumab as maintenance either at 80mg or 240mg over 30 minutes (-5 minutes / +15 minutes) every 2 weeks 
(Day 1 & 15 of each cycle). Treatment will continue until disease progression, intolerable side effects, or patient withdraws consent or is 
removed from the study for any other reason.
11 Correlative blood work will be collected for all patients in a 10mL NaHep tube at baseline, post Y-90 treatment (pre-dose on Cycle 1 Day 1) and 
during nivolumab treatment as follows: pre-dose every 8 weeks for the first 24 weeks (C3D1, C5D1, and C7D1), and every 16 weeks 
thereafter (every 4 cycles starting with C11D1). This will be used for peripheral lymphocyte analysis and correlative studies as detailed in 
the protocol. 
12 If patient has archival tissue present, it will be collected after registration for next-generation sequencing (NGS) and immunohistochemistry as 
described in section 9.0 and the separate lab manual.
13 An End of Treatment visit should occur 30 days (+/- 7 days) after the last dose of nivolumab.
14 Patients will be followed for survival for up to 2 years after treatment discontinuation. If a patient discontinues treatment prior to 24 weeks (6 
cycles), they should undergo follow-up (either by routine clinic visit or by phone call) every 2 weeks until the end of the 24-week period from 
start of study treatment to document survival and disease progression. After this period, patients should be followed for survival every 6 
months for 2 years (by routine clinic visit or phone call). Patients should also be followed for SAE’s for 100 days after discontinuing study 
drug.

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6.0
ENDPOINT ASSESSMENT
6.1
Definitions
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) [6]. 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 start of study treatment. 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. 
Radiographic tumor assessments will be conducted at screening, 21-28 days after Y-90 
administration (during Cycle 1 of nivolumab), Cycle 3 Day 1 (±7 days, 1 cycle = 28 days) 
and every 2 cycles (±7 days) thereafter for the first 13 months. Imaging will then occur 
every 3 cycles (±7 days) until disease progression or treatment discontinuation. Imaging 
will include either CT of Chest/Abdomen/Pelvis or MRI as indicated. Contrast should be 
used to the greatest extent possible. 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 establishing the maximum tolerated dose for the 
combination therapy of nivolumab and Y-90. Patients who received at least one dose of 
nivolumab will be considered for evaluation. 
6.3
Secondary Endpoints
For the purposes of this study, patients who have received at least one dose of 
nivolumab will be considered for evaluation of the safety and toxicity profile of the 
combination therapy. 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. 
All patients should be re-evaluated for response 21-28 days after Y-90 then every 8 
weeks (every 12 weeks after 13 months) using RECIST criteria. 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.
Disease control rate will be determined at 24 months from the start of nivolumab 
treatment by the sum of complete response, partial response and stable response 
according to measurement of target and non-target lesions as described below.
Patients who have a response sufficient enough where by shrinkage of the tumors 
allows them to be considered for transplant will be determined by established BCLC 
transplant guidelines for individual tumor sizes. 
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 
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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.
6.3.1
Definitions:
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with nivolumab. 
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. RECIST measurements should be used when available. When 
RECIST measurements cannot be made due to infiltrative disease, evaluable 
disease needs to be confirmed by pathology. 
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. 
6.3.2
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 
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themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non- nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
6.3.3
Response criteria
6.3.3.1 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.
6.3.3.2 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 confirmed at a later 
time by the review panel (or Principal Investigator). 
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6.3.3.3 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)
6.3.3.4 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. 
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to NOTIS 
for additional information). The level of risk attributed to this study requires High Intensity 
Monitoring as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.  
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 and 7.2.5 for time points). 
In addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
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7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality:

results in study withdrawal

is associated with a serious adverse event

is associated with clinical signs or symptoms

leads to additional treatment or to further diagnostic tests

is considered by the investigator to be of clinical significance
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available 
at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
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7.2.3
Serious Adverse Event
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 100 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be reported 
as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency.
7.2.4 
Unanticipated Problems Involving Risks to Subject or Others
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.   
7.2.5
Adverse Event Reporting Period
For this study, adverse events will be followed from the time of informed consent 
until 30 days following the last administration of study treatment. SAE’s will also 
be collected from the time of consent until 100 days following the last 
administration of study treatment. For patients registered and never treated with 
study drug, SAE’s should be collected for 30 days from the date of consent.
7.2.6
Preexisting Condition
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period.
7.2.7
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event. 
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7.2.8
Post-study Adverse Event
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.  The investigator should notify the DSMC of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should 
also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a 
subject that has participated in this study. 
7.2.9
Abnormal Laboratory Values
All clinical laboratory abnormalities should be documented as adverse events.
7.2.10
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should 
be documented as an adverse event if the condition meets the criteria for and 
adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances:

Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study.

Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator.
7.2.11
Reporting of Serious Adverse Events
If a previous adverse event that was not initially deemed reportable is later 
found to fit the criteria for reporting, the study sponsor will submit the adverse 
event in a written report to the FDA as soon as possible, but no later than 15 
calendar days from the time the determination is made.
7.2.12
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event.  All 
occurrences of potential DILIs, meeting the defined criteria, must be reported 
as SAEs. Potential drug induced liver injury is defined as:
1.
ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND
2.
Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase)
AND
3.
No other immediately apparent possible causes of AST/ALT elevation 
and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-
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existing chronic or acute liver disease, or the administration of other 
drug(s) known to be hepatotoxic.
7.2.13
Pregnancy
If, following initiation of the investigational product, it is subsequently 
discovered that a study subject is pregnant or may have been pregnant at the 
time of investigational product exposure, including during at least 6 half lives 
after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety). 
The investigator must immediately notify Worldwide Safety @BMS of this 
event via the Pregnancy Surveillance Form in accordance with SAE reporting 
procedures. 
Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable, offspring information 
must be reported on the Pregnancy Surveillance Form [provided upon request 
from BMS]
Any pregnancy that occurs in a female partner of a male study participant 
should be reported to BMS. Information on this pregnancy will be collected on 
the Pregnancy Surveillance Form.
7.2.14
Overdose
An overdose is defined as the accidental or intentional administration of any 
dose of a product that is considered both excessive and medically important. 
All occurrences of overdose must be reported as an SAE.
7.3
Adverse Event Reporting
7.3.1
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 and Safety Monitoring Committee (DSMC) according to 
the study’s phase and risk level, as outlined in the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
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
the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM (as well as BMS – see 
section 7.3.3.3) 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 DSMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)

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.
7.3.3.3 Reporting to Bristol Myers Squibb
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 209-615). 
The assigned study coordinator will facilitate all reporting to the 
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
Yttrium-90 (Theraspheres)
8.1.1
Other names 
TheraSphere®-MDS Nordion 
8.1.2
Classification - type of agent
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Insoluble glass microspheres where yttrium-90 is an integral constituent of the 
glass.
8.1.3
Mode of action
Yttrium-90, a pure beta emitter, decays to stable zirconium-90 with a  physical half-
life of 64.2 hours (2.67 days). The average energy of the beta emissions from 
yttrium-90 is 0.9367 MeV. Following embolization of the yttrium-90 glass 
microspheres in tumorous liver tissue, the beta radiation emitted provides a 
therapeutic effect. The microspheres are delivered into the liver tumor through a 
catheter placed into the hepatic artery that supplies blood to the tumor. The 
microspheres, being unable to pass through the vasculature of the liver due to 
arteriolar capillary blockade, are trapped in the tumor and exert a local 
radiotherapeutic effect with some concurrent damage to surrounding normal liver 
tissue.
8.1.4
Storage and stability
Each TheraSphere dose vial contains one of six available dose sizes of yttrium-
90, a high-energy beta emitter. Even with low-density materials such as the acrylic 
vial shield, the attenuation of beta particles gives rise to Brehmsstrahlung radiation 
that requires lead shielding. Users should avoid exposure by leaving the vial in the 
acrylic product container, and by leaving the acrylic container in the lead shield as 
much as possible. The use of additional shielding is recommended. Finger-ring 
dosimeters should be worn in the orientation most likely to record the highest 
exposure to the fingers. The TheraSphere dose vial should not be removed from 
its acrylic vial shield. It should be stored in the lead pot and acrylic shield in which 
it is packaged. The TheraSphere dose vial, TheraSphere Administration Set and 
TheraSphere Administration Accessory Kit should be stored at room temperature. 
The requirements of the applicable regulatory agency for safe handling and 
storage of radioactive materials should be consulted and must be followed.  
8.1.5
Protocol dose specifics
According to Treatment Plan. The amount of radioactivity required to deliver the 
desired dose to the liver may be calculated using the following formula:  
The liver volume and corresponding liver mass may be determined using CT or 
ultrasound scans. 
For the purpose of ordering TheraSphere, use the Yttrium-90 Physical Decay 
Table (according to appendix 4 Table 3) to determine the appropriate time of 
injection. For determining the actual liver dose (Gy) delivered to the liver after 
injection, the following formula is used: 
where F is the fraction of injected radioactivity localizing in the lungs, as 
measured by Tc-99m MAA scintigraphy. The upper limit of injected activity 
shunted to the lungs is F x A = 0.61 GBq. 
8.1.6
Preparation and Route of Administration
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The entire contents of the TheraSphere dose vial are administered to the patient. 
The administration instructions must be followed to optimize delivery of the 
calculated dose. 
1. Place the Accessory Kit on an appropriate platform, remove the top shield and 
place the TheraSphere dose vial in its lead pot into the pot holder in the acrylic box 
base. Adjust the catheter extension arm to the desired position by pulling out the 
spring lock. Place the hook in its holder on the side of the kit. 
2. Turn the radiation dosimeter 'ON', set it to the 'dose rate - mR/h' setting, and 
then secure the dosimeter to the holder located on the acrylic box. Record the 
stabilized dose rate reading as the initial reading. 
3. Remove the sterile Administration Set and empty vial from the packaging and 
place them next to the acrylic box on a sterile surface such as a sterile towel or 
drape. 
4. Insert the piercing bag spike into the flushing fluid bag, and hang the bag on the 
hook provided on the kit. 
5. Insert the vented vial spike into the sterile empty vial and place the vial in its 
stand on the exterior of the kit. Snap the relief valve line within the gripper clip A. 
6. Remove the red shield cap from the plunger assembly and place sterile 
absorbent material under plunger assembly. 
7. Fill and discharge the syringe to remove air from the Administration Set inlet and 
outlet lines. Visually determine that there are no air bubbles in the lines. Verify that 
there are two steady streams of sterile solution flowing from the plunger assembly. 
8. Remove the lead pot lid from the TheraSphere dose vial. Remove the tamper- 
evident seal from the top of the acrylic vial shield using a remote handling tool. 
Then remove the acrylic plug. The acrylic plug may be removed by placing surgical 
tape onto the plug and lifting upward. 
9. Swab the exposed top of the dose vial septum with disinfectant using a remote 
handling tool such as a Kelly clamp 
10. Push the plunger assembly into the top of acrylic TheraSphere vial shield until 
a "click" or "snap" is heard or felt. 
11. Place the tubing set through the appropriate openings in the acrylic box. The 
inlet line B goes through opening B on the near side of the box and the outlet line 
D goes through the U-shaped opening D on the catheter side of the box. Loop the 
line around the side of the acrylic box so that connection C rests in the priming 
valve holder C. 
12. Insert the inlet and outlet needles into the vial by pushing the plunger tabs 
down with sufficient force until a "click" or "snap" is heard or felt. 13. Disconnect the 
outlet line luer fitting E from the priming extension line and firmly connect the outlet 
line luer E to the patient catheter luer fitting. Place this luer connection firmly into 
the holder E on the end of the extension arm on the Accessory Kit. Ensure a 
vertical orientation of the lines and fittings with the outlet line luer connection above 
the patient catheter fitting. 
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14. Place the top shield lid on the Accessory Kit. Ensure that none of the lines 
(including the infusion catheter) are pinched or have a visible kink. Replace a 
kinked catheter before proceeding. 
15. Flush the TheraSphere microspheres into the patient by pushing approximately 
20 mL of sterile solution with the syringe. For subsequent flushes pull back on the 
syringe plunger to the back stop of the syringe and then push the plunger again. 
Repeat dose vial flushing until electronic dosimeter reading indicates that an 
appropriate proportion of TheraSphere microspheres have been delivered to the 
patient catheter. A minimum of 3 flushes for a total of 60 mL is recommended. The 
dose vial (still in lead pot) can be gently shaken or tapped to release microspheres 
that may have become trapped on the top of the product vial during shipping. Note: 
Excessive force on the syringe will result in fluid being transferred through the 
pressure relief valve into the attached empty vial. If this occurs, reduce the infusion 
syringe force until there is no fluid flow into the empty vial. 
16. Once the infusion is complete, cut the inlet line at the indicated position 
upstream of the check valve. Monitor the radiation fields along the lines and use 
remote handling tools to handle areas where radiation fields may be present. Do 
not disconnect the catheter inlet luer fitting from the outlet line. Remove the 
catheter from the patient, and place it into the Nalgene waste container (within the 
acrylic shielding container) with all potentially contaminated materials including the 
acrylic vial shield with the needle plunger assembly still attached, as well as outer 
gloves. Seal the Nalgene container cap in place and place the top lid on the acrylic 
shielding container. Remove the waste for disposal. 
17. Appropriate radiation protection measures must be employed to remove 
draping materials. The room, equipment and personnel must be monitored for any 
potential radioactive contamination.
8.1.7
Incompatibilities
The use of TheraSphere is contraindicated in patients: 

whose Tc-99m macroaggregated albumin (MAA) hepatic arterial perfusion 
scintigraphy shows any deposition to the gastrointestinal tract that may not 
be corrected by angiographic techniques (see package insert);  

who show shunting of blood to the lungs that could result in delivery of 
greater than 16.5 mCi of yttrium-90 to the lungs. Radiation pneumonitis has 
been seen in patients receiving doses to the lungs greater than 30 Gy  in a 
single treatment (see package insert);  

in whom hepatic artery catheterization is contraindicated; such as patients 
 with vascular abnormalities or bleeding diathesis;

  who have severe liver dysfunction or pulmonary insufficiency; and  

 who present with complete occlusion of the main portal vein (see package 
 insert). 
8.1.8
Availability & Supply 
Commercially available 
8.1.9
Side effects
Yttrium-90 (Theraspheres) – expected adverse events
Based on clinical and preclinical animal experience with TheraSphere and other 
yttrium-90 microspheres, certain adverse reactions have been identified [4-6, 15, 
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16, 17, 18]. Serious adverse events that occurred under clinical studies and that 
were definitely, probably or possibly related to TheraSphere, or if the relationship 
was unknown, are summarized in Table 1. In addition to these serious adverse 
events, lymphocyte depression, which may be graded as moderate to severe but 
with no clinical sequellae, is expected to occur in some patients.
The introduction of microspheres into the vasculature of the stomach, duodenum 
or other organs of the gastrointestinal tract may cause chronic pain, ulceration and 
bleeding. Microsphere shunting to the lungs may cause edema and fibrosis that 
may not be reversible.
Extrahepatic shunting may be identified through the injection of Tc-99m MAA into 
the hepatic artery [19,20]. Flow of radioactivity to the gastrointestinal tract may be 
avoided by the use of balloon catheterization or other angiographic techniques to 
block such flow [21]. In addition, placement of the delivery catheter in the hepatic 
branch distal to collateral vessels provides a safety margin with respect to 
inadvertentdeposition of microspheres.
Some adverse events observed may be explained by the effect of attenuated 
radiation from the treated liver. Pleural effusion may be caused by attenuated 
radiation when the treated tumor is positioned proximal to the base of the lung. 
Similarly, treatment of tumors in the left lobe of the liver, in proximity to the gut, 
may explain some of the gastrointestinal events observed. Putative attenuated 
radiation effects to extrahepatic structures have generally been found to resolve 
over time.
The use of this product leads to irradiation of both tumorous and normal liver tissue. 
As a result, patients with diseases that compromise the functioning of their normal 
liver tissue or patients with either diffuse tumors or a high tumor burden may be at 
greater risk of liver function impairment.
A number of patient baseline characteristics, indicative of either impaired normal 
liver function or tumor status, correlated with a higher incidence of liver-related 
serious adverse events in clinical trials.
A retrospective study of 121 patients from 5 clinical trials has shown that the 
following 5 Pre-treatment High Risk Factors have been associated with at least 
48% of all serious adverse events that were possibly related to use of the device 
and with 11 of the 12 deaths that were possibly related to use of the device:
• infiltrative tumor type
• “Bulk disease” (tumor volume > 70% of the target liver volume, or tumor nodules 
too numerous to count)
• AST or ALT > 5 times ULN
• bilirubin > 2 mg/dL
• tumor volume > 50% combined with an albumin < 3 g/dL
8.1.10
Nursing implications
Radioactive products should be used only by physicians who are qualified by 
specific training in the safe use and handling of radionuclides and whose 
experience and training have been approved by the appropriate government 
agency authorized to license the use of radionuclides. Adequate shielding and 
precautions for handling radioactive material must be maintained. As in the use of 
any radioactive material, care should be taken to ensure minimum radiation 
exposure to the patient extraneous to the therapeutic objective and to ensure 
minimum radiation exposure to workers and others in contact with the patient. 
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Since adequate studies have not been performed in animals to determine whether 
this device affects fertility in males or females, has teratogenic potential, or has 
other adverse effects on the fetus, this product should not be administered to 
pregnant or nursing women unless it is considered that the benefits to be gained 
outweigh the potential hazards. Ideally the use of this radioactive device in women 
of childbearing capability should be performed during the first few (approximately 
10) days following the onset of menses. Dose rate to personnel should be 
monitored during administration. Any spills or leaks must be cleaned up 
immediately and the area monitored for contamination at the end of the procedure. 
The TheraSphere dose vial is supplied secured within a clear acrylic vial shield to 
limit radiation exposure to personnel. The dose rate at the vial shield surface is still 
high enough to require caution including the use of tongs and a lead shielded 
container when possible. The TheraSphere dose vial should always be stored in a 
shielded location away from personnel. 
8.2
Nivolumab
8.2.1
Other names 
ONO-4538, BMS-936558, or MDX1106, Opdivo
8.2.2
Classification - type of agent
Human IgG4 anti-PD-1 monoclonal antibody
8.2.3
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.
8.2.4
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 or 5% Dextrose solution in IV containers made of polyvinyl chloride (PVC) 
or non-PVC material. Opened or accessed vials should be immediately used to 
prepare the infusion solution in the IV bag and the infusion solution should be 
immediately administered. 
After preparation, store the Nivolumab infusion either:

at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container 
and time for administration of the infusion or

under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation.

Do not freeze.
8.2.5
Protocol dose specifics
The first 3 patients in Phase I will be dosed at 80mg q2weeks. Patients will then 
be dosed at 240mg q2weeks, and the study will continue into Phase Ib provided 
240mg is the MTD.  
Nivolumab is to be administered as an approximately 30-minute IV infusion, 
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% Sodium Chloride or 5% 
Dextrose for delivery with minimum allowable concentration of 0.35% mg/mL.  It 
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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. 
8.2.6
Preparation
Refer to most recent investigator’s brochure for nivolumab preparation 
instructions.  
8.2.7
Route of administration for this study
Nivolumab will be given as an 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 in-line filter. At the end of the infusion period, flush the line 
with a sufficient quantity of approved diluents.
8.2.8
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. 
No formal pharmacokinetic drug-drug interaction studies have been conducted 
with nivolumab. 
8.2.9
Availability & Supply 
The supply for this study will be investigational – not commercially available. 
Supply will be provided by BMS free of charge. Nivolumab will be supplied as 
100 mg/vial (10mg/mL). Drug is protocol specific, but not patient specific.
A supply of nivolumab may be ordered from by completing a Drug Request Form 
provided by BMS. The first request may take place upon screening of the first 
patient. The initial order should be limited to 20 vials. Allow 5 business days for 
shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug product will be shipped by courier in a 
temperature-controlled container. It is imperative that only drug product 
designated for this protocol number be used for this study.
Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date.  Deliveries will be made Tuesday through 
Friday.
When assessing need for resupply, keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. 
8.2.10
Side effects
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%)
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Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): ventricular arrhythmia, iridocyclitis, infusion-related reactions, 
increased amylase, increased lipase, dizziness, peripheral and sensory 
neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
Deaths thought to be related to nivolumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people).
For the most recent safety update, please refer to the current Investigator’s 
Brochure or Study Agent Prescribing Information.
8.2.11
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.
Table 8.1 – Nivolumab Product Information
Product 
Description 
and Dosage 
Form
Potency
Primary 
Packaging
(Volume)/ 
Label Type
Appearance
Storage 
Conditions
(per label)
Nivolumab 
BMS-936558-01 
Solution for 
Injectiona
100 mg 
(10 
mg/vial)
10 mL vial
Clear to 
opalescent 
colorless to pale 
yellow liquid. 
May contain 
particles
2 to 8ºC. 
Protect form 
light and 
freezing
9.0
CORRELATIVES/SPECIAL STUDIES
The goal of the planned laboratory correlative studies is to identify biomarkers that help predict 
benefit and/or toxicities from the study drug. A separate Laboratory Manual will be developed and 
maintained with detailed sample collection and procurement guidelines, processing instructions, 
and additional assay descriptions. The Laboratory Manual will also include all contact information 
for key personnel and departments involved with correlative studies for this protocol.
9.1
Sample Collection Guidelines
Peripheral blood samples will be collected for all patients pre-dose on Cycle 1 Day 1 as 
well as every 8 weeks for the first 24 weeks, and every 16 weeks thereafter. 
If patient has archival tissue available, it will be collected for next-generation sequencing 
(NGS) and immunohistochemistry (IHC). See lab manual for collection details.
9.2
Sample Processing, Storage, and Shipment
All samples will be processed by PCF-CTU according to instructions in the lab manual. 
Samples will be labeled with the subject’s de-identified study number and collection date.
 
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9.3
Assay Methodology
9.3.1
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 a pathologist. 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.
9.3.2
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 co-expression 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. 
9.4
Specimen Banking
Patient samples collected for this study will be retained at the Northwestern University 
Biorepository. 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. Aparna Kalyan 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
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10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
This is a single-center Phase I/Ib study aiming to evaluate the safety, efficacy, and 
tolerability of nivolumab combined with therasphere, Y-90, in patients with advanced 
hepatocellular carcinoma. 
The expected number of patients on dose escalation will be in the range of 9-15 based 
on the 3+3 design. Six patients will be treated at the MTD in the dose escalation phase.  
The dose calculation for Yttrium-90 Therasphere will be done according to standard 
protocol at Northwestern Memorial Hospital. Please note - details of this are located in 
section 8.1.
 
Phase Ib Expansion Cohort:
A Simon two stage optimum Phase II design (1989) will be used to test the null 
hypothesis that the response rate is 10% versus an alternative hypothesis of 30 [36].  Up 
to 29 evaluable patients will be entered into Phase 1b.  The 6 patients at the MTD in 
Phase 1 will be counted as part of the 29 in Phase 1b.  In the first stage, 10 patients will 
be entered.  If none or 1 show a response, then consideration will be given to trial 
termination due to inactivity of the treatment.  If 2 or more of 10 show a response, then an 
additional 19 patients will be added.  If 5 or fewer of 29 show a response, then the trial 
will conclude that the response rate could be as low as 10%.  If 6 or more respond, then 
the trial will conclude that the response rate is greater than 10%.  This design has a 20% 
chance of falsely concluding the rate is 10% (Type II error = 20%), and a 5% chance of 
falsely concluding that the rate is greater than 10% (Type I error = 5%).  There is a 74% 
chance that the trial will show 0 or 1 responses in the first stage if the true response rate 
is 10%.  
For the total sample size, Phase 1 requires 9-15 patients, Phase 1b requires 29 patients 
in a two-stage optimum Simon design.  The 6 at the MTD in Phase 1 are counted as part 
of the 29.  This would require up to 15 in Phase 1, 23 new patients in Phase 1b for a total 
of 38 patients.  Target accrual is 40 patients to account for potentially unevaluable 
patients.  
Treatment duration:
Treatment will continue until disease progression (imaging done every 8 weeks), 
intolerable side effects, or patient withdraws consent or is removed from the study for any 
other reason.
10.2
Data Analyses Plans
Any subject who has received the investigational combination will be analyzed in an 
intention to treat format. The MTD will be determined as described in Section 4.3.  
Objective response rate (ORR = CR + PR) as defined in Section 6.3.3.1 and disease 
control rate (CR+PR+SD) will be calculated and a 95% confidence interval for response 
will be obtained using the methods of Porcher and Desseaux (2012) [37].  Progression-
free survival will be summarized using the Kaplan-Meier product limit curve.  Besides the 
required reporting of adverse events, adverse events will be summarized for all patients 
in the trial by type, duration, severity, timing and attribution (probable cause of adverse 
event).  Whole exome sequencing and computational analyses will be performed to 
assess mutanome and immunome (subpopulations of immune cells).  Change in clonal 
burden landscape of various mutanome and immunome will be analyzed to investigate its 
correlation with treatment response or development of resistance to treatment. 
11.0
STUDY MANAGEMENT
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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
Subject Recruitment and Screening
Subjects will be recruited through hepatology clinic, hepatocellular carcinoma clinic, pre-
transplant clinic and medical oncology clinics.  They will be identified by the PI, or 
referred to the PI from other hepatologists, transplant surgeons or medical oncologists.  
The PI or sub-investigator will discuss the protocol with potential subjects (patients from 
one of the above clinics) that may qualify for the study based on the inclusion/exclusion 
criteria in this protocol.  If the patient is interested they will discuss the study in depth and 
if they prefer, they can take home information (combination consent/HIPAA form) on the 
study to discuss with their family/significant other/primary care provider.
Once a potential subject decides they’d like to participate in the study they will come in to 
meet with the research coordinator/PI and/or sub-I to sign the consent after any other 
questions are answered.  It is only after the informed consent is signed that any study-
related procedures can be performed.  The subject will be given a signed copy of the 
informed consent and the consent process will be documented in the subject’s medical 
record.
11.3
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 Bristol-
Meyers Squibb. Amendments will be distributed by the lead institution (Northwestern) to 
all affiliate sites upon approval by the Northwestern University IRB.
11.4
Registration Procedures
For potential patients, study teams are asked to inform the QAM of the date and time that 
the patient will need to be registered (croqualityassurance@northwestern.edu).  
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)
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The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of 
registration to involved personnel. Registration will then be complete and the patient may 
begin study treatment. 
11.5
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document).  
Generally, all data for phase I patients during the time period patients are evaluated for 
Dose Limiting Toxicities (DLTs) must be submitted on a weekly basis. 
11.6
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission to the 
local IRB

A copy of the official IRB approval letter for the protocol and informed consent. 

CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation.
11.7
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 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. Please refer to study-specific data submission guidelines.
11.8
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. 
11.8.1
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. 
11.8.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
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A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.9
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. 
11.10
Publication Policy
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor (Dr. Aparna Kalyan) for the purposes 
of performing the study, will be published or passed on to any third party without the 
consent of Dr. Aparna Kalyan.  Results of this study may be used for teaching, research, 
publications, or presentations at scientific meetings.  
All potential publications and/or data for potential publications (e.g. manuscripts, articles, 
data, text, diagrams, abstracts, posters, charts, slides, pictures, or clinicaltrials.gov 
releases) must be approved in accordance with the policies and processes set forth in 
the Lurie Cancer Center DSMP. For trials that require high intensity monitoring, the 
assigned QAM will prepare a preliminary data summary (to be approved by the DSMC) 
no later than 3 months after the study reaches its primary completion date (the date that 
the final subject is examined or receives an intervention for the purposes of final data 
collection for the primary endpoint). If the investigator’s wish to obtain DSMC-approved 
data prior to this point (or prior to the point dictated by study design), the PI must send a 
written request for data to the QAM which includes justification. If the request is 
approved, data will be provided no later than 4 weeks after this request approval. The 
data will be presented to the DSMC at their next available meeting, and a final, DSMC-
approved dataset will be released along with any DSMC decisions regarding publication. 
The investigators are expected to use only DSMC-approved data in future publications. 
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Initial Version: 4/19/2016
Amendment 7: 07/16/2020
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The investigators should submit a copy of the manuscript to the biostatistician to confirm 
that the DSMC-approved data are used appropriately.  Once the biostatistician gives final 
approval, the manuscript may be submitted to external publishers. 
NU shall provide BMS with a copy of each Publication at the earliest practicable time, but 
in any event not less than thirty (30) days prior to its submission to a journal, publisher or 
meeting or fifteen (15) days prior to any public disclosure of any manuscript or other 
public disclosure (e.g., presentations). To the extent applicable, BMS personnel shall be 
acknowledged (including authorship where applicable) in accordance with customary 
scientific practice.
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NU Study Number: NU 16I01
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Amendment 7: 07/16/2020
53
REFERENCES
 1.
Altekruse, S. F., McGlynn, K. A. & Reichman, M. E. Hepatocellular carcinoma incidence, mortality, 
and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27, 1485–91 (2009).
2.
El-Serag, H. B. & Mason, A. C. Rising incidence of hepatocellular carcinoma in the United States. 
N. Engl. J. Med. 340, 745–50 (1999).
3.
Lin, S.-M. & Chu, C.-M. Secondary prevention of hepatitis C virus-related hepatocellular 
carcinoma. J. Gastroenterol. Hepatol. 20, 1475–7 (2005).
4.
Beaugrand, M., N’kontchou, G., Seror, O., Ganne, N. & Trinchet, J.-C. Local/regional and systemic 
treatments of hepatocellular carcinoma. Semin. Liver Dis. 25, 201–11 (2005).
5.
Bruix, J., Gores, G. J. & Mazzaferro, V. Hepatocellular carcinoma: clinical frontiers and 
perspectives. Gut 63, 844–55 (2014).
6.
Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: analysis of survival according 
to the intention-to-treat principle and dropout from the waiting list. Liver Transpl. 8, 873–83 (2002).
7.
Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in 
patients with cirrhosis. N. Engl. J. Med. 334, 693–9 (1996).
8.
Regalia, E. et al. Liver transplantation for small hepatocellular carcinoma in cirrhosis: analysis of 
our experience. Transplant. Proc. 33, 1442–4
9.
Duffy, J. P. et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 
22-year experience with 467 patients at UCLA. Ann. Surg. 246, 502–9; discussion 509–11 (2007).
10.
Pang, R. & Poon, R. T. P. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. 
Cancer Lett. 242, 151–67 (2006).
11.
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–90 
(2008).
12.
Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B 
lymphocytes. Int. Immunol. 8, 765–72 (1996).
13.
Ingham, M. & Wu, J. Immunotherapy and Hepatocellular Carcinoma. J Liver e108, 
doi:10.4172/2167–0889.1000e108 (2013). at 
<http://www.omicsgroup.org/journals/Immunotherapy-and-Hepatocellular-Carcinoma-2167-
0889.1000e108.pdf>
14.
Urbani, S. et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with 
HCV-specific CD8 exhaustion. J. Virol. 80, 11398–403 (2006).
15.
Wenjin, Z., Chuanhui, P., Yunle, W., Lateef, S. A. & Shusen, Z. Longitudinal fluctuations in PD1 
and PD-L1 expression in association with changes in anti-viral immune response in chronic 
hepatitis B. BMC Gastroenterol. 12, 109 (2012).
16.
Zeng, Z. et al. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation 
prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One 6, e23621 (2011).
17.
Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic 
HBV infection. J. Virol. 81, 4215–25 (2007).
18.
Urbani, S. et al. Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV 
infection: effect of viremia levels and antiviral treatment. J. Hepatol. 48, 548–58 (2008).
19.
Poon, R. T.-P., Lau, C., Yu, W.-C., Fan, S.-T. & Wong, J. High serum levels of vascular 
endothelial growth factor predict poor response to transarterial chemoembolization in 
hepatocellular carcinoma: a prospective study. Oncol. Rep. 11, 1077–84 (2004).
20.
SIR-Spheres Yttrium-90 Microspheres Package Insert, SIRTeX Medical. Lane Cove. at 
<http://www.sirtex.com/media/29845/ssl-us-10.pdf>
21.
Otto, G. et al. Response to transarterial chemoembolization as a biological selection criterion for 
liver transplantation in hepatocellular carcinoma. Liver Transpl. 12, 1260–7 (2006).
22.
Porrett, P. M. et al. Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular 
cancer in the current MELD era. Liver Transpl. 12, 665–73 (2006).
23.
Mejia, G. A. et al. Correlation between the radiologic and histologic size of hepatocellular 
carcinoma in patients eligible for liver transplantation. Transplant. Proc. 38, 1394–5 (2006).
24.
Ho, M.-H. et al. Locoregional therapy-induced tumor necrosis as a predictor of recurrence after 
liver transplant in patients with hepatocellular carcinoma. Ann. Surg. Oncol. 18, 3632–9 (2011).
25.
Mardor, Y. et al. Early detection of response to radiation therapy in patients with brain 
IRB #: STU00203003-CR0005 Approved by NU IRB for use on or after 2/11/2021 through 2/10/2022.

NU Study Number: NU 16I01
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Amendment 7: 07/16/2020
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malignancies using conventional and high b-value diffusion-weighted magnetic resonance 
imaging. J. Clin. Oncol. 21, 1094–100 (2003).
26.
Hall, D. E. et al. Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as 
an early surrogate marker. Clin. Cancer Res. 10, 7852–9 (2004).
27.
Kamel, I. R. et al. Role of diffusion-weighted imaging in estimating tumor necrosis after 
chemoembolization of hepatocellular carcinoma. AJR. Am. J. Roentgenol. 181, 708–10 (2003).
28.
Kamel, I. R. et al. The role of functional MR imaging in the assessment of tumor response after 
chemoembolization in patients with hepatocellular carcinoma. J. Vasc. Interv. Radiol. 17, 505–12 
(2006).
29.
Deng, J. et al. Diffusion-weighted MR imaging for determination of hepatocellular carcinoma 
response to yttrium-90 radioembolization. J. Vasc. Interv. Radiol. 17, 1195–200 (2006).
30. 
Goin JE, Dancey JE, Roberts CA, et al. Comparison of Post-embolization Syndrome in the 
Treatment of Patients with Unresectable Hepatocellular Carcinoma: Trans-catheter Arterial 
Chemo-embolization versus Yttrium-90 Glass Microspheres.  World J of Nuc Med 3:49-56, 2004
31. 
Goin JE, Salem R, Carr BI, et al.  Treatment of unresectable hepatocellular carcinoma with 
intrahepatic yttrium-90 microspheres: factors associated with liver toxicities.  J Vasc Interv Radiol 
16:205-13, 2005
32. 
Goin JE, Salem R, Carr BI, et al.  Treatment of unresectable hepatocelllular carcinoma with 
intrahepatic yttrium-90 microspheres: a risk-stratification analysis.  J Vasc Interv Radiol 16:195-
203, 2005 
33. 
Salem R, Lewandowski RJ, Atassi B, et al.  Treatment of unresectable hepatocellular carcinoma 
with the use of 90-Yttrium microspheres (TheraSphere): safety, tumor response, and survival.  J 
Vasc Interv Radiol 16:1627-39, 2005
34. 
Dancy JE, Shepherd FA, Paul K, et al.  Treatment of nonresectable hepatocellular carcinoma with 
intrahepatic 90-Yttrium- microspheres.  J Nucl Med 41:1673-81, 2000
35. 
Llovet JM, Real MI, Montana X, et al.  Arterial embolisation or chemoembolisation versus 
symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised 
controlled trial.  Lancet 359:1734-9, 2002 
36. 
Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 10:1-
10, 1989).  
37. 
Porcher R, Desseaux K. What inference for two-stage phase II trials.  BMC Medical Research 
Methodology 12:117, 2012.
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NU Study Number: NU 16I01
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Amendment 7: 07/16/2020
55
APPENDICES
APPENDIX 1:
Treatment-Emergent Serious Adverse Events from 5 Clinical Studies (N=121) for Patients 
Undergoing TheraSphere® Treatment Therapy 
Expected Adverse Device Effects
Adverse Device Effect
Expected
Frequency (%)
TheraSphere
Elevated alkaline phosphatase
75
Elevated SGOT
75
Elevated SGPT
75
Lymphocyte depression (asymptomatic)
35
Fatigue
29
Fever
25
Nausea
15
Heartburn
14
Vomiting
15
Pain
15
Decreased albumin
10
Ascites
10
Elevated bilirubin
10
Pleural effusion
10
Ulcer, GI
10
Anorexia
10
Constipation
5
Dizziness
5
Muscle pain
5
Renal Failure
5
Cholecystitis
< 5
Pneumonitis
<1
Death
< 1
Angiographic Procedure
Allergic reaction (e.g. contrast media)
< 5
Medication reaction (e.g nausea from narcotics)
< 5
Vascular spasm
< 1
Vessel dissection
< 1
Vessel rupture
< 1
Thrombosis / embolism (vascular access)
< 1
Bleeding / Hematoma
< 1
Infection
< 1
Venipuncture
Discomfort/pain
5
Fainting
< 1
Bleeding at site
< 1
Infection
< 1
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Initial Version: 4/19/2016
Amendment 7: 07/16/2020
56
APPENDIX 2: 
Pregnancy and 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 from the time of treatment initiation to 5 months (for FOCBP) or 7 months (for 
males with FOCBP partners) after the last dose of nivolumab. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method being 
highly effective and the other method being either highly effective or less effective as listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
a)
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.
b)
Nonhormonal IUDs, such as ParaGard®
c)
Tubal ligation
d)
Vasectomy.
e)
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 
section.
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Amendment 7: 07/16/2020
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APPENDIX 3:
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, neurologic 
toxicity, pulmonary toxicity, renal toxicity and skin toxicity

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
58

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
59

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
60

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
61

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
62

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
63

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
64
APPENDIX 4:
Yttrium-90 Dosage and Administration
To correct for the physical decay of yttrium-90, the fractions that remain at selected time intervals 
from calibration are shown in Table 3.
Table 3: Yttrium-90 Physical Decay Table
Half-Life 64.2 Hours
Fraction
Fraction
  Fraction
Hours
Remaining
Hours
Remaining
Hours
Remaining
-4
1.044
26
0.755
56
0.546
-2
1.022
28
0.739
58
0.534
0*
1.000
30
0.723
60
0.523
2
0.979
32
0.708
62
0.511
4
0.958
34
0.692
64
0.500
6
0.937
36
0.677
66
0.489
8
0.917
38
0.663
68
0.479
10
0.897
40
0.649
70
0.469
12
0.878
42
0.635
72 (Day 3)
0.459
14
0.859
44
0.622
96 (Day 4)
0.354
16
0.841
46
0.609
120 (Day 5)
0.273
18
0.823
48 (Day 2)
0.596
144 (Day 6)
0.210
20
0.806
50
0.583
168 (Day 7)
0.162
22
0.789
52
0.570
24 (Day 1)
0.772
54
0.558
*Calibration Time
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APPENDIX 5:
Summary of Changes
Original Version Approved by the Northwestern University IRB – July 22, 2016
Amendment 1 – July 27, 2016 
Approved by Scientific Review Committee 8-12-2016
Section(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
4.2.2 (Nivolumab 
Treatment 
Administration); 
8.2.5 (Protocol 
Dose Specifics)
Nivolumab infusion duration 
listed as 60 minutes
Changes infusion duration to 
30 minutes
Updated, as requested 
by BMS, to reflect new 
dosing strategy for 
nivolumab
4.3 (Phase I 
Dose Escalation 
Scheme)
If a DLT occurred at dose 
level 1, de-escalation to level 
-1 was to occur
If a DLT occurs at dose level 
1, “the PI will discuss with 
DMC and BMS to determine 
the necessary outcome”
The protocol was 
originally written with a 
dose level -1, and this 
language was 
mistakenly left in the 
protocol when dose 
level 
-1 was removed. The 
likelihood of a DLT 
occurring at level 1 is 
low, so further 
discussion will be 
warranted in this case.
4.4.1 (Dosing 
Delays); 
Appendix 3
n/a
Adds recommended 
algorithms for investigators 
to reference related to 
immuno-oncology specific 
AE’s
Additional information 
provided by BMS 
5.0 (Study 
Procedures)
#7: 
n/a
#7: Removes specific 
language about hepatitis 
eligibility and refers to 
inclusion criteria 3.1.5. 
Previously stated that 
patients with active 
hepatitis B would see a 
hepatologist and begin 
hepatitis treatment before 
study treatment
Adds note in table 
   “1 cycle = 28 days”
Adds specific time points 
for treatment (C3, 5, 7, 11 
etc.) in footnote 11
To clarify prior 
discrepancy from 
eligibility criteria 
(3.1.5)
Clarifications
7.3.3.1 
(Reporting to the 
Northwestern 
n/a
Adds language that SAE’s 
must be reported to BMS, 
regardless of attribution and 
Clarifications
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Amendment 7: 07/16/2020
66
University 
QAM/DMC); 
7.3.3.3 
(Reporting to 
Bristol Myers 
Squibb)
adds the BMS study 
reference number (CA209-
615)
8.1.5 (Protocol 
Dose Specifics)
Referred to Appendix F, 
Table 3 for the Physical 
Decay Table to order 
TheraSphere based on the 
appropriate time of injection.
Replaces references to 
Appendix F with Appendix 4 
and adds Appendix 4 with 
the relevant table. 
Adds previously 
missing information 
related to Y-90 dosing.
8.2 (Nivolumab)
n/a
Adds “Product Information 
Table” for nivolumab
Additional information 
provided by BMS
9.3.1 (Tumor 
Biopsy IHC)
Included instructions for IHC 
analysis involving Dako kits 
and pathology analysis at MD 
Anderson
Removes references to 
Dako kits and MD Anderson
Dako kits are not being 
provided. Pathology 
analysis will take place 
at Northwestern.
11.3 
(Amendments)
Amendments were listed as 
needing to be approved by 
Janssen Scientific Affairs
Removes reference to 
Janssen – amendments 
must be approved by Bristol-
Myers Squibb
Correction of 
typographical error 
11.10 
(Publication 
Policy)
n/a
Includes language specific to 
NU’s publication agreements 
with BMS
Updated to reflect 
contract
Amendment 2 – March 2nd, 2017 
Approved by Scientific Review Committee: 1/31/2017
Section(s) 
Affected
Prior Version
Amendment 2 Changes
Rationale
Cover Page
Northwestern Medicine 
Developmental Therapeutics 
Institute (NMDTI)
Northwestern Medicine 
Developmental Therapeutics 
Program (NMDTP)
Administrative; 
department 
underwent name 
change
Cover Page
n/a
Adds Valerie Nelson as sub-
investigator.
Removes Jason Kaplan, Frank 
Giles, Benedito Carneiro, Young 
Chae and Sunandana Chandra 
as sub-Is
Administrative; 
new faculty. Not all 
DTP faculty are 
listed as sub-I’s in 
newest protocol 
template.
Cover Page
IND Number/Holder: Pending
IND Number/Holder: Exempt
Clarification; we 
are not waiting on 
information about 
the IND
Cover Page
“Bristol Meyers Squibb”
“Bristol-Myers Squibb”
Typographical 
error
Study Schema
Listed eligibility criteria related to 
autoimmune disease to describe 
study population
Removes autoimmune 
requirement, only listing 
diagnosis details to describe 
study population
Simplification
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Amendment 7: 07/16/2020
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Study Schema; 
Study 
Summary; 
4.1 (Overview); 
4.2.2 
(Nivolumab); 
4.3 (Phase I 
Dose 
Escalation 
Scheme); 5.0 
(Study 
Procedures 
#10); 8.2.5 
(Protocol dose 
specifics)
Nivolumab was to be given at a 
starting dose of 80mg with a dose 
escalation to 240mg and then 
480mg IV.
“The first 3 patients in Phase I 
are treated at 80mg IV every 2 
weeks. Patients will then follow 
the standard regimen of 240mg 
every 2 weeks until progression, 
unacceptable toxicity or 
withdrawal of consent (see 
section 4.3 for dose 
escalation).” 
The study will no 
longer include an 
escalation to 
480mg IV 
nivolumab 
q2weeks given 
that the drug is 
approved at 
240mg IV 
q2weeks. 
Study Schema; 
5.0 (Study 
Procedures #3)
Imaging is required “every 8 
weeks”
Expands on imaging 
requirements: “every 8 weeks (2 
cycles) for the first 13 cycles, 
and every 12 weeks (3 cycles) 
thereafter”
Clarification to 
incorporate cycles
Study Summary
Included a short title: 
“Y-90 + nivolumab in advanced 
HCC”
Removes short title
To align with 
current NU 
protocol template; 
short title is not 
required
Study 
Summary; 
2.1 (Primary 
Objectives & 
Endpoints); 2.2 
(Secondary 
Objectives & 
Endpoints)
One primary objective: “To identify 
MTD of nivolumab for combination 
treatment of nivolumab and Y-90 
in this population.”
Secondary objectives include: “To 
evaluate the proportion of patients 
with ORR to the combination 
treatment nivolumab with Y-90
Changes MTD to the Phase I 
primary objective, and moves 
ORR from a secondary 
objective to the Phase Ib 
primary objective. 
Expands “this population” to 
state “patients with advanced 
hepatocellular carcinoma”. 
Given that 
nivolumab is FDA-
approved at 
240mg IV, it is 
important to look 
at efficacy as a 
more prominent 
study objective. It 
is also appropriate 
to have a primary 
objective for each 
study phase.
Study 
Summary; 
3.0 (Patient 
Eligibility)
“Phase 1: 9-15 patients, Phase 
1b: 20 patients”
“Phase 1: 9-15 patients, 
Phase 1b: requires 29 patients 
in a two-stage optimum Simon 
design.  The 6 at the MTD in 
Phase 1 are counted as part of 
the 29.  This would require up to 
15 in Phase 1, 23 new patients 
in Phase 1b for a total of 38 
patients.  Target accrual is 40 
patients to account for 
potentially unevaluable 
patients.”
Statistical 
clarification to 
account for 
removal of the 
480mg dose level.
Study 
Summary; 10.1 
(Study Design / 
Study 
Endpoints)
Phase Ib Expansion Cohort:
Twenty patients will be enrolled 
with the maximum tolerated dose 
(MTD). The 6 patients at the MTD 
in the dose escalation phase will 
be included in this expansion 
cohort.  A one sample Bayesian 
The Phase 1b expansion cohort 
will be a two-stage optimum 
Simon design with 29 patients.  
See Section 10.0 for details.
Statistical 
clarification to 
account for the 
need for a two-
stage Simon 
design rather than 
a one-sample 
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design for the dichotomous 
primary endpoint of ORR will be 
used for the Phase Ib portion of 
the trial.  
Bayesian design.
1.3.1 (Rationale 
for Nivolumab 
Dosing)
n/a
Adds justification for the dose 
escalation from 80mg to 240mg 
IV nivolumab, indicating that 
nivolumab is now FDA-
approved at 240mg
Additional 
information 
provided to justify 
stopping 
escalation at 
240mg nivolumab.
3.1.9 (Inclusion 
Criteria)
n/a
Included screening 
requirements for lipase, 
amylase, and magnesium
Adds note to PT/INR 
requirement: “Performed at 
time of screening angiogram; 
can be outside 14 days if 
applicable.”
Removes screening 
requirements for lipase, 
amylase, and magnesium
Clarification 
requested by 
study team.
Clarification to fix 
discrepancy – 
screening 
chemistry panel 
does not include 
lipase, amylase, 
or magnesium
3.2.24 
(Exclusion 
Criteria)
Excluded patients with 
hypertension (>150/90) and 
cardiac arrhythmia
No longer excludes cardiac 
arrhythmia and removes 
numerical value for 
hypertension.
PI determined that 
these exclusion 
criteria were not 
clinically relevant 
or necessary.
4.1 (Overview); 
4.2.2 
(Nivolumab); 
5.0 (Study 
Procedures 
#10)
Nivolumab was to be given over 
30 minutes with a window of ±5 
minutes
The window for nivolumab 
infusion has been extended to -
5 minutes / +15 minutes
BMS approved this 
extension in order 
to allow greater 
flexibility in 
infusion times. 
4.3.1.1 (Grade 
≥3 non-
hematological 
toxicity)
Grade ≥ 3 metabolic toxicities 
unable to be corrected within 24 
hours were considered dose-
limiting
Adds an exception if patient had 
metabolic abnormalities at 
baseline.
Also adds: “Other Grade 3 lab 
abnormalities will only be 
considered a DLT if they do not 
resolve within 2 weeks”
Clarifications. 
Patients with 
metabolic 
abnormalities at 
baseline are 
allowed more 
flexibility. Grade 3 
lab abnormalities 
were not 
previously 
accounted for 
outside of  
metabolic 
abnormalities 
4.3.1.1 (Grade 
≥3 non-
hematological 
toxicity); 4.4.1 
(Dosing delays)
Dose delays and DLT’s were to 
take place for any bilirubin 
abnormality ≥Grade 3
Grade 3 bilirubin ≤3.5mg/dL is 
not considered dose limiting and 
does not require delay during 
Cycle 1. However, if bilirubin 
worsens after the first dose of 
nivolumab a delay in dosing 
may be warranted per physician 
discretion.
Patients often 
experience 
elevated bilirubin 
as a result of Y-90; 
a cut-off of 
3.5mg/dL is felt to 
be appropriate 
during cycle 1, 
with criteria being 
more strict 
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NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
69
thereafter (Grade 
3: >3.0mg/dL 
requires delay)
4.4.1 (Dosing 
delays)
Patients were allowed to delay 
nivolumab by up to 14 days.
Adds an exception for patients 
who undergo prolonged steroid 
tapers to manage drug-related 
AE’s, who can be delayed up to 
6 weeks 
Clarification of 
discrepancy in 
section 4.4.3
4.4.1 (Dosing 
delays)
Nivolumab should be delayed 
until resolution to ≤Grade 1 
If baseline AST, ALT, or bilirubin 
is within Grade 1 toxicity range, 
delay dosing for drug-related 
Grade 3 toxicity
Nivolumab should be delayed 
until resolution to ≤Grade 1 or 
baseline
If baseline AST, ALT, or bilirubin 
is within Grade 1 or 2 toxicity 
range, delay dosing for drug-
related Grade 3 toxicity
To account for 
discrepancies in 
protocol eligibility 
and patients with 
baseline 
abnormalities.
4.4.4 
(Treatment with 
nivolumab 
beyond 
progression)
“Subjects must provide separate 
consent to continue treatment 
despite radiological scans 
indicating PD. Separate consent 
must be provided when 
progression is first detected.”
Removes statement for 
treatment beyond progression 
requiring a separate consent 
To fix discrepancy. 
Separate consent 
is not necessary, 
and there is no 
such consent 
available.
5.0 (Study 
Procedures 
#11, #12)
n/a
Expands on correlative details: 
to be collected in a 10mL 
NaHep tube every 16 weeks (4 
cycles) starting with C11D1, 
and references lab manual
Clarifications for 
easier referencing
7.2.9 (Abnormal 
Laboratory 
Values)
Listed conditions for documenting 
abnormal labs as adverse 
events.
Removes conditions and 
specifies that all lab 
abnormalities should 
documented as AE’s.
To align with 
Northwestern 
University policies 
to record all lab 
abnormalities.
10.2 (Data 
Analyses 
Plans); 
References
n/a
Adds specific plans and 
references for analyzing 
response (ORR, CBR), PFS, 
adverse events, and exploratory 
objectives.
Elaboration of 
statistical plans for 
clarity. 
Amendment 3 – February 6th, 2018 
Section(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
Study Schema; 
4.8 (Duration of 
Follow Up); 5.0 
(Study 
Procedures 
#14)
Discrepancies in follow-up timing:
Schema says to follow up every 6 
months for 2 years from treatment 
discontinuation.
Other sections only require follow-
up for 24 weeks from start of 
treatment.
Updates protocol to require 
both. If a patient discontinues 
treatment prior to 24 weeks (6 
cycles), patient will be followed 
for survival every 2 weeks up to 
24 weeks from starting 
treatment. Patients will then be 
followed for survival every 6 
months for 2 years.
Clarification for 
consistency.
3.1.2 (Inclusion 
Criteria); 6.3.1 
n/a
Adds note: “For patients with 
infiltrative disease, evaluable 
Clarification to 
allow for patients 
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NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
70
(Definitions)
disease needs to be confirmed 
by pathology if RECIST 
measurements cannot be 
made.”
with infiltrative 
disease where 
lesions are not 
measurable but 
still evaluable as 
HCC.
4.1 (Overview 
of Treatment 
Plan); 4.7 
(Duration of 
Therapy)
Patients were to receive 
nivolumab 4 weeks after Y-90 
administration
Clarifies that 4-6 weeks are 
allowed between Y-90 and 
nivolumab administration 
Clarification to 
address 
discrepancy
4.1 (Overview 
of Treatment 
Plan); 4.7 
(Duration of 
Therapy)
Y-90 was to be given one time 
with a brief note stating it could be 
repeated if needed.
Adds clarifying note: “Repeat 
therapy to the treated lesion or 
additional untreated lesions 
may be warranted. If a patient 
requires additional Y-90 after 
starting nivolumab treatment, it 
may be given once approval 
from the interventional 
radiologist and treating 
physician has been confirmed. 
In such cases, nivolumab 
should be held for 14 days prior 
to administering Y-90. 
Nivolumab can be resumed 
within 14 days after receiving 
additional Y-90, but can be 
delayed for up to 6 weeks if 
needed.”
Clarification – p
4.3 (Phase I 
Dose 
Escalation); 
4.4.3 
(Treatment 
Discontinuation 
Criteria); 7.3 
(Adverse Event 
Reporting)
Referenced DMC (Data 
Monitoring Committee)
Updates to DSMC (Data and 
Safety Monitoring Committee)
Updated to reflect 
new internal 
policies 
4.4.1 (Dosing 
Delays)
Nivolumab dosing delays up to 14 
days were permitted with a 6 week 
exception in the case of prolonged 
steroid tapers
Updated to state that nivolumab 
dosing may be delayed up to 6 
weeks in general.
Clarification to 
address 
discrepancy 
throughout 
protocol.
4.4.4 
(Treatment with 
nivolumab 
beyond 
progression)
Nivolumab treatment was to be 
discontinued in the case of 
confirmed PD (confirmed by 
repeat evaluation 4 weeks after 
initial suspicion)
Treatment should be 
discontinued in the case of 
confirmed PD without clinical 
benefit. Adds a stipulation that 
if a patient with confirmed PD is 
still receiving clinical benefit in 
the investigator’s opinion, study 
drug may be continued after 
discussion and agreement 
between the treating physician 
and PI. 
4.7 (Duration of 
Therapy); 6.3 
Patients were to have scans every 
8 weeks
Patients will have scans every 8 
weeks (2 cycles) for the first 13 
To address 
discrepancy 
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NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
71
(Secondary 
Endpoints)
months, and every 12 weeks (3 
cycles) thereafter.
throughout 
protocol. Scans 
will move to 
q3months after 
one year of 
treatment.
5.0 (Study 
Procedures)
Imaging will occur every 3 cycles 
with no window listed
Adds a window of ±7 days
Clarification
6.1 (Definitions)
Listed scan frequency in terms of 
weeks (every 8 weeks for 13 
months, then every 12 weeks 
thereafter), and did not list 
screening or prior to nivolumab
Lists scan frequency in terms of 
cycles. Adds the scan at 
screening and within 7 days 
prior to starting nivolumab.
Clarifications for 
consistency.
8.2.4 (Storage 
and Stability); 
8.2.6 
(Preparation)
n/a
Replaces language with internal 
nivolumab template language 
(same content)
For consistency 
with other 
protocols involving 
nivolumab
8.2.9 
(Availability & 
Supply)
Did not specify timing for drug re-
supply requests
Replaces language with internal 
nivolumab template language. 
Drug re-supply should be 
submitted 10 business days 
before the delivery date
Updated for 
accuracy per BMS
8.2.12 (Return 
& Retention of 
Study Drug)
n/a
Updates table to reflect 
accurate packaging of 
nivolumab product
Clarification 
Appendix 2
n/a
Adds timeframe of 
contraception requirements for 
both females (5 months) and 
males (7 months) after the last 
dose of nivolumab
To align with BMS 
template and 
requirements
Appendix 3
Contained outdated AE 
Management Algorithms. Specific 
outdated parameters include:
Hepatic:
Discontinue for AST/ALT 
>5xULN and/or Tbili >3xULN
Pulmonary (G3-4):
Includes example 
immunosuppression
Renal (G2-3):
“Consider renal biopsy”
Skin (G3-4):
n/a
Updates AE Management 
Algorithms to align with 
nivolumab IB v16. Specific 
changes to AE management 
include:
Hepatic:
Discontinue for AST/ALT > 
5xULN or Tbili > 3xULN
Pulmonary (G3-4):
Removes examples of 
immunosuppression 
Renal (G2-3):
“Consider renal biopsy with 
nephrology consult”
Skin (G3-4):
Adds footnote: “If SJS/TEN is 
suspected, withhold I-O 
therapy and refer patient for 
specialized care for 
assessment and treatment. If 
SJS or TEN is diagnosed, 
permanently discontinue I-O 
therapy.”
Updated per BMS 
for consistency 
with new 
nivolumab IB v16 
and additional or 
clarified safety 
measures.
Amendment 4 – September 26th, 2018 
Approved by Scientific Review Committee: 10/31/2018
IRB #: STU00203003-CR0005 Approved by NU IRB for use on or after 2/11/2021 through 2/10/2022.

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
72
Section(s) 
Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page
Listed Northwestern’s Clinical 
Research Office as 
coordinating center
Updates to Clinical Trials 
Office
To align with internal 
administrative changes
Study Schema; 
Study 
Summary; 4.1 
(Overview); 4.2 
(Treatment 
Administration); 
4.7 (Duration of 
Therapy); 5.0 
(Study 
Procedures, 
#10)
Nivolumab treatment was 
planned to start 4 weeks after 
Y-90 administration. A delay 
of 6 weeks will be permitted in 
case of toxicity.
Nivolumab treatment will 
now start 7-14 days after 
Y-90 administration. A 
delay of 4 weeks will be 
permitted in case of 
toxicity. Also applies to 
cases where Y-90 is 
repeated during the study.
Shortening the window 
allows for patients to be 
treated sooner in a setting 
where treatment is needed 
somewhat urgently. In 
patients treated so far, 
lymphopenia has not been 
an issue which was the 
initial reason for the 4-
week treatment delay. The 
new of window of 7-14 
days is sufficient to 
account for generalized 
fatigue that may occur with 
Y-90 and given the short 
half-life of Y-90, it is out of 
the system.
Study Schema; 
4.2 (Treatment 
Administration); 
5.0 (Study 
Procedures, 
#3); 6.1 
(Definitions); 
6.3 (Secondary 
Endpoints); 
Scans were to take place 
“within 7 days prior to 
starting nivolumab”
Scans will take place “21-
28 days after Y-90 
administration”
To align with new, shorter 
window between Y-90 and 
nivolumab. Scans will still 
occur the same amount of 
time after Y-90, which falls 
after starting nivolumab
5.0 (Study 
Procedures, #6)
Chemistry panel required 
within 14 day of registration
Required within 14 days 
prior to registration
Clarification of ambiguous 
language
6.1 (Definitions)
Includes scan timing of every 
8 weeks 
Removes first paragraph 
with scan timing
Language was redundant 
and inaccurate
Amendment 5 – February 8, 2019
Approved by Scientific Review Committee: 02/08/2019
Section(s) 
Affected
Prior Version
Amendment 5 Changes
Rationale
8.2.6 
(Preparation)
Listed detailed instructions for 
preparing nivolumab
Removes specific 
instructions and instead 
refers to most recent 
nivolumab investigator’s 
brochure
BMS request; removing 
specific details allows for 
variance if needed and 
ensures the most recent IB 
is always followed
8.2.9 
(Availability and 
Supply)
Specified that nivolumab 
comes cartons of 5 or 10 mL
Removes details about 
carton sizes
BMS request; removed 
unnecessary details in 
case of variance
8.2.11 (Return 
& Retention of 
Study Drug)
Included a column for 
secondary packaging details 
(5-10 vails per carton)_
Removes details about 
secondary packaging
BMS request; removed 
unnecessary details in 
case of variance
Amendment 6 – April 10, 2019
Section(s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
IRB #: STU00203003-CR0005 Approved by NU IRB for use on or after 2/11/2021 through 2/10/2022.

NU Study Number: NU 16I01
BMS Study Number: CA 209-615
Initial Version: 4/19/2016
Amendment 7: 07/16/2020
73
4.1.0 (Patient 
Replacement)
Stated that patients who 
cannot start nivolumab within 
6 weeks of Y-90 treatment 
may be replaced.
States that patients who 
cannot start nivolumab 
within 4 weeks of Y-90 
treatment may be replaced.
To correct discrepancy; 
language now aligns with 
other sections of the 
protocol which state that 
patients must start 
nivolumab within 4 weeks 
of Y-90 treatment.
Cover Page
Listed Alfred Rademaker as 
the biostatistician
Replaces Alfred 
Rademaker with Denise 
Scholtens
Administrative change to 
account for new 
biostatistician
Table of 
Contents
Listed incorrect page numbers
Corrects page numbers
Administrative update
Amendment 7 – July 16, 2020
Section(s) 
Affected
Prior Version
Amendment 7 Changes
Rationale
Title Page
Denise Scholtens, PhD
Northwestern University
dscholtens@northwestern.edu
Hui Zhang, PhD
Northwestern University
hzhang@northwestern.edu
Statistician change.
IRB #: STU00203003-CR0005 Approved by NU IRB for use on or after 2/11/2021 through 2/10/2022.