Conditions: Intermediate Stage of Hepatocellular Carcinoma Hepatocellular Carcinoma
Keywords: HCC Durvalumab Tremelimumab Immunotherapy PD-L1 Antibodies Hepatocellular Carcinoma CTLA-4 DEB-TACE
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and efficacy of immunotherapy durvalumab and tremelimumab combined with DEB-TACE in patients with Hepatocellular Carcinoma.

Detailed description:

Arms:
arm 1: Drug: Durvalumab 1500mg IV + Tremelimumab 300 mg IV , single infusion about 2 weeks after first DEB-TACE procedure.

Drug: Durvalumab (monotherapy) 1500 mg IV infusion every 4 weeks, for maximum 13 doses/cycles.

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: Durvalumab 1500mg IV every 4 weeks for up to a maximum of 13 cycles (about 12 months) or until confirmed disease progression. intervention 2: Tremelimumab 300 mg IV in combination with Durvalumab 1500mg about 2 weeks after their first DEB-TACE.

Protocol document:
Prot_SAP_000.pdf: 
 
1
   
 
 
Investigational Drug 
Substance(s) 
 
Durvalumab (MEDI4736) 
and tremelimumab 
 
 
Study Number 
ESR-17-12965 
 
Version Number 
11.0 
 
Date 
August 21, 2024 
 
 
 
 
 
 
The effect of CTLA-4/PD-L1 Blockade following drug-eluting bead transarterial 
chemoembolization (DEB-TACE) in patients with intermediate stage of HCC
using Durvalumab (MEDI4736) and Tremelimumab  
 
IND Sponsor: Ana De Jesus-Acosta 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ClinicalTrials.gov        NCT03638141 


 
2
TITLE:  
The effect of CTLA-4/PD-L1 Blockade following drug-eluting bead transarterial 
chemoembolization (DEB-TACE) in patients with intermediate stage of HCC using 
Durvalumab (MEDI4736) and Tremelimumab 
 
Johns Hopkins #: 
J18118 , IRB00179347 
AZ Protocol #: 
ESR-17-12965 
 
Principal Investigator: 
            Ana De Jesus-Acosta, M.D. 
 
Co-Principal Investigator: 
Amy K. Kim, M.D. 
                                                            
 
 
Astra Zeneca Supplied Agent: 
Durvalumab 
Tremelimumab 
 
IND: 
140414 
 
 
 
 
 
 
 
 
IND Sponsor: 
Ana De Jesus-Acosta, M.D. 
 
Protocol Type / Version # / Version Date: Original/ Version 3.2 / September 13, 2018 
 
 
Version 3.3 / October 3, 2018 
 
 
Version 4.0 / May 15, 2019 
 
 
Version 5.0 / October 16, 2019 
 
 
Version 5.1 / July 7, 2020 
 
 
Version 6.0 / July 9, 2020 
 
 
Version 7.0 / December 29, 2021 
 
Version 8.0 / May 10, 2022 
 
Version 9.0 / September 1, 2022 
                                                                                       Version 10.0 / February 16, 2023 
 
Version 11.0 / August 21, 2024 
 
                           


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PROTOCOL SYNOPSIS 
Clinical Protocol ESR-17-12965 
Study Title:  The effect of CTLA-4/PD-L1 Blockade following drug-eluting bead transarterial 
chemoembolization (DEB-TACE) in patients with intermediate stage of HCC using 
Durvalumab (MEDI4736) and Tremelimumab 
Protocol Number: ESR-17-12965, J18118, IRB00179347 
Clinical Phase: Phase II 
Study Duration: 2 years 
Investigational Product(s) and Reference Therapy: 
Durvalumab (MEDI4736) will be supplied in glass vials containing 500 mg of liquid solution 
at a concentration of 50 mg/mL for intravenous (IV) administration. 
Tremelimumab will be supplied as a sterile solution for IV infusion, filled in 20 mL clear glass 
vials with a rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal 
fill of 20 mL, accounting to 400 mg/vial) of tremelimumab, in an isotonic solution at pH 5.5.
Research Hypothesis    
We hypothesize that the anti-tumor effect of PD-L1/CTLA-4 blockade therapy is potentiated by 
the local ischemic treatment of transarterial chemo-embolization (DEB-TACE) in HCC by 
triggering a TH1 pro-inflammatory signal. We hypothesize that there are immediate changes in 
the tumor microenvironment and T cell diversity in serum after DEB-TACE. Thus, we 
hypothesize that the combined treatment with DEB-TACE followed by PD-L1/CTLA-4 
blockade will synergistically enhance anti-tumor response in patients with HCC, and result in 
increased objective response rate (ORR). 
Objectives: 
Primary Objectives: 
1. To evaluate the objective response rate (ORR) of patients with intermediate stage HCC 
treated with CTLA-4 (Tremelimumab) and PD-L1 (Durvalumab) with transarterial 
chemoembolization (DEB-TACE), according to modified response evaluation criteria in 
solid tumors (mRECIST). 
Secondary Objectives: 
1. To assess the safety of combining DEB-TACE with durvalumab and tremelimumab in 
patients with intermediate stage HCC  
Exploratory Objectives: 
1. To evaluate progression-free survival (PFS) and 6-month PFS of combining durvalumab 
and tremelimumab with DEB-TACE.  
2. To evaluate the tumor response of non-targeted lesion evaluated by objective response 
(mRECIST).  
3. To evaluate a 2 year overall survival (OS) of combining durvalumab and tremelimumab 
with DEB-TACE


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4. To determine the effect of combined immune checkpoint and DEB-TACE versus DEB-
TACE only on tumor microenvironment by comparing pre- and post-treatment tissue 
samples and peripheral blood tumor biomarkers including T cell receptor repertoire, 
circulating tumor cells, and circulating tumor DNA.  
5. To explore potential molecular determinants of response, progression, and disease stability 
using next generation sequencing, other sequencing techniques, and other biomarkers. 
Study Design: 
This is an open-label, single institution study of combination treatment of tremelimumab and 
durvalumab with trans-arterial chemoembolization with drug-eluting microsphere beads (DEB-
TACE) in patients with intermediate stage HCC. The purpose of this study is to determine the 
safety and efficacy of durvalumab and tremelimumab in this population who are receiving DEB-
TACE as standard of care. Patients who have intermediate stage HCC according to Barcelona 
Clinic Liver Cancer (BCLC) criteria, who are eligible for locoregional treatment with DEB-
TACE will be enrolled. 20 HCC patients will undergo DEB-TACE, followed by durvalumab 
1500mg q4weeks and tremelimumab 300mg once within 2 weeks. Patients will continue with 
durvalumab q4weeks until progression of disease or the end of study or maximum 13 cycles. 
Patients will have radiographic surveillance every 6-8 weeks from their last DEB-TACE, and if 
there is residual tumor that can be targeted, patients will receive repeat DEB-TACE. 
 
All patients will have pre- and post-TACE biopsies during the first DEB-TACE treatment and 
post-immunotherapy infusion biopsy.  
 
Patients who are clinically stable at an initial confirmed progression may continue to receive 
study treatment, after the first overall time point assessment of PD until PD is confirmed on a 
follow-up scan (confirmed PD) if they do not show any significant toxicities. Patients will get a 
confirmatory scan, following the assessment of PD, at the next scheduled visit. Patients that 
continue on study after an initial PD will continue to receive durvalumab and tremelimumab at 
the same dose and schedule as they were treated with initially. 
 
In addition, we will have 20 patient data for patients with HCC from our institutional database 
as exact matched control based on age, gender, tumor stage and Child-pugh score. We will 
evaluate the objective response rate (ORR) in comparison to the study group, using McNemar 
paired-sample test. 
Number of Centers: 1 
Study Population: 20 
Patients with intermediate stage HCC, defined by the Barcelona Clinic Liver Cancer (BCLC) 
stage B with compensated cirrhosis who would be eligible for liver-directed therapy (e.g. DEB-
TACE) as standard treatment. 
Inclusion Criteria: 
 Patients with diagnosis of HCC either by high-resolution imaging (triple-phase CT or MRI) 
and/or by tumor biopsy. 


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 Patient is not on systemic treatment for  HCC. Prior local therapy with TACE is allowed if 
treatment was more than 1 month prior to enrollment with evidence of viable HCC or 
recurrence. Patients who were on tyrosine-kinase inhibitors (sorafenib, regorafenib, 
lenvatinib) or other systemic treatments for HCC but considered non-responders or 
intolerant to treatment are allowed to participate.  
 Age ≥18  
 ECOG performance status 0-1 
 Body weight >30 kg  
 HCC meeting Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate stage), with 
measurable lesions on CT or MRI and without extrahepatic spread. Patients with BCLC 
stage A not considered candidates for transplant or surgery at the time of enrollment can 
participate if committed to remain on study for 6 months prior to consideration for 
alternative local therapies.  
 Disease that is technically amenable to DEB-TACE. At least 1 radiographically 
measurable lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter (except lymph nodes, which must have a short axis ≥15 mm) with CT or MRI. 
 Patients with Child Pugh score of A or early B (score ≤8) without clinical evidence of 
ascites. Trace or small amounts of radiographic ascites without associated peritoneal 
carcinomatosis may be approved by the Protocol Chair. 
 Adequate end-organ function as manifested by 
a) Absolute neutrophil count of ≥ 1000/mm3  
b) Hemoglobin ≥9.0 g/dL 
c) platelets ≥ 75,000/mm3 
d) Creatinine ≤ 2.0 mg/dL or calculated creatinine clearance > 50mL/minute 
e) AST ALT ≤ 5 x ULN (pre-treatment value) 
f) Total bilirubin: If cirrhosis present: Part of Child Pugh requirement.  
 
If no cirrhosis present: total bilirubin ≤ 2 mg/dL 
g) Albumin ≥ 2.5 g/dL 
h) INR ≤ 1.8 
 Negative urine or serum pregnancy test or evidence of post menopausal status (female 
patients only, post-menopausal status defined in protocol Section 4.1) 
 Patient who is willing to get tumor biopsies per the study schedule. 
Exclusion Criteria: 
 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
 Participation in another clinical study with an last dose of investigational product ≤ 30 
days prior to start of study treatment. 
 Any concurrent anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) or 
receipt of the last dose ≤30 days prior to start of study treatment (TACE). Concurrent 
use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement 
therapy) is acceptable. 
 Patients with vascular invasion or extrahepatic tumor.


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 Main portal vein tumor-related thrombosis present on imaging. Non-tumor related 
thrombosis is allowed.  
 Uncontrolled hepatic encephalopathy at the time of enrollement. 
 Ascites that require ongoing paracentesis, within 4 weeks prior to the first scheduled 
dose, to control symptoms. 
 Any contraindications for embolization, including hepatofugal blood flow or 
portosystemic shunt. 
 Patients with detectable HBV viral load without active anti-viral treatment. 
- Patients with positive HepB surface antigen (HBsAg) and/or HepB core antibodies 
(anti-HBc) with detectable HBV DNA (≥10 IU/mL or above the limit of detection 
per local lab standard) are permitted on study if they are being treated with antiviral 
therapy with evidence of HBV stabilization or signs of viral response prior to 
enrollment. Patients who test positive for anti-HBc with undetectable HBV DNA 
(<10 IU/ml or under the limit of detection per local lab standard) do not require anti-
viral therapy prior to enrollment. (see Section 7.2.1 for additional on-study testing 
and anti-viral requirements)   
 Any prior or concurrent malignancy or myeloproliferative disorder whose natural history 
or treatment has the potential to interfere with safety or efficacy assessment of this study’s 
investigational drug.  
 History of leptomeningeal carcinomatosis 
 History of active primary immunodeficiency. 
 Active infection including tuberculosis or human immunodeficiency virus. 
 Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
− Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
− Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician. 
 Active or prior documented GI bleeding due to ulcer or esophageal varices bleeding 
within 6 months of enrollment. Note: For patients with history of esophageal variceal 
bleeding or assessed as high risk for esophageal variceal by the treating investigator, 
adequate endoscopic therapy according to institutional standards is required for 
assessment of esophageal varices. History of bleeding from other causes adequately 
treated are allowed. 
 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
− Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
− Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
− Steroids as a premedication for hypersensitivity reactions (e.g. CT scan 
premedication)


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 Active or prior documented autoimmune or inflammatory disease (examples end 
exceptions listed in Section 4.1).  
 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after last dose of durvalumab or 180 days after last dose of 
durvalumab + tremelimumab combination therapy 
 Patients with hypothyroidism (e.g., following Hashimoto syndrome) who are not stable 
on hormone replacement. 
 Any chronic skin condition that require systemic therapy. 
 History of allogenic organ transplantation. 
 History of pericarditis, cardiomyopathy or current use of defibrillator. 
 Patients with celiac disease not controlled by diet alone. 
 Uncontrolled intercurrent illness (see list of examples in Section 4.1) 
 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 
days after the last dose of IP. 
 Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
 Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment.  
 Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4 including 
durvalumab and tremelimumab. 
 Judgment by the investigator that the patient is unsuitable to participate in the study and 
the patient is unlikely to comply with study procedures, restrictions and requirements. 
Investigational Product(s), Dose, and Mode of Administration: 
Durvalumab 1500mg Q4W plus tremelimumab 300mg once via IV infusion, starting at 2 weeks 
after first DEB-TACE procedure. This will be followed by durvalumab monotherapy 1500 mg 
via IV infusion Q4W, until progression or unacceptable toxicity (maximum 13 doses/cycles). 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
To ensure that the combination is safe, the first six patients will be treated and observed  for 
toxicity for 1 cycle before continuation with further accrual. If ≤ 1 limiting toxicity events occur 
in the first 6 patients, we will proceed with additional accrual to complete a total of 20 patients 
for the safety evaluation. If > 1 limiting toxicity events occur among the first 6 patients, then 
three additional patients will be enrolled (i.e. a total of 9 patients).  If ≤ 2 limiting toxicity events 
occur in the 9 patients, we will proceed with additional accrual to complete a total of 20 patients 
for the safety assessment. If > 2 limiting toxicity events occur, we will pause the enrollment 
pending safety review. 
 
Efficacy Assessments: 
The primary endpoint is objective response using modified RECIST (mRECIST) criteria.  The 
regimen would be considered of insufficient activity for further study if the response rate is 30% 


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or less, and the minimum required level of efficacy that would warrant further study with the 
proposed regimen is a 60% response rate.  
Statistical Methods and Data Analysis: 
The safety evaluation will be based on the safety population, which includes all patients who 
receive DEB-TACE and at least one dose of either durvalumab or tremelimumab. Frequency of 
toxicity and adverse events will be summarized by type and grade. Primary efficacy analysis of 
best overall response will be based on response-evaluable population, which includes all 
patients who receive DEB-TACE and both durvalumab and tremelimumab, and have baseline 
scan and at least one on treatment scan or die without on treatment scan. Objective response 
rate, defined as the percent of patients who have CR or PR per mRECIST, will be estimated 
along with 95% confidence interval. Kaplan-Meier curves will be used to characterize 
progression-free survival (PFS) and overall survival. PFS rate at 6 month will be estimated from 
the Kaplan-Meier curve.  
 
Objective response rate (ORR) from the exact matched control group (n=20) will be compared 
to the ORR of the study cohort using McNemar paired-sample test. 
Sample Size Determination: 
An optimal Simon two-stage design is planned. A total of 8 patients will be entered in the first 
stage. If ≤2 subjects respond, the treatment will be terminated and we will conclude the regimen 
is ineffective. If ≥3subjects respond, then additional 12 patients will be studied.  If a total of 8 
or fewer subjects respond in stage one and two combined, the regimen is considered ineffective. 
If a total of 9 or more respond, we conclude the regimen is promising and warrants further study. 
The maximum sample size will be 20 evaluable patients. To account for 10% unevaluable 
patients who do not receive durvalumab/tremelimumab following DEB-TACE, or do not have 
any on treatment scans for reasons other than death, we plan to enroll 22 patients.   
This design provides 90% power to detect a 30% absolute increase in ORR, from 30% to 60%, 
with one-sided type I error 0.1. The chance of stopping early for lack of efficacy at the interim 
analysis is 0.55, if the response rate is 30%.  
 
 
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................ 3 
STUDY SCHEMA................................................................................................................... 9 
TABLE OF CONTENTS ....................................................................................................... 10 
LIST OF TABLES ................................................................................................................. 13 
LIST OF FIGURES ............................................................................................................... 13 
LIST OF APPENDICES ........................................................................................................ 13 
ABBREVIATIONS AND DEFINITION OF TERMS.......................................................... 14 
1. INTRODUCTION ........................................................................................................... 18 
1.1 Disease background ................................................................................................... 18 
 Hepatocellular Carcinoma ..................................................................................... 18 
 Immunotherapies ................................................................................................... 18 
 Durvalumab ........................................................................................................... 20 
 Tremelimumab ...................................................................................................... 20 
 Durvalumab in combination with tremelimumab ................................................. 20 
1.2 Research hypothesis ................................................................................................... 21 
1.3 Rationale for conducting this study ........................................................................... 21 
 Hepatocellular Carcinoma (HCC) and Immune Checkpoint Inhibition ................ 21 
 Rationale for patients with intermediate stage HCC ............................................. 22 
 Justification for Viral Hepatitis and HCC ............................................................. 22 
 Justification for Tumor Biopsies ........................................................................... 23 
 Durvalumab + tremelimumab combination therapy dose rationale ...................... 23 
1.4 Benefit-risk and ethical assessment ........................................................................... 26 
 Potential benefits ................................................................................................... 26 
 Overall risks .......................................................................................................... 27 
2. STUDY OBJECTIVE ...................................................................................................... 30 
2.1 Primary Objective ...................................................................................................... 30 
2.2 Secondary Objectives................................................................................................. 30 
2.3 Exploratory Objectives .............................................................................................. 30 
3. STUDY DESIGN............................................................................................................. 31 
4. PATIENT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL .............................................................. 32 
4.1 Inclusion criteria ........................................................................................................ 32 
4.2 Exclusion criteria ....................................................................................................... 33 
4.3 Withdrawal of patients from study treatment and/or study ....................................... 36 


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4.4 Replacement of patients ............................................................................................. 37 
5. INVESTIGATIONAL PRODUCT(S) ............................................................................. 37 
5.1 Durvalumab and tremelimumab ................................................................................ 37 
 Formulation/packaging/storage............................................................................ 37 
5.2 Dose and treatment regimens ..................................................................................... 38 
 Treatment regimens ............................................................................................. 38 
 Duration of treatment and criteria for retreatment ............................................... 38 
 Study drug preparation of durvalumab and tremelimumab ................................. 39 
 Monitoring of dose administration....................................................................... 41 
5.3 Specific procedure for DEB-TACE (Drug-eluting Bead Trans-arterial 
chemoembolization) ................................................................................................... 42 
6. TREATMENT PLAN ...................................................................................................... 42 
6.1 Patient enrolment ....................................................................................................... 42 
 Procedures for handling patients incorrectly enrolled ......................................... 42 
6.2 Dosage and administration ......................................................................................... 42 
6.3 Definition of Unacceptable Toxicity ......................................................................... 43 
6.4 Dose modification and toxicity management ............................................................ 44 
 Durvalumab and tremelimumab .......................................................................... 44 
7. RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) ............................................................................................................ 46 
7.1 Restrictions during the study ..................................................................................... 46 
7.2 Concomitant treatment(s) ........................................................................................... 47 
 Antiviral Therapy for HBV+ Patients .................................................................. 48 
 Permitted concomitant medications ..................................................................... 48 
 Excluded concomitant medications ..................................................................... 49 
8. STUDY PROCEDURES ................................................................................................. 50 
8.1 Schedule of study procedures .................................................................................... 50 
 Screening phase ................................................................................................... 50 
 Treatment phase ................................................................................................... 54 
 End of treatment ................................................................................................... 54 
8.2 Description of study procedures ................................................................................ 54 
 Medical history .................................................................................................... 54 
 Physical examination ........................................................................................... 54 
 MRI or CT............................................................................................................ 55 
 Electrocardiograms .............................................................................................. 55 
 Vital signs ............................................................................................................ 55 
 Clinical laboratory tests ....................................................................................... 56 
8.3 Biological sampling procedures ................................................................................. 58 
 Biomarker sampling and evaluation methods ...................................................... 58 
 Tumor tissue sampling ......................................................................................... 59 


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 PD-L1 Testing ...................................................................................................... 59 
 Patient blood samples collected for correlative studies ....................................... 60 
 Fresh tumor samples ............................................................................................ 60 
 Protocol Completion ............................................................................................ 60 
 Withdrawal of informed consent for donated biological samples ....................... 61 
9. DISEASE EVALUATION AND METHODS ................................................................ 61 
9.1 Measure of Objective Response ................................................................................. 61 
10. ASSESSMENT OF SAFETY .......................................................................................... 63 
10.1 Safety parameters ....................................................................................................... 63 
 Definition of adverse events ............................................................................... 63 
 Definition of serious adverse events .................................................................. 64 
 Durvalumab + tremelimumab adverse events of special interest ....................... 64 
10.2 Assessment of safety parameters ............................................................................... 66 
 Assessment of severity ....................................................................................... 66 
10.3 Recording of adverse events and serious adverse events ........................................... 67 
 Study recording period and follow-up for adverse events and serious 
adverse events ..................................................................................................... 68 
 Causality collection ............................................................................................ 68 
 Relationship to protocol procedures ................................................................... 68 
 Expectedness ...................................................................................................... 69 
 Adverse events based on signs and symptoms ................................................... 69 
 Adverse events based on examinations and tests ............................................... 69 
 Hy’s Law ............................................................................................................ 69 
 Disease progression ............................................................................................ 70 
 New cancers ....................................................................................................... 70 
 Deaths ................................................................................................................. 70 
 Reporting of serious adverse events ................................................................... 70 
 Other events requiring reporting ........................................................................ 72 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........... 74 
11.1 Description of analysis sets ........................................................................................ 74 
 Safety analysis set ............................................................................................. 74 
 Efficacy analysis set .......................................................................................... 74 
11.2 Methods of statistical analyses ................................................................................... 74 
 Safety analyses ................................................................................................... 74 
 Efficacy analyses ................................................................................................ 74 
 Correlative analyses ........................................................................................... 75 
 Safety run-in ....................................................................................................... 75 
11.3 Determination of sample size ..................................................................................... 76 
12. ETHICAL AND REGULATORY REQUIREMENTS ................................................... 77 
12.1 Ethical conduct of the study ....................................................................................... 77 
13. STUDY MANAGEMENT .............................................................................................. 77 


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13.1 Monitoring of the study ............................................................................................. 77 
14. DATA MANAGEMENT................................................................................................. 77 
14.1 Study governance and oversight ................................................................................ 77 
15. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .............................. 78 
15.1 Identity of investigational product(s) ......................................................................... 78 
16. LIST OF REFERENCES ................................................................................................. 79 
 
 
LIST OF TABLES 
Table 1. Highly effective methods of contraception (<1% failure rate) ....................................... 47 
Table 2. Supportive medications................................................................................................... 48 
Table 3. Prohibited concomitant medications ............................................................................... 49 
Table 4. Clinical chemistry and other miscellaneous labs ............................................................ 57 
Table 5. Hematology ..................................................................................................................... 57 
Table 6. Urinalysis ........................................................................................................................ 57 
Table 7. Blood, Urine, and Tissue to be obtained from each patient ............................................ 60 
Table 8. List of investigational products for this study ................................................................ 78 
 
 
LIST OF FIGURES 
Figure 1.  Example of TACE on tumor microenvironment .......................................................... 22 
Figure 2.  Study Schedule ............................................................................................................. 51 
 
 
LIST OF APPENDICES 
Appendix 1 - Dosing Modification and Toxicity Management Guidelines (TMGs) ................... 83 
Appendix 2. Durvalumab dose volume calculations ................................................................ 108 
Appendix 3. Tremelimumab dose volume calculations ........................................................... 109 
 
 
 


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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AFP 
ALK 
Alpha-feto protein 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BCLC 
BICR 
Barcelona Clinic Liver Cancer  
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
CTC 
ctDNA 
Computed tomography 
Circulating tumor cell 
Circulating tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 


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Abbreviation or 
special term 
Explanation 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board and Independent 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HCC 
hCG 
Hepatocellular carcinoma  
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  


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Abbreviation or 
special term 
Explanation 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
mRECIST 
Micro-ribonucleic acid 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 


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Abbreviation or 
special term 
Explanation 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T3 
Triiodothyronine 
T4 
Thyroxine 
DEB-TACE 
TSH 
Trans-arterial chemo-embolization 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
 
 


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1. 
INTRODUCTION 
HCC is becoming the fastest growing cancer in the world, now becoming the second most frequent 
cause of cancer death worldwide (Jemal et al., 2011; National Cancer Institute, 2016).  There is an 
estimated 748,300 new liver cancer cases annually with 39,230 new cases in the US alone in 2016.  
The rising incidence over the past 40 years in the US currently impose a high toll in morbidity, 
mortality and health care costs in the US and it is expected to continue to rise with the increasing 
prevalence of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease. Despite the 
increased awareness for screening in people at risk for HCC, only 10-30% of the patients are 
diagnosed in early stage where curative treatments, such as resection or liver transplantation, are 
offered (Kudo, Okanoue, & Japan Society of, 2007). Thus, the majority of the patients are 
diagnosed in intermediate to advanced stages with unresectable cancer where the prognosis 
remains poor with the median survival of less than a year.  
The overall aim of this study is to investigate the use of durvalumab and tremelimumab for patients 
with intermediate stage hepatocellular carcinoma (HCC) who will receive liver-directed treatment 
with trans-arterial chemoembolization (DEB-TACE).  We hypothesize that the anti-tumor effect 
of PD-L1/CTLA-4 blockade therapy is potentiated by the local ischemic treatment of transarterial 
chemo-embolization (DEB-TACE) in HCC by triggering a TH1 pro-inflammatory signal. We will 
test the hypothesis that combined treatment with DEB-TACE followed by PD-L1/CTLA-4 
blockade will synergistically enhance anti-tumor response in patients with HCC resulting in 
increased objective response rate (ORR). By applying this novel concept to this particular patient 
cohort with intermediate stage disease burden, this study can potentially expand the current use of 
immunotherapy to earlier stages of HCC, with the possibility of downstaging patients to curative 
treatments including resection and liver transplantation. 
1.1 Disease background 
 Hepatocellular Carcinoma 
To date, only sorafenib, approved in 2007 and regorafenib as a 2nd line treatment in 2016 have 
shown marginal benefit in those with advanced cancer. Notably, patients with intermediate stage 
of HCC, who account for approximately more than 50% of all who present with HCC, are not 
eligible for surgery or chemotherapy as sorafenib is only FDA approved for more advanced stage 
of HCC (BCLC stage C).  Hence, they undergo liver-directed treatments such as trans-arterial 
chemo-embolization (DEB-TACE) or radio-embolization, as a palliative treatment (Zeng, Lv, & 
Mei, 2016). While this standard of care using DEB-TACE is widely prevalent and widely used 
in the community, survival at 2 years remain under 50%. There is an urgent need for improved 
therapy options in this large group of patients.  
 Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors (Dunn, Old, & 
Schreiber, 2004). PD-L1 is a member of the B7 family of ligands that inhibit T-cell activity 
through binding to the PD-1 receptor and to CD80 (Butte, Keir, Phamduy, Sharpe, & Freeman, 
2007). PD-L1 expression is an adaptive response that helps tumors evade detection and 
elimination by the immune system. (Expression of PD-L1 protein is induced by inflammatory 
signals that are typically associated with an adaptive immune response (e.g., IFNγ) and can be 


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found on both tumor cells (TC) and tumor infiltrating IC. The binding of PD L1 to PD-1 on 
activated T cells delivers an inhibitory signal to the T cells, preventing them from killing target 
TC, and protecting the tumor from immune elimination. PD-L1 may also inhibit T cells through 
binding to CD80, although the exact mechanism is still not elucidated (Butte et al., 2007; 
Paterson et al., 2011). 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells. This activity overcomes PD-L1–mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is 
different from direct agonism of a stimulatory receptor such as CD28. 
In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T 
cell-dependent mechanism (Stewart et al., 2015). 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-
L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (Brahmer JR, 2014; Brahmer et al., 2012; Hirano 
et al., 2005; Iwai et al., 2002; Okudaira et al., 2009; Topalian et al., 2012; C. Zhang et al., 2008) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 
(Powles et al., 2014; Rizvi N, 2015; Segal NH, 2015). In addition, high mutational burden e.g., 
in bladder carcinoma (Alexandrov et al., 2013) may contribute to the responses seen with 
immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed 
by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative regulatory 
signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting 
cells (Fife & Bluestone, 2008). Blockade of CTLA-4 binding to CD80/86 by anti-CTLA-4 
antibodies results in markedly enhanced T-cell activation and antitumor activity in animal 
models, including killing of established murine solid tumors and induction of protective 
antitumor immunity. Therefore, it is expected that treatment with an anti-CTLA-4 antibody will 
lead to increased activation of the human immune system, increasing antitumor activity in 
patients with solid tumors. 
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death ligand 1 (PD-L1) has promising clinical activity. Ipilimumab was granted 
United States (US) Food and Drug Administration (FDA) approval for the treatment of 
metastatic melanoma and is currently under investigation for several other malignancies whilst 
nivolumab and pembrolizumab, two anti-PD-1 agents and atezolizumab, an anti PD-L1 agent 
have been granted approvals by agencies such as the United States of America Food and Drug 
Administration and the European Medicines Agency approval for the treatment of a number of 
malignancies including metastatic melanoma, squamous and non-squamous cell non-small-cell 


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lung cancer and urothelial carcinoma. In addition, data from agents in the anti-PD-1/PD-L1class 
shows clinical activity in a wide range of tumor types.  
 Durvalumab  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-
1 on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) Durvalumab has been engineered to reduce antibody-dependent 
cellular cytotoxicity and complement-dependent cytotoxicity. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in 
their restored proliferation and release of interferon gamma (IFNγ; Stewart et al. 2015).  
 As of the DCO date (12 July 2016), a total of 2878 patients have been exposed to 1or more 
doses of durvalumab in ongoing open-label AstraZeneca-or MedImmune-sponsored Phase I-III 
monotherapy and combination therapy studies across all indications. Details on the safety profile 
of durvalumab monotherapy are summarized in Section 6.3. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics. 
 Tremelimumab  
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4; cluster 
of differentiation [CD]152), a cell surface receptor that is expressed primarily on activated T 
cells and acts to inhibit their activation. Tremelimumab completely blocks the interaction of 
human CTLA-4 with CD80 and CD86, resulting in increased release of cytokines (interleukin 
[IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood mononuclear cells and 
whole blood (Tarhini & Kirkwood, 2008). Tremelimumab is being developed by AstraZeneca 
for use in the treatment of cancer.  
To date tremelimumab has been given to more than 1000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of tremelimumab monotherapy are summarized in Section. Refer to the current 
tremelimumab Investigator’s Brochure for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics. 
 Durvalumab in combination with tremelimumab  
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant targeting both PD-1 
and CTLA-4 pathways may have additive or synergistic activity (Pardoll, 2012); therefore, in 
addition to evaluating both agents in the monotherapy setting in a number of cancer indications 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy 
for the treatment of cancer. 
Study D4190C00006 is a Phase Ib dose-escalation study to establish the safety, 
PK/pharmacodynamics, and preliminary anti-tumor activity of durvalumab + tremelimumab 
combination therapy in patients with advanced NSCLC. The dosing schedule utilized is 
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Q4W up to Week 24 for 7 doses then every 12 weeks (Q12W) for 2 additional doses for up to 
12 months. The study is ongoing and continues to accrue. In addition, other clinical studies have 
since started looking at the combination in both NSCLC and other oncology indications. 
To date more than 800 patients have received the combination using a number of doses and 
dosing schedules. Details on the safety profile of durvalumab + tremelimumab combination 
therapy are summarized in Sections 1.4.2. Refer to the current editions of the durvalumab and 
tremelimumab IBs for a complete summary of non-clinical and clinical information including 
safety, PK and efficacy. 
1.2 Research hypothesis 
A. Anti-tumor effect of PD-L1/CTLA-4 blockade therapy is potentiated by local ischemic 
treatment of transarterial chemo-embolization (DEB-TACE) in HCC. Combined treatment 
with DEB-TACE followed by PD-L1/CTLA-4 blockade will synergistically enhance anti-
tumor response in patients with HCC, measured by objective response rate. 
B. Locoregional treatment with DEB-TACE in HCC influences T-cell immune response in the 
tumor microenvironment and changes in specific immune checkpoint pathway.  
 We aim to test this hypothesis by obtaining image-guided tumor biopsy at (1) 
baseline, (2) after 1st DEB-TACE and (3) after combined PD-L1/CTLA-4 blockade 
following DEB-TACE from patients. 
1.3 Rationale for conducting this study 
 Hepatocellular Carcinoma (HCC) and Immune Checkpoint Inhibition 
Immune checkpoint inhibitors have brought immunotherapy into the mainstream treatment of 
cancer and are revolutionizing cancer therapy. Anti-PD1 (programmed cell death protein 1) 
immunotherapy has shown benefit in a broad range of cancer types. In several retrospective 
series of Asian patients, PD-L1 and HLA class I expression in HCC was shown to be prognostic 
for OS and relapse free survival (Gao et al., 2009; Umemoto et al., 2015). Since PD-
L1expression in tumors is associated with response to anti-PD-1 therapy (Topalian et al., 2012), 
we and others have hypothesized that PD-L1 blockade in patients with HCC may be an effective 
therapy.  A recent clinical study of treatment with nivolumab, a monoclonal antibody against 
PD-1, in patients with advanced HCC (with Child-Pugh score ≤ 7) showed 20% objective 
response in this advanced stage group (El-Khoueiry et al., 2017). More importantly, the therapy 
was well tolerated and no patients had to be withdrawn because of treatment-related adverse 
events. 
Accumulating evidence also suggest that pre-existing antitumor immune responses and immune 
checkpoint molecules such as programmed death-ligand (PD-L1) are closely related to anti-PD-
L1 treatment efficacy. Furthermore, eliciting tumor-specific T-cell immune responses can 
potentiate current checkpoint inhibitor therapy. This was suggested in mice models with liver 
metastasis from colorectal cancer, where combined radiofrequency ablation and anti-PD1 
treatment provided longer duration of tumor regression and survival than single treatment group 
(Shi et al., 2016). Additionally, CTLA-4 has an inhibitory effect of T cell activation, and 
blockade of its target ligand (B7) shows been shown to markedly enhance T cell activation and 
antitumor activity in animal models. Clinically, we know that liver-directed treatments such as 
DEB-TACE induce inflammatory response in patients, shown with rising cytokines levels and 


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other inflammatory markers including neutrophils and lymphocytes obtained from peripheral 
blood samples (Xue et al., 2015).  
 
 Justification for Viral Hepatitis and HCC  
Recent study on tremelimumab and HCC has shown that their subset of the patients who had 
hepatitis C (HCV) actually had a reduction of HCV viral load suggesting objective enhancements 


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of antiviral immunity. A significant and progressive decline in serum HCV viral load was 
observed (median values: baseline 3.78x105 copies/ml vs. day 120 3.02x104 copies/ml, P = .02; 
vs. day 210 1.69x103 copies/ml, P = .04) with three patients demonstrated a complete viral 
response for the duration of the follow- up (Sangro B, 2013). There’s also evidence that CTLA-
4 blockade may have antiviral effect in hepatitis B (HBV). Studies have shown cases of antibody 
response against hepatitis B surface antigen (X. Wang et al., 2018). We will be enrolling patients 
who have HCC with background etiology of viral hepatitis (HBV and HCV), as well as non-
viral hepatitis. Patients with chronic active hepatitis B will with detectable viral load will be 
recommended to be on anti-viral treatment at the time of the study. Those with viral hepatitis 
will have close monitoring of their viral hepatitis status with serial blood tests.  
 Justification for Tumor Biopsies  
While immunotherapy, including PD-L1 blockade, demonstrated remarkable clinical impact in 
a number of different solid tumors, not all tumors and patients respond to the therapy. 
Overexpression of PD-L1 is has been demonstrated in many types of these cancers, and it has 
shown that the assessment of intratumoral PD-L1 expression through immunohistochemistry 
could predict anti-PD1 therapy response (Brahmer et al., 2010; Topalian et al., 2012). Therefore, 
it is important to obtain a baseline tissue sampling of the patients in this trial to understand if 
specific tumoral expression of immune checkpoint pathway can be used as a selection criteria 
for those with treatment response. Furthermore, while we have preclinical data to suggest 
immune-regulatory effects of radiation or hypoxic injury, there is no published data on humans 
in liver cancer. It is scientifically critical to obtain more information on the tumor 
microenvironment from baseline stage, after embolic treatment and finally after administration 
of immunotherapy proposed in this study. Also, biopsies will be combined with their scheduled 
transarterial chemo-embolization procedure with our interventional radiologists, which also 
decreases the potential risk of bleeding as artery to the tumor will be embolized and allow 
additional clinical monitoring. If the tumor is considered technically challenging for a biopsy or 
if there are additional risks to the biopsy procedure, the investigators will forgo the biopsy 
procedure.  
 Durvalumab + tremelimumab combination therapy dose rationale 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal 
of selecting an optimal combination dose of durvalumab and tremelimumab that would yield 
sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable 
safety profile.  
 
1.3.5.1 Dose rationale for combination regimen of durvalumab 1500 mg Q4W plus 
tremelimumab 300 mg × 1 dose 
A summary of the existing PK and pharmacodynamic data has been utilized to guide the 
regimen selection for the combination of durvalumab 1500 mg plus single dose of 
tremelimumab 300 mg. 
 
Pharmacokinetics/pharmacodynamics data 
 
The supporting data for this regimen are based on PK and pharmacodyamic data from regimens 
that used tremelimumab doses of greater than 1 mg/kg from Study D4190C00006. An 


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approximate dose-proportional increases in PK exposure (maximum serum concentration and 
area under the serum drug concentration-time curve from time 0 to Day 28 post-dose) was 
observed with increasing doses of tremelimumab (1, 3, and 10 mg/kg). An exploratory 
pharmacodynamic analysis bioanalytically evaluated the effects of tremelimumab on 
proliferating T-cells from NSCLC patients who received tremelimumab (1, 3, or 10 mg/kg) 
and durvalumab (15 or 20 mg/kg) combination treatment. Monotonic increases in 
pharmacodynamic activity with the combination (increased activation/ proliferation markers 
on CD4 and CD8 T-cells in periphery) were observed with increasing doses of tremelimumab 
(1, 3, 10 mg/kg). The peak increase (%) from baseline of CD4+Ki67+ T-cells was observed 8 
days post administration, and the peak level was significantly increased (p ≤ 0.05) as increasing 
dose of tremelimumab in the range of 1 to 10 mg/kg. Study data also suggested that higher 
peak exposure (maximum serum concentration [Cmax]) of tremelimumab is related to a higher 
maximum pharmacodynamic effect in the NSCLC patient population. Overall, the 
PK/pharmacodynamic data suggest that tremelimumab of dose greater than 1 mg/kg with a 
higher peak exposure may be associated with a higher pharmacodynamic effect. Additionally, 
based on simulation data, the Cmax (78 μg/mL) post single dose administration of 
tremelimumab 4 mg/kg is approximately 4-fold higher than the predicted Cmax (19 μg/mL) 
post the first dose of tremelimumab 1 mg/kg, and is 3-fold higher than the predicted Cmax (25 
μg/mL) post the fourth dose of tremelimumab 1 mg/kg in a Q4W×4 doses setting. 
 
Clinical data 
 
The safety and preliminary efficacy of combination of durvalumab 1500 mg plus single dose 
of tremelimumab 300 mg in unresectable HCC population will be evaluated in the ongoing 
Phase I/II study (Study D4190C00022). No clinical data on this regimen is available at the time 
of drafting of this protocol. 
 
In summary, a single dose of tremelimumab 4 mg/kg, while maintaining a similar overall 
exposure, has a 3- to 4-fold higher Cmax compared to the 4 doses of tremelimumab 1 mg/kg. 
Therefore, this single administration of the higher dose of tremelimumab may have the 
potential for better anti-tumor activity while potentially avoiding any cumulative toxicity 
associated with repeated dosing of the 1 mg/kg tremelimumab. Therefore, the regimen of 
durvalumab 1500 mg plus tremelimumab 300 mg×1 dose is being evaluated in the current 
study. 
 
1.3.5.2 Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy  
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 
22%. Furthermore, the survival curve in this population reached a plateau at 3 years and was 
maintained through 10 years of follow up (Sangro et al., 2013; Schadendorf et al., 2015).  
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  
Nivolumab (anti–PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation 
and expansion study, and showed responses were maintained for a median of 22.94 months for 


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melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), 
and 12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data 
analysis (Gettinger et al., 2015). Furthermore, responses were maintained beyond treatment 
discontinuation in the majority of patients who stopped nivolumab treatment (either due to 
protocol specified end of treatment, complete response [CR], or toxicity) for up to 56 weeks at 
the time of data analysis (Topalian et al., 2014) MPDL3280a (anti–PD-L1) and the 
combination of nivolumab with ipilimumab, in which patients were dosed for a finite time 
period and responses maintained beyond treatment discontinuation have been reported 
(Wolchok et al., 2013). 
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti–CTLA-4 antibodies such as tremelimumab, anti–PD-L1 antibodies 
such as durvalumab, or the combination of the two.  
The durvalumab + tremelimumab combination regimen will be administered for 4 doses Q4W 
followed by durvalumab monotherapy Q4W until disease progression, for up to a maximum 
further 8 doses unless other specific discontinuation criteria are met.  
1.3.5.3 Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase 
I study (study 1108; N=292; doses=0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-patient variability with fixed 
dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses=0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) (E. 
Wang et al., 2014). Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 
mg/kg Q4W; based on median body WT of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a 
simulated population of 1000 patients with body weight distribution of 40 kg to 120 kg. Similar 
to durvalumab, simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
patient variability with fixed dosing regimen. 
Similar findings have been reported by others (Narwal, Roskos, & Robbie, 2013; Ng, Lum, 
Gimenez, Kelsey, & Allison, 2006; D. D. Wang, Zhang, Zhao, Men, & Parivar, 2009; S. 
Zhang, Shi, Li, Parivar, & Wang, 2012). Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed 
dosing being better for 7 of 12 antibodies(D. D. Wang et al., 2009). In addition, they 


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investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed 
better for 12 of 18 in terms of reducing the between-patient variability in 
pharmacokinetic/pharmacodynamics parameters (S. Zhang et al., 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg and the pharmacodynamic data as summarized above, a fixed dose of 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) and a fixed dose of 300mg tremelimumab once 
and a fixed dose of 1500 mg Q4W durvalumab  and 75 mg tremelimumab Q4W(equivalent to 
1mg/kg Q4W) is included in the current study. 
1.4 Benefit-risk and ethical assessment 
 Potential benefits 
1.4.1.1  Durvalumab + tremelimumab  
It is hypothesized that durvalumab and tremelimumab may have a synergistic anti-tumor effect 
above what would be anticipated from their individual anti-tumor activity. We have seen in 
preclinical studies which show that combination therapy (dual targeting of PD-L1 and CTLA-
4) has been shown in preclinical studies with a mouse model to cause tumor regression of 
Other combinatorial trials using nivolumab (PD1 inhibitor) plus ipilimumab (CTLA-4) for 
stage III or IV measurable, unresectable melanoma have recently been reported with promising 
results. At the maximum tolerated combination dose—1mg/kg anti-PD1 plus 3 mg/kg 
ipilimumab every three weeks administered concurrently, 53% of patients had an objective 
response, all with tumor reduction of 80% or more. Adverse effects occurred in 53% of patients 
and were similar in quality and intensity to those observed with ipilimumab monotherapy. 
Sequential administration resulted in a lower response rate and lower toxicity rate.  
1.4.1.2 DEB-TACE and Immunotherapy 
Accumulating evidence also suggest that eliciting tumor-specific T-cell immune responses can 
potentiate current checkpoint inhibitor therapy. This was suggested in mice models with liver 
metastasis from colorectal cancer, where combined radiofrequency ablation and anti-PD1 
treatment provided longer duration of tumor regression and survival than single treatment 
group (Shi L et al 2016). Additionally, CTLA-4 has an inhibitory effect of T cell activation, 
and blockade of its target ligand (B7) shows been shown to markedly enhance T cell activation 
and antitumor activity in animal models. Clinically, we know that liver-directed treatments 
such as DEB-TACE induce inflammatory response in patients, shown with rising cytokines 
levels and other inflammatory markers including neutrophils and lymphocytes obtained from 
peripheral blood samples (Xue et al. 2015)  


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 Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are generally 
events with a potential inflammatory or immune mediated mechanism and which may require 
more frequent monitoring and/or unique interventions such as immunosuppressants and/or 
endocrine therapy. These risks can include gastrointestinal AEs such as colitis and diarrhoea, 
pancreatitis, pneumonitis/interstitial lung disease (ILD), renal AEs such as nephritis and 
increases in creatinine, hepatic AEs such as hepatitis and liver enzyme elevations, skin events 
such as rash and dermatitis, endocrinopathies such as hypo- and hyper-thyroidism, 
hyophysitis,adrenal insufficiency, diabetes mellitus type I and diabetes insipidus, and 
neurotoxicities such as myasthenia gravis and Guillain-Barre syndrome. 
1.4.2.1 Durvalumab 
Risks with durvalumab include diarrhea, colitis, pneumonitis /ILD, encephalitis 
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus (which may present as 
diabetic ketoacidosis), diabetes insipidus, hypophysitis and adrenal insufficiency) 
hepatitis/hepatotoxicity/increases 
in 
transaminases, 
immune 
thrombocytopenia, 
neurotoxicities, nephritis/increases in creatinine, pancreatitis, rash/pruritus/dermatitis, 
myocarditis, infusion-related reactions, anaphylaxis, hypersensitivity or allergic reactions, 
pemphigoid, subcutaneous injection site reaction, and immune complex disease.  
Further information on these risks can be found in the current version of the durvalumab IB. 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, headache, rash, and 
pruritus. Approximately 8% of patients experienced an AE that resulted in permanent 
discontinuation of durvalumab and approximately 5% of patients experienced an SAE that was 
considered to be related to durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see the Dosing Modification and Toxicity 
Management Guidelines in Appendix 1. 


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A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 
1.4.2.2 Tremelimumab 
Risks with tremelimumab monotherapy are GI effects (colitis, diarrhoea, enterocolitis and 
intestinal perforation), endocrine disorders (hypo and hyperthyroidism, hypophysitis and 
adrenal insufficiency), skin effects (rash, and pruritus), elevations in lipase and amylase, other 
gastrointestinal events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic events 
including hepatitis, and liver enzyme elevations; pneumonitis and ILD; clinical manifestations 
of pancreatitis; nervous system events including encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barre and proximal muscle weakness; cytopenias including 
thrombocytopenia, anemia and neutropenia; infusion-related reactions, anaphylaxis, and 
allergic reactions; renal events including renal failure, acute kidney injury, nephritis, nephrotic 
syndrome, autoimmune nephritis and electrolyte abnormalities such as hypokalemia; 
autoimmune diseases including autoimmune arthritis, Sjögren’s syndrome and giant cell 
temporal arteritis; hyperglycemia and diabetes mellitus; and pyrexia Further information on 
these risks can be found in the current version of the tremelimumab IB.  
Using pooled data from monotherapy clinical studies AEs (all grades) reported very commonly 
(≥10% of patients) were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting, 
dyspnea, constipation, cough, pyrexia, abdominal pain, decreased weight, headache, asthenia, 
and anaemia. Approximately 16% of patients experienced an AE that resulted in permanent 
discontinuation of tremelimumab and approximately 45% of patients experienced an SAE. A 
detailed summary of tremelimumab monotherapy AE data can be found in the current version 
of the tremelimumab IB. 
1.4.2.3 Durvalumab + tremelimumab  
The safety of durvalumab + tremelimumab combination therapy is being evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and has so 
far shown a manageable safety and tolerability profile.  
The potential risks with the combination of durvalumab + tremelimumab are similar to those 
for durvalumab and tremelimumab monotherapy. Emerging data from study 006 and from 
combinations of other agents in the same class indicate an increased frequency and/or severity 
of some of these potential immune-mediated toxicities.  
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, diarrhoea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, 
constipation, cough, abdominal pain, pyrexia, back pain, hyponatremia and rash.  
Approximately 13% of patients experienced an AE that resulted in permanent discontinuation 
of study drug and approximately 13% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study investigator. 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB. 


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1.4.2.4 Overall benefit-risk of DEB-TACE with Durvalumab + tremelimumab 
Currently we do not have effective systemic treatment recommendation for patients with 
intermediate HCC, who are often outside the criteria for surgical resection but also not 
indicated for the FDA approved sorafenib.  2 year overall survival ranges from 30-40% at best 
with median survival ranging from 11-20months. This is a large subset of patients with HCC 
who can benefit from targeted immunotherapy while receiving locoregional treatment with 
DEB-TACE as standard of care. If our hypothesis proves to be true with clear benefit of 
combinatorial treatment, this will also increase the possibilities for patients with intermediate 
stage HCC to have enough tumor burden reduction to undergo curative treatments, such as 
resection or liver transplantation.  
For this proposal, we will select those with compensated liver disease, with Child-Pugh score 
less than 7 (early B). The risk of side effects has been reviewed, and to prevent serious 
complications, we have designed this study to assess early for any adverse effects.  
 
 
 


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2. 
STUDY OBJECTIVE 
2.1 Primary Objective 
 To evaluate the objective response rate (ORR) of patients with intermediate stage HCC 
treated with anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) with 
transarterial chemoembolization (DEB-TACE), according to modified response evaluation 
criteria in solid tumors (mRECIST). 
2.2 Secondary Objectives 
 To assess the safety of combining DEB-TACE with durvalumab and tremelimumab in 
patients with intermediate stage HCC.  
2.3 Exploratory Objectives 
 To evaluate progression-free survival (PFS) and 6-month PFS of patients treated with the 
combination of durvalumab and tremelimumab with DEB-TACE.  
 To evaluate the tumor response of non-targeted lesion evaluated by objective response 
(mRECIST).  
 To evaluate a 2 year overall survival (OS) of patients treated with the combination of 
durvalumab and tremelimumab with DEB-TACE 
 To determine the effect of combined immune checkpoint and DEB-TACE versus DEB-
TACE only on tumor microenvironment by comparing pre- and post-treatment tissue 
samples and peripheral blood tumor biomarkers including T cell receptor repertroire and 
circulating tumor cells/ circulating tumor DNA. 
 To explore potential molecular determinants of response, progression, and disease stability 
using next generation sequencing, other sequencing techniques, and other biomarkers. 
 
 
 


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3. 
STUDY DESIGN 
This is an open-label, single institution, single arm study of combination treatment of durvalumab 
and tremelimumab in patients with intermediate stage HCC (BCLC B) undergoing trans-arterial 
chemoembolization.  
Patients will be recruited from the Johns Hopkins Multidisciplinary Liver Cancer Clinic, general 
liver clinic, inpatient admissions with newly diagnosed HCC, and direct referrals to Interventional 
Radiology for DEB-TACE treatment. Once their diagnosis and staging is confirmed in Liver 
radiology tumor board as intermediate stage, patients will be screened for enrollment. 
Enrolled patients will proceed with DEB-TACE procedure along with pre-treatment biopsy of 
tumor and surrounding non-tumor tissue. Following their DEB-TACE procedure, patients will be 
followed in 7-10 days in hepatology clinic with labs for any new decompensating signs or 
symptoms. If the patient does not have any ongoing new decompensation, they will proceed with 
a 2nd biopsy, followed by 1st infusion of durvalumab 1500mg and tremelimumab 300mg 2 weeks 
after DEB-TACE. This will be followed by durvalumab 1500mg q4weeks until progression of 
disease, the end of study, or maximum 13 cycles. 
All patients will receive repeat DEB-TACE every 8 weeks if there is residual tumor that can be 
targeted.  A third biopsy will be done after 2 doses of durvalumab infusion during their second 
DEB-TACE procedure at week 8, unless the patient has CR. 
 
Patients will have an MRI (or CT if contraindicated) at Week 6 and Week 14, then every 3 months 
unless additional DEB-TACE is needed.  Patients who are clinically stable at initial disease 
progression may continue to receive study treatment until PD is confirmed on a follow-up scan 
(confirmed PD) if they do not show any significant toxicities. Patients will get a confirmatory scan, 
following the assessment of PD, at the next scheduled visit. Patients will continue to receive 
durvalumab and tremelimumab with the same dose and schedule as they were treated with initially.  
Additionally, 20 patients from the institutional database will be selected as exact matched control 
based on age, gender, tumor stage and Child-Pugh score. We will evaluate the objective response 
rate (ORR) in comparison to the study group, using McNamer paired-sample test.  
 
Considering approximately 3-5 new patients with HCC seen through our tumor board and 
multidisciplinary liver cancer clinic per week, with an average of 300-400 DEB-TACE cases per 
year, we expect to finish the enrolment in 12 months of time. 
 
 
 


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4. 
PATIENT 
SELECTION, 
ENROLLMENT, 
RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL  
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion criteria 
(Section 4.2) for this study. Under no circumstances will there be exceptions to this rule.  
4.1 Inclusion criteria 
For inclusion in the study, patients should fulfill the following criteria: 
 
1. Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU 
Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-
related procedures, including screening evaluations.  
 
2. Age >18 years at time of study entry 
 
3. Patients with diagnosis of HCC either by high-resolution imaging (triple-phase CT or MRI) 
and/or by tumor biopsy.   
 
4. Patient is not on systemic treatment for diagnosis of HCC. Prior local therapy (eg.TACE, 
radioembolization, radiation) is allowed if treatment was more than 1 month prior to 
enrollment with evidence of viable HCC or recurrence.  Patients who were on tyrosine-kinase 
inhibitors (sorafenib, regorafenib, lenvatinib) or other systemic treatments for HCC but 
considered non-responders or intolerant to treatment are allowed to participate.  
 
5. HCC meeting Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate stage), with 
measurable lesions on CT or MRI and without extrahepatic spread. Patients with BCLC stage 
A not considered candidates for transplant or surgery at the time of enrollment can participate 
if committed to remain on study for 6 months prior to consideration for alternative local 
therapies. 
 
6. Disease that is technically amenable to DEB-TACE. Cases will be discussed with 
interventional radiology. At least 1 measurable lesion, that can be measured at baseline as ≥10 
mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with 
CT or MRI. 
 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
 
8. Body weight >30kg  
 
9. Child-Pugh Score of A or early B (score  ≤8) without clinically significant ascites. Trace or 
small amounts of radiographic ascites without prior concern for malignant ascites or not 
associated with peritoneal carcinomatosis may be approved by the Protocol Chair.  
 
10. Liver associated lab values:  
 AST ALT  ≤  5x ULN (pre-treatment)  
 Total bilirubin: If cirrhosis present: Part of Child Pugh requirement.  


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If no cirrhosis present: total bilirubin ≤ 2 mg/dL 
 
11. Lab parameters to ensure adequate organ function (other than liver):  
 Absolute neutrophil count of ≥ 1,000/mm3 
 Hemoglobin ≥ 9.0g/dL 
 Platelets ≥ 75,000/mm3 
 Albumin ≥ 2.5 g/dL 
 INR ≤1.8 mg/dL 
 Creatinine ≤ 2.0 mg/dL or calculated creatinine clearance > 50mL/minute or  
Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance 
CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-
hour urine collection for determination of creatinine clearance: 
Males:
Creatinine CL 
(mL/min)
= 
Weight (kg) x (140 – Age) 
   
72 x serum creatinine (mg/dL)
Females:
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
  x 0.85 
72 x serum creatinine (mg/dL) 
 
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female 
pre-menopausal patients. Women will be considered post-menopausal if they have been 
amenorrheic for 12 months without an alternative medical cause. The following age-specific 
requirements apply:  
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy).  
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
 
13. Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
 
14. Patient who is willing to get tumor biopsies per the study schedule. 
 
4.2 Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 


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2. Participation in another clinical study with last dose of an investigational product ≤ 30 days 
prior to start of study treatment. 
3. Any concurrent anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) or receipt 
of the last dose ≤30 days prior to start of study treatment (TACE). Concurrent use of 
hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) 
is acceptable.  
4. Patients with vascular invasion or extrahepatic tumor.  
5. Main portal vein tumor-related thrombosis present on imaging. Non-tumor related 
thrombosis is allowed.  
6. Uncontrolled hepatic encephalopathy at time of enrollement. 
7. Ascites that require ongoing paracentesis, within 4 weeks prior to the first scheduled 
dose, to control symptoms. 
8. Any contraindications for embolization, including hepatofugal blood flow or portosystemic 
shunt. 
9. Patients with detectable HBV viral load without active anti-viral treatment. 
 Patients with positive HepB surface antigen (HBsAg) and/or HepB core antibodies 
(anti-HBc) with detectable HBV DNA (≥10 IU/mL or above the limit of detection 
per local lab standard) are permitted on study if they are being treated with antiviral 
therapy with evidence of HBV stabilization or signs of viral response prior to 
enrollment. Patients who test positive for anti-HBc with undetectable HBV DNA 
(<10 IU/ml or under the limit of detection per local lab standard) do not require anti-
viral therapy prior to enrollment. (See Section 7.2.1 for additional on-study testing 
and anti-viral requirements)  
10. Any prior or concurrent malignancy or myeloproliferative disorder whose natural history or 
treatment has the potential to interfere with safety or efficacy assessment of this study’s 
investigational drug 
11. History of leptomeningeal carcinomatosis. 
12. History of active primary immunodeficiency. 
13. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
or human immunodeficiency virus (positive HIV 1/2 antibodies).  
14. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy with the exception 
of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: 
 Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 


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 Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician. 
15. Active or prior documented GI bleeding due to ulcer or esophageal varices bleeding within 
6 months Note: For patients with history of esophageal variceal bleeding or assessed as 
high risk for esophageal variceal by the treating investigator, adequate endoscopic therapy 
according to institutional standards is required for assessment of esophageal varices. 
History of bleeding from other causes adequately treated are allowed. 
16. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
17. Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab or tremelimumab. The following are exceptions to this criterion: 
 Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent 
 Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
18. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]).  
19. Patients with hypothyroidism (e.g., following Hashimoto syndrome) who are not stable on 
hormone replacement. 
20. Any chronic skin condition that require systemic therapy. 
21. History of allogenic organ transplantation. 
22. History of pericarditis, cardiomyopathy or current use of defibrillator. 
23. Patients with celiac disease not controlled by diet alone. 
24. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs or compromise the 
ability of the patient to give written informed consent. 


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25. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, 
if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the 
last dose of IP. 
26. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of 
durvalumab + tremelimumab combination therapy. 
27. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
28. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment.  
29. Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4 including 
durvalumab and tremelimumab. 
30. Judgment by the investigator that the patient is unsuitable to participate in the study and 
the patient is unlikely to comply with study procedures, restrictions and requirements. 
31. Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3. 
 
4.3 Withdrawal of patients from study treatment and/or study 
Permanent discontinuation of Durvalumab and Tremelimumab  
An individual patient will not receive any further investigational product if any of the following 
occur in the patient in question: 
 An individual patient will not receive any further durvalumab + tremelimumab 
combination therapy or if their weight falls to 30kg or less 
 An individual patient will not receive any further tremelimumab monotherapy if their 
weight falls to 35kg or less 
 Withdrawal of consent  
 Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing 
 Patient is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a safety 
risk 
 Pregnancy or intent to become pregnant 
 Any AE that meets criteria for discontinuation as defined in Appendix 1. 
 Unacceptable toxicity (See Section 6.5 for definition)  
 Grade ≥3 infusion reaction 
 Patient noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
 Initiation of alternative anticancer therapy including another investigational agent 
 Confirmation of PD and investigator determination that the patient is no longer benefiting 
from treatment with durvalumab + tremelimumab. Patients who are permanently 


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discontinued from further receipt of investigational product, regardless of the reason 
(withdrawal of consent, due to an AE, other), will be identified as having permanently 
discontinued treatment 
 Patients who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10 and Study Schedule in Section 8, including the collection 
of any protocol-specified blood specimens, unless consent is withdrawn or the patient is 
lost to follow-up or enrolled in another clinical study. All patients will be followed for 
survival and information about subsequent cancer therapies. Patients who discontinue 
treatment without confirmed disease progression will continue to receive standard of care 
scans. Patients who decline to return to the site for evaluations will be offered follow-up 
by phone every 3 months as an alternative. 
 
Withdrawal of consent 
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice to 
further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further IP 
or further study observation, with the exception of follow-up for survival, which will continue until 
the end of the study unless the patient has expressly withdrawn their consent to survival follow-
up. Note that the patient may be offered additional tests or tapering of treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
 all further participation in the study including any further follow up (e.g., survival contact 
telephone calls) 
 withdrawal of consent to the use of their study generated data 
 withdrawal to the use of any samples  
 
4.4 Replacement of patients  
If a patient is lost to follow up after the first DEB-TACE or deemed not appropriate for further 
treatment with durvalumab or tremelimumab due to medical complications, patients will be 
replaced. If patients do not have treatment scans for reasons other than death, patients will be 
replaced.   
5. 
INVESTIGATIONAL PRODUCT(S) 


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Tremelimumab 
5.2 Dose and treatment regimens 
 Treatment regimens 
All patients in this study will receive durvalumab and tremelimumab 2 weeks after initial DEB-
TACE treatment. Patients will subsequently continue with their combination immunotherapy, 
while receiving DEB-TACE Q8W.  Patients will only receive repeat DEB-TACE if there is 
residual tumor that can be targeted.   


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 Study drug preparation of durvalumab and tremelimumab 


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 Monitoring of dose administration 


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5.3 Specific 
procedure 
for 
DEB-TACE 
(Drug-eluting 
Bead 
Trans-arterial 
chemoembolization) 
For this study, patients will continue to receive DEB-TACE as standard of care. Patients 
undergoing trans-arterial chemoembolization are pre-medicated with analgesics, antibiotics and 
anti-emetics per clinical standards. 
 
6. 
TREATMENT PLAN 
6.1 Patient enrolment 
 Procedures for handling patients incorrectly enrolled 
Patients who are incorrectly enrolled and do not meet the eligibility criteria, but are not yet 
initiated on treatment should be withdrawn from the study. The treating physician will determine 
subsequent treatment plans. 
 
6.2 Dosage and administration 
 


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6.3 Definition of Unacceptable Toxicity 
The combination of tremelimumab and durvalumab has been previously tested in a dose-escalation 
study performed by AstraZeneca employing dose ranges of 1-10mg/kg q4weeks (tremelimumab) 
and10-20mg/kg q2-4weeks (durvalumab). Patients treated in the 20 mg/kg durvalumab + 1 mg/kg 
tremelimumab group had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations 
due to AEs, but still showed strong evidence of clinical activity. This cohort had a lower number 
of treatment-related Grade ≥3 AEs or treatment related SAEs. No dose-limiting toxicities were 
reported. This is the dose level we will be administering for this study. Also, PK analysis indicated 
only minor impact of body weight (WT) on PK of both agents so to minimize errors and for ease 
of use the company have moved to a fixed-dose schedule of 1500 mg Q4W durvalumab (equivalent 
to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1mg/kg Q4W).  
 
Unacceptable toxicities will be evaluated from the time of first administration of durvalumab or 
tremelimumab until the Week 6 evaluation (prior to the second dose of durvalumab).  Patients who 
do not remain on the study through the completion of this safety run-in period for reasons other 
than DLT will be replaced with another patient (see Section 11.2.4 for details of safety run-in). 
Grading of unacceptable toxicities will follow the guidelines provided in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.  
 
An unacceptable toxicity will be defined as any toxicity occuring during the study that meets the 
criteria below. Toxicity that is clearly and directly related to the primary disease or to another 
etiology is excluded from this definition. The following will be unacceptable toxicities: 
 Any Grade 4 irAE 
 Any ≥Grade 3 colitis 
 Any Grade 3 or 4 non-infectious pneumonitis irrespective of duration 
 Any Grade 2 pneumonitis that does not resolve to ≤Grade 1 within 3 days of the initiation 
of maximal supportive care 
 Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤Grade 1 or baseline within 14 days 
 Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN (other than the 1st 
week following DEB-TACE) 
 Any Grade ≥ 3 asymptomatic amylase or lipase levels, hold study drug/study regimen, and 
if complete work up shows no evidence of pancreatitis, study drug/study regimen may be 
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 Any grade ≥ 2 myocarditis 
 Any ≥ Grade 3 non-irAE, except for the exclusions listed below 
 
The definition excludes the following conditions:  
 Grade 3 fatigue lasting ≤ 7 days 
 Grade 3 dermatologic AEs that are considered mild in severity but only considered grade 
3 because of >30% body surface involvement 
 Diarrhea, nausea, or vomiting that resolves to < grade 3 within 24 hours of intervention 
 Grade 3-4 hyperglycemia 
 Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the patient is asymptomatic 
 Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
 Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) 
that resolves within 6 hours with appropriate clinical management 
 Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be 
an unacceptable toxicitiy regardless of duration or reversibility 
 Grade 3 or 4 lymphopenia 
 Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days 
 Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days. 
Isolated Grade 3 amylase or lipase abnormalities that are not associated with clinical 
signs/symptoms or findings on imaging consistent with pancreatitis 
 
Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to designation 
as an unacceptable toxicity.  
 
6.4 Dose modification and toxicity management 
 Durvalumab and tremelimumab 


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7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
Female patient of child-bearing potential 
Females of childbearing potential who are sexually active with a non-sterilized male partner 
must use at least 1 highly effective method of contraception (Table 1) from the time of 
screening and must agree to continue using such precautions for 180 days after the last 
dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose 
of durvalumab monotherapy. Non-sterilized male partners of a female patient must use 
male condom plus spermicide throughout this period. Cessation of birth control after this 
point should be discussed with a responsible physician. Not engaging in sexual activity 
for the total duration of the drug treatment and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control. Female patients should also refrain from 
breastfeeding throughout this period. 
Male patients with a female partner of childbearing potential 
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a male condom plus spermicide from screening through 180 days after receipt of 
the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt 
of the final dose of durvalumab monotherapy. Not engaging in sexual activity is an 
acceptable practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. Male patients should 
refrain from sperm donation throughout this period. 
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period (Table 1).  
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause. The following age-specific requirements apply:  
 Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  


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 Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in Table 1. Note that 
some contraception methods are not considered highly effective (e.g., male or female condom with 
or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which 
is considered highly effective]; and triphasic combined oral contraceptive pills). 
Table 1. Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine 
methods 
Hormonal Methods 
 
Copper T intrauterine 
device 
 
Levonorgestrel-
releasing intrauterine 
system (e.g., 
Mirena®)a 
 
 
Implants: Etonogestrel-releasing implants: e.g. Implanon® or 
Norplant®  
 
Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal 
devices: e.g. NuvaRing®  
 
Injection: Medroxyprogesterone injection: e.g. Depo-Provera®  
 
Combined Pill: Normal and low dose combined oral 
contraceptive pill 
 
Patch: Norelgestromin/ethinylestradiol-releasing transdermal 
system: e.g. Ortho Evra®   
 
Minipillc: Progesterone based oral contraceptive pill using 
desogestrel: Cerazette® is currently the only highly effective 
progesterone based pill 
a 
This is also considered a hormonal method 
 
Blood donation 
Patients should not donate blood while participating in this study. 
7.2 Concomitant treatment(s) 
The Principal Investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be recorded 
in the CRF.  
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer to Section 6.4 for guidance on management of IP-related toxicities. 


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 Antiviral Therapy for HBV+ Patients 
Patients with HBV infection, characterized by positive hepB surface antigen (HBsAg) and/or 
HepB core antibodies (anti-HBc) with detectable HBV DNA (≥10 IU/ml or above the limit of 
detection per local lab standard), must be treated with antiviral therapy as per institutional 
practice to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to enrollment. 
Patients must remain on antiviral therapy for the study duration and for 6 months after the last 
dose of study medication. These subjects will be tested at every cycle to monitor HBV DNA 
levels 
 
Patients who test positive for anti-hepatitis B core (anti-HBc) with undetectable HBV DNA (<10 
IU/ml or under the limit of detection per local lab standard) do not require anti-viral therapy prior 
to enrollment. These subjects willbe tested at every cycle to monitor HBV DNA levels and 
initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit of detection per 
local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy 
for the study duration and for 6 months after the last dose of study medication. 
 
 Permitted concomitant medications 
Table 2. Supportive medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or supportive 
care, except for those medications identified as 
“prohibited,” as listed below  
To be administered as prescribed by the 
Investigator 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza vaccine 
 Permitted 
 
 


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 Excluded concomitant medications 
 
Table 3. Prohibited concomitant medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy 
other than those under investigation in 
this study 
Should not be given concomitantly whilst the patient is on 
study treatment 
mAbs against CTLA-4, PD-1, or PD-
L1 other than those under investigation 
in this study 
Should not be given concomitantly whilst the patient is on 
study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or 
biologic or hormonal therapy for 
cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the patient is on 
study treatment. (Concurrent use of hormones for non-
cancer-related conditions [e.g., insulin for diabetes and 
hormone replacement therapy] is acceptable. Local 
treatment of isolated lesions, excluding target lesions, for 
palliative intent is acceptable [e.g., by local surgery or 
radiotherapy]) 
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding 10 
mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to the I-O infusions. The following are 
allowed exceptions: 
 
Use of immunosuppressive medications for the 
management of IP-related AEs,  
 
Use in patients with contrast allergies.  
 
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted. 
  
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the patient (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc). 
Drugs with laxative properties and 
herbal or natural remedies for 
constipation 
Should be used with caution through to 90 days after the 
last dose of tremelimumab during the study 
Sunitinib 
Should not be given concomitantly or through 90 days after 
the last dose of tremelimumab (acute renal failure has been 
reported with combination therapy of tremelimumab and 
sunitinib) 


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Prohibited medication/class of drug: 
Usage: 
EGFR TKIs  
Should not be given concomitantly. 
Should be used with caution in the 90 days post last dose of 
durvalumab. 
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with 1st generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly. 
Live attenuated vaccines 
Should not be given through 30 days after the last dose of 
IP (including SoC) 
Herbal and natural remedies which 
may have immune-modulating effects 
Should not be given concomitantly unless agreed by the 
sponsor 
8. 
STUDY PROCEDURES 
8.1 Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments. Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated. The Schedules of 
Assessments during the screening and treatment period is provided following the Protocol 
Synopsis  
For all patients 
 Tumor efficacy (modified RECIST) assessment dates are affected by dose delays as 
subsequent treatment with DEB-TACE will be delayed with the same interval change.   
 All other scheduled assessments must be performed relative to the start of the dosing 
cycle such that all laboratory procedures, etc. required for dosing should be performed 
within 3 days prior to dosing. 
 Patients may delay dosing under certain circumstances.   
 Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-related AE. 
 If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible 
 
 Screening phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified. 
All patients must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed. After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, patients will be enrolled in the study. Procedures 
that are performed prior to the signing of the ICF and are considered standard of care may be used 
as screening assessments if they fall within the 28-day screening window. See Figure 2 for all 
screening procedures. 


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Figure 2 : Study Schedule 
Week
Pre-study
 
(Day -28 
to Day 0) 
0 
 
1 
 
 
2 
+/- 
7d 
 
6 
+/- 
7d 
 
8 
+/- 
7d
9a 
 
 
10 
+/- 
7d 
 
14 
+/- 
7d 
 
16 
+/- 
7d 
17a
 
Weeks 
18, 22, 26, 
30, 34, 38, 
42, 46, 50 
+/- 7d 
17-52 
Time since last dose of Durvalumab 
Q6 
months 
+/- 2 
wks 
EOTo 
30 days 
+/- 7d 
2 months 
+/- 7d 
3 months 
+/- 7d 
6, 9, 12 
months 
+/- 2 wks
TACEa 
 
X 
 
 
 
Xa 
 
 
 
Xa
 
 
Q3months 
Hepatolog
y visit 
starting 
week 17e 
 
Q3months 
MRI 
starting 
week 14 
 
 
Durvalumab 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Tremelimumab 
 
 
 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examb and  
Vital signsc 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Concomitant Meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Evaluationd 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
 
 
ECOG Performance Status 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X
X 
X 
 
 
Hepatology Visits 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
Oncology Visits 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
MRI / CTe 
X 
 
 
 
X 
 
 
 
X 
 
 
Xe 
Xe 
 
 
 
 
ECGf 
X 
 
 
X 
 
 
 
 
 
Urinalysisg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMPh 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
CBC with differentialsh 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
PT, INR, PTT h, i 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
 
Thyroid Panel h, j 
X 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
 
 
 
Creatinine clearance h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magnesiumh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gamma-glutamyl 
transferase (GGT)h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-fetoprotein (AFP)h 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
Amylase/Lipaseh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDHh 
X 
 
 
 
 
 
 
 
 
HBV, HCV, HIVh, k 
X 
 
 
Xk 
Xk 
 
 
Xk 
Xk 
 
 
Xk 
X
 
 
 
 
HLA-A,B,C phenotyping 
X 
 
 
 
 
 
 
 
 


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Urine hCG or serum βhCG l 
X 
 
 
 
 
 
 
 
 
Research Blood m, p 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X
 
 
 
 
Research urine m, p 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Liver Biopsies p 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue q 
X 
 
 
 
 
 
Subsequent anticancer 
therapyn 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Survival Statusn 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person clinical trial visits or portions of clinical trial visits where determined to 
be appropriate and where determined by the investigator not to increase the participants risks.  Prior to initiating telemedicine for study visits the study team will explain to the participant, 
what a telemedicine visit entails and confirm that the study participant is in agreement and able to proceed with this method.  In the event telemedicine is not deemed feasible, the study visit 
will proceed as an in-person visit.  Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions.  
a. 
DEB-TACE will be repeated every 8 weeks as long as there is residual tumor that can be targeted after the first dose (we expect most patients will receive at least 2 doses, and more than 
3 doses of DEB-TACE are possible). Patients with a complete response by mRECIST will stop DEB-TACE and continue the rest of the study regimen. When DEB-TACE will no longer 
be given, the entire DEB-TACE visit and evaluations (e.g. Week 16) and follow-up visit 1 week after the skipped DEB-TACE (e.g. Week 17) may be dropped.     
b. 
Full physical examination at baseline; targeted physical examination at other time points 
c. 
Patients will have their blood pressure and pulse measured before, during, and after the infusion at the following times (based on a 60-minute infusion): 
 At the beginning of the infusion (at 0 minutes) 
 At 30 minutes during the infusion (±5 minutes) 
 At the end of the infusion (at 60 minutes ±5 minutes) 
d. 
for AEs/SAEs reported during prescreening additional information such as medical history and concomitant medications may be needed. 
e. 
Timing of MRI/CTscans: Scans at baseline and Week 6 (+/- 7 days), then every 8 weeks (+/- 7 days) for the first 15 weeks, then every 3 months (-3/+1 weeks) unless repeat TACE is 
done. Scans may be done earlier if clinically indicated and subsequent scans should reset to every 3 months from this new scan date when possible. EOT tumor assessments do not need 
to be repeated if performed within 28 days of EOT visit. For patients who have completed study treatment and achieved disease control: tumor assessments should be performed 
every 8-12 weeks until confirmed PD by mRECIST by investigational site.  For patients who discontinue study treatment due to PD: tumor assessments should be performed according 
to local clinical practive and may be submitted to investigational site for review (these are optional). 
f. 
ECG during screening and at the Week 2 visit within 1hr prior to the start of the first study treatment. Thereafter as clinically indicated. Baseline and abnormal ECG at any time in 
triplicate, others single.  
g. 
Urinalysis performed at Screening and as clinically indicated 
h. 
Labs and research bloods may be done within 3 days of scheduled visits. Results for safety bloods must be available and reviewed before commencing an infusion.  
i. 
Coagulation tests: prothrombin time done at each indicated visit., aPTT and INR only performed at Screening and as clinically indicated. 
j. 
TSH only. Free T3 and free T4 will be measured if TSH is abnormal or if there is clinical suspicion of an adverse event related to the endocrine system. 
k. 
Screening: HBV surface antigen (HBsAg), anti-HBV core antibody (anti-HBc), anti-HCV antibody, and HIV-1/2 Ab. HBV viral load if HBsAg and/or anti-HBc positive.  
Hepatitis serologies do not need to be repeated if done within 3m prior to enrollment. On Study Labs: HBV antigen and/or antibody positive patients allowed to participate per eligibility 
criteria will have HBV viral load monitored prior to each subsequent durvalumab treatment visit.    
l. 
Pre-menopausal female patients of childbearing potential only 
m. Approximately 40 ml of blood and 100 ml urine will be collected at 4 time points (Week 0, Week 2, Week 8, and at end of study.  Blood and urine should be collected before any treatment.  
n. 
Patients will be contacted for survival status and information about subsequent anticanter therapies (by phone, email, or visit) monthly for the first 3 months after last dose of study 
treatment, then  every 3 months until 1 year, then every 6 months thereafter until study closes or patient withdraws from follow-up. 
o. 
All required EOT procedures may be completed within ±7 days of the end of treatment visit (EOT). Repeat disease assessment is not required if performed within 28 days prior to the end 
of treatment visit. 
p. 
Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff.  If patient not deemed candidate for TACE on week 8, we 
will still collect biopsy, research blood/urine samples. These blood/urine samples can be obtained any time prior to or including at the next in person treatment visit.  Biopsy should be 
obtained through IR at week 8 (+/-14 days). 


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q. 
Archival tissue samples may be collected if patient had a standard of care biopsy of tumor or non-tumor liver or other HCC metastatic sites (see section 8.3.2) 


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 Treatment phase  
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments.  
 
Patients will be treated with DEB-TACE. Transarterial chemoembolization is percutaneous 
procedure performed under conscious sedation. (See Section 5.3 for details). Following DEB-
TACE, patients will have surveillance imaging at 7 weeks, and if there are viable tumor lesions 
that can be targeted by DEB-TACE (either SD or PR), patients will be scheduled for another 
procedure. We estimate that patients may receive upto 4 DEB-TACE treatments in 1 year time 
of the study.  
 
From the time of first DEB-TACE, patients will receive their first combined immune checkpoint 
inhibition in 2 weeks, and continue with q4week cycle schedule as described in detail in Section 
3.1.  
 
  End of treatment 
End of treatment (EOT) visit is defined as approximately 30 days after the last dose of study 
treatment. All required procedures may be completed within ±7 days of the end of treatment 
visit. Repeat disease assessment is not required if performed within 28 days prior to the end of 
treatment visit. 
 
Assessments for patients who have completed durvalumab and tremelimumab treatment are 
provided in the Study Schedule above.  
 
All patients will be followed for survival and subsequent anti-cancer therapies until the end of 
the study regardless of further treatments. 
 
8.2 Description of study procedures 
 Medical history 
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
 
 Physical examination 
Physical examinations will be performed according to the assessment schedule. Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at Screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 


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observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 10.    
 
 MRI or CT  
Patients will be recommended to have an MRI at week 6 following their first DEB-TACE date. 
If MRI is contraindicated for any medical reasons (e.g. history of metals in the body, severe 
claustrophobia), patients may have a CT scan (liver-dedicated CT). Tumor response will be 
assessed according to the modified RECIST criteria (mRECIST). mRECIST takes into account 
reduction in viable tumor using contrast-enhanced radiologic imaging rather than strict tumor 
size. Details of response measurement are under Section 9. If there is complete response at the 
1st surveillance imaging, patients will continue with their monthly infusion with durvalumab and 
tremelimumab for total of 4 cycles, with repeat MRI as scheduled at week 14. If there’s ongoing 
CR, they will have MRI monitoring every 3 months. For all other response after the 1st MRI, 
patients will get repeat DEB-TACE, along with scheduled immunotherapy treatment and scans 
per the study schedule.  
 Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening, baseline and as clinically indicated 
throughout the study. ECGs should be obtained after the patient has been in a supine position for 
5 minutes and recorded while the patient remains in that position. ECG during screening and at 
the Week 2 visit within 1 hr prior to the start of the first study treatment. Thereafter as clinically 
indicated. Baseline and abnormal ECG at any time in triplicate, others single..  
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm 
the finding.  
Situations in which ECG results should be reported as AEs are described in Section 10.3.1. 
 Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules. Body weight is also recorded at each visit along with 
vital signs. 
First infusion 
On the first infusion day, patients will be monitored and vital signs collected/recorded in eCRF 
prior to, during and after infusion of IP as presented in the bulleted list below.  
BP and pulse will be collected from patients in the I-O arms before, during, and after each 
infusion at the following times (based on a 60-minute infusion): 
 Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [i.e., the beginning of the infusion]) 
 Approximately 30 minutes during the infusion (halfway through infusion)  


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 At the end of the infusion (approximately 60 minutes ±5 minutes). If the infusion takes 
longer than 60 minutes, then BP and pulse measurements should follow the principles as 
described above or be taken more frequently if clinically indicated. A 1-hour observation 
period is recommended after the first infusion of durvalumab and tremelimumab.  
 
Subsequent infusions 
BP, pulse and other vital signs should be measured, collected/recorded in eCRF prior to the start 
of the infusion. Patients should be carefully monitored and BP and other vital signs should be 
measured during and post infusion as per institution standard and as clinically indicated. Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
CRF page.  
 Clinical laboratory tests 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the times indicated in the assessment schedules and as clinically indicated (see Table 
2 through Table 5).  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Urine pregnancy 
tests may be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal 
clinically significant laboratory results should be repeated as soon as possible (preferably within 
24 to 48 hours). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF. 
The laboratory variables to be measured are presented in Table 4 (clinical chemistry), Table 5 
(hematology), and  
Table 6 (urinalysis). 
Other safety tests to be performed at screening include assessment for hepatitis B surface antigen, 
hepatitis C antibodies and HIV antibodies. 
The following laboratory variables will be measured: 


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Table 4. Clinical chemistry and other miscellaneous labs 
Albumin 
a 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must 
be conducted and assessed concurrently. If total bilirubin is ≥2 ×
upper limit of normal (and no evidence of Gilbert’s syndrome) then 
fractionate into direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. 
For sites where only 1 of these parameters is routinely measured 
then either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, creatinine clearance, 
gamma glutamyltransferase, and magnesium testing are to be
performed at screening, on Day 0 (unless screening laboratory
assessments are performed within 3 days prior to Day 0), and if 
clinically indicated. 
d   
Free T3 or free T4 will only be measured if TSH is abnormal or if 
there is a clinical suspicion of an AE related to the endocrine 
system 
 
Abbreviations: ALT Alanine aminotransferase; AST Aspartate
aminotransferase, TSH Thyroid Stimulating Hormone 
Alkaline phosphatasea 
ALTa 
Amylaseb 
ASTa 
Bicarbonatec 
Bilirubin, totala 
Calcium  
Chloridec 
Creatinine  
Creatinine clearancec 
Gamma glutamyltransferasec 
Glucose 
Lactate dehydrogenase 
Lipaseb 
Magnesiumc 
TSH 
T3, freed 
T4, freed 
 
Table 5. Hematology 
Absolute neutrophil count 
 
Note: 
For 
coagulation 
parameters, 
activated 
partial 
thromboplastin time and international normalized ratio are to 
be assessed at baseline and as clinically indicated 
Hemoglobin 
Absolute lymphocyte count 
Platelet count 
 
Table 6. Urinalysis 
Urinalysis should be done at baseline (screening) and then as clinically indicated 
Bilirubin 
 
Note: Microscopy should be used as appropriate to investigate 
white blood cells and use the high power field for red blood 
cells.  
Blood 
Color and appearance 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
 
If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to 
Appendix 1 for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for 
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All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months (±1 
week) and 3 months (±1 week) after permanent discontinuation of IP (see Study Schedule in 
Section 8). 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 10.3.6. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease. 
8.3 Biological sampling procedures 
 Biomarker sampling and evaluation methods 
Peripheral blood samples will be collected as per the study schedule. Samples will be processed 
for CTCs, and plasma for ctDNA analysis. All the samples will be stored in the Translational 
Research Enhancement Core of the Hopkins Conte GI Center. 


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 Protocol Completion 
Following completion of this study, samples will remain in storage as described above. Access 
to these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. The PI will report destroyed samples to the IRB if samples become 


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unsalvageable because of environmental factors or if a patient withdraws consent. Samples will 
also be reported as lost if they are lost in transit between facilities or misplaced by a researcher.   
 
 Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented.  
 All biological samples from that patient stored in our Core Center will be immediately 
identified, disposed of /destroyed, and the action documented. Furthermore, clinical or research 
data collected from the patient will also be destroyed from the database. We will notify both the 
patient and AstraZeneca. 
9. 
DISEASE EVALUATION AND METHODS 
9.1 Measure of Objective Response 
Tumor response to treatment will be assessed by modified response evaluation criteria in solid 
tumors (mRECIST) which takes into account reduction in viable tumor using contrast-enhanced 
radiologic imaging rather than strict tumor size (Lencioni R, 2011).  Conventional RECIST criteria 
can be misleading when applied to locoregional therapies in HCC and mRECIST adapted the 
concept of viable tumor-tumoral tissue showing uptake in arterial phase of contrast-enhanced 
radiologic imaging techniques. mRECIST has been adapted by the AASLD-JNCI (Journal of the 
National Cancer Institute) guidelines. The measurement of the longest diameter of the viable tumor 
may be challenging in lesions showing partial internal necrosis. Therefore, the measurement of the 
viable tumor should be performed on CT or MRI obtained in the arterial phase, when the contrast 
between viable vascularized tumor tissue and non-enhancing necrotic tissue is the highest.   The 
longest diameter of the viable tumor is not necessarily located in the same scan plane in which the 
baseline diameter was measured. The measurement of the viable tumor diameter should not include 
any major intervening areas of necrosis.  
 
Assessment of Target Lesion Response: mRECIST Assessment for HCC Following the AASLD-
JNCI Guideline
CR = Disappearance of any intratumoral arterial enhancement in all target lesions 
PR = At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target 
lesions, taking as reference the baseline sum of the diameters of target lesions 
SD = Any cases that do not qualify for either partial response or progressive disease 
PD = An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking 
as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since 
treatment started 
AASLD, American Association for the Study of Liver Diseases; JNCI, Journal of the National Cancer Institute; HCC, 
hepatocellular carcinoma; mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, 
partial response; SD, stable disease; PD, progressive disease. 
 


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As response to immunotherapy may be delayed compared to conventional chemotherapy, patients 
with PD will have confirmatory assessment after 4 weeks from the initial assessment of PD in the 
absence of clinically significant deterioration. Treatment with durvalumab + tremelimumab would 
continue between the initial assessment of progression and confirmation for progression. In 
addition, patients may continue to receive durvalumab + tremelimumab beyond confirmed PD in 
the absence of clinically significant deterioration and if investigators consider that patients 
continue to receive benefit from treatment until the next surveillance imaging. 
 
Patients who have disease control following completion of 12 months of treatment or patients who 
are withdrawn from durvalumab + tremelimumab treatment for reasons other than confirmed PD 
will continue to have objective tumor assessments (see Study Schedule in Section 8Error! 
Reference source not found.). 
 
Confirmation of progression guidelines are set for the following reasons:  
 for patient management and treatment decisions 
 in the absence of significant clinical deterioration, to promote the collection of additional 
scans after the first radiologic mRECIST  assessment of progressive disease (PD) in order 
to distinguish pseudoprogression from true radiologic progression, also known as 
mRECIST modified for confirmation of progression 
 When scans are evaluated by Investigator and by BICR, to reduce informative censoring 
by Investigator assessments (Investigator assesses PD at a time-point earlier than does 
BICR). 
 
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration followed by a radiologic verification scan (PD by mRECIST); or 2. in 
the absence of significant clinical deterioration, radiologic PD by mRECIST followed by a second 
radiologic confirmation scan with PD assessed according to the specific confirmation of 
progression criteria listed below. mRECIST modified for confirmation of progression refers to the 
second scenario above. The confirmatory scan should occur preferably at the next scheduled 
imaging visit and no earlier than 4 weeks following the date of the immediate prior assessment of 
mRECIST PD. 
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan: 
 ≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 2 
consecutive visits, with an absolute increase of at least 5 mm in sum of diameters 
compared to nadir, 
 and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-
existing new lesions at the confirmatory scan time-point compared with the immediate 
prior time-point (Note: Pre-existing new lesions are evaluated as NTLs at the 
confirmatory scan time-point), 
 And/or additional new unequivocal lesions at the confirmatory scan time-point. 
 
NOTE: In order to have confirmed objective disease progression, there should be two consecutive 
PD’s, the first PD by mRECIST and the second PD using the confirmation of progression criteria 


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(above). If the first PD by mRECIST is not confirmed, continue with assessments until the next 
PD by RECIST 1.1, which in turn will need its own immediate subsequent confirmation scan. 
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with PD should be 
declared as the date of progression. 
If progression is not confirmed, in the absence of significant clinical deterioration, then the patient 
should continue study drug and on-treatment assessments until the next PD which will also require 
a follow-up confirmation scan. If the first PD is not confirmed by the immediate next scan, 
then the Investigator should not change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression. 
Following confirmed progression, patients should continue to be followed up for survival every 2 
months (8 weeks) as outlined in the follow-up schedules of assessments. 
Patients in the durvalumab + tremelimumab combination arm who complete 4 doses/dosing cycles 
(with clinical benefit per Investigator judgment) and subsequently have PD during treatment with 
durvalumab alone may restart combination treatment if they meet eligibility criteria for retreatment 
(see Section 5.2.2). Patients who restart treatment after PD must have a baseline tumor assessment 
within 28 days of restarting treatment with durvalumab + tremelimumab combination therapy; all 
further scans should occur every 8 weeks (±7 days) relative to the date of previous scheduled study 
scan until confirmed disease progression 
 
10. ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar 
with the content of this section. 
10.1 Safety parameters 
 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition (other than progression 
of the malignancy under evaluation) or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest 
pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if no study 
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The term AE is used to include both serious and non-serious AEs. 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be recorded 
as pre-treatment signs and symptoms. After study treatment administration, all grade 3 and 4 
clinical laboratory results that represent an increase in severity from baseline will be reported as 
AEs. A grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it is 
considered clinically significant by the investigator (i.e. it induces clinical signs or symptoms or 
requires therapy). 
 Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization >24 hours 
 Results in persistent or significant disability or incapacity  
 Is a congenital abnormality or birth defect in offspring of the patient 
 Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, or stillbirth. 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above:  
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
 
Events not considered to be SAEs are hospitalizations for:  
 Admissions as per protocol for a planned medical/surgical procedure or to facilitate a 
procedure. 
 Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) . 
 Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these cases.  
 Admission encountered for another 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). 
 Admissions for monitoring of treatment-related infusion reactions that do not otherwise 
meet the criteria for a SAE.  
 
 Durvalumab + tremelimumab adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator. An AESI may be serious or non-serious. The rapid reporting 
of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 


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AESIs for durvalumab ±tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should 
be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESIs observed with durvalumab ±tremelimumab include: 
 Diarrhea / Colitis and intestinal perforation 
 Pneumonitis / ILD 
 hepatitis / transaminast increasses 
 Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
 Endocrinopathies (i.e. events of hypophysitis/hypopituitarism adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
 Rash / Dermatitis 
 Nephritis / Blood creatinine increases 
 Pancreatitis / serum lipase and amylase increases  
 Myocarditis 
 Myositis / Polymyositis 
 Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, haematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator’s Brochures. More specific guidelines for 
their evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (see Appendix 1). These guidelines have been prepared by the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator. 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive 
of pneumonitis/interstitial lung disease is observed, toxicity management as described in detail 
in the Dosing Modification and Toxicity Management Guidelines (see Appendix 1) will be 
applied. The results of the full diagnostic workup (including high-resolution computed 
tomography (HRCT), blood and sputum culture, hematological parameters etc) will be captured 
in the eCRF. It is strongly recommended to perform a full diagnostic workup, to exclude 


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alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, 
or pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be 
considered and the Dosing Modification and Toxicity Management Guidelines should be 
followed.  
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected. 
 Physical examination 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including auscultation 
for lung field will be assessed. 
Saturation of peripheral oxygen (SpO2) 
 Other items 
 
When pneumonitis (ILD) is suspected during study treatment, the following markers should be 
measured where possible: 
 ILD Markers (KL-6, SP-D) and β-D-glucan 
 Tumour markers: Particular tumour markers which are related to disease progression.  
 Additional Clinical chemistry: CRP, LDH 
10.2 Assessment of safety parameters 
 Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs 
and SAEs. Severity will be graded according to the NCI CTCAE v5.0. 
 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below. 
 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the patient. 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the patient. 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 


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an imminent risk of death or with physical or mental disabilities that affect 
or limit the ability of the patient to perform activities of daily living 
(eating, ambulation, toileting, etc). 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 3 AE need 
not necessarily be considered an SAE. For example, a Grade 3 headache that persists for several 
hours may not meet the regulatory definition of an SAE and would be considered a nonserious 
event, whereas a Grade 2 seizure resulting in a hospital admission would be considered an SAE. 
 
10.3 Recording of adverse events and serious adverse events 
Adverse events will be recorded in RedCap database using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets criteria 
of an SAE and therefore requires immediate notification to AstraZeneca/MedImmune Patient 
Safety.  
The following variables will be collected for each AE (and SAE as applicable): 
 AE (verbatim) 
 The date when the AE started and stopped 
 The maximum CTCAE grade reported 
 Changes in CTCAE grade 
 Whether the AE is serious or not 
 Investigator causality rating against the IPs (yes or no) 
 Action taken with regard to IPs 
 Administration of treatment for the AE 
 Outcome 
 
In addition, the following variables will be collected for SAEs: 
 Date the AE met criteria for SAE 
 Date the Investigator became aware of the SAE 
 Seriousness criteria fulfilled 
 Date of hospitalization 
 Date of discharge 
 Probable cause of death 
 Date of death 
 Whether an autopsy was performed 
 Causality assessment in relation to study procedure(s) 
 Causality assessment in relation to other medication 
 Description of the SAE 
 
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events with 
an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 


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CTCAE grades should be used. A copy of the CTCAE version 5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
 
 Study recording period and follow-up for adverse events and serious adverse 
events 
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the 
last dose of durvalumab + tremelimumab).  
During the course of the study all AEs and SAEs should be proactively followed up for each 
patient. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a patient discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the patient returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
 Causality collection 
The Investigator will assess causal relationship between the IPs and each AE and answer “yes” 
or “no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?” 
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship is 
implied as “yes.” 
A guide to the interpretation of the causality question is found in Appendix 1. 
 Relationship to protocol procedures 
The Investigator is also required to provide an assessment of the relationship of SAEs to protocol 
procedures on the SAE report form. This includes both non-treatment–emergent (i.e., SAEs that 
occur prior to the administration of IP) and treatment-emergent SAEs. A protocol-related SAE 
may occur as a result of a procedure or intervention required during the study (e.g., blood 
collection). The following guidelines should be used by Investigators to assess the relationship 
of SAEs to the protocol: 
 Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record. 


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 Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol. The alternative etiology must be 
documented in the study patient’s medical record. 
 Expectedness 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, package insert, safety reports or informed consent is considered 
“unexpected”.  
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety 
reports. An AE is considered “expected”, only if it is included in the IB document as a risk. 
 Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: “Have you had any health problems since the previous visit/you were last 
asked?” or revealed by observation will be collected and recorded in the eCRF. When collecting 
AEs, the recording of diagnoses is preferred, when possible, to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
 Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfill any of the SAE 
criteria or are the reason for discontinuation of treatment with the IPs. 
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result or vital sign 
will be considered as additional information. Whenever possible, the reporting Investigator 
should use the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AEs. 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
 Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. This precludes the week following DEB-TACE. Please refer to Appendix 1 
for further instruction on cases of increases in liver biochemistry and evaluation of Hy’s law. 


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 Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new or 
progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events that are unequivocally due to disease progression 
should not be reported as an AE during the study. 
 New cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after the 
patient’s inclusion in this study. 
 Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-
up period after the administration of the last dose of study drug, must be reported as an SAE 
Deaths occurring after the protocol defined safety follow up period after the administration of 
the last dose of study drug should be documented in the eCRF. If the death occurred as a result 
of an event that started after the defined safety follow up period and the event is considered to 
be due to a late onset toxicity to study drug, then it should also be reported as an SAE. 
AstraZeneca/MedImmune retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 Reporting of serious adverse events 
 
All SAEs (including deaths) occurring from time of signature of informed consent through 90 
days after the last dose of durvalumab or until the initiation of alternative anticancer therapy will 
be collected and reported.  
 
SAEs will be reported promptly to the IND Sponsor and AstraZeneca within 24 hours of initial 
notification of the SAE. If this falls on a weekend or holiday, an email notification is acceptable 
but must be followed by an SAE reporting form on the next business day. 
 
SAE reports and any other relevant safety information are to be sent to:  
 
A cover page should accompany the SAE form when submitting to AstraZeneca indicating the 
following: 
 
“Notification from an Investigator Sponsored Study” 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number (ESR-17-12965) 


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 
Sponsor must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
 
10.3.11.1 Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regard to the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to the 
IND Sponsor and AstraZeneca. 
 
10.3.11.2 Institutional Review Board (IRB)  
 
All serious adverse events will be reported to the IRB per institutional standards. Upon receipt, 
follow-up information will be given to the IRB (as soon as relevant information is available) 
per institutional standards. 
 
10.3.11.3 Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the investigational 
agent.  Such reports are to be telephoned or faxed (301-827-9796) to the FDA within 7 calendar 
days of first learning of the event. Follow-up information will be submitted to the FDA as soon 
as relevant information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and related to 
the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 


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similar events should be analyzed.  The new report should contain comments on the 
significance of the new event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA 
within 15 calendar days of first learning of the event. Follow-up information will be submitted 
to the FDA as soon as relevant information is available. 
 
IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the adverse events 
and progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 
312.33 for a list of the elements required for the annual report.  All IND annual reports will be 
submitted to the FDA by the IND Sponsor. 
 
 Other events requiring reporting 
10.3.12.1 Overdose 
Use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is 
considered to be an overdose. There is currently no specific treatment in the event of overdose 
of durvalumab or tremelimumab, and possible symptoms of overdose are not established.  
 An overdose with associated AEs will be recorded as the AE diagnosis or symptoms in 
the relevant AE modules of the eCRF and in the Overdose eCRF module. 
 An overdose without associated symptoms will only be reported in the Overdose eCRF 
module. 
10.3.12.2 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the IND Sponsor and 
AstraZeneca. 
 
Maternal exposure 
 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately, and the pregnancy should be reported to the IND Sponsor and AstraZeneca.  
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.  
 
Paternal exposure  
 


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Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 180 days after the last 
dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy, whichever is the longer time period should, if possible, be followed 
up and documented.  
 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
 
10.3.12.3 Medication Error 
 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient.  
 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient. 
 
Medication error includes situations where an error: 
 occurred 
 was identified and intercepted before the patient received the drug 
 did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
 Drug name confusion 
 Dispensing error e.g. medication prepared incorrectly, even if it was not actually given 
to the patient 
 Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
 Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet  
 Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature  
 Wrong patient received the medication (excluding IVRS/IWRS errors) 
 Wrong drug administered to patient (excluding IVRS/IWRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
 Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
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 Patient accidentally missed drug dose(s) e.g. forgot to take medication 
 Accidental overdose (will be captured as an overdose) 
 Patient failed to return unused medication or empty packaging 
 Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, the IND Sponsor and AstraZeneca 
should be notified within 1 day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
 
11. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION  
11.1 Description of analysis sets 
 Safety analysis set 
Safety analysis set includes all patients who receive any study treatment including DEB-TACE 
or at least one dose of either durvalumab or tremelimumab. 
 Efficacy analysis set 
Evaluable population for objective response includes all patients who receive DEB-TACE and 
both of   durvalumab/tremelimumab, and have baseline scan with measurable disease, and either 
have at least one on treatment scan or die without any on treatment scans.  
 
11.2  Methods of statistical analyses 
 Safety analyses 
Safety will be summarized by the percentage of patients with AEs, by type and grade according 
to NCI CTCAE version 5.0 and attribution. The analysis will be based on safety analysis set. 
 Efficacy analyses 
The primary endpoint is objective response. Objective response rate, defined as the percent of 
patients with at least one visit response of CR or PR via mRECIST and will be based on the 
Evaluable Population.   
 
As a secondary endpoint, the response of non-target lesions will be described. Other secondary 
efficacy endpoints include duration of response, 6-month progression-free survival , and overall 
survival (OS). Duration of response is defined as date of having CR or PR to the date of 
progression per mRECIST among the patients who have CR or PR. Progression free survival 
will be defined as the time from the date of start of the treatment until the documentation of 
disease progression according to mRECIST or death due to any cause, whichever occurs first. 
Patients who have not progressed or died at the time of the analysis will be censored at the time 
of the latest date of assessment from their last evaluable mRECIST assessment. Kaplan-Meier 


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curves will be used to characterize PFS and OS, and 6-month PFS will be estimated from Kaplan-
Meier.  
 
 Correlative analyses 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation burden, and 
bioinformatic analysis may be performed either at an on-campus laboratory or at an off-campus 
sequencing service. All the samples will be de-identified before sending to any laboratory for 
sequencing.  The FASTQ files, BAM files and VCF files will be generated and analyzed. Other 
sequencing assays may be performed on a subset of samples according to specific requirements 
of collaboration projects. Genomic sequencing data will be stored and computations conducted 
using a JH IT managed subscription of Azure. 
 
 Safety run-in 
To ensure that the combination is safe, the first six patients will be treated and observed for 
toxicity for 1 cycle before continuation with further accrual. If ≤ 1 limiting toxicity events occur 
in the first 6 patients, we will proceed with additional accrual to complete a total of 20 patients 
for the safety evaluation. If >1 limiting toxicity events occur among the first 6 patients, then 
three additional patients will be enrolled (i.e. a total of 9 patients).  If ≤ 2 limiting toxicity events 
occur in the 9 patients, we will proceed with additional accrual to complete a total of 20 patients 
for the safety evaluation. If > 2 limiting toxicity events occur, we will pause the enrollment 
pending safety review. 


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11.3  Determination of sample size 
The standard of care treatment with DEB-TACE results in a objective response rate (ORR) of 30%. 
The regimen would be considered of insufficient activity for further study if the ORR is 30% or 
less, and the minimum required level of efficacy that would warrant further study with the 
proposed regimen is a 60% response rate. An optimal Simon two-stage design is planned. A total 
of 8 patients will be entered in the first stage. If ≤2 subjects respond, the treatment will be 
terminated and we will conclude the regimen is ineffective. If ≥3subjects respond, then additional 
12 patients will be studied.  If a total of 8 or fewer subjects respond in stage one and two combined, 
the regimen is considered ineffective. If a total of 9 or more respond, we conclude the regimen is 
promising and warrants further study. The maximum sample size will be 20 evaluable patients. To 
account for 10% unevaluable patients who do not receive durvalumab/tremelimumab following 
DEB-TACE, or do not have any on treatment scans for reasons other than death, we plan to enroll 
22 patients.   
 
This design provides 90% power to detect a 30% absolute increase in ORR, from 30% to 60%, 
with one-sided type I error 0.1. The chance of stopping early for lack of efficacy at the interim 
analysis is 0.55, if the response rate is 30%. 
 
 
 


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12. ETHICAL AND REGULATORY REQUIREMENTS 
12.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Patient data protection. 
13. STUDY MANAGEMENT 
13.1 Monitoring of the study 
The clinical research team will meet on a regular basis when patients are being actively treated on 
the trial to discuss each patient. All data will be collected in a timely manner and reviewed by the 
principal investigator or a co-principal investigator. Adverse events will be reported as required 
above. Any safety concerns, new information that might affect either the ethical and or scientific 
conduct of the trial, or protocol deviations will be immediately reported to the IRB, and the 
Sponsor. The principal investigator will review adverse event and response data on each patient to 
ensure safety and data accuracy. The principal investigator and co-PI will personally conduct and 
supervise the investigation and provide appropriate delegation of responsibilities to other members 
of the research staff. 
14. DATA MANAGEMENT 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (RedCap) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with Johns Hopkins security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. At the end of the study, data will be stored 
according to JHH and FDA Schedule regulations as applicable.  
Loss or destruction of data: If there is a major breech in the protection of subject confidentiality 
and trial data, the IRB will be notified.  
DATA SHARING PLANS De-identified human data generated in this research for future research 
in a NIH-funded or approved public repository at the time of publication or shortly thereafter. 
14.1 Study governance and oversight 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 


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addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators. 
15. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
15.1 Identity of investigational product(s) 
 
Table 8. List of investigational products for this study 
Investigational product
Dosage form and strength 
Manufacturer 
Durvalumab 
50 mg/mL solution for infusion after dilution  
MedImmune 
Tremelimumab 
20 mg/mL solution for infusion after dilution  
MedImmune 
 
 
 
 
 
 


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84
 


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
85


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
86


 
87


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
88


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
89


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
90


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
91


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
 
95


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
r


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
97


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
98


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
99


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
100


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
101


 
102


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
103
 
 


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
104


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
105
 
 


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
 
106
 
 
 


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
107


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
 
108
 
Appendix 2. Durvalumab dose volume calculations 
 
Example:  


J18118; ESR-17-12965 
Durvalumab + Tremelimumab 
Protocol Version 11.0 – August 21, 2024  
 
 
109
Appendix 3. Tremelimumab dose volume calculations  
 
Example: