An Open-Label Preoperative Pilot Study Evaluating Nivolumab (Anti-PD-1 Antibody) Alone Versus Nivolumab Plus Ipilimumab (Anti-CTLA-4 Antibody) in Patients With Resectable (HCC)
Phase: PHASE2
Conditions: Hepatocellular Carcinoma, Resectable Hepatocellular Carcinoma
Sponsor: M.D. Anderson Cancer Center

 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2017-0097 
Protocol Title 
A Study to Test Drug A and Drug B with cancer 
patients  
Protocol Phase 
II 
Protocol 
Version 
09 
Version Date 
01/30/20 
 
Protocol PI 
Ahmed Kaseb 
Department 
GI Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
135,932 

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Clinical Protocol  
 
BMS CA209-956 
 
 
An Open-Label Preoperative Pilot Study Evaluating Nivolumab (Anti-PD-1 Antibody) Alone 
Versus Nivolumab Plus Ipilimumab (Anti-CTLA-4 Antibody) in Patients with Resectable HCC  
 
 
Principal Investigator:  
Ahmed Kaseb, MD 
 
Department of Gastrointestinal Medical Oncology  
 
U.T. M. D. Anderson Cancer Center 
 
1515 Holcombe Blvd 
 
Houston, TX 77030 
Collaborators: 
 
                                                Surgical Oncology  
 
Jean-Nicolas Vauthey, MD 
                                                Yun Chun, MD 
                                                Thomas Aloia, MD 
                                                Ching-Weie Tzeng 
 
 
Department of Gastrointestinal Medical Oncology 
 
James Yao, MD 
 
Kanwal Raghav, MBBS 
 
 
 
Melanoma 
 
Adi Diab, MD 
 
 
Pathology 
 
Asif Rashid, MD 
 
 
 
Division of Cancer Medicine 
 
Marc Uemura, MD, MBA  
 
 
Department of Statistics 
 
Lianchun Xiao, MS 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Page 
1.0  
Research Hypothesis 
4 
2.0 
Objectives 
4 
3.0  
Disease Background 
4-18 
4.0 
Study Population 
18-23 
5.0  
Treatment Plan 
23-26 
6.0  
Study Medications 
26-32 
7.0  
Dosing Modifications 
32 
8.0  
Discontinuation of Therapy 
33-36 
9.0 
Concomitant Therapy 
37 
10.0 
Study Assessments and Procedures 
37-57 
11.0  Adverse Event Reporting 
58-64 
12.0  Statistical Methodology 
60-64 
13.0  Administrative Section 
65-66 
14.0 
References 
67-71 
Appendix I: Adverse Events I-O Algorithms 
72-78 
Appendix II: Study Design Version Comparison  
79 
 
 
 
 
 
 
 
 
 

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Table 1. LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
HCV 
Hepatitis C virus 
HBV 
Hepatitis B virus 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
HCC 
Hepatocellular Carcinoma 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
irRC 
Immune related Response Criteria 
MRI 
Magnetic Resonance Imaging 
NAFLD 
Non-alcoholic fatty liver disease 
PD 
Progressive Disease 
PD-1 
Programmed Death Receptor-1 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TTP 
Time to Tumor Progression 
UNOS 
United Network for Organ Sharing 

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1.0  
RESEARCH HYPOTHESIS 
Anti-PD1 antibody (nivolumab) alone or in combination with anti-CTLA-4 antibody 
(ipilimumab) can be safely administered and may induce augmented immunological and clinical 
responses in patients with resectable hepatocellular carcinoma (HCC).  
2.0 
OBJECTIVES 
Primary Objective:  
1. 
To evaluate the safety and tolerability of therapy with nivolumab alone or nivolumab + 
ipilimumab in resectable HCC in the context of presurgical therapy. 
 
Note: As of January 8, 2020, 30 patients have been enrolled and 27 patients have been 
randomized. The PI decided to stop enrollment since the study has reached its primary 
endpoint of safety.  
 
Secondary Objectives:  
1. 
To assess the efficacy of presurgical nivolumab alone or nivolumab + ipilimumab therapy 
in HCC by estimating the objective response rate (ORR) and time to progression (TTP) per 
RECIST 1.1 progression-free survival (PFS). 
 
Exploratory Objectives: 
 
1. 
To assess the immunological/biomarker changes in tumor tissues and peripheral blood in 
response to nivolumab alone or nivolumab + ipilimumab in HCC therapy (pre- vs post-
treatment), and explore any potential association between these biomarker measures and 
antitumor response and immune-related response criteria (iRC) assessed by MD Anderson 
Department of Diagnostic Imaging. 
 
3.0 
DISEASE BACKGROUND 
3.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is a highly lethal malignancy of worldwide significance 
and has become increasingly important in the United States. Overall, it is the most common 

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primary liver cancer, the sixth most common cancer, and the third most common cause of cancer-
related deaths worldwide [1]. Various risk factors are responsible for the majority of HCC cases. 
these include liver cirrhosis (multiple etiologies), hepatitis B virus (HBV) infection, hepatitis C 
virus (HCV) infection, alcohol abuse, and non-alcoholic fatty liver disease [2]. Notably, although 
treatment for HCV has dramatically improved over the past several years, HCC incidence in the 
United States is rising especially among patients chronically infected with HCV. This is likely due 
to the long latency period between initial HCV infection and HCC incidence [3, 4].  
Treatment options for HCC depend on the cancer stage at initial presentation and degree 
of synthetic liver dysfunction. Although a number of different staging systems have been used to 
provide accurate prognostic assessment (i.e. AJCC, Okuda, GRETCH, CLIP, etc.), all have 
limitations. The Barcelona Clinic Liver Cancer staging system provides an easy reference 
algorithm that links HCC stage and evidence-based treatment recommendations (Fig. 1) [5-7].  
 
3.2  
Standard Therapy for Hepatocellular Carcinoma 
 
Surgical Resection and Liver Transplantation 
 
Figure 1:  BCLC staging system and therapeutic strategy. Llovet, J. M. et al. (2016) Hepatocellular carcinoma 
Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.18 

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The only potentially curative treatment modalities for HCC include surgical resection 
(partial hepatectomy) and liver transplantation. Unfortunately, the actual number of patients who 
qualify for these modalities is small (approximately 10-30%) because most patients present with 
locally advanced or metastatic disease, or have significant liver dysfunction that precludes curative 
options. Surgical resection is typically considered for patients with a solitary tumor of any size 
who have adequate liver remnant and no evidence of major vascular invasion or portal 
hypertension [8]. Recent evidence has shown that partial hepatectomy procedures in carefully 
selected patients can be done with low operative morbidity and mortality [9, 10]. However, despite 
these favorable surgical outcomes, in those patients who are fortunate to undergo surgical 
resection, tumor recurrence is common. In fact, the 5-year tumor recurrence rate following surgical 
resection have been reported to be as high as 70% [11-13].  
 
Although there is no FDA-approved medication for use in the adjuvant setting after surgical 
resection, the recently reported phase III STORM trial evaluated the efficacy and safety of 
sorafenib, an antiangiogenic agent approved for use in advanced HCC [14]. In this study, 1,114 
HCC patients with a complete radiological response after surgical resection or local ablative 
therapy were given sorafenib 400 mg or placebo twice a day for a maximum of 4 years. Treatment 
related adverse events were high in both study groups and there was no difference seen between 
the two groups in regard to recurrence-free survival (RFS), time to recurrence (TTR) or overall 
survival (OS). At this time, there remains no evidence to support a particular adjuvant therapy in 
HCC.  Of note, our pilot study is important as it will generate for the first time PFS data in HCC 
with combination nivolumab plus ipilimumab.  
 
Liver transplantation is the other potentially curative treatment option for HCC patients 
that removes both the underlying HCC tumors and background cirrhosis. In 1996, Mazzaferro and 
colleagues proposed the Milan criteria (single lesion ≤ 5 cm or 2-3 lesions each ≤ 3 cm, no 
macrovascular invasion, no extrahepatic disease) for patients with small, unresectable HCC in the 
setting of cirrhosis [15]. For patients meeting this criterion who underwent orthotropic liver 
transplantation, the OS and RFS rates at 4 years were 85% and 92%, respectively. Subsequent 
studies have confirmed the results reported in this initial Mazzaferro study. Because of this, the 
United Network for Organ Sharing (UNOS) has adopted the Milan criteria for determining 
candidates for liver transplantation with HCC. Moreover, in 2001, Yao and colleagues proposed 
expanded criteria (UCSF Criteria) for HCC liver transplantation (single lesion ≤ 6.5 cm or 2-3 
lesions, each ≤ 4.5 cm + sum of lesions ≤ 8 cm, no macrovascular invasion, no extrahepatic 
disease) that demonstrated 1- and 5-year survival rates of 90% and 75%, respectively [16]. Because 

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UNOS specifies that patients undergoing evaluation for liver transplantation are not eligible for 
partial hepatectomy, liver transplantation is usually reserved for those patients with early-stage 
HCC and moderate to severe cirrhosis (i.e., Child’s Pugh B or C). On the other hand, partial 
hepatectomy is considered for those patients with mild cirrhosis (i.e., Child’s Pugh A) having an 
HCC tumor amenable to resection as deemed by the performing surgeon.  
 
Local-regional therapies for HCC 
 
Conceptually, local-regional therapies are designed to induce local tumor necrosis and are 
indicated for those patients with primarily liver-only disease but who are not resection or 
transplantation candidates. Even though there is no absolute HCC size-cut off for use of these 
treatment modalities, there are a number of contraindications to use. These include poor synthetic 
liver function (i.e. Child Pugh C), elevated bilirubin > 2.5, significant ascites, hepatic 
encephalopathy, recent variceal bleeding, and main portal vein thrombosis. Local-regional 
therapies are generally divided into two categories: ablation and arterially directed therapies.  
 
Ablative modalities include thermal ablation (radiofrequency ablation or microwave 
ablation), cryoablation, or chemical ablation (percutaneous ethanol infusion or acetic acid 
injection).  Ablative procedures may be curative in treating tumors ≤ 3 cm and have shown 
increased overall survival in tumors 3 - 5 cm in largest diameter [17-19] . Radiofrequency ablation 
(RFA), which we consider the most commonly used method of the ablative options, involves the 
local application of radiofrequency thermal energy to small HCC lesions. In fact, some centers 
even consider RFA the treatment of choice for small tumors (<2 cm) in an appropriate location. 
This is based on studies demonstrating similar outcomes for these tumors when compared to 
surgical resection with less cost and procedure-related complications [20].  
 
Arterial directed therapies involve selective catheter-based infusion of particular 
substances into the hepatic artery. These therapies are possible because the liver has a dual blood 
supply; the portal vein supplies blood to normal liver parenchyma whereas the hepatic artery 
supplies blood to HCC lesions. Such modalities are particularly attractive because all tumors, 
irrespective of location, can be treated with an arterial approach provided the blood supply to the 
tumor can be manipulated without causing undo harm to surrounding, normal tissue. In general, 
arterial based treatments are used for larger tumors not amenable to resection, transplantation or 
an ablative approach.  Currently available arterial directed therapies include transarterial bland 
embolization, transarterial chemoembolization, transarterial radioembolization and yttrium-90 
microspheres.  
 
External-beam Radiation Therapy (EBRT) 

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Because HCC is a radiosensitive tumor, EBRT can be employed in patients with 
unresectable or inoperable HCC to deliver high doses of radiation to the underlying HCC tumors 
while sparing the normal liver parenchyma. Like arterial based approaches, EBRT can be used to 
treat all tumor regardless of location. Specific EBRT modalities include intensity-modulated 
radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton beam therapy 
(PBT). Notably, SBRT is usually considered in patients with liver-only disease who have failed 
ablative or arterial-based approaches, and for those with partial vein thrombosis [21].  
 
 
Sorafenib for advanced HCC 
 
Sorafenib is an orally bioavailable agent originally developed as a Raf kinase inhibitor. 
Further studies revealed that sorafenib was also a potent inhibitor of vascular endothelial growth 
factor receptors (VEGFR-1, -2, and -3), as well as platelet derived growth factor receptor 
(PDGFR), KIT and FLT3. Currently, sorafenib is the only FDA-approved therapy for advanced or 
unresectable HCC. This approval was based on the phase III SHARP study, which evaluated 602 
patients with advanced HCC who had not received previous systemic therapy who received either 
sorafenib (400 mg BID) or placebo [22]. Median overall survival was 10.7 months in the sorafenib 
group compared to 7.9 months in the placebo group; there was also a benefit in time to 
symptomatic progression (5.5 months for sorafenib vs. 2.8 months for placebo). Additionally, in 
the phase III Asia-Pacific study, 226 patients with advanced HCC were randomized to receive 
either sorafenib (400 mg BID) or placebo [23]. This study, which included a large number of HBV 
infected patients, also demonstrated improved OS (6.5 months vs. 4.2 months) and TTP (2.8 
months for 1.4 months) for the sorafenib group.   
 
Of note, there currently is no second line therapy approved for advanced HCC.  
Regorafenib for advanced HCC 
 
Regorafenib is an orally bioavailable agent that inhibits multiple membrane-bound and 
intracellular kinases involved in cell growth (RET, VEGFR-1, VEGFR-2, VEGFR-3, KIT, 
PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, 
SAPK2, PTK5 and ABI). Although regorafenib is not yet approved for advanced HCC, the 
recently reported phase III RESORCE Trial evaluated 573 patients with intermediate or advanced 
stage HCC who had been previously treated with sorafenib (data unpublished). Patients were 
randomized 2:1 to receive either regorafenib 160 mg daily or placebo for 1-3 of each four-week 
cycle. This trial, which has not been formally published, demonstrated improvements in both 

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median OS (10.6 months vs. 7.8 months) and PFS (3.1 months vs. 1.5 months) for the regorafenib 
group.  
Other systemic therapies for advanced HCC 
 
Multiple chemotherapy regimens and targeted agents have been tested in advanced HCC 
with modest benefit; however, no single regimen has shown superiority to any other. Most 
randomized trials have demonstrated median OS benefits of < 12 months. Monotherapy agents 
that have been tested in HCC include doxorubicin, epirubicin, mitoxantrone, 5-fluorouracil (5-
FU), capecitabine, gemcitabine, irinotecan, thalidomide, cisplatin, bevacizumab (VEGF inhibitor) 
and ramicirumab (VEGF inhibitor). In addition, a number of combination chemotherapy regimens 
have also been tested with limited clinical efficacy. These include FOLFOX (infusional 5-
fluorouracil, leucovorin, oxaliplatin), cisplatin doublets, gemcitabine doublets and PIAF (cisplatin, 
interferon alpha, doxorubicin, and infusional 5-FU). Notably, our group recently performed a 
clinical trial which tested the efficacy of modified PIAF in patients without cirrhosis or hepatitis 
who had initially unresectable HCC [24]. Our results demonstrated an ORR=36% and a rate of 
conversion to curative surgery = 33%.  
3.3 
Anti-PD1 (Nivolumab) 
3.3.1 Mechanism of Action 
Immune activation is tightly regulated by co-stimulatory (e.g. CD28 and ICOS) and co-
inhibitory (e.g. CTLA-4 and PD-1) receptors expressed on T cells. Agonistic antibodies against 
co-stimulatory T cell receptors and blocking antibodies against co-inhibitory T cell surface 
receptors have both been shown to potentiate T cell activation for tumor cell killing. 
PD-1 (programmed death receptor-1) is mainly expressed by activated CD4+ and CD8+ T 
cells, as well as APCs. It has two ligands, PD-L1 and PD-L2, with distinct expression profiles [25]. 
PD-L1 is expressed not only on APCs, but also on non-hematopoietic cells, including tumor cells. 
Expression of PD-L2 is largely restricted to APCs including macrophages and myeloid dendritic 
cells, as well as mast cells.  The role of PD-1 as a negative regulator of T cells was best 
demonstrated by the finding that PD-1 deficient mice developed significant autoimmunity with 
high titers of autoantibodies [26, 27]. Subsequently, blocking antibodies against PD-1 were shown 
to activate immune responses that resulted in reduction of tumor metastasis and tumor growth in a 
number of experimental tumor models [28, 29]. Consistent with the immune inhibitory role of PD-
1/PD-L1/2 signaling, forced expression of PD-L1 in murine tumor cell lines allowed increased 
tumor growth in vivo, which was otherwise kept in check by T cells. The inciting effect of PD-L1 

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on tumor growth was reversed by blocking anti-PD-L1 antibodies [30]. Patients with high tumor 
and/or lymphocyte PD-L1 levels are 4.5 times more likely to die from their cancer than those with 
low levels of PD-L1 expression.  
Notably, the PD-1 pathway regulates T cell responses in chronic inflammatory liver 
conditions (HBV, HCV, autoimmune hepatitis, and NAFLD) that are responsible for the large 
majority of HCC. Interestingly, in a previous study examining the PD-1 expression profiles, it was 
shown that patients with chronic inflammatory hepatitis have significantly increased numbers of 
PD-1 expressing lymphocytes [31]. Subsequent reports have confirmed that there is up-regulation 
of PD-1 in patients infected with HBV or HCV [32, 33].  
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype, monoclonal antibody 
that binds PD-1. Blockade of the PD-1 pathway by nivolumab was studied using the mixed 
lymphocyte reaction (MLR). PD-1 blockade resulted in a reproducible enhancement of both 
proliferation and IFN-γ release in the MLR. The effect of nivolumab on antigen-specific recall 
response was investigated using a CMV-restimulation assay with human peripheral blood 
mononuclear cells (PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, 
versus an isotype-matched control antibody, augmented IFN-γ secretion from CMV-specific 
memory T cells in a dose-dependent manner. PD-1 blockade by nivolumab is therefore considered 
a promising immunotherapeutic strategy.  
3.3.2 Nivolumab in Hepatocellular Carcinoma  
 
El-Khoueiry AB, et al. presented results from the interim analysis of the phase 1/2 
nivolumab trial (CA209-040) in patients with advanced hepatocellular carcinoma at the 2015 
annual ASCO meeting [34]. In the presentation, the dose escalation study demonstrated safety and 
tolerability of nivolumab at 0.1 mg/kg to 10 mg/kg in patients with HCC due to HCV, HBV or 
who were uninfected with viral hepatitis. The only grade 4 adverse event was elevated lipase (1 
patient) while grade 3 elevations in liver enzymes were seen in 9 patients (AST = 5, ALT = 9). 3 
mg/kg was selected for the dose expansion in the uninfected and HCV cohorts; the dose escalation 
for the HBV cohort was ongoing. In 42 patients evaluable to response, the ORR by RECIST 1.1 
criteria was 19% (8) with 2 patients achieving a complete response. The preliminary overall 
survival at 12 months was 62% (95% CI 42-76%). Moreover, Sangro B, et al. recently presented 
interim results of 214 patients in the expansion CheckMate-040 study who received Nivolumab 3 
mg/kg every 2 weeks [35]. This report demonstrated a preliminary ORR = 16%.  

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Because of these results, a phase III study comparing nivolumab to sorafenib for patients 
with advanced HCC has been launched in the frontline setting with an estimated enrollment of 726 
patients and primary completion date of July 2017 (NCT02576509).  
3.3.3 Summary of Results from Nivolumab Program 
For a complete review of clinical information, please refer to the nivolumab Investigator 
Brochure. 
3.3.3.1  
Summary of Safety 
In clinical trial CA209001 (n = 39), patients received a single dose of nivolumab with 
possible retreatment at 3 months. The most frequent adverse events (AEs) were fatigue (56%), 
nausea (44%), proteinuria (38%), constipation (33%), back pain (33%), dry mouth (28%), 
vomiting (28%), rash (26%) and dyspnea (26%). There was no clear correlation between the 
incidence or severity of AEs and the nivolumab dose levels (0.3, 1, 3, or 10 mg/kg IV single dose, 
with possible retreatment at 3 months). Among 39 (100%) patients who had at least one AE, 32 
(82%) had Grade 3 or 4 AEs. Three treatment-related severe adverse events (SAEs) were reported: 
hypothyroidism (Grade 2), colitis (Grade 3), and anemia (Grade 2). Among 12 deaths, none were 
considered drug-related.  
In CA209003 (n = 306), as of the database lock date of 18-March-2013, nivolumab-related 
AEs of any grade occurred in 75.2% of patients [36]. The most frequent drug-related AEs 
occurring in ≥ 5% of patients included fatigue (28.1%), rash (14.7%), diarrhea (13.4%), pruritus 
(10.5%), nausea (9%), decreased appetite (9%), and fever (6%). The majority of AEs were low 
grade, with Grade 3/4 drug-related AEs observed in 14% of patients. The most common Grade 
3/4 drug-related AEs occurring in ≥ 1% of patients were fatigue (2%), pneumonitis (1%), diarrhea 
(1%), AST/ALT increase (0.3% each) Drug-related SAEs occurred in 17% of patients. Grade 3/4 
drug-related SAEs occurring in ≥ 1% of patients were: pneumonitis (1.3%), and diarrhea (1%). 
The spectrum, frequency, and severity of nivolumab-related AEs were generally similar across 
dose levels and histological subtypes. Other drug-related AEs included vitiligo, hepatitis, 
hypophysitis, and thyroiditis.  
Hepatic or gastrointestinal events were managed with treatment interruption and 
administration of corticosteroids, and were generally completely reversible. Endocrine events were 
managed with hormone replacement therapy. Several patients in these categories successfully 
reinitiated treatment with nivolumab. Drug-related pneumonitis occurred in 3% of patients; Grade 
≥ 3 pneumonitis developed in 3 patients (1%). No clear relationship was identified between the 

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occurrence of pneumonitis and tumor type, dose level, or the number of doses received. Low-grade 
pneumonitis was generally reversible with treatment discontinuation and corticosteroid 
administration. In three patients, infliximab and/or mycophenolate were utilized for additional 
immunosuppression, with unclear effectiveness. There were three (1%) drug-related deaths due to 
pneumonitis. In two of these cases, the patients did not receive the early and aggressive 
intervention (including systemic corticosteroid therapy) that is likely key in the management of 
this toxicity, while in the third case, other anti-cancer agents (erlotinib and vinorelbine) may have 
contributed to the fatal event. 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the Investigator Brochure.  
3.3.3.2  
Summary of Clinical Activity 
In CA209001 and CA209003, the clinical activity of nivolumab was demonstrated in a 
variety of tumor types, including melanoma, RCC, non-small cell lung cancer (NSCLC), and 
colorectal cancer (CRC). Clinical activity was noted across a range of doses (0.1 mg/kg, 0.3 mg/kg, 
1 mg/kg, 3 mg/kg, 10 mg/kg) and across dosing schedules (every 2 weeks dosing for CA209003, 
single administration with possibility of retreatment at 3 months in CA209001). 
In CA209001, all treated patients (n = 39) were evaluable for tumor response [37]. Partial 
response (PR) was reported in 3 patients and stable disease (SD) was reported in 10 patients. 
Patients with PRs included 1 patient with CRC treated at 3 mg/kg and 1 patient each with 
melanoma and RCC, both treated at 10 mg/kg. Tumor responses were maintained in these patients 
as of their last radiological tumor assessments at 26, 3, and 18 months, respectively as of the 
clinical data cut-off date. The patient with RCC had received multiple prior therapies, including 
sunitinib and sorafenib. In 2 of the 10 patients with SD, stable disease was maintained for more 
than 6 months. 
In CA209003, as of the database lock date of 18-March-2013, a total of 306 patients with 
melanoma, RCC, and NSCLC were evaluated for clinical activity [36]. A response of either CR 
or PR, as determined by the investigator based on modified RECIST 1.0, has been reported at all 
dose levels. No responses (CR or PR) have been reported in patients with colorectal carcinoma or 
castrate-resistant prostate cancer. 
3.3.3.3  
Clinical Pharmacology Summary 
Single dose pharmacokinetics (PK) of nivolumab was evaluated in patients with multiple 
tumor types in CA209001 whereas multiple dose PK is being evaluated in patients in CA209003. 

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In addition, a preliminary population pharmacokinetic (PPK) model has been developed with data 
from ~350 patients from CA209001, CA209002, and CA209003. 
Single dose PK of nivolumab was evaluated in 39 patients with multiple tumor types in 
study MD1106-01 in the dose range of 0.3 to 10 mg/kg. The median Tmax across single doses 
ranged from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours. The PK of 
nivolumab is linear in the range of 0.3 to 10 mg/kg with dose- proportional increase in Cmax and 
AUC (INF) with low to moderate inter-subject variability observed at each dose level (i.e., CV 
ranging from 7 to 45%). Geometric mean clearance (CL) after a single intravenous (IV) dose 
ranged from 0.13 to 0.19 mL/h/kg, while mean volume of distribution (Vz) varied between 83 to 
113 mL/kg across doses. The mean terminal T-HALF of nivolumab is 17 to 25 days, which is 
consistent with half-life of endogenous IgG4, indicating that the elimination mechanism of 
nivolumab may be similar to IgG4. Both elimination and distribution of nivolumab appear to be 
independent of dose in the dose range studied. Additional details are provided in investigator 
brochure. 
A preliminary PPK model was developed by nonlinear mixed effect modeling using data 
from 350 patients from CA209001, CA209002, and CA209003. The body weight normalized 
dosing produces approximately constant trough concentrations over a wide range of body weights, 
and hence is appropriate for future clinical trials of nivolumab. 
3.4 
Ipilimumab (Yervoy): Background 
Ipilimumab (anti-CTLA-4) is a fully humanized IgG1 monoclonal antibody to cytotoxic 
T-cell lymphoma-4 (CTLA-4). Ipilimumab is an approved therapy for metastatic melanoma and 
has demonstrated improved overall survival as monotherapy (as compared to peptide vaccine 
gp100) and in combination with dacarbazine (as compared to dacarbazine alone) [38, 39]. It has 
been studied in combination with multiple standard-of-care therapies including chemotherapy for 
squamous and non-squamous NSCLC and radiotherapy for hormone resistant prostate cancer [40].  
Ipilimumab toxicity profile includes side effects associated with an immune mechanism of 
action (immune-related adverse events, irAEs). At 3 mg/kg given every 3 weeks as monotherapy 
[38], the following AEs were observed in at least 10% of subjects: fatigue (42%), diarrhea (33%), 
nausea (35%), decreased appetite (27%), vomiting (24%), pruritus (24%), constipation (21%), rash 
(19%), cough (16%), abdominal pain (15%), headache (15%) and pyrexia (12%). Additional irAEs 
occurring in < 10% of subjects but with clinical relevance included: colitis (8%); endocrinopathies 
(8%) including hypothyroidism, hypopituitarism, hypophysitis, adrenal insufficiency, increased 

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serum thyrotropin and decreased corticotropin; hepatotoxicity (4%) including hepatitis and 
elevations in AST/ALT; and vitiligo (2%). Other reported irAEs include nephritis, pneumonitis, 
meningitis, pericarditis, uveitis, iritis and hemolytic anemia. Overall irAEs occurred in 
approximately 60% of subjects, of which 13% were Grade 3-4, and 0.8% were Grade 5 [38, 40].  
Seven deaths were associated with an irAE - GI perforation (4), colitis (1), liver failure (1), and 
Guillain-Barré Syndrome (1). In addition, 1 subject in the ipilimumab plus gp100 group of 
MDX010-20 clinical trial had a Grade 4 skin irAE (Stevens Johnson syndrome/toxic epidermal 
necrolysis/Lyell’s syndrome), but died due to a treatment-related acute respiratory distress 
syndrome. The irAEs are related to T-cell activation and can be serious or life threatening. Specific 
management guidelines were addressed by Weber et al [41]. 
3.4.1  Ipilimumab in Hepatocellular Carcinoma 
 
There are currently no published data testing ipilimumab in HCC. However, Checkmate 
040, which is currently enrolling, is testing the combination of nivolumab plus ipilimumab in 
patients with advanced HCC.  
 
Interestingly, anti-CLTA-4 therapy (tremelimumab) was previously tested in a pilot study 
to evaluate the safety, preliminary antitumor/antiviral effect of tremelimumab in patients with 
HCC and chronic HCV [42]. In the 21 patients enrolled in this study, 20 were evaluable for toxicity 
and 17 for tumor response. Tremelimumab had an acceptable safety profile with only 1 patient 
developing grade 3 toxicity (encephalopathy); the partial response rate was 17.6% and disease 
control rate was 76.4%.  
3.4.2  Nivolumab in combination with ipilimumab in melanoma 
Since anti-PD1 and anti-CTLA-4 use distinct mechanisms for immune activation from anti-
CTLA-4 and anti-PD1 as well as supportive preclinical data, a phase I study was conducted on 
nivolumab and ipilimumab combination therapy in patients with advanced melanoma [43]. In this 
trial, patients were treated with intravenous doses of nivolumab and ipilimumab in patients every 
3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). 
The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a 
sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 
weeks for up to 48 doses.  
A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 
received sequenced treatment. The ORR (according to modified WHO criteria) for all patients in 
the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, 
or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At 

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the maximum doses that were associated with an acceptable level of adverse events (nivolumab at 
a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% 
of patients had an objective response, all with tumor reduction of 80% or more 
Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the 
concurrent-regimen group but were qualitatively similar to previous experience with monotherapy 
and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 
or 4 adverse events related to therapy and the objective-response rate was 20%. 
A follow-up phase 3 study examined 945 previously untreated patients with advanced 
melanoma [44]. Patients were randomized in a 1:1:1 ratio to receive one of three regimens: 
nivolumab 3 mg/kg every 2 weeks plus placebo; nivolumab 1 mg/kg every 3 weeks plus 
ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks; or 
ipilimumab 3mg/kg every 3 weeks for 4 doses plus placebo. The investigator-assessed ORR for 
the 3 treatment regimens were 43.7% (95% CI, 38.1 to 49.3) in the nivolumab alone group, 57.6% 
(95% CI, 52.0 to 63.0) in the combination nivolumab plus ipilimumab group, and 19% (95% CI, 
14.9 to 23.8) in the ipilimumab alone group. The median progression-free survival was 6.9 months 
(95% CI, 4.3 to 9.5), 11.5 months (95% CI, 8.9 to 16.7), and 2.9 months (95% CI, 2.8 to 3.4), 
respectively. In addition, grade 3-4 treatment-related adverse events occurred in 16.3% in the 
nivolumab group, 55% in the nivolumab-ipilimumab group, and 27.3% in the ipilimumab group, 
with diarrhea and fatigue being the most common adverse events.  
 

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3.4.3  Nivolumab in combination with ipilimumab in other malignancies 
 
Recently, interim data from phase 1 studies in NSCLC and MSI-high colorectal cancer 
testing combination nivolumab and ipilimumab were presented. In particular, CheckMate 012 in 
first-line advanced NSCLC tested nivolumab and ipilimumab in the following combinations: 
nivolumab 1mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4 cycles then nivolumab 3 mg/kg 
every 2 weeks; nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg given every 6 weeks; 
nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 12 weeks; and nivolumab 3 
mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks [45]. Of notable interest, the nivo 3 
Q2W + ipi 1 Q12 (n=38) and nivo 3 Q2W + ipi Q6W (n=39) showed improved toxicity profiles, 
Figure 1. Clinical Activity in Patients Who Received the Concurrent Regimen 
of Nivolumab and Ipilimumab. Panel A shows changes from baseline in the  
tumor burden. Panel B shows a representative waterfall plot of the maximum  
percentage change in target lesions, as compared with baseline measurements. 

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and grade 3-4 treatment-related adverse events were 37% and 33%, respectively. In addition, the 
confirmed ORR for these two groups were 47% (95% CI, 31 to 64) and 39% (95% CI, 23 to 55), 
respectively.  
Based upon these data, it is important to determine whether combination therapy with 
nivolumab and ipilimumab can offer similar clinical benefit to patients with resectable or 
unresectable HCC, a disease in which there is no standard preoperative therapy.  
3.4.5 Study Rationale 
As mentioned, surgical resection or liver transplantation are the only potentially curative 
treatment modalities for localized HCC in select patients. Local-regional therapies (ie: ablation, 
arterial-based therapies, or EBRT) can palliate and sometimes downstage non-resectable lesions, 
but are not typically curative procedures. Sorafenib is the only FDA-approved systemic therapy 
for advanced HCC. Therefore, patients with unresectable HCC have poor survival and there is a 
high recurrence rate (~50% or more) for those receiving potentially curative therapy. Novel 
treatment approaches taking advantage of the higher response rates seen in early-phase HCC 
studies and long-term survival of immunotherapies clearly need to be studied in order to improve 
the treatment of HCC.  As a basis for future research in HCC, immunological pathways in response 
to monotherapy versus combinational therapy need to be evaluated in the context of clinical 
outcome in order to identify predictive and prognostic biomarkers as well as other potential 
therapeutic targets. 
Anti-PD-1 antibody, nivolumab, has recently been shown in a phase 1-2 clinical trial on 42 
patients with advanced or unresectable HCC to result in 19% ORR; many of these responses were 
durable with a response duration of 1-8+ months in patients achieving a PR [34]. Subsequent 
analysis of 214 patients on this study confirmed a 16% ORR. Of note, these response rates compare 
favorably to those seen for sorafenib where the ORR = 2% (without any observable CRs).  Anti-
CTLA-4 antibody, ipilimumab, has not been tested in HCC. However, an alternative anti-CLTA-
4 blocking agent, tremelimumab, has been reported to have a partial response rate of 17% in 
patients with HCC and chronic HCV [42].  
Based on strong preclinical data supporting the hypothesis that PD-1 and CTLA-4 are both 
non-redundant pathways that negatively regulate effector T cells, multiple recent clinical studies 
in other cancer types suggest that combination nivolumab and ipilimumab may induce even greater 
anti-tumor responses than either agent alone. While this combination has yet to be tested in HCC, 
considering the immunosuppressive environment especially characteristic of hepatitis-related 
HCC, combination therapy may lead to enhanced responses.   

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Lastly, multiple recent studies have demonstrated that checkpoint inhibitors can be safely 
administered in the preoperative setting. For example, two preoperative trials have evaluated anti-
CTLA-4 antibody therapy prior to curative surgery both in early stage breast cancer [46] and 
bladder cancer [47]. In addition, anti-PD-1 antibody therapy is current being tested in the 
preoperative setting in renal cell carcinoma at MD Anderson.  
  
Based upon the above functional mechanisms and clinical activities of nivolumab and 
ipilimumab, we propose to use nivolumab alone, or nivolumab + ipilimumab in the presurgical 
setting for a number of reasons. First, it will offer patients with resectable HCC the promising 
clinical benefits of nivolumab and ipilimumab. This may result in improved recurrence rates for 
those patients receiving curative surgery. Second, it will allow us to further evaluate potentially 
synergistic or additive activities on HCC between nivolumab + ipilimumab. Third, this proposed 
trial will allow us to evaluate the immunological pathways in HCC tissues after treatment with 
nivolumab alone, or with nivolumab + ipilimumab, to interrogate potential predictive/prognostic 
biomarkers of clinical response.  
We hypothesize that therapy with nivolumab alone, or combination therapy with 
nivolumab + ipilimumab will have acceptable safety profile and may lead to measurable 
immunological changes, with identification of novel biomarkers that can be used for correlation 
of clinical outcomes in patients with resectable HCC.  
4.0 
Study Population 
For entry into the study, the following criteria MUST be met within 4 weeks (+/- 7 days) 
prior to 1st dose of therapy on this trial.  Any exceptions from the protocol-specific selection 
criteria must be approved by principle investigator. A PI override will be submitted to the 
UTMDACC IND Office before obtaining UTMDACC IRB approval for enrolling a patient on an 
active protocol who has a minor deviation from the stated eligibility criteria which will not affect 
the analysis or interpretation of the study. 
4.1  
Inclusion Criteria 
Signed written informed consent 
1. 
Patients must give written informed consent prior to initiation of therapy, in keeping with 
the policies of the institution. Patients with a history of major psychiatric illness must be 
judged able to fully understand the investigational nature of the study and the risks 
associated with the therapy.  

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Target population 
2. 
Patients with histologically confirmed HCC (Documentation of original biopsy for 
diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by AASLD 
criteria in cirrhotic subjects is required (presence of arterial hypervascularity with venous 
washout). For subjects without cirrhosis, histological confirmation is mandatory. The 
determination of resectability status will ultimately lie in the clinical judgment of the 
surgical oncologist and medical oncologist involved in the care of the patient.  
3. 
Patient must have measurable disease defined as a lesion that can be accurately measured 
in at least one dimension (longest diameter to be recorded) and measures ≥ 15 mm with 
conventional techniques or ≥ 10 mm with more sensitive techniques such as MRI or spiral 
CT scan.  
4. 
Patient can have had prior treatment for HCC including prior surgery, radiation therapy, 
local-regional therapy (abalation or arterial directed therapies), and systemic therapy 
including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4 therapy) 
5. 
ECOG performance status ≤ 1. 
6. 
Within 14 days of the first dose of study drug, patients must have adequate organ and 
marrow function as defined below: 
• 
Absolute neutrophil count ≥ 1,500/μL 
• 
Platelets ≥100,000/μL 
• 
Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain 
or exceed this level) 
• 
Total bilirubin ≤ 1.5 mg/dl 
• 
Serum creatinine ≤ 1.5 times the upper limit of normal or estimated CrCL >40mL/min. 
• 
AST (SGOT) and/or ALT (SGPT) ≤ 5 X institutional upper limit of normal  
Age and Sex 
7. 
Men and women ≥ 18 years of age 
8. 
Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug. 
9. 
Women must not be breastfeeding 

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10. 
WOCBP must agree to follow instructions for method(s) of contraception from the time of 
enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug 
(s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment 
completion. 
11. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study 
drug (s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment 
completion. 
12. 
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy 
testing as described in these sections. 
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with 
WOCBP on the use of highly effective methods of contraception. Highly effective methods of 
contraception have a failure rate of < 1% per year when used consistently and correctly. 
At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less effective 
as listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide 
• 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. 
• Nonhormonal IUDs, such as ParaGard 
• Tubal ligation 
• Vasectomy 
• Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Abstinence is only acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation 

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methods) and withdrawal are not acceptable methods of contraception. 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 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge 
• Male Condom without spermicide* 
• Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
• Female Condom* 
*A male and female condom must not be used together 
4.2 
Exclusion Criteria  
Any of the following criteria will disqualify the patient from participation: 
Target Disease Exceptions 
1. 
Any other malignancy from which the patient has been disease-free for less than 2 years, 
except for non-melanoma skin cancer, or in situ carcinoma of any site. 
Medical History and Concurrent Disease 
2. 
Patients who have organ allografts. 
3. 
Patients who have had a major surgical procedure, open biopsy, or significant traumatic 
injury with poorly healed wound within 6 weeks prior to first dose of study drug; or 
anticipation of need for major surgical procedure during the course of the study (other than 
defined by protocol); fine needle aspirations or core biopsies within 7 days prior to first 
dose of study drug. NOTE: Patients will be allowed to start cycle 1 day 1 therapy after 24 
hours from pre-treatment biopsy. 
4. 
Autoimmune disease: Patients with a history of inflammatory bowel disease (including 
crohn’s disease and ulcerative colitis) are excluded from this study as are patients with a 
history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis 

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[scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., wegener’s 
granulomatosis]). 
5. 
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).  
6. 
Any underlying medical condition, which in the opinion of the Investigator, will make the 
administration of study drug hazardous or obscure the interpretation of adverse events, 
such as a condition associated with frequent diarrhea. 
7. 
Patients who have had a history of acute diverticulitis, abdominal fistula, gastrointestinal 
perforation, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis which are 
known risks factors for bowel perforation, should be excluded from the study. 
8. 
Patients who have a primary brain tumor (excluding meningiomas and other benign 
lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled 
with standard medical therapy, or history of stroke within the past year. 
9. 
History of serious systemic disease, including myocardial infarction or unstable angina 
within the last 12 months, history of hypertensive crisis or hypertensive encephalopathy, 
uncontrolled hypertension (blood pressure of >140/90 mmHg) at the time of enrollment, 
New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable 
symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., 
atrial fibrillation or paroxysmal supraventricular tachycardia are eligible),  significant 
vascular disease or symptomatic peripheral vascular disease. 
10. 
Patients who have history of other diseases, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of an investigational drug or that might affect the interpretation 
of the results of the study or render the subject at high risk from treatment complications. 
11. 
Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or other 
more potent immune suppression medications (e.g. infliximab)  
12. 
Patients who have had influenza, hepatitis, or other vaccines within a month prior to 
initiation of study drugs.  
13. 
Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis within 
the past year.  
14. 
Patients who have serious, non-healing wound, ulcer, or bone fracture. 

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15. 
Pregnancy (positive pregnancy test) or lactation. 
16. 
Patients with prior orthotropic liver transplantation.  
17. 
Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C).  
Prohibited Therapies and/or Medications 
18. 
Patients must not have received prior anticancer therapy with anti-CLTA-4 or anti-PD1 
for HCC. Patients receiving any concomitant systemic therapy for HCC are excluded.  
19. 
Patients must not be scheduled to receive another experimental drug while on this study. 
20. 
Patients who require ongoing anticoagulation will be excluded. Only aspirin will be 
permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted.  
21. 
Patients must not require total parenteral nutrition with lipids. 
Other Exclusion Criteria 
22. 
Any patients who cannot be compliant with the appointments required in this protocol 
must not be enrolled in this study.  
5.0  
TREATMENT PLAN 
5.1  
Registration  
This is a randomized preoperative pilot study evaluating nivolumab alone or in 
combination with ipilimumab in patients with resectable HCC. Patients will be registered by the 
responsible study nurse or research coordinator. 
5.2 
Data Collection 
Data will be collected and stored in an approved database as required. 
5.3  
Study Design and Duration 
This is a pilot, randomized, open-label study of preoperative nivolumab alone (Arm A) or 
nivolumab plus ipilimumab (Arm B) in patients with resectable HCC. A total of 30 patients will 
be enrolled as follows: Arm A (15 patients) and Arm B (15 patients). Patients will be 
randomized into either Arm A or B. 
Note: As of January 8, 2020, 30 patients have been enrolled and 27 patients have been 
randomized. The PI decided to stop enrollment since the study has reached its primary 
endpoint of safety.  

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During screening, patients will be evaluated by a surgeon to determine if they are good 
candidates for conservative hepatic resection or liver resection with curative intent. All patients 
will also be required to provide a pre-treatment biopsy with documented tumor involvement by 
pathologist review. 
Originally, this study included a third arm (Arm C) in which 15 unresectable patients were 
to receive nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 
of therapy (3 doses of nivolumab, 1 dose of ipilimumab; 6 weeks) followed by post-treatment 
biopsy. The study objective in Arm C was to estimate the conversion rate to surgery for potentially 
resectable patients. However, the study has been amended in June 2019 to remove exclude this 
objective and enrollment of Arm C (Appendix II).    
Patients in Arm A (resectable cohort) will receive nivolumab at 240 mg IV every 2 weeks 
for 3 doses followed by liver imaging and hepatic resection on day 1 of week 7, followed (after 4 
weeks from surgery) by nivolumab 480 mg IV every  4 weeks in the adjuvant setting until disease 
progression or for 2 years, whichever is sooner. Patients in Arm B (resectable cohort) will receive 
nivolumab 240 mg IV every 2 weeks for 3 doses plus ipilimumab 1 mg/kg IV on day 1 of therapy 
(3 doses of nivolumab, 1 dose of ipilimumab) followed by hepatic resection followed (after 4 
weeks from surgery) by nivolumab  480 mg IV every  4 weeks plus ipilimumab 1 mg/kg IV every 
6 weeks to 4 doses in the adjuvant setting. Adjuvant therapy will start after 4 weeks from surgery 
with nivolumab 480 mg IV every 4 weeks (Both Arms A and B) plus ipilimumab 1 mg/kg IV 
every 6 weeks (in Arm B only) for up to 4 doses in the adjuvant setting until disease recurrence or 
for total of 2 years from first cycle, whichever is sooner. For Arm B, ipilimumab will be 
administered before nivolumab since the toxicities for ipilimumab are already well-known. Since 
the doses of nivolumab and ipilimumab either as monotherapy or combination are within 
maximum tolerated doses as previously defined, no dose increases or reductions will be allowed. 
Patients will return at week 6 for a pre-surgical evaluation. A small portion of patients with 
rapid disease progression (We anticipate 1-3 of a total of 30 patients in Arms A and B) may not 
have hepatic resection per discretion of the treating surgical and medical oncologists. These 
patients will be off protocol and treated with other standard or investigational agents. They will be 
asked to return for an optional biopsy that will be scheduled in place of their surgery. For patients 
who had significant progression of disease pre-operatively but are still eligible for hepatic resection 
or transplantation, they will be treated with other investigational agents vs. observation post-
operatively as there is no standard adjuvant therapy in surgically resected HCC. 

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After finishing the last treatment, hepatic resection or biopsy will occur on day 1 of week 
7 (+/- 7 days). We will obtain surveillance scans (MRI of abdomen and pelvis with/without 
contrast, and CT chest with/without contrast of chest) 8 weeks after surgery. Patients who show 
significant progression of disease post-operatively will be taken off study and an optional biopsy 
will be taken at that time for immunological analysis.  
Patients who complete the study or discontinue study treatment should be scheduled for an 
end of treatment visit (EOT) as soon as possible. All patients who complete the study or 
discontinue treatment will have a safety follow-up visit 30 (+/- 14 days) after the last dose of study 
drug or surgery, whichever comes last. Please refer to Figure 2 below for the study design.  
Patients will receive baseline staging studies with CT or MRI and be assessed for treatment 
response by scans: MRI or CT of abdomen and pelvis with/without contrast, and CT chest 
with/without contrast of chest (according to RECIST 1.1 and irRC) at week 6 (+/- 7 days). Each 
patient will have post-surgical (day 1 of week 11 +/- 7 days), staging studies as above. 
Subsequently, restaging will be carried out every 12 weeks unless, in the investigators’ opinion, 
follow-up intervals need to be shorter. Studies to confirm a complete response or document 
progressive disease will be performed as needed. Patients will be allowed to continue study therapy 
after initial investigator-assessed RECIST 1.1/irRC-defined progression if they are deemed by the 
investigator to be deriving clinical benefit and tolerating study drug(s), as described in Section 8.3.  

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26
       
 
        
 
 
6.0 
STUDY MEDICATIONS 
6.1 
Nivolumab (Anti-PD1, nivolumab) 
The vials are not subject specific although there will be specific vial assignments by subject 
distributed by the Pharmacy in order to track drug usage and re-supply. 
6.1.1 Dose Calculation of nivolumab 
Nivolumab will be dosed at the the currently FDA-approved dose of 240 mg/dose every 
two weeks or 480 mg/dose every 4 weeks. The flat dose was recently deemed similar to the 3mg/kg 
dosing that was previously used. Dose adjustment is not allowed. 
Figure 2. Study Design of preoperative nivolumab alone or in combination with 
ipilimumab. There are 2 arms to this study: A) Nivolumab monotherapy in resectable HCC; 
B) Combination nivolumab plus ipilimumab in resectable HCC.  

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6.1.2 Preparation and Dispensing of Nivolumab 
The product storage manager should ensure that the study drug is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by the Investigator 
Brochure. If concerns regarding the quality or appearance of the study drug arise, do not dispense 
the study drug and contact the sponsor immediately.  
Investigational product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g. required diluents, administration sets). 
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected 
from light. If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab include laboratory coats and gloves. 
For details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the Investigator Brochure section for 
“Recommended Storage and Use Conditions”.  Care must be taken to assure sterility of the 
prepared solution as the product does not contain any anti-microbial preservative or bacteriostatic 
agent. No incompatibilities between nivolumab and polyolefin bags have been observed. 
Nivolumab is to be administered as a 30 +/- 15-minute IV infusion, using a volumetric 
pump with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted 
with 0.9% normal saline or D5W for delivery but the total drug concentration of the solution cannot 
be below 0.35 mg/ml. It is not to be administered as an IV push or bolus injection. At the end of 
the infusion, flush the line with a sufficient quantity of normal saline. 
6.1.3 Administration of nivolumab 
Patients in all two arms (a total of 30  will receive preoperative treatment with nivolumab 
as a 30 +/- 15-minute IV infusion on Day 1 of a treatment cycle every 2 weeks for arms A and B. 
Post-surgery adjuvant maintenance nivolumab will be given at 480 mg IV every 4 weeks until 
disease progression or intolerability. There will be no nivolumab dose escalations or reductions 
allowed. Patients in each arm may be dosed no less than 12 days from the previous dose.  All post-
surgical patients may be dosed no less than 12 days from the previous dose. If a subject cannot 
receive a following dose of the cycle within the designated time frame, it will be omitted and the 
next dose received will be considered Day 1 of the next cycle. 

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Nivolumab should be administered under the supervision of a physician experienced in the 
use of IV agents. Nivolumab is administered as an IV infusion only. 
Calculate Total Infusion Volume as follows: 
(Total nivolumab dose in mg ÷ 10 mg/mL) + dilution volume = total infusion volume in mL 
Calculate Total Drug Concentration as follows: 
Total nivolumab dose in mg ÷ Total infusion volume nivolumab dose in ml = total infusion volume 
in mg/mL. 
Total concentration cannot be below 0.35 mg/mL. 
Calculate Rate of Infusion as follows: 
Total infusion volume in mL ÷ 30 minutes = rate of infusion in mL/min. 
Example: 
Flat dosing of 240 mg of nivolumab used. 
The total infusion volume would be 24 mL (240 mg ÷ 10 mg/mL = 24 mL) if no dilution volume 
is added. 
The total drug concentration would be 10 mg/mL (240 mg ÷ 24 mL = 10 mg/mL). 
The rate of infusion would be 0.80 mL/min in 30 minutes (24 mL ÷ 30 minutes = 0.80 mL/min). 
6.1.4  Patient Monitoring During Infusion 
Patient vital signs should be monitored prior to dosing, about 15 minutes after initiation of 
the infusion (then every 15-20 minutes as indicated), at 30 and 60 minutes after completion of the 
infusion, or longer if indicated, until the vital signs normalize or return to baseline. For subsequent 
infusions, vital signs should be collected prior to dosing, every 30 minutes during dosing, and 1-
hour post dosing. All vital sign time points will be afforded a 10-minute window. 
6.1.5  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, 
hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions 
should be reported within 24 hours to the BMS and reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (version 4.0) guidelines. 
Treatment recommendations for nivolumab related infusion reactions are provided below 
and may be modified based on MD Anderson treatment standards and guidelines, as appropriate: 

Protocol 2017-0097 
 
 
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• For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention 
not indicated): 
o Remain at bedside and monitor subject until recovery from symptoms. The 
following prophylactic pre-medications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at 
least 30 minutes before additional nivolumab administrations. 
• For Grade 2 symptoms (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): 
o 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 325 
to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. 
If the infusion is interrupted, then restart the infusion at 50% of the original infusion 
rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate. Monitor subject 
closely. If symptoms recur, then no further nivolumab will be administered at that 
visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused must 
be recorded on the case report form (CRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 325 to 1000 mg should be administered at least 
30 minutes before additional nivolumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used. 
• For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae (e.g. renal impairment, pulmonary infiltrates), Grade 4: life-threatening; pressor 
or ventilatory support indicated]: 
o Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows: Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg 

Protocol 2017-0097 
 
 
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30
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. 
Institutional guidelines will be followed for the treatment of anaphylaxis. Remain 
at bedside and monitor subject until recovery from symptoms. In the 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). 
6.2  
Ipilimumab (BMS-734016) 
Ipilimumab is a human immunoglobulin G (IgG1) κ anti-CTLA-4 monoclonal antibody 
(mAb). It is supplied in clear, colorless solution at a concentration of 5 mg/ml in 40ml vial.  
Ipilimumab (BMS-734016) Injection (5 mg/ml), must be stored refrigerated (2 - 8°C) with 
protection from light. In preparation of infusion, ipilimumab may be stored in IV infusion bags 
(PVC, non-PVC/non-DEHP) or glass infusion containers at room temperature or refrigerated (2°C 
- 8°C) for up to 24 hours. Drug must be completely delivered to the subject within 24 hours of 
preparation. This includes any time in transit plus the total time for the infusion. 
6.3.1 Dose Calculation of Ipilimumab 
Total dose should be calculated as in the following example: 
Subject’s actual body weight in kg x 1 mg = total dose in mg 
Therefore, a subject weighing 70 kg who is to receive a dose of 1 mg/kg would be administered 
70 mg of ipilimumab (70 kg x 1 mg/kg = 70 mg). Dose adjustment is not allowed. 
6.3.2 Administration of Ipilimumab 
Each patient in Arm B is to receive ipilimumab at 1 mg/kg dose IV every 6 weeks of 
treatment for up to 4 dses after surgery. Ipilimumab will be administered as a 90 +/- 15-minute IV 
infusion, using a volumetric pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified 
dose. The drug can be diluted with 0.9% normal saline or 5% Dextrose Injection to concentrations 
between 1 mg/mL and 4 mg/mL. It is not to be administered as an IV push or bolus injection. Care 
must be taken to assure sterility of the prepared solutions, since the drug product does not contain 
any antimicrobial preservatives or bacteriostatic agents.  

Protocol 2017-0097 
 
 
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31
Please refer to the ipilimumab Investigator Brochure for further details regarding 
preparation/administration. 
6.3.3 Patient monitoring during Ipilimumab infusion 
Patient vital signs should be monitored prior to dosing, about 15 minutes after initiation of 
the infusion (then every 15-20 minutes as indicated), at 30 and 60 minutes after completion of the 
infusion, or longer if indicated, until the vital signs normalize or return to baseline. For subsequent 
infusions, vital signs should be collected prior to dosing, every 30 minutes during dosing, and 1-
hour post dosing. All vital sign time points will be afforded a 10-minute window. 
6.3.4 Treatment of Ipilimumab infusion Reactions 
Since ipilimumab contains only human protein sequences, it is less likely that any allergic 
reaction will be seen in patients. However, it is possible that infusion of ipilimumab will induce a 
cytokine release syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, hypo- or 
hypertension, bronchospasm or other symptoms. No prophylactic pre-medication will be given 
unless indicated by previous experience in an individual patient.  
Reactions should be treated based upon the following recommendations:  
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, rash):  
• 
Decrease the rate of infusion until recovery from symptoms, remain at bedside and monitor 
patient; 
• 
Complete the ipilimumab infusion at the initial planned rate; 
• 
Diphenhydramine 50 mg IV will be given prior to subsequent doses for patient who 
experience infusion reactions of ≥ grade 1.  
• 
Premedication with diphenhydramine may otherwise be given at the discretion of the 
Investigator for subsequent doses of ipilimumab. 
 
For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe 
symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic BP 
>80 mmHg):  
• 
Interrupt ipilimumab; 
• 
Administer diphenhydramine 50 mg IV;  
• 
Monitor patient closely until resolution of symptoms; 
• 
Corticosteroids may abrogate any beneficial immunologic effect, but may be administered 
at the discretion of the treating physician; 
• 
Resume ipilimumab infusion after recovery of symptoms; 
• 
At the discretion of the treating physician, ipilimumab infusion may be resumed at one half 
the initial infusion rate, then increased incrementally to the initial infusion rate.  

Protocol 2017-0097 
 
 
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• 
If symptoms develop after resumption of the infusion, the infusion should be discontinued 
and no additional ipilimumab should be administered that day; 
• 
The next dose of ipilimumab will be administered at its next scheduled time and may be 
given with pre-medication (diphenhydramine and acetaminophen) and careful monitoring, 
following the same treatment guidelines outlined above;  
• 
At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing with ipilimumab. 
 
For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, systolic 
blood pressure <80 mm Hg, or angioedema):  
• 
Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the 
subject; 
• 
Consider 
bronchodilators, 
epinephrine 
1 mg 
IV 
or 
subcutaneously, 
and/or 
diphenhydramine 50 mg IV, with Solu-Medrol 100 mg IV, as needed. 
• 
Patients should be monitored until the Investigator is comfortable that the symptoms will 
not recur; 
• 
No further ipilimumab will be administered; 
 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after 
treatment of a localized or generalized pruritus), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids). 
 
7.0 
DOSE MODIFICATIONS 
Based upon toxicity profiles on past clinical trials (e.g. nivolumab plus ipilimumab in 
melanoma [43, 44]), the doses of nivolumab and ipilimumab proposed in this protocol are within 
the maximum tolerated doses. Therefore, dose reductions or modifications of nivolumab and/or 
ipilimumab will not be allowed.  
For detailed management of toxicities related to nivolumab or ipilimumab, please refer to 
Appendix 1 (AE I-O Algorithms). If a patient experiences a grade 3 or greater drug-related adverse 
event after a dose of nivolumab or ipilimumab, and did not respond to steroid treatment within 2 
weeks (i.e. improve from G4 to < G3; or from G3 to < G2), then the next dose will not be 
administered and the patient will proceed to surgery after the adverse event has resolved or been 
ameliorated sufficiently so that the patient can proceed safely to surgery.  If a patient experiences 
a grade 3 or greater non-drug related adverse event after a dose of nivolumab or ipilimumab then 
the patient may receive additional doses of nivolumab or ipilimumab, at the discretion of the PI, if 
the grade 3 or greater event has resolved or has been reduced sufficiently as assessed by the treating 
PI prior to administration of the additional doses of nivolumab or ipilimumab. 

Protocol 2017-0097 
 
 
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8.0 
DISCONTINUATION OF THERAPY 
Patients MUST be discontinued from study therapy AND withdrawn from the study for 
the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Any clinical adverse event, laboratory abnormality or inter-current illness which, in the 
opinion of the Investigator, indicates that continued treatment with study therapy is not in 
the best interest of the subject 
• 
Termination of the study by MD Anderson Cancer Center 
• 
Imprisonment or the compulsory detention for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness. 
 
8.1 
Discontinuation Criteria of Nivolumab and Ipilimumab 
Nivolumab and Ipilimumab administration should be 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 bronchospasm, hypersensitivity 
reactions, and infusion reactions: 
− 
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation. 
 Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 
• 
AST or ALT > 5-10x ULN for > 2 weeks 
• 
AST or ALT > 10x ULN 
• 
Total bilirubin > 5x ULN 
• 
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
− 
Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction of 
any duration requires discontinuation 

Protocol 2017-0097 
 
 
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34
• 
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 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset.  
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation: 
− 
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. It is recommended to consult with the PI for 
Grade 4 amylase or lipase abnormalities. 
• 
Any dosing interruption lasting > 6 weeks 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 
interruption lasting > 6 weeks, the principle investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted. 
− 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the principle investigator. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the UTMDACC IND Office 
must be notified.  Tumor assessments should continue as per protocol even if dosing 
is interrupted. 
• 
Any adverse event, laboratory abnormality, or inter-current illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing. 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin: Grade 3 amylase or lipase 
abnormalities that are not associated with symptoms or clinical manifestations of 
pancreatitis do not require a dose delay. It is recommended to consult with the PI for Grade 
3 amylase or lipase abnormalities. 
• 
Any Grade 3 colitis, neurologic toxicity, symptomatic pancreatitis, or pneumonitis.  
• 
Any Grade ≥3 Stevens-Johnson Syndrome of Toxic Epidermal Necrolysis(TEN).  

Protocol 2017-0097 
 
 
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8.2 
Continued Treatment beyond Progression of Disease 
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit from continued treatment despite initial evidence of progressive disease 
[48]. For this reason, patients receiving nivolumab +/- [ipilimumab] will be permitted to continue 
study therapy beyond initial investigator-assessed RECIST 1.1-defined progression as long as they 
meet the 2 criteria listed below.  
• Investigator-assessed clinical benefit, and 
• Subject is tolerating study drug 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression post-surgery must be discussed with the MDACC 
IND Office and documented in the study records. 
Patients should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
target lesions and new measurable lesions). 
New lesions are considered measurable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm). 
For statistical analyses that include the investigator-assessed progression date, patients who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event. 
8.3  
Destruction of Study Drug 
Nivolumab and ipilimumab are to be destroyed onsite. It is the Investigator’s responsibility 
to ensure that arrangements have been made for disposal and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained. 

Protocol 2017-0097 
 
 
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8.4  
Return of Study Drug 
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by BMS. 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. 

Protocol 2017-0097 
 
 
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37
9.0 
CONCOMITANT THERAPY 
Concurrent medications related to co-morbidity (e.g. hypertension, diabetes, etc.) and pre-medications prescribed by the protocol for infusion reactions 
will be recorded in the database.  Hydration, supportive medications, and routine surgical drugs will not be recorded in the database. The patient will provide a 
list of medications taken within 4 weeks prior to screening, and will provide a new list during each clinic visit (see section 10.0). The name, dose, date of start, 
date of stop (if use for short term), indication of the medication will be listed. 
The patient should not start a new prescription medication or over-the-counter medication before consulting with the study investigator, except in the 
case of a medical emergency. No other cancer/investigational therapies should be started during the current study without consulting with the study investigator.  
10.0 STUDY ASSESSMENTS AND PROCEDURES 
Table 1: Study Assessments and Procedures for Arm A 
Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before surgery  then 
after surgery (4-Week Cycles), patients may receive up to 2 years of 
therapy depending on response and every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinue 
Safety 
Follow-
upl 
Follow-
Up Visits 
Survival  
Follow-
Upa 
Treatment Cycle/Day: 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks 
post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for future 
biomedical research (optional) 
X 
 
 
 
 
 
 
  
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 

Protocol 2017-0097 
 
 
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38
Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before surgery  then 
after surgery (4-Week Cycles), patients may receive up to 2 years of 
therapy depending on response and every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinue 
Safety 
Follow-
upl 
Follow-
Up Visits 
Survival  
Follow-
Upa 
Treatment Cycle/Day: 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks 
post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full physical examination 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Directed physical examination c 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Child-Pugh score 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and vital signs 
(T, P, RR, BP)c 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
 
 
12-Lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
Upper endoscopyp  
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Nivolumab administration 
 
Xb 
X 
X 
 
Xb 
X 
X 
 
 
 
 
LOCAL Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
PT/INR and PTT 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC with differentialf 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

Protocol 2017-0097 
 
 
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39
Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before surgery  then 
after surgery (4-Week Cycles), patients may receive up to 2 years of 
therapy depending on response and every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinue 
Safety 
Follow-
upl 
Follow-
Up Visits 
Survival  
Follow-
Upa 
Treatment Cycle/Day: 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks 
post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
Chemistry panelf 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysisg 
Xe 
 X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
T3, FT4, TSH , ACTH, and total 
cortisolg 
Xe 
X 
X 
X 
X 
 
Xq 
 
 
X 
X 
 
 
AFPp 
Xe 
X 
 
 
X 
 
Xq 
 
 
X 
X 
 
 
C -Reactive protein, amylase, 
lipase 
 
X 
 
 
X 
 
Xq 
 
 
X 
 
 
 
Serum IGF 
Xq 
X 
 
 
X 
 
Xq 
 
X 
 
 
 
Hepatitis C antibody (HCV Ab, 
anti-HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-HBc (Total and IgM), anti-
HBs, HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
If Anti-HCV (Hepatitis C 
antibody) positive: 
 
 
 
 
 
 
 
 
 
 
 
 
• HCV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
• HCV viral loadn 
X 
X 
 
 
X 
 
Xq 
 
X 
 
 
 
If (1) HBsAg positive or (2) 
anti-HBc positive, anti-HBs 
negative, and HBsAg negative: 
 
 
 
 
 
 
 
 
 
 
 
 
• Anti-HDV 
X 
 
 
 
 
 
 
 
 
 
 
 
• Anti-HBe  and HBeAg 
X 
 
 
 
 
 
 
 
 
 
 
 

Protocol 2017-0097 
 
 
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40
Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before surgery  then 
after surgery (4-Week Cycles), patients may receive up to 2 years of 
therapy depending on response and every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinue 
Safety 
Follow-
upl 
Follow-
Up Visits 
Survival  
Follow-
Upa 
Treatment Cycle/Day: 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks 
post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
• HBV viral loadn 
X 
 
 
 
X 
 
Xq 
 
X 
 
 
 
 
• Anti-HBc (total), anti-HBs, 
and HBe Ag 
X 
 
 
 
 
 
 
 
 
 
 
 
CENTRAL Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for genetic analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Whole blood for biomarker 
studies (serum and plasma)h 
 
X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
Whole blood for correlative 
studies (RNA and DNA)h 
 
X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
Tumor tissue collectionj 
X 
 
 
 
X 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imagingk 
Xi, n 
 
 
 
X 
 
Xq 
 
X 
 
 
 

Protocol 2017-0097 
 
 
 January 30, 2020  
 
 
 
 
 
 
 
41
AFP = alpha fetoprotein; aPTT = activated partial thromboplastin time; Anti-HBc (total) = Total hepatitis B core antibody; Anti-HDV = hepatitis D virus antibody (previously 
known as ‘delta’); anti-HBs = hepatitis B surface antibody; BP = blood pressure; CBC = complete blood count; Discon = discontinuation; ECOG = Eastern Cooperative Oncology 
Group; FT4 = free thyroxine; HBeAb or anti-HBe = hepatitis B e antibody; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; HBcAg = hepatitis B core antigen; HBsAb = 
hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HCV Ab = hepatitis C antibody; INR = international normalized ratio; P = pulse; 
Q12W = every 12 weeks; RR = respiratory rate; T = temperature; PT = prothrombin time; T3 = triiodothyronine; TSH = thyroid-stimulating hormone, ACTH = 
adrenocorticotropic hormone .  
a. 
In subjects that experience site-assessed PD or start a new anti-cancer therapy, contact should be made (example; by telephone) q12W to assess for survival status. 
b. 
Cycle 1 treatment must be given within 3 days of allocation.  The window for each visit is ±3 days until the end of treatment and ±7 days during follow-up. Nivolumab 
is given every 4 weeks after surgery.  
c. 
Height will be measured at Visit 1 only.  
d. 
For women of reproductive potential, a urine or serum pregnancy test should be performed within 24 hours prior to C1D1, C5D1 and 30 days post treatment.  May use 
screening pregnancy test if performed within 24 hours of first dose.  A serum test can be done if urine is not appropriate.  Additionally, if urine test is positive or is not 
evaluable, a serum test is required.  Subjects must be excluded/discontinued in the event of a positive test results.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines. 
e. 
ECOG Performance Status and laboratory tests for screening and determining eligibility are to be performed within 28 days prior to the first dose of trial treatment.  
f. 
CBC with differential and chemistry to be performed every 2 weeks before surgery. After surgery, CBC with differential and chemistry are performed on every 
nivolumab administration day. 
g. 
Urinalysis and thyroid/hormonal function tests will be performed at every cycle before surgery, at time of surgery (C4D1), at C6D1 and at every restaging thereafter 
(q12 weeks). 
h. 
Blood will be collected prior to dose one (C1D1), Cycle 2 and 3 (before the 2nd and 3rd dose of Nivolumab), at time of surgery (C4D1), at 8 weeks after surgery 
(C6D1), at every restaging thereafter (q12 weeks), and finally at treatment discontinuation (confirmed progression or end of therapy).    
i. 
Screening tumor imaging will be performed within 28 days prior to allocation for confirmation of baseline measurable disease per RECIST 1.1 as required prior to 
subject allocation, then at time of surgery. After surgery, imaging will be repeated and therapy starts at C7D1, then surveillance imaging will be repeated q12W (72±7 
days). 
j. 
Biopsies will be required pre-treatment and at time of surgery.   
k. 
The first on-study imaging time point will be performed at 6 weeks around time of surgery (42±7 days) calculated from the date of allocation and then 8 weeks after 
surgery, and will continue to be performed q12W.  
l. 
SAEs will be followed through 100 days following cessation of treatment, or 100 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 
m. HBV/HCV viral loads (for subjects who have known history of chronic infection) will be measured during screening, then at C1D1, at time of surgery (C4D1), at 8 
weeks after surgery (C6D1), at every restaging thereafter (q12 weeks), and at time of discontinuation.  
n. 
The following imaging studies are required at screening, at time of surgery, at 8 weeks after surgery, then at every restaging thereafter (q12 weeks):  CT chest with or 
without contrast; MRI of abdomen and pelvis with or without contrast unless patient has contraindication for MRI or severely claustrophobic.     
o. 
Every time imaging is done for re-staging (q12 weeks). 

Protocol 2017-0097 
 
 
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Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before surgery  then 
after surgery (4-Week Cycles), patients may receive up to 2 years of 
therapy depending on response and every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinue 
Safety 
Follow-
upl 
Follow-
Up Visits 
Survival  
Follow-
Upa 
Treatment Cycle/Day: 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks 
post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
p. 
Unless performed within 6 months of enrollment day. 
q. 
Starting with Cycle 6, assessments are to be done q12 weeks. 
Table 1: Study Assessments and Procedures for Arm B 
Trial Period: 
Screening 
Phase 
Treatment Cycles. 3 cycles (2-Week Cycles) planned before 
surgery  then after surgery (4-Week Cycles), patients may 
receive up to 2 years of therapy depending on response and 
every restaging scans every 12 weeks 
End of 
Treatment 
 
Post-treatment 
Title: 
Screening 
 
 
 
Surgery 
 
 
 
Discontinu
e 
Safety 
Follow-
upm 
Follow-Up 
Visits 
Survival  
Follow-Upa 
Treatment Cycle/Day 
0 
C1D1 
 
C2D1 
C3D1 
C4D1 
C5D1 C6D1 
C7+D1 
At time of 
discon 
30 days 
post  last 
dose 
Every 
9 weeks post-
discon 
Every 12 
weeks 
Scheduling Window (Days)b 
-28 to -1 
±3 
±3 
±3 
±7 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for future biomedical 
research (optional) 
X 
 
 
 
 
 
 
  
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication review 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
 

Protocol 2017-0097 
 
 
 January 30, 2020  
 
 
 
 
 
 
 
43
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Review adverse events 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
 
Full physical examination 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Directed physical examinationc 
 
X 
X 
X 
X 
X 
X  
X 
 
 
 
 
Child-Pugh score 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and vital signs (T, P, RR, 
BP)c 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
 
 
12-Lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
Upper endoscopy  
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
Xe 
X 
X 
X 
X 
X 
X  
X 
X 
 
 
 
Nivolumab administration 
 
Xb 
X 
X 
 
Xb 
X 
X 
 
 
 
 
Ipilimumab administration  
 
Xb 
 
 
 
 Xr 
 
 
 
 
 
 
LOCAL Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
PT/INR and PTT 
Xe 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
 
CBC with differentialf 
Xe 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
 
Chemistry panelf 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysisg 
Xe 
 X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
T3, FT4, TSH , ACTH, and total 
cortisolg 
Xe 
X 
X 
X 
X 
 
Xq 
 
X 
X 
 
 
AFPo 
Xe 
X 
 
 
X 
 
Xq 
 
X 
X 
 
 
C -Reactive protein, amylase, lipase 
 
X 
 
 
X 
 
Xq 
 
X 
 
 
 
Serum IGF 
Xq 
X 
 
 
X 
 
Xq 
 
X 
 
 
 
Hepatitis C antibody (HCV Ab, anti-
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-HBc (Total and IgM), anti-HBs, 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
If Anti-HCV (Hepatitis C antibody) 
positive: 
 
 
 
 
 
 
 
 
 
 
 
 
• HCV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
• HCV viral loadn 
X 
X 
 
 
X 
 
Xq 
 
X 
 
 
 

Protocol 2017-0097 
 
 
 January 30, 2020  
 
 
 
 
 
 
 
44
\ 
AFP = alpha fetoprotein; aPTT = activated partial thromboplastin time; Anti-HBc (total) = Total hepatitis B core antibody; Anti-HDV = hepatitis D virus antibody (previously known 
as ‘delta’); anti-HBs = hepatitis B surface antibody; BP = blood pressure; CBC = complete blood count; Discon = discontinuation; ECOG = Eastern Cooperative Oncology Group; FT4 
= free thyroxine; HBeAb or anti-HBe = hepatitis B e antibody; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; HBcAg = hepatitis B core antigen; HBsAb = hepatitis B 
surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HCV Ab = hepatitis C antibody; INR = international normalized ratio; P = pulse; Q12W = every 12 
weeks; RR = respiratory rate; T = temperature; PT = prothrombin time; T3 = triiodothyronine; TSH = thyroid-stimulating hormone, ACTH = adrenocorticotropic hormone .  
a. 
In subjects that experience site-assessed PD or start a new anti-cancer therapy, contact should be made (example; by telephone) q12W to assess for survival status. 
b. 
Cycle 1 treatment must be given within 3 days of allocation.  The window for each visit is ±3 days until the end of treatment and ±7 days during follow-up. Nivolumab is 
given every 4 weeks after surgery.  
c. 
Height will be measured at Visit 1 only. Timepoints of directed physical examination will follow nivolumab and ipilimumab administration day. 
d. 
For women of reproductive potential, a urine or serum pregnancy test should be performed within 24 hours prior to C1D1, C5D1 and 30 days post treatment.  May use 
screening pregnancy test if performed within 24 hours of first dose.  A serum test can be done if urine is not appropriate.  Additionally, if urine test is positive or is not 
evaluable, a serum test is required.  Subjects must be excluded/discontinued in the event of a positive test results.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines. 
e. 
ECOG Performance Status and laboratory tests for screening and determining eligibility are to be performed within 28 days prior to the first dose of trial treatment.  
f. 
CBC with differential and chemistry to be performed every 2 weeks before surgery. After surgery, CBC with differential and chemistry are performed on every nivolumab 
and ipilimumab’s administration day. 
If (1) HBsAg positive or (2) anti-HBc 
positive, anti-HBs negative, and HBsAg 
negative: 
 
 
 
 
 
 
 
 
 
 
 
 
• Anti-HDV 
X 
 
 
 
 
 
 
 
 
 
 
 
• Anti-HBe  and HBeAg 
X 
 
 
 
 
 
 
 
 
 
 
 
• HBV viral loadm 
X 
 
 
 
X 
 
Xq 
 
X 
 
 
 
• Anti-HBc (total), anti-HBs, and HBe 
Ag 
X 
 
 
 
 
 
 
 
 
 
 
 
CENTRAL Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for genetic analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Whole blood for biomarker studies 
(serum and plasma)h 
 
X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
Whole blood for correlative studies 
(RNA and DNA)h 
 
X 
X 
X 
X 
 
Xq 
 
X 
 
 
 
Tumor tissue collectionj 
X 
 
 
 
X 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imagingk 
Xi,n 
 
 
 
X 
 
Xq 
 
X 
 
 
 

Protocol 2017-0097 
 
 
 January 30, 2020  
 
 
 
 
 
 
 
45
g. 
Urinalysis and thyroid/hormonal function tests will be performed at every cycle before surgery, at time of surgery (C4D1), at C6D1 and at every restaging thereafter (q12 
weeks). 
h. 
Blood will be collected prior to dose one (C1D1), Cycle 2 and 3 (before the 2nd and 3rd dose of Nivolumab), at time of surgery (C4D1), at 8 weeks after surgery (C6D1), at 
every restaging thereafter (q12 weeks), and finally at treatment discontinuation (confirmed progression or end of therapy).    
i. 
Screening tumor imaging will be performed within 28 days prior to allocation for confirmation of baseline measurable disease per RECIST 1.1 as required prior to subject 
allocation, then at time of surgery. After surgery, imaging will be repeated and therapy starts at C7D1, then surveillance imaging will be repeated q12W (72±7 days). 
j. 
Biopsies will be required pre-treatment and at time of surgery.   
k. 
The first on-study imaging time point will be performed at 8 weeks around time of surgery (42±7 days) calculated from the date of allocation and then 8 weeks after surgery, 
and will continue to be performed q12W.  
l. 
SAEs will be followed through 100 days following cessation of treatment, or 100 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 
m. HBV/HCV viral loads (for subjects who have known history of chronic infection) will be measured during screening, then at C1D1, at time of surgery (C4D1), at 8 weeks 
after surgery (C6D1), at every restaging thereafter (q12 weeks), and at time of discontinuation.  
n. 
The following imaging studies are required at screening, at time of surgery, at 8 weeks after surgery, then at every restaging thereafter (q12 weeks):  CT chest with or 
without contrast; MRI of abdomen and pelvis with or without contrast unless patient has contraindication for MRI or severely claustrophobic.     
o. 
Every time imaging is done for re-staging (q12 weeks). 
p. 
Unless performed within 6 months of enrollment day. 
q. 
Starting with Cycle 6, assessments are to be done q12 weeks. 
r. 
Ipilimumab 1 mg/kg IV is administered in the adjuvant setting, starting with Cycle 5, every 6 weeks to 4 doses maximum. 
 
 

Protocol 2017-0097 
 
 
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46
10.1 
Procedures by Visit 
The Time and Events Schedule above (Table 1 - attached) summarizes the frequency and timing 
of various measurements. The evaluations and procedures for patients enrolled in this study at 
specific time points are further described in the following sections. 
10.1.1 Screening/Pre-study (Day -28 to Day -1) 
The following procedures will be completed for each patient prior to inclusion in the study. All 
screening diagnostic imaging studies MUST be performed within 28 days of the first treatment.  
• Confirmation of the eligibility of patients (see Section 4 for detailed Inclusion/Exclusion 
criteria)  
• Histologic diagnosis of HCC  
• Demographics  
• Medical history relevant to the patient’s cancer 
• Vital sign measurements including weight, height, temperature, pulse, oxygen saturation by 
pulse oximetry, and resting systolic and diastolic blood pressure 
• Complete physical examination 
• ECOG Performance Status 
• Clinical laboratory tests  
• Hematology: CBC 
• Serum Chemistry Panel 
• T3 (free), T4 (free) & TSH  
• ACTH and Total Cortisol 
• Amylase and Lipase 
• Hepatitis B and C screening tests 
• AFP (alpha fetoprotein)  
• Serum IGF 
• Blood samples for Immune Testing 
• Urinalysis: Gross examination including specific gravity, protein, glucose, and blood; 
microscopic examination including WBC/HPF, RBC/HPF and any additional findings. 
• A pregnancy test will be done for women of childbearing potential every 4 weeks during 
enrollment, beginning 24 prior to starting therapy, and prior to post-operative nivolumab 
treatment as explained in Section 4.1. 
• Chest radiography 
• Diagnostic imaging, including CT of the chest, abdomen and pelvis or MRI abdomen/pelvis.   

Protocol 2017-0097 
 
 
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47
• EKG 
• Current medications 
• Baseline signs and symptoms 
• Tumor tissue Collection-  
• Diagnostic/confirmatory biopsy 
10.1.2 Pre-surgical Phase  
Patients who complete the screening evaluations and are confirmed to be eligible for the study will 
begin treatment on this study.  
Eligible patients in Arm A will receive nivolumab at 240 mg IV every 2 weeks for 3 doses (6 
weeks) followed by hepatic resection.   
Eligible patients in Arm B will receive nivolumab 240 mg IV every 2 weeks for 3 doses plus 
ipilimumab 1 mg/kg IV on day 1 of therapy (3 doses of nivolumab, 1 dose of ipilimumab; 6 weeks) 
followed by hepatic resection.  
The following procedures will be performed within +/- 3 days of each scheduled visit or as 
indicated in Section 10. 
• Vital sign measurements including weight, temperature, pulse, oxygen saturation by pulse 
oximetry, and resting systolic and diastolic blood pressure.  
• Vital sign measurements of pulse, oxygen saturation by pulse oximetry, and systolic and 
diastolic blood pressure will be collected every 30 minutes for the duration of nivolumab +/-  
ipilimumab infusion, 1 hour following the completion of the infusion, and routinely unless 
otherwise indicated. 
• Physical examination  
• ECOG Performance Status   
• Blood samples for Immune Tests  
• Hematology: (see Section 10, PT and PTT will be done at baseline and prior to surgery or 
future procedures)  
• Serum chemistry (see Section 10)  
• Amylase & Lipase 
• AFP 
• T3 (free), T4 (free) & TSH (see Section 10)  
• A pregnancy test will be done for women of childbearing potential on the day of starting 
therapy as explained in Section 4.1. 
• Concomitant medications (see Section 9) 

Protocol 2017-0097 
 
 
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48
• Adverse event assessment 
• Each patient will be restaged with CT of the chest, abdomen and pelvis or MRI abdomen/pelvis 
at baseline, prior to surgery, 8 weeks post-surgery follow up, and during future follow up visits 
(every 12 weeks) as indicated in Section 10, unless, in the investigators’ opinion, follow-up 
intervals need to be shorter. Studies to confirm a complete response or document progressive 
disease will be performed as needed.Unscheduled visits are permitted to evaluate adverse 
events and possible disease progression. 
10.1.3 Pre-surgical Visit  
During the Pre-Surgical Evaluation, the patient will have labs and imaging performed and be 
assessed by the physician and surgeon to determine if they are still good candidates for surgery. 
For the pre-surgical visit, patients will return to the clinic at week 6 (+/- 7 days). The following 
assessments will be conducted during this visit: 
• Vital Signs Measurement 
• Physical examination  
• ECOG Performance Status   
• Blood samples for Immune Tests  
• Hematology, PT and PTT 
• Serum chemistry (see Section 10)  
• Amylase and Lipase 
• AFP 
• T3 (free), T4 (free) & TSH (see Section 10) 
• ACTH and Total Cortisol 
• Concomitant medications (see Section 9) 
• Adverse event assessment 
• Each patient will be restaged with CT of the chest, abdomen and pelvis or MRI abdomen/pelvis 
at baseline, prior to surgery, 8 weeks post-surgery follow up, and during future follow up visits 
(every 12 weeks) as indicated in Section 10, unless, in the investigators’ opinion, follow-up 
intervals need to be shorter. Studies to confirm a complete response or document progressive 
disease will be performed as needed.  
10.1.4 Surgery Visit 
During the Surgical Visit the patient will have a hepatic resection or biopsy performed by the 
surgeon and tissue will be collected. For the surgical visit, patients will return to the clinic at week 
7 (+/- 7 days). The following assessments will be conducted during this visit: 
• Surgery or biopsy 

Protocol 2017-0097 
 
 
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49
• Tumor tissue collection for immune tests  
• Additional safety lab tests at the surgeon’s discretion 
• Tumor tissue collection for immunological testing (at surgery).   
• As an optional procedure, tissue will also be collected during procedures performed while 
patients are enrolled in this study. No new procedures will be required. This tissue will also be 
banked for future research related to immunological response. 
10.1.5 Post-surgical Follow-Up (4 Weeks Post Surgery) & Post-Op Nivolumab or 
Nivolumab/Ipilimumab Maintenance  
The Post-Surgical Follow Up begins for all patients after surgery. Patients will return to the clinic 
for a follow-up visit 4 weeks postsurgery. The following assessments will be conducted during 
this visit: 
• Vital Signs Measurement 
• Physical examination  
• ECOG Performance Status   
• Blood samples for Immune Tests  
• Hematology  
• Serum chemistry (see Section 10)  
• Amylase and Lipase 
• AFP 
• T3 (free), T4 (free) & TSH (see Section 10) 
• Concomitant medications (see Section 9) 
• Adverse event assessment 
• Each patient will be restaged with CT of the chest, abdomen and pelvis or MRI abdomen/pelvis 
at baseline, prior to surgery, 8 weeks post-surgery follow up, and during future follow up visits 
(every 12 weeks) as indicated in Section 10, unless, in the investigators’ opinion, follow-up 
intervals need to be shorter.   Studies to confirm a complete response or document progressive 
disease will be performed as needed.  
 
Patients will be followed for clinical responses, anti-cancer medications and delayed 
autoimmune toxicity and TTP. If a possible delayed Immune-related adverse event (IRAE) is 
suspected, the patient will be requested to return to the Investigator’s clinic or office for a physical 
examination and blood work, and other relevant laboratory assessments. All patients will be 
followed for immune-related adverse events for at least 30 days after finishing therapy.  

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50
10.1.6 End of Treatment Visit 
Patients who complete the study or discontinue study treatment should be scheduled for an 
EOT visit as soon as possible, at which time all of the assessments listed for the EOT visit will be 
performed. At the time of study early withdrawal, the reason for early withdrawal and any new or 
continuing AEs should be documented. If study drug administration is discontinued, the reason for 
discontinuation will be recorded. 
10.1.7 Safety Follow-up Visit 
All patients who discontinue study treatment will have a safety follow-up visit for safety 
evaluations 30 days (+/- 14 days) after the last dose of study drug or surgery, whichever comes 
last. If study drug administration is discontinued, the reason for discontinuation will be recorded. 
10.2 
Details of Procedures 
10.2.1 Study Materials 
BMS will provide nivolumab and ipilimumab. 
10.2.2 Safety Assessments 
Adverse events will be assessed at each patient visit, documented in the medical record, 
and entered into CRFs. Patients who report visual changes on therapy will be referred to 
Ophthalmology for evaluation of potential inflammatory or immune-related adverse events 
(uveitis, optic neuritis, etc.) In addition, any occurrence of a SAE from the time of the first protocol 
specific intervention forward, until 100 days after the last dose of study drug, will be reported. 
Refer to safety reporting Section 10.3.  
Safety will be evaluated for all treated patients using the NCI CTCAE version 4.0 
(http://ctep.cancer.gov). Safety assessments will be based on medical review of AE reports and the 
results of vital sign measurements, physical examinations and clinical laboratory tests. 
10.3 
Criteria for Evaluation 
10.3.1 Safety Evaluation 
Refer 
to 
Common 
Terminology 
Criteria 
Adverse 
Events 
(CTCAE) 
version 
4.0 
(http://ctep.cancer.gov) 

Protocol 2017-0097 
 
 
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51
10.3.1.1 Medical History, Physical Exam, Physical Measurements 
Physical examination will be performed at the time points outlined in Section 10.0. If the 
screening physical is conducted within 24 hours of dosing on Cycle 1 Day 1, then a single 
examination may count as both the screening and pre-dose evaluation. Pertinent medical history 
(physician discretion) will be recorded. 
10.3.1.2 Vital Signs 
Blood pressure, heart rate, respiratory rate, oxygen saturation by pulse oximetry and 
temperature will be obtained as outlined in Section 10.0. Orthostatic (supine and standing) blood 
pressure and heart rate are to be measured for any subject who experience lightheadedness, 
dizziness, syncope or any similar complaints. 
10.3.1.3 ECOG Status 
ECOG performance status will be evaluated continuously and documented at Screening 
and at each visit as outlined in Section 10.0. 
10.3.1.4 Assessment of Baseline Symptoms 
Baseline signs and symptoms present within 2 weeks of starting therapy, whether or not 
related to current disease will be documented. Assessment of these baseline signs and symptoms 
will be done at each treatment and Follow-Up Visit (see Section 10.1). Any worsening by > 1 
Grade change from baseline is to be documented as an adverse event. 
10.3.1.5 Adverse Event Monitoring 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to be 
related to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
Adverse events will be evaluated according to the NCI CTCAE Version 4.0 on a 
continuous basis starting from when the patient takes the first dose of nivolumab or ipilimumab to 
follow up visits. Events, such as abnormal laboratory values, considered by the principal 
investigator to be not clinically significant (related to the study or study drug) will not be 
documented. The investigator (or physician designee) is responsible for verifying and 

Protocol 2017-0097 
 
 
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52
providing source documentation for all adverse events and assigning the attribution for all 
adverse events for subjects enrolled. If abnormal lab values, which were not pre-existing or 
which worsened after the first dose of study drug, meet Common Terminology Criteria (CTC) for 
reporting as adverse events (AE), they will be documented in the AE source document and 
captured in the CORe/PDMS Database. For the lab results that do not meet the CTC for reporting 
as an AE, they will be considered not clinically significant (NCS). No additional documentation 
will be required to neither specify NCS lab results nor require physician investigator signature. 
 
Adverse events will be treated appropriately. Such treatment may involve changes in 
nivolumab or ipilimumab therapy including possible interruption or discontinuation, starting or 
stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalization, or any other medically required intervention. Refer to Sections 6.1-3 for treatments 
of nivolumab or ipilimumab infusion reaction and toxicities. 
Once an adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit of any changes in severity, the suspected relationship to nivolumab 
or ipilimumab, the interventions required to treat it, and the outcome. Reporting of adverse events 
will be done according to NCI CTCAE version 4.0. The following items will be recorded at least: 
• Event description 
• Date of onset of AE 
• CTCAE grade/severity (1, 2, 3, 4, 5) 
• Relationship to treatment with nivolumab or ipilimumab (unrelated, unlikely, possible, 
probable, highly probable/definite) 
• Action taken (none, temporarily discontinued agent, drug treatment given/specify, 
permanently discontinued agent, non-drug treatment given/specify, hospitalization) 
• Date of AE stop 
• Outcome (recovered without sequelae, recovered with sequelae, ongoing, worsened, death) 
• Serious AE (yes, no) 
• Serious Adverse Events (SAEs) must be collected from the time of the first protocol specific 
intervention until 100 days after the last dose of study drug. 
 

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53
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) AT (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 AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
 

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54
10.3.2 Laboratory Test Assessments 
Any abnormal laboratory test result considered clinically significant by the Investigator 
must be recorded. 
10.3.2.1 Serum Chemistry 
Serum chemistry tests include: LDH, glucose, total protein, albumin, BUN or urea, 
creatinine, ALT, AST, serum alkaline phosphatase, direct and total bilirubin, sodium, potassium, 
chloride, HCO3, calcium, magnesium, and uric acid. Serum Chemistry is to be obtained as outlined 
in Section 10.0. Three (3) ml of blood will be drawn for serum chemistry, exclusive of TSH. In 
addition, TSH, free T3, free T4, ACTH and total cortisol will also be obtained as described in 
Section 10.0 to monitor endocrine side effects of nivolumab or ipilimumab. Lastly, AFP for tumor 
marker assessment will also be monitored.  
10.3.2.2 Hematology 
CBC with differential are to be obtained as outlined in Section 5.1.  Complete Blood Count 
(CBC) with differential includes hemoglobin, hematocrit, white blood cells, platelets, neutrophils, 
lymphocytes, eosinophils and monocytes. PT and PTT will be drawn at baseline and prior to 
surgery or future procedures. Additional draws must be incorporated to monitor recovery from any 
hematologic laboratory AE. Two and a half (2.5) ml blood will be drawn for hematology. 
10.3.2.3 Tumor Tissue 
Available tumor tissue, obtained at pre-treatment and the time of surgical resection or 
biopsy (if unresectable) will be collected for immune monitoring studies as described below 
(Section 10.3.3). 
10.3.3 Immune Tests 
The Immunotherapy Platform will perform immune monitoring, including but not limited 
to evaluation of CD4 and CD8 T cells in peripheral blood and available tumor samples as 
previously published [52-59]. All samples will be collected and analyzed as per a separate IRB-
approved lab protocol. 
All blood collection will be compliant with institutional safety standards and will not 
exceed the maximum blood draw per venipuncture policy. 

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55
10.3.4 Evaluation of Clinical Responses 
10.3.4.1 Efficacy Assessments 
Progression-free survival (PFS) and objective response rate (ORR), each based on RECIST 
1.1 criteria, are two of the primary efficacy assessments of this study. See Sections 12.2.2.1 and 
12.2.2.4 for the definitions of ORR and PFS, respectively. 
10.3.4.2 Criteria for Progression and Responses 
Evaluation of response will follow the Response Evaluation Criteria in Solid Tumors 
(RECIST) Guidelines. All tumor measurements must be recorded in centimeters. 
• Target Lesions: 
All measurable lesions up to a maximum of five lesions per organ and 10 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 (those with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter for all target lesions will be calculated and 
reported as the baseline sum longest diameter. The baseline sum of longest diameters will be used 
as the reference by which the objective tumor response is characterized. 
• 
Non-target Lesions:  
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
• 
Evaluation of Target Lesions: 
− 
Complete Response: The disappearance of all target lesions. 
− 
Partial Response: At least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. 
− 
Progressive Disease: At least a 20% increase in the sum of the longest diameter of 
target lesions, taking as reference the smallest sum longest diameter recorded since 
the treatment started or the appearance of one or more new lesions. 
− 
Stable Disease: Insufficient shrinkage to qualify for partial response, or insufficient 
increase to qualify for progressive disease, taking as reference the smallest sum 
longest diameter since the treatment started. 
• 
Evaluation of Non-target Lesions: 
− 
Complete Response: The disappearance of all non-target lesions. 

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56
− 
Incomplete Response/Stable Disease: The persistence of one or more non-target 
lesion(s) 
− 
Progressive Disease: The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
• 
Evaluation of Best Overall Response: (see Table 4) 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
Table 4. Evaluation of Best Overall Response 
10.3.4.3 
Immune related Response Criteria (irRC) 
Table 5. irRC outcome measures [64] 

Protocol 2017-0097 
 
 
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57
New, measurable lesions 
Incorporated into tumor burden 
New, non- measurable lesions 
Do not define progression (but precludes 
irCR) 
Non-index lesions 
Contribute to defining irCR (complete 
disappearance is required 
Complete response (CR) 
Disappearance of all lesions in two 
consecutive observations not less than 4 
weeks apart 
Partial response (PR) 
≥50% decrease in tumor burden compared 
with baseline in two observations at least 4 
weeks apart 
Stable disease (SD) 
50% decrease in tumor burden compared 
with baseline cannot be established nor 
25% increase compared with nadir 
Progression of disease (PD) 
≥25% increase in tumor burden compared 
with nadir (at any single time point) in two 
consecutive observations at least 4 weeks 
apart 
 
Note: According to the irRC, disease progression of non-index lesions or appearance of new non-
measurable lesions will not classify the subject as PD, and therefore the subject may stay in the 
study if it is the in the subject’s best interest. A confirmatory tumor assessment may be performed 
no less than 4 weeks after the first indication of progression to provide additional data for the 
investigator to decide if the subject should stay in the trial or be discontinued due to clinical 
progression based on the investigator’s decision.  
10.3.4.4 
Time -to- Event Assessment of Response 
Time to Response: From the start of study drug to the first observation of a response (the first of 
two confirmatory measurements). 
Duration of Response: From the first observation of a response (the first of the two confirmatory 
statements) to the first observation of progressive disease, or to death due to any cause, or early 
discontinuation of treatment due to progressive disease. 
Time to Progression: From the start of study drug to the first evidence of progression. 

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11.0 ADVERSE EVENT REPORTING 
11.1 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-sponsored IND 
Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more 
severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.   

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• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 days after the last dose of study drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 100 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
11.2 
Reporting to FDA 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
11.3 
Investigator Communication with Supporting Companies 
• 
Adverse events classified as "serious" require expeditious handling and reporting to BMS 
to comply with regulatory requirements.  
• 
All SAEs whether related or unrelated to nivolumab or ipilimumab must be immediately 
reported to BMS (by the investigator or designee) within 24 hours of becoming aware of 
the event, using the M. D. Anderson SAE forms.  If only limited information is initially 
available, follow-up reports are required.  The original SAE form must be kept on file at 
the study site. 
All SAEs should be faxed (or emailed) to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s or 
institution’s initial receipt of the information.  The investigator will provide BMS with a 
simultaneous copy of all adverse events filed with the FDA.  SAEs will be reported on the 
MDACC SAE Form.  

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• 
AE Reporting Period: For nivolumab and ipilimumab, all AEs must be collected which 
occur after the first dose through within 100 days of discontinuation of dosing or 
completion of the patient’s participation in the study if the last scheduled visit occurs at a 
later time.  In addition, the Investigator should notify BMS of any SAE that may occur 
after this time period which they believe to be certainly, probably, or possibly related to 
nivolumab and/or ipilimumab. 
• 
Worldwide.Safety@bms.comaepbusinessprocess@bms.com 
 
Notes: 
• 
Cancer/Overdose: An overdose is defined as the accidental or intentional ingestion of any 
dose of a product that is considered both excessive and medically important. For reporting 
purposes, any form of overdose, regardless of adverse outcome, will be considered as an 
important medical event and reported immediately to BMS.  
• 
Hospitalizations (exceptions):  Criteria for hospitalizations not reported as SAEs include 
admissions for: 
− 
Planned as per protocol medical/surgical procedure 
− 
Routine health assessment requiring admission for baseline/trending of health status 
documentation (e.g., routine colonoscopy) 
− 
Medical/surgical admission for purpose other than remedying ill health state (planned 
prior to entry into study trial; appropriate documentation required)  
− 
Admission encountered for other life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
11.4 
Pregnancy 
Patients must agree to use adequate contraception (barrier method of birth control) prior to study 
entry, and for up to 23 weeks after the last study drug dose (for female study participants) or up to 
31 weeks after the last study drug dose (for male study participants). The treating physician, 
principle investigator and BMS should be notified immediately, should a patient or patient’s sexual 
partner become pregnant or suspect she is pregnant while participating in this study. 
12.0 STATISTICAL METHODOLOGY 
12.1 
Preliminaries and Objectives 
This is a randomized, pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as 
pre-operative treatment for patients with hepatocellular carcinoma who are eligible for surgical 
resection. Each patient in both Arms A and B will be given nivolumab at 240 mg every 2 weeks 

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for a total of 6 weeks. Patients in Arm B will additionally be treated concurrently with ipilimumab 
at 1mg/kg every 6 weeks. No dose increases or reductions will be allowed for nivolumab or 
ipilimumab. Surgical resection or post-treatment biopsy will occur within 4 weeks after finishing 
the last cycle of therapy. The rationale is that nivolumab and ipilimumab activate the immune 
system via distinct mechanisms and therefore, the combination of nivolumab and ipilimumab may 
result in synergistic activation of the immune system against hepatocellular carcinoma. The 
primary objective is to assess the safety and tolerability of nivolumab +/- ipilimumab.  Secondary 
objectives include estimating the ORR and TTP of the 2 different arms.  Exploratory objectives 
include evaluating the pre- and post-treatment immunological changes in tumor tissues and 
peripheral blood.  
As of January 8, 2020, 30 patients have been enrolled and 27 patients have been randomized. 
The PI decided to stop enrollment since the study has reached its primary endpoint of safety.  
 
12.2 
Endpoints  
12.2.1 Primary Endpoint: Safety 
Safety will be recorded through the incidence of adverse events, serious adverse events and 
specific laboratory abnormalities (worst grade) in each treatment arm. Toxicities will be graded 
using the NCI CTCAE version 4.0. For trial monitoring and decisions about future trials, extreme 
toxicities (TOX) will be defined as any grade 3 or higher adverse event that is possibly, probably, 
or definitely related to any therapy received on this protocol and occur within the first 6 weeks of 
therapy with one exception. Any grade 3 or higher adverse event that is potentially treatable with 
steroids will only count as an extreme toxicity if it does not improve to grade 1 or better within 2 
weeks. Additionally, a delay of greater than 3 months from the expected surgery date will count 
as a TOX. 
Success will be predefined as having at least 13 of 15 subjects receiving their assigned 
therapy without grade 3 or higher adverse events necessitating a delay in the pre-established 
surgical resection date (a clinically driven end-point defined by the multidisciplinary MD 
Anderson hepatocellular cancer team).   

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12.2.2 Secondary Endpoints  
12.2.2.1. 
Objective Response Rate (ORR) 
Objective response rate (ORR) is defined as the number of subjects with a best response of CR or 
PR after 12 weeks of therapy by RECIST 1.1 criteria divided by the number of randomized subjects 
as described in Section 10.3.4.2  
12.2.2.2.  
Time to progression (TTP) 
TTP is defined as the time from the start of study drug  to the first documented tumor progression 
or recurrence of tumor as determined by the investigator using RECIST 1.1 or iRC criteria. Patients 
who are alive and free of known progression at the time of analysis will be censored on the date 
of last tumor assessment. 
12.2.2.3 
PFS 
PFS is defined as the time from the start of treatment to date of PD or recurrence or date of death 
whichever occurs first if patients have a event, or to the last follow-up date if patients are alive 
without PD. 
12.2.3 Exploratory Endpoints  
Tissue and blood immune monitoring will be conducted through the Immunotherapy Platform 
based on samples collected at the following time points: 1) Pre-treatment; 2) time of surgical 
resection or biopsy (if unresectable); and 3) at time of discontinuation (peripheral blood 
collection).   
12.3 
Sample Size 
Up to 30 patients will be enrolled, for 15 patients each in arm. This sample size is based on having 
sufficient patients to assess toxicities in each arm while providing preliminary estimates of 
secondary endpoints for future trials.   
12.4  Randomization 
Patients in the resectable cohorts will be randomized in a 1:1 fashion through the Clinical Trial 
Conduct website (https://biostatistics.mdanderson.org/ClinicalTrialConduct), which is housed on 
a secure server at MDACC and maintained by the MDACC Department of Biostatistics. Access 
to the website will be gained through usernames and passwords provided by the MDACC 
Department of Biostatistics to personnel responsible for enrolling patients. Training on the use of 

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the Clinical Trial Conduct website to enroll patients on the study will be provided by the study 
biostatistician for study personnel. 
12.5 
Safety Monitoring 
All patients who receive at least one dose of nivolumab or nivolumab plus ipilimumab will be 
considered evaluable for toxicity. 
Safety assessments will include a comprehensive evaluation of AEs and/or toxicity based on:  
• Results of monitoring vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature)  
• Results of clinical chemistry, hematology/coagulation, complement testing, thyroid 
function testing, and urine analysis tests  
• ECG results  
• Changes in physical examination  
• Need for concomitant medications  
• ISRs  
• ECOG performance status  

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12.6 
Data Analyses  
This is a two arm, open-label pilot study evaluating nivolumab alone or in combination with 
ipilimumab in the preoperative or prebiopsy setting.  Since no effective treatments are available in 
this setting, a response rate of 15% (within 95% CI) is considered acceptable – i.e., the signal for 
launching further, larger studies with nivolumab or nivolumab + ipilimumab in this patient 
population is ≥ 1 response in the current study (each arm).  If no response is observed, the treatment 
with nivolumab alone or in combination with ipilimumab will be considered ineffective. A total 
of 15 patients will be enrolled in each arm and treated to rule out a response rate of 15% or less 
with 90% power when at least one response is observed.  In other words, with 15 patients treated, 
the probability of observing at least one response is more than 90% if the response rate is at least 
15%.  Descriptive statistics including with 90% confidence interval will be computed. Observed 
response profile, clinical benefit rate at 6 months and TTP along with relevant confidence intervals 
will be used to guide future development decisions. 
Total evaluable patients 
Number of responders 
Response rate 
Lower 90% CI* 
Upper 90% CI* 
15 
0 
0% 
<1% 
18% 
15 
1 
7% 
<1% 
27% 
15 
2 
13% 
2% 
36% 
15 
3 
20% 
6% 
44% 
15 
4 
27% 
10% 
51% 
15 
5 
33% 
14% 
58% 
15 
6 
40% 
19% 
64% 
15 
7 
47% 
24% 
70% 
15 
8 
53% 
30% 
76% 
15 
9 
60% 
36% 
81% 
15 
10 
67% 
43% 
86% 
15 
>10** 
>67% 
>43% 
>86% 
* Exact confidence interval computed by the method of Clopper and Pearson (Biometrika 26:404-
413, 1934) 
The Kaplan-Meier method will be used to estimate probability of PFS for each treatment arm. 
 
Our exploratory objectives are to characterize the immune response for both treatment arms and 
its correlation to treatment response.  Immune responses, such as infiltration of CD8+/CD4+ T 
cells and dendritic cells, and cytokine levels in blood, will be compared between pre-treatment and 
post-treatment via paired t-test and Wilcoxon signed rank test. The overall treatment response rate 
will be summarized descriptively by dose with the n, percentage, and 95% CIs. Comparison of the 
response rates between two treatment arms will be made via Fisher’s exact test  Association 

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between the binary overall treatment response and immune responses will be assessed by two-
sample t-test and Wilcoxon rank sum test. 
 
The Investigator is responsible for completing a Safety/Efficacy Summary Report, and submitting 
it to the IND Office Medical Affairs and Safety Group, for review and approval.  This should be 
submitted after the first 5 evaluable patients per arm, complete 14 weeks of study treatment, and 
every 5 evaluable patients per arm, thereafter. On every summary submission, toxicity will be 
assessed at week 6, and response at week 14 of study treatment. 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
13.0 ADMINISTRATIVE SECTION  
13.1 
Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in the final approved protocol.  Documentation 
of approval signed by the chairperson or designee of the IRB(s) must be sent to BMS protocol 
managers by the PI/research team.  All revisions (protocol amendments, administrative letters, and 
changes to the informed consent) must be submitted to BMS protocol managers.  The Investigator 
should not implement any deviation or change to the protocol without prior review and 
documented approval/favorable opinion from the IRB of an Amendment, except where necessary 
to eliminate an immediate hazard(s) to study patients. 
13.2 
Informed Consent 
The Investigator must ensure that patients or their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks, and other critical issues regarding 
clinical trials in which they volunteer to participate.  Preparation of the consent form is the 
responsibility of the Investigator and must include all elements required by CFR 21 Part 50.25 and 
the local IRB.  The consent form must be sent to BMS for review prior to IRB approval. 
13.3 
Records and Reports 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation (e.g. case report 
form) on each individual treated with nivolumab +/- [ipilimumab]. The investigator is required to 

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retain, in a confidential manner, the data pertinent to the study. CORe/PDMS will be used as the 
electronic case report form for this study. All protocol specific data, including adverse events, will 
be entered into CORe/PDMS. This study will be monitored for compliance by the IND Office. 
13.4 
Institutional Review Board (IRB) 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to study subjects. The 
Investigator should also provide the IRB with a copy of the Investigator Brochure or product 
labeling information to be provided to patients.  
The Investigator should provide the IRB with reports, updates and other information (e.g., 
Amendments, Administrative Letters) according to regulatory requirements or Institution 
procedures. A detailed list of required regulatory documents also to be submitted to BMS will be 
sent upon final approval of the protocol. 
13.5 
Record Retention 
The Investigator must retain nivolumab and nivolumab plus ipilimumab disposition 
records, source documents, and case histories designed to record all observations and other data 
pertinent to the investigation (e.g. case report form) for the maximum period required by applicable 
regulations and guidelines, or Institution procedures. If the Investigator withdraws from the study 
(e.g. relocation, retirement), the records shall be transferred to a mutually agreed upon designee 
(e.g. another Investigator, IRB). Documentation of such transfer must be provided to BMS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tang DN, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P: Increased 
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Chen H, Fu T, Suh W, Tsavachidou D, Wen S, Gao J, Ng D, He Q, Sun J, Sharma P: 
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52. Liakou, C. I. et al. CTLA-4 blockade increases IFNg-producing CD4+ICOShi cells to shift 
the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 105, 14987-
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53. Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in 
the setting of a presurgical clinical trial. Clinical cancer research: an official journal of the 
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54. Tang, D. N. et al. Increased Frequency of ICOS+ CD4 T Cells as a Pharmacodynamic 
Biomarker for Anti-CTLA-4 Therapy. Cancer Immunol Res 1, 229–234 (2013).  
55. Chen, H. et al. CD4 T Cells Require ICOS-Mediated PI3K Signaling to Increase T-Bet 
Expression in the Setting of Anti-CTLA-4 Therapy. Cancer Immunol Res 2, 1-10 (2014). 
56. Eng, C. Circulating DNA biomarkers: a primer for metastatic colorectal cancer. Lancet 
Oncol 16, 878 - 879 (2015) 
57. Subudhi, S. K. et al. Clonal expansion of CD8 T cells in the systemic circulation precedes 
development of ipilimumab-induced toxicities. Proc Natl Acad Sci USA 113, 11919-1192 (2016) 
58. Wargo, J. A. et al. Analysis of Immune Signatures in Longitudinal Tumor Samples Yields 
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Anti-CTLA-4 Therapy. Cell 167, 397-404 (2016) 
 
 

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Appendix I: AE I-O Algorithms 
 
 
 

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Appendix II: Study Design Version Comparison 
       Protocol Version 1-8 
 
 
 
 
 
 
 
Protocol Version 9