An Open Label Pilot Study to Evaluate Efficacy and Safety of Durvalumab(MEDI 4736) With Hepatic Artery Infusion Chemotherapy (HAIC) in the Chinese Advanced HCC Patients With Severe Portal Vein Tumor Thrombosis (PVTT)(Vp3 or Vp4) DurHope
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Sun Yat-sen University

Clinical Trial Protocol
An Open Label Pilot Study to Evaluate Efficacy and Safety of Durvalumab
(MEDI 4736) With Hepatic Artery Infusion Chemotherapy (HAIC) in the
Chinese Advanced HCC Patients With Severe Portal Vein Tumor Thrombosis
(PVTT) (Vp3 or Vp4) DurHope
Principal Investigator
Ming Zhao, MD
Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and
Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China
Email: zhaoming@sysucc.org.cn
Study Drug: Durvalumab, Oxaliplatin, Leucovorin, Fluorouracil
Protocol Number: ESR-20-20719
NCT Number: NCT04945720
Date of the document: 2024.01.15

PROTOCOL SYNOPSIS
Clinical Protocol ESR-20-20719
Study Title:
Durvalumab plus arterial FOLFOX followed by maintanance durvalumab for hepatocellular carcinoma
with major portal invasion: the phase 2 DurHope study with biomolecular analyses
Protocol Number: ESR-20-20719
Clinical Phase: Phase 2
Study Duration
Patient enrollment for 15 months
Follow-up of last enrolled patients for 1 year
Investigational Product(s)
Durvalumab, Oxaliplatin, Leucovorin, Fluorouracil
Objectives
Primary Objectives:
• 1-year overall survival rate
Secondary Objective(s):
• Safety
• Objective response rate (RECIST 1.1)
• Progression-free survival (RECIST 1.1)
Exploratory Objective(s):
• PD-L1 expression
• Transcriptome analysis
• Peripheral dynamic biomarker
Study Design: Non-randomized, non-blinded, non-comparative, single-center, open-label study
Number of Patients: 30 patients
Study Population
Patients had portal vein invasion of vp3-vp4 without previous treatment for hepatocellular carcinoma

Inclusion Criteria
1.
Provided written informed consent to participate in the study before the start of the study
2.
Age > 18 years at time of study entry
3.
Diagnosis of HCC based on the diagnostic criteria for HCC used by the European
Association for the Study of the Liver (EASL)
4.
At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL)
at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance
imaging (MRI) must be performed within 30 days prior to screen
5.
HCC with Vp3/4 PVTT patients who meet any of the following criteria are considered to
have HCC with PVTT:
a)
Biopsy-confirmed HCC. Ultrasound-guided percutaneous tumor biopsy is performed
with a gauge needle
b)
HCC and PVTT confirmed by two image techniques, including contrast-enhanced
ultrasound, dynamic contrast-enhanced computerized tomography and dynamic contrast-
enhanced magnetic resonance imaging
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7.
Body weight >30 kg
8.
Disease not amenable to curative surgery or transplantation or patient refuses for surgery
9.
No cirrhosis or cirrhotic status of Child-Pugh class A-B7
10. Adequate normal organ and marrow function as defined below:
a)
Haemoglobin ≥8.5 g/dL
b)
Absolute neutrophil count (ANC) ≥1.5 × 109 /L
c)
Platelet count ≥50 × 109/L
d)
Serum total bilirubin ≤2.0 x institutional upper limit of normal (ULN)
e)
AST (SGOT)/ALT (SGPT) ≤5 x institutional upper limit of normal
f)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN.
g)
Serum creatinine clearance (CL) ≥30 mL/min or by the Cockcroft-Gault formula 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)
11. 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
12. Must have a life expectancy of at least 12 weeks
13. 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:
a)
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)
b)
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)
14. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen
(HBsAg) and/or hepatitis B core antibodies(anti-HBcAb) 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 ≤104
IU/mL) prior to randomization. Patients must remain on antiviral therapy for the study
duration and for 6 months after the last dose of study medication. Patients who test positive
for anti-hepatitis B core (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 randomization.
These subjects will be 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
15. Patients with HCV infection must have management of this disease per local institutional
practice throughout the study. HCV diagnosis is characterized by the presence of detectable

HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment
Exclusion Criteria
1.
Evidence of hepatic decompensation including moderate ascites, gastrointestinal bleeding or
hepatic encephalopathy
2.
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
3.
Known history of human immunodeficiency virus (HIV) or organ allograft. 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])
4.
Known or suspected allergy to the investigational agents or any agent given in association
with this trial
5.
Patients with clinically significant gastrointestinal bleeding within 30 days prior to study
entry or evidence of bleeding diathesis
6.
Known central nervous system tumors including metastatic brain disease
7.
Patients who are pregnant or breastfeeding
8.
History of another primary malignancy except for:
a)
Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of IP and of low potential risk for recurrence
b)
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease
c)
Adequately treated carcinoma in situ without evidence of disease
9.
Patient who had received anti PD-1, anti PD-L1 or anti CTLA-4 treatment before the first IP
administration
10. Previous history of HAIC treatment
11. Previously received systemic anti-cancer therapy for HCC.
Any biologic, or hormonal

therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable
12. Current or prior use of immunosuppressive medication within 14 days before the first dose of
durvalumab. The following are exceptions to this criterion:
a)
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular
injection)
b)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
its equivalent
c)
Steroids as premedication for hypersensitivity reactions
13. Live attenuated vaccine was inoculated 30 days before the first IP administration. (If
enrolled, patients should not be inoculated live attenuated vaccine during IP treatment and
within 30 days after the last IP administration)
Treatment Flow
Single-arm phase 2 trial
-
HAIC (Oxaliplatin 130mg/m2, leucovorin 200mg/m2 and fluorouracil 400mg/m2 via
arterial bolus, then fluorouracil infusion 2400mg/m2) every 3 weeks.
-
Durvalumab 1120mg via intravenous infusion every 3 weeks
-
21 days of study treatment is regarded as 1 cycle
-
Response assessment will be performed every 8 weeks with RECIST 1.1
-
Patients will continue receiving Durvalumab until RECIST 1.1 defined radiological
progression or intolerable AE.

Investigational Product(s), Dose and Mode of Administration:
HAIC
-
Oxaliplatin 130mg/m2, leucovorin 200mg/m2 and fluorouracil 400mg/m2 via arterial
bolus, then fluorouracil infusion 2400mg/m2 every 3 weeks.
Durvalumab
-
1120mg via intravenous infusion every 3 weeks.
Study Assessments and Criteria for Evaluation
Safety Assessments
Safety assessments will include the incidence, nature, and severity of adverse events and
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 5.0 (NCI CTCAE v5.0). In addition, serious adverse events, adverse
events CTCAE grade ≥3, and will be summarized accordingly. Multiple occurrences of the same
event will be counted once at the maximum grade. Physical examination, vital signs, laboratory test,
ECOG performance status, Child-Pugh classification compared to baseline will be summarized.
Efficacy Assessments
Response Evaluation Criteria in Solid Tumors (RECIST) Version1.1
Exploratory Analysis
Archived tumor biopsy:
-
Patients’ tumor biopsy will be used to test transcriptomic sequencing, the summary the
result to analyzed the relationship between clinical efficacy (OS, PFS, ORR) with
different gene expression and molecular pathways.
-
PD-L1 testing outcome will be listed individually for each patient and summarized
according to the status (Positive\Negative\Not Evaluable). Clinical efficacy (OS, PFS
and ORR) will be summarized by PD-L1 expression status.
Serum and peripheral blood mononuclear cells (PBMC)
-
Serum samples from patients will be evaluated by protein detection methods to detect
serum biomarkers related to clinical efficacy.
-
PBMC samples will be used to detect the phenotypic characteristics of peripheral
immune cells to 0065plore the relationship between clinical efficacy and specific

immune cell subpopulations in peripheral blood.
Statistical Methods and Data Analysis:
Confidence intervals were estimated using the Clopper-Pearson method. Survival analyses will be
performed using the Kaplan-Meier method. SPSS version 26.0 will be used for all statistical analysis.
Sample Size Determination:
To determine the appropriate sample size, we used a one-stage binomial design with a one-sided alpha
level of 0.05 and statistical power of 80%. Previous studies have reported a median OS of
approximately 7.6 months in high-risk HCC patients treated with atezolizumab plus bevacizumab,
corresponding to an estimated 1-year OS rate of 35%6,25. We hypothesized that the combination of
hepatic arterial infusion chemotherapy (HAIC) and durvalumab would improve the 1-year OS rate to
60%. Assuming an anticipated dropout rate of 10%, the target sample size was set at 30 patients.

SCHEDULE OF STUDY ASSESSMENTS
Table1.Schedule of assessments for durvalumab + HAIC, treatment to progression
Cyclea
Screening
HAIC + durvalumab
For details
see Section
/
HAIC
C1D1-2
Durva
C1D3
HAIC
C2D1-2
Durva
C2D3
HAIC
C3D1-2
Durva
C3D3
C4-C15
Survival
Follow up
phone calls
Day
-30 to -1
0
Q3W ±2 days unless dosing needs to be held for toxicity reasons and;
Q4W±2 days after last HAIC
Q12W
Visit window
/
/
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±14 days
Informed Consent
Informed consent: study proceduresb
X
4.1
Study procedures
Eligibility criteria
X
X
4.1/4.2
Physical exam (full)
X
X
X
X
X
7.1
Vital signsc
X
X
X
X
X
7.2
ECGd
X
As clinically indicated
7.3
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------------------->
5.3
Demography, including baseline
characteristics and
X
4.1
Child-Pugh classification
X
X
X
X
X
X
X
X
7.6
Monitoring
ECOG performance status
X
X
As clinical indicated
7.5
AE/SAEs/AESI assessmente
<-------------------------------------------------------------------------------------------------------------------------------->
8.1
Laboratory Assessments
Clinical chemistryf
X
X
X
X
X
Table 7
Hematology f
X
X
X
X
X
Table 6

Cyclea
Screening
HAIC + durvalumab
For details
see Section
/
HAIC
C1D1-2
Durva
C1D3
HAIC
C2D1-2
Durva
C2D3
HAIC
C3D1-2
Durva
C3D3
C4-C15
Survival
Follow up
phone calls
Day
-30 to -1
0
Q3W ±2 days unless dosing needs to be held for toxicity reasons and;
Q4W±2 days after last HAIC
Q12W
TSHg (reflex free T3 or free T4h)
X
X
X
X
X
Table 7
Urinalysis
X
As clinically indicated
Table 8
Pregnancy test i
X
X
X
X
X
8.14.1
Hepatitis B and C and HIV j
X
X
X
X
X
7.4
IP administration
Durvalumab k
/
X
X
X
X
5.1.2
HAICl
/
X
HAIC will be repeated every 3 weeks (4-8 cycles)
5.1.2
Other evaluations
Tumor biopsy (if available)
X
6.6.2
Tumor biopsy (archival, if available,
for patients who submit a newly
acquired biopsy at screening for PD-
L1 status)
X
6.6.2
Efficacy evaluations
Tumor evaluation (CT or MRI)
(RECIST 1.1)
X
Q6W from week6, Q2M after 6 month, Q3-6M from 1year and depends on investigator’s
decision(w6, w12, w18, w24,w32 , w40and w48
6.3
QoL Questionnaire
X
Q3W during HAIC+Durvalumab treatment, Q8W after last HAIC treatment
6.5
a
HAIC + Durvalumab will be repeated every 3 weeks. Durvalumab will be given on day 3±2 days after HAIC treatment.
b
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 30-day screening window, if necessary, in order to permit tumor biopsy sample acquisition
and analysis prior to enrollment. The collection of additional biopsies upon progression is strongly encouraged. If laboratory or imaging procedures were performed for alternate

reasons prior to signing consent, these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging results must have been obtained
within 30 days of enrollment.
c
Body weight is recorded at each visit along with vital signs.
d
Any clinically significant abnormalities detected require triplicate ECG results.
e
For AEs/SAEs/AESI reported during screening, additional information such as medical history and concomitant medications may be needed.
f
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated. If screening clinical chemistry and
haematology assessments are performed within 7 days prior to Day 1 (first HAIC day), they do not need to be repeated at Day 1.
g
If TSH is measured within 14 days prior to Day 1 (first Durvalumab infusion day), it does not need to be repeated at day 1.
h
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
i
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 7 days prior to
the first dose of study drug and then every 3 weeks. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or Investigator prior to
commencing an infusion
j
For patients with known hepatitis B, results of anti-HCV and anti-HDV antibody assays were collected only during the screening period. For patients with known hepatitis C, HCV
genotype, anti-HCV antibody, HBsAg qualitative and anti-HBc determination results were collected only during the screening period.
k
Durvalumab will be administered 3 days after the first HAIC treatment, q3w (±2 days). Results for LFTs, electrolytes and creatinine must be available before commencing an infusion
(within 3 days) and reviewed by the treating physician or Investigator prior to dosing.
l
HAIC was suggested 4-8 cycles, at the doctor’s decision.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
AE Adverse event; AFP alpha-fetoprotein; C Cycle; D Day; Durva Durvalumab; ECG Electrocardiogram; HAIC Hepatic arterial chemotherapy infusio;LFT Liver function test;
q3w Every3 weeks; SAE Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone.

Table2.Schedule of assessments for patients who have discontinued durvalumab treatment.
Time Since Last Dose of durvalumab
Evaluation
Days（±3）
Months（±1week）
12months and every
6 months（±2week）
For details
see Section
30
2
3
4
6
8
10
Physical exam (full)
X
7.1
Vital signs a
X
7.2
Pregnancy test
X
X
X
As clinically indicated
8.14.2
AE/SAE assessment
X
X
X
8.1
Concomitant medications
X
X
X
5.3
ECOG performance status
At the time of tumor assessment, and then at the beginning of subsequent anticancer therapy.
7.5
Subsequent anticancer therapy
<------------------------------------------------------------------------------------------------------------------------------------>
6.4
Survival status
X
X
X
X
X
X（every 12 weeks）
6.4
Clinical chemistry
X
X
X
Table 7
Hematology
X
X
X
Table 6
TSH b, (reflex free T3 or free T4) c
X
X
X
Table 7
AFP
X
X
X
Table 7
Tumor evaluation (CT or MRI)
(RECIST 1.1)
Q6W from week6, Q2M after 6 month, Q3-6M from 1year and depends on investigator’s decision.
6.3
a
Body weight is recorded at each visit along with vital signs.
b
If TSH is measured within 14 days prior to Day 1 (first Durvalumab infusion day), it does not need to be repeated at day 1.
c
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
Note: AE Adverse event; AFP alpha-fetoprotein; ECOG ; q3w Every3 weeks; q4w Every 4 weeks; SAE Serious adverse event; T3 Triiodothyronine; T4
Thyroxine;
TSH Thyroid-stimulating hormone.

TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS.........................................................................................................2
SCHEDULE OF STUDY ASSESSMENTS............................................................................9
TABLE OF CONTENTS.......................................................................................................13
ABBREVIATIONS AND DEFINITION OF TERMS..........................................................18
1.
INTRODUCTION.................................................................................................20
1.1
Hepatocellular carcinoma..................................................................................20
1.2
Hepatic arterial infusion chemotherapy (HAIC)...............................................20
1.3
Immunotherapies...............................................................................................21
1.4
Durvalumab background/non-clinical and clinical experience......................... 22
1.5
Benefit/risk and ethical assessment................................................................... 23
1.5.1
Potential benefits........................................................................................... 23
1.5.2
Overall risks...................................................................................................23
1.5.3
Overall benefit-risk........................................................................................25
2.
OBJECTIVES........................................................................................................26
2.1
Primary objective...............................................................................................26
2.2
Secondary objectives......................................................................................... 26
2.3
Exploratory objective.........................................................................................26
3.
STUDY DESIGN.................................................................................................. 27
3.1
Overview of study design..................................................................................27
3.1.1
Description of Study Design..........................................................................27
3.1.2
Study schema.................................................................................................28
3.1.3
Follow up.......................................................................................................28
3.2
Rationale for this study design.......................................................................... 29
3.2.1
Primary endpoint rationale............................................................................ 29
3.2.2
Key secondary endpoints rationale................................................................30
3.3
Dose rationale....................................................................................................31
3.3.1
Durvalumab monotherapy dose rationale......................................................31
3.3.2
Rationale for fixed dosing............................................................................. 32

3.4
Discontinuation of Study Intervention...............................................................33
3.5
End of study definition...................................................................................... 33
4.
PATIENT SELECTION........................................................................................33
4.1
Inclusion criteria................................................................................................33
4.2
Exclusion criteria...............................................................................................36
4.3
Withdrawal of patients from study treatment and/or study............................... 37
4.4
Premature Termination of Study/Closure of Center..........................................40
5.
TREATMENT PLAN............................................................................................40
5.1
Treatments to be Administered..........................................................................40
5.1.1
Investigational Product(s)..............................................................................40
5.1.2
Duration of treatment and criteria for treatment through progression...........44
5.2
Dose modification..............................................................................................46
5.2.1
FOLFOX regimen..........................................................................................46
5.2.2
Durvalumab of dose administration...............................................................46
5.3
Concomitant treatment(s).................................................................................. 47
5.3.1
Drug interactions........................................................................................... 47
5.3.2
Permitted concomitant medications...............................................................48
5.3.3
Excluded concomitant medications...............................................................48
6.
ASSESSMENT OF EFFICACY........................................................................... 50
6.1
Imaging examination schedule.......................................................................... 50
6.2
Image acquisition and evaluation...................................................................... 50
6.3
Tumor assessment..............................................................................................51
6.4
Survival tracking................................................................................................51
6.5
Clinical efficacy evaluation...............................................................................51
6.6
Biological sample analysis................................................................................ 51
6.6.1
Blood sample................................................................................................. 51
6.6.2
Tissue sample.................................................................................................51
7.
ASSESSMENT OF SAFETY................................................................................52
7.1
Physical examinations....................................................................................... 52
7.2
Vital signs..........................................................................................................52
7.3
Electrocardiogram..............................................................................................53
7.4
Laboratory tests................................................................................................. 53
7.5
ECOG performance status.................................................................................56

7.6
Child-Pugh classification...................................................................................56
7.7
Other safety assessments................................................................................... 57
8.
ADVERSE EVENTS.............................................................................................58
8.1
Adverse Event Definitions.................................................................................58
8.1.1
Adverse events...............................................................................................58
8.1.2
Adverse Drug Reaction..................................................................................59
8.1.3
Serious adverse events...................................................................................59
8.1.4
Adverse events of special interest..................................................................60
8.2
Adverse Event Collections................................................................................ 61
8.2.1
Collection mode.............................................................................................61
8.2.2
Collection schedule........................................................................................61
8.2.3
Follow up and collection............................................................................... 62
8.3
Assessment of severity...................................................................................... 62
8.4
Recording of adverse events and serious adverse events.................................. 63
8.5
Causality collection........................................................................................... 64
8.6
Relationship to protocol procedures..................................................................65
8.7
Adverse events based on signs and symptoms.................................................. 65
8.8
Adverse events based on examinations and tests.............................................. 65
8.9
Hy’s Law........................................................................................................... 66
8.10
Disease progression........................................................................................... 66
8.11
New cancers.......................................................................................................66
8.12
Deaths................................................................................................................ 67
8.13
Safety data to be collected following the final DCO of the study.....................67
8.14
Safety reporting and medical management........................................................68
8.14.1
Reporting of Adverse Events.........................................................................68
8.14.2
Pregnancy...................................................................................................... 68
8.14.3
Paternal exposure...........................................................................................69
8.14.4
Toxicity management guidelines...................................................................69
Durvalumab............................................................................................................70
FOLFOX regimen.................................................................................................. 70
9.
DATA COLLECTION AND MANAGEMENT...................................................71
9.1
Data Collection..................................................................................................71
9.2
Data Management..............................................................................................71

10.
STATISTICAL METHODS AND DATA ANALYSIS.......................................71
10.1
Statistical and Analytical Plans......................................................................... 71
10.1.1
Analysis Populations..................................................................................... 71
10.1.2
Baseline and Demographic Characteristics................................................... 72
10.1.3
Primary Efficacy analysis..............................................................................72
10.1.4
Other Efficacy analysis..................................................................................72
10.1.5
Safety analysis............................................................................................... 73
10.1.6
Biomarker analysis........................................................................................ 73
10.2
Determination of sample size............................................................................ 74
11.
USE OF DATA AND PUBLICATION................................................................ 74
12.
ETHICAL CONSIDERATIONS...........................................................................74
12.1
Ethics Committee (EC) or Institutional Review Board (IRB)Ethics and
regulatory review...............................................................................................74
12.2
Ethical Conduct of the Study.............................................................................75
12.3
Regulatory Authority Approvals/Authorizations.............................................. 75
12.4
Informed consent............................................................................................... 75
13.
REFERENCES...................................................................................................... 76
14.
APPENDICES.......................................................................................................82
14.1
The Barcelona Clinic Liver Cancer (BCLC) staging system............................ 82
14.2
RECIST 1.1 criteria........................................................................................... 82
14.3
ECOG Performance Status Classification......................................................... 85
14.4
Child–Pugh Classification................................................................................. 85
14.5
Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion-Related, and Non-Immune–Mediated Reactions of
Durvalumab 17 October 2019 Version (CTCAE v5.0).....错误！未定义书签。
LIST OF TABLES
Table 1 Schedule of assessments for durvalumab + HAIC, treatment to progression错误！未定
义书签。
Table 2 Schedule of assessments for patients who have discontinued durvalumab treatment...8
Table 3 Supportive Medications............................................................................................... 43
Table 4 Prohibited Concomitant Medications.......................................................................... 44
Table 5 Hematology Laboratory Tests..................................................................................... 49
Table 6 Clinical Chemistry (Serum or Plasma) Laboratory Tests............................................49

Table 7 Urinalysis Test............................................................................................................. 50
LIST OF FIGURES
Figure 1. Study Flow Chart...........................................................................................................27
Figure 2. Treatment schedule of HAIC..........................................................................................39
Figure 3. HAIC + Durvalumab Combined Therapy Dosing Schedule......................................... 40
LIST OF APPENDICES
Appendix 14.1 The Barcelona Clinic Liver Cancer (BCLC) staging system...........................74
Appendix 14.2 RECIST 1.1 criteria.........................................................................................75
Appendix 14.3 ECOG Performance Status Classification........................................................78
Appendix 14.4 Child–Pugh Classification................................................................................ 79

ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APC
Antigen-presenting cells
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CL
Clearance
Cmax
Peak concentration
Cmax,ss
Peak concentration at steady state
Cmin
Trough concentration
Cmin,ss
Trough concentration at steady state
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form
CT
Computed tomography
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
DC
Disease control
DCR
Disease control rate
EASL
European Association for the Study of the Liver
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HAIC
Hepatic arterial chemotherapy infusion

Abbreviation or
special term
Explanation
HCC
Hepatocellular carcinoma
HCl
Hydrochloride
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IgG1
Immunoglobulin G1
IgG2
Immunoglobulin G2
imAE
Immune-mediated adverse event
IRB
Institutional Review Board
IV
Intravenous(ly)
Mab
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
Events
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
PVTT
Portal vein tumor thrombosis
Q3W
Every 3 weeks
Q4W
Every 4 weeks

Abbreviation or
special term
Explanation
QoL
Quality of life
QTc
Time between the start of the Q wave and the end of the T wave corrected
for heart rate
QTcF
QT interval on ECG corrected using the Frederica’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Stable disease
sPD-L1
Soluble programmed cell death ligand 1
SoA
Schedule of study assessment
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
1. INTRODUCTION
1.1 Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the fourth most common cancer and the second leading
cause of cancer-related death in the world (Ferlay et al 2015). In Japan, HCC is associated with
chronic hepatitis caused by persistent infection with hepatitis C virus (HCV) or hepatitis B virus
(HBV) and subsequent cirrhosis of the liver. It is estimated that about 24,536cases were newly
diagnosed in the Chinese Cancer Registry annual report in 2009. Advanced-stage disease is
found in 25%-70% of HCC at diagnosis, with a median survival time of only 4.2-7.9 months due
to limited treatment options (Llovet et al 2008). To date, sorafenib and lenvatinib is the standard
of care which shown to extend overall survival for advanced hepatocellular carcinoma. However,
low response rates, modest survival benefit and high-level heterogeneity of individual response,
such limitations them prohibit its widespread use and more alternative therapies are highly
required at present.
1.2 Hepatic arterial infusion chemotherapy (HAIC)
Hepatic arterial infusion chemotherapy (HAIC) can provide chemotherapeutic agents to liver
at higher concentration with lower toxicity and has been reported favorable results in advanced
HCC and liver metastases from colorectal cancer (Kemeny et al 2009). FOLFOX (infusion 5-FU,

leucovorin, and oxaliplatin) was a regimen first used in colon cancer with liver metastasis and
reported to be effective both by systemic and HAIC in the clinical trials (Goere et al 2013).
EACH study has provided proof to suggest that the FOLFOX regimens may become a
potentially more efficacious alternative to doxorubicin with advanced HCC in HBV infected
population (Qin et al 2014).
Many patients are diagnosed as advanced disease, and systemic therapy is recommended as
the first choice in the international guidelines. In Asia, HAIC, which involves direct infusion of
anticancer drugs into the hepatic artery, was developed and used for patients with advanced HCC,
especially HCC with portal vein tumor thrombosis (PVTT). In the previous studies, the median
overall survival (OS) and progression-free survival (PFS) were estimated to be 7-9 months and
2-6 months, respectively (Liu et al 2020).
1.3 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 et al 2004).
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-
cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells (Keir
et al 2008).
It has 2 known ligands: PD-L1 (B7- H1; CD274) and PD-L2 (B7- DC;
CD273). The PD-1 and PD-L1/PD- L2 belong to the family of immune checkpoint proteins that
act as co-inhibitory factors, which can halt or limit the development of T cell response. When
PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine
production and suppresses T-cell proliferation.
Tumor cells exploit this immune checkpoint
pathway as a mechanism to evade detection and inhibit immune response.
PD-L1 is constitutively expressed by B- cells, dendritic cells, and macrophages. Importantly,
PD-L1 is commonly over- expressed on tumor cells or on non-transformed cells in the tumor
microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 receptors
on the activated T- cells leading to the inhibition of cytotoxic T cells. These deactivated T cells
remain inhibited in the tumor microenvironment.
The PD-1/PD- L1 pathway represents an
adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous
anti-tumor activity.

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.
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 et al, 2012; Hirano et al, 2005;
Iwai et al, 2002; Okudaira et al, 2009; Topalian et al, 2012; 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 et al 2015; Segal et al 2015). In addition, high mutational burden (e.g., in bladder
carcinoma [Alexandrov et al, 2013]) may contribute to the responses seen with immune therapy.
1.4 Durvalumab background/non-clinical and clinical experience
The non-clinical and clinical experience is fully described in the most current version of the
durvalumab Investigator’s Brochure.
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa
subclass that inhibits binding of PD-L1 and 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.)). The
proposed mechanism of action (MOA) for durvalumab is interference in the interaction of
PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions
releases the inhibition of immune responses, including those that may result in tumor
elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of
PD-L1 on primary human T cells resulting in the restored proliferation of IFN-γ (Stewart et al
2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models
via a T- cell- dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is
expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting

the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-
dependent cellular cytotoxicity and complement-dependent cytotoxicity.
To date durvalumab has been given to more than 8000 patients as part of ongoing studies
either as monotherapy or in combination with other anti-cancer agents. Details on the safety
profile of durvalumab monotherapy are summarized in Section 5.1. Refer to the current
durvalumab Investigator’s Brochure for a complete summary of non-clinical and clinical
information including safety, efficacy and pharmacokinetics.
1.5 Benefit/risk and ethical assessment
1.5.1 Potential benefits
Previous studies have reported that HAIC with fluorouracil or cisplatin achieved favourable
results in advanced HCC patients with PVTT, even in patients with major PVTT, which had a
median OS of 5.4–9.3 months (Lin et al. 2015). HAIC with oxaliplatin and fluorouracil was
recently confirmed to be effective and safe for colorectal cancer liver metastasis. At present,
most of the safety and efficacy data for PVTT patients receiving HAIC with oxaliplatin and
fluorouracil, which had shown that the median OS was 20.8 months and the median PFS was 9.6
months (Hu et al. 2020).
At present, most of the safety and efficacy data for HCC patients receiving durvalumab
monotherapy are based on the first monotherapy study 1108 (NCT01693562) in patients with
advanced solid tumors such as HCC. As of October 16, 2017, the median follow-up time of 40
patients with HCC was 16.2 months and the median OS was 13.2 months.
In this study, study drug Durvalumab and required test is covered by investigator or the
patient’s health insurance. Participation in this study will have additional financial or therapeutic
benefits over routine care.
In conclusion, the above data suggest that HAIC plus durvalumab may bring clinical benefits
to HCC patients.
1.5.2 Overall risks
In 2010, a phase I study of HAIC of oxaliplatin in advanced HCC suggested that HAIC-
oxaliplatin 130 mg/m2 every 3 weeks was well tolerated and demonstrated activity (Rathore et al.

2010). About toxicity of FOLFOX regimens, there have been studies proved that compared with
intra-arterial, systemic and portal vein routes, the administration of fluorouracil via the hepatic
arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest
systemic/hepatic vein exposure ratio (Didolkar et al. 1989). It was identified that urinary
excretion (53.8 ± 9.1%) was the predominant route of oxaliplatin elimination, and hepatic
impairment had no obviously effect on the clearance of ultrafilterable platinum after oxaliplatin
administration (Graham et al. 2000).
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 immune mediated effects can occur in nearly any organ system,
and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea,
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme
elevations, skin events such as rash and dermatitis and endocrinopathies including hypo- and
hyper-thyroidism.
Risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD,
diabetes insipidus, encephalitis, immune thrombocytopenia, subcutaneous injection site reaction,
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus (including diabetic
ketoacidosis), hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases,
nephritis/increases
in
creatinine,
pancreatitis/increases
in
amylase
and
lipase,
rash/pruritus/dermatitis,
pemphigoid,
cytokine
release
syndrome,
uveitis,
non-infective
encephalitis, subcutaneous injection site reactions, immune-meditated arthritis, myocarditis,
myositis/polymyositis, other rare or less frequent inflammatory events including neurotoxicities,
infusion-related reactions, hypersensitivity reactions, and infections/serious infections.

For information on all identified and potential risks with durvalumab please always refer to the
current version of the durvalumab IB.
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 (≥15% of patients)
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus.
Approximately 9.4% of patients experienced an AE that resulted in permanent discontinuation of
durvalumab and approximately 6.5 % 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 (See Section 8.14.7).
1.5.3 Overall benefit-risk
Although there are many treatment options for patients with advanced HCC, there are still
unmet medical needs. Most patients achieved initial remission after HAIC treatment, but they
were limited by the following factors, such as tumor vascularization, micrometastasis and liver
function reserve after HAIC treatment. These limitations lead to residual tumor cells, some of
which may not be shown by radiographs.
HAIC can directly deliver chemotherapy drugs to cancer cells through hepatic artery, which
can increase the local drug concentration and enhance the killing effect of tumor cells. FOXAI
study had shown that the median PFS was 6.1 months and the objective response rate (ORR) was
28.6% receiving HAIC treatment, and HCC patients have the opportunity to seek further
treatment after disease progression. Chemotherapy used with HAIC, generally is oxaliplatin, can
kill cancer cells by inducing ribosome biogenesis. The release of new tumor antigen can promote
a permanent antitumor immune response.
PD-1 and PD-L1 pathways play an important role in HCC, suggesting that drugs that can
block PD-L1 may improve clinical outcomes by reversing the immunosuppressive environment
and stimulating host immune response to HCC（Gao et al 2009）. In phase I/Ib study 1108,
durvalumab monotherapy showed sustained clinical efficacy and controllable safety in HCC

patients with ORR of 10.0% (95% CI: 2.8%, 23.7%), and a median OS of 13.2 months (95% CI:
6.3, 23.0 months). In another phase I study, five (26.3%) of 19 HCC patients who received
Tremelimumab combined with local therapy (ablation or TACE) achieved confirmed partial
response (PR) （Duffy et al 2017）.
In conclusion, the above data suggest that durvalumab treatment in combination with HAIC
treatment can enhance the anti-tumor immune response, resulting in a significant and consistent
clinical benefit in advanced HCC patients.
Therefore, the overall benefit-risk assessment results support the development of this study to
assess the efficacy and safety of HAIC combined with durvalumab in the treatment of advanced
HCC patients with PVTT.
2. OBJECTIVES
This study is a prospective, phase 2, open-label, single center study to evaluate efficacy and
safety of durvalumab with hepatic artery infusion chemotherapy in the Chinese advanced HCC
patients with severe portal vein tumor thrombosis.
2.1 Primary objective
The 1-year overall survival (OS) rate.
2.2 Secondary objectives
1. To assess the safety and tolerability of HAIC + durvalumab in HCC patients through
collecting AE/SAE/AESI, analyzing data of physical examination, vital signs, laboratory
test, ECOG performance status and Child-Pugh classification.
2. Objective Response Rate (ORR) and Progression-free Survival (PFS) (Assessed by the
Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1).
2.3 Exploratory objective
To investigate the relationship between the clinical efficacy and PD-L1 expression status, gene
mutations status, immune cell subpopulations in peripheral blood.

3. STUDY DESIGN
3.1 Overview of study design
3.1.1 Description of Study Design
This study is a prospective, pilot, open-label, single center study to evaluate efficacy and
safety of durvalumab with hepatic artery infusion chemotherapy in the Chinese advanced HCC
patients with severe portal vein tumor thrombosis. Approximately 30 patients in single site will
be recruited into the study in order to power the study efficiently to measure a clinically
meaningful improvement for survival. Tumor response will be assessed according to the
RECIST 1.1 criteria.
The study will include subjects diagnosed with advanced stage HCC with PVTT according to
the Barcelona-Clinic Liver Cancer (BCLC) and the Tumor-Node-Metastasis (TNM) staging
system.
In the combined therapy phase, subjects will be given a procedure of HAIC on day 1-2.
Medication was started within 2 days after catheter insertion. The therapeutic scheme was
modified FOLFOX6 including oxaliplatin (130 mg/m2 infusion for 3 hours on day 1), leucovorin
(200 mg/m2 from hour 3 to 5 on day 1) and fluorouracil (400 mg/m2 bolus, and then 2400 mg/m2
continuous infusion 46 hours). HAIC was suggested 4-8 cycles, at the doctor’s decision.
Durvalumab 1120 mg will be administered intravenously 3±2 days after the first HAIC
treatment. The combination therapy with HAIC and Durvalumab will be repeated every 3 weeks.
In the durvalumab monotherapy phase, durvalumab changed to 1500mg every 4 weeks, after the
last cycle of HAIC.
The primary efficacy objective for this study are one-year overall survival rate (1-year OS
rate). However, subjects will receive 4-8 cycles of combined therapy (HAIC+ Durvalumab)
followed by durvalumab monotherapy until RECIST 1.1 defined radiological progression,
intolerable adverse events, withdraws informed consent or other termination criteria.

3.1.2 Study schema
Figure 1. Study Flow Chart
ECOG：Eastern Cooperative Oncology Group；HAIC：Hepatic artery infusion chemotherapy；
HCC：Hepatocellular carcinoma；IV：Intravenous injection；PS: Performance status.
3.1.3 Follow up
During the combined treatment period, subjects will have study visits on Day 1 of every cycle
(every 3 weeks from start of study), At the stage of durvalumab monotherapy, subjects will have
study visits on Day 1 of every cycle (repeated every 4 weeks).
CT/MRI assessment will be Q6W from week0, Q2M from 6 month, Q3-6M from 1 year and
depends on investigator’s decision (w0, w6,w12,w18,w24,w32,w40 and w48)
At the end of the treatment period, a safety follow-up visit will take place (90 days after
stopping the last cycle of durvalumab). All potential adverse events and changes in concomitant
medication will be collected. In addition, all serious adverse events should be followed to
resolution or stabilization unless, in the investigator’s opinion, the condition is unlikely to
resolve due to the subject’s underlying disease.
The subject will continue taking study procedure until disease progression or intolerable AE is
documented.
The end of the study for regulatory purposes will be considered the date when the last subject
has completed their last end of study visit.

3.2 Rationale for this study design
3.2.1 Primary endpoint rationale
The primary endpoint of this study will be 1-year OS rate. Overall survival was selected as the
primary endpoint because it is the most widely accepted direct and objective measure of clinical
effectiveness.
HAIC can reduce the tumor burden of most patients, and a large proportion of them achieved
complete response (Lyu et al. 2018). However, some patients treated with HAIC experienced
tumor recurrence because of the limited therapeutic effect of HAIC on potential extrahepatic
micro metastasis. Therefore, effective systemic therapy, such as immunosuppressive checkpoint
inhibitors, is needed to prevent local and distal recurrence. Cisplatin-based HAIC has been
widely employed as an alternative therapy to sorafenib for hepatocellular carcinoma patients
with portal vein invasion in Japan. This procedure provides direct delivery of chemotherapeutic
agents into the tumor-feeding arteries and minimizes systemic toxic effects through a first-pass
effect in the liver. In advanced HCC with vp3-vp4, HAIC or HAIC plus sorafenib has shown a
prolonged PFS with 4-6.4months and prolonged OS with 10.3-13.5months (He et al. 2019).
Chemotherapy used with HAIC, generally is oxaliplatin, can kill cancer cells by inducing
ribosome biogenesis. The release of new tumor antigen can promote a permanent antitumor
immune response. This immune response may be amplified by an immune checkpoint blockade
(Bruno et al 2017). Immunotherapies (IO) that inhibit the immune checkpoint interaction
between PD-1 and PD-L1 have shown substantial survival benefit in some patients with
metastatic carcinomas of multiple tissue origins. Current evidence showed IO mono is not
effective enough compared with current systemic therapy to prolong survival in advanced HCC.
However, IO combination tyrosine kinase inhibitor (TKI) has been demonstrated to prolong
survival for advanced HCC (generally for vp1-3), with up to 9.7months of PFS and up to
20.4months of OS.
HAIC focus on the local control of the tumor, in the targeted area and avoiding anticancer
drug exposure in other organs. However, IO is a systemic regime to mobilize the immune system
of the whole body. HAIC combined with IO may prolong the survival of advanced HCC patients
with PVTT.

3.2.2 Key secondary endpoints rationale
The key secondary endpoints of this study will be PFS, ORR and safety endpoint. Tumor
response will be assessed using RECIST 1.1. Assessments will be made based on changes in the
diameter of surviving tumors deemed viable by a modality such as contrast CT/MRI that are
observed until completion or discontinuation of the protocol treatment.
Studies have shown that the median PFS was 6.1 months and the objective response rate (ORR)
was 28.6% receiving HAIC treatment, and HCC patients have the opportunity to seek further
treatment after disease progression. Therefore, PFS and ORR are important secondary endpoints
in this study.
The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to
tabulate data for the safety population. The incidence and causality of each adverse event and
serious adverse event will be tabulated by group and by CTCAE v5.0 grade. A study to evaluate
the safety and efficacy of FOLFOX regimen HAIC in advanced HCC showed good safety, much
better than that from systemic use of FOLFOX4. In the study, the rate of treatment-related event
≥grade 3 severity was 7.1%, and most common AE is fatigue 63.1%, elevated aspartate
aminotransferase (AST) 48.8%, weight loss 38.1%, abdominal pain 32.1% and leukopenia
28.6%. AEs with grade ≥3 were leukopenia 4.8%, reduced hemoglobin 1.2% and elevated AST
1.2%. In addition, a study to evaluate the safety and efficacy of durvalumab monotherapy, or
combined with Tremelimumab in 2nd line advanced HCC. This study showed good safety in
durvalumab monotherapy group. The rate of treatment-related event ≥grade 3 severity was 25%
(16/64). Only 1 treatment-related death (1/64). The most common AE is AST elevation 25%
(16/64) and alanine aminotransferase (ALT) elevation 22% (14/64).
Biological samples will be used to explore potential biomarkers in tumor, plasma and / or
serum that may affect cancer progression and / or durvalumab treatment response. Blood samples
were collected to study PK and immunogenicity of durvalumab treatment.
The correlation between PD-L1 expression level and therapeutic effect was evaluated as an
exploratory endpoint. PD-L1 is a target of durvalumab, and its expression is assumed to be
related to clinical efficacy.

3.3 Dose rationale
3.3.1 Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity,
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with
advanced solid tumors and from a Phase I trial performed in Japanese patients with advanced
solid tumor (D4190C00002).
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging
from
0.1
to
10
mg/kg
Q2W
or
15
mg/kg
Q3W,
durvalumab
exhibited
non-linear
(dose- dependent) PK consistent with target-mediated drug disposition. The PK approached
linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a particular
regimen given the linearity seen at doses higher than 3 mg/kg. The expected half- life with doses
≥3 mg/kg Q2W is approximately 17 days. A dose-dependent suppression in peripheral sPD-L1
was observed over the dose range studied, consistent with engagement of durvalumab with PD-
L1. A low level of immunogenicity has been observed. No patients have experienced immune-
complex disease following exposure to durvalumab (For further information on immunogenicity,
please see the current IB).
A population PK model was developed using the data from Study 1108 (doses=0.1 to
10 mg/kg Q2W or 15 mg/kg Q3W (Fairman et al 2014). Multiple simulations indicate that a
similar overall exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W
regimens, as represented by AUCss (4 weeks). Median Cmax,ss is expected to be higher with
20 mg/kg Q4W (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W
(~1.25 fold). Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be
consistent with 10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to
(a) achieve complete target saturation in majority of patients; (b) account for anticipated
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations;
(c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that
yielded maximal antitumor activity in animal models.
Given the similar area under the plasma drug concentration-time curve (AUC) and modest
differences in median peak and trough levels at steady state, the observation that both regimens

maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles,
supporting further development with a dose of 20 mg/kg Q4W.
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical
information including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen.
3.3.2 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.
Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, Zhang
et al 2012, Narwal et al 2013). 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 (Wang et al 2009)]. In addition, they 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
(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, a fixed dose of 1120 mg Q3W durvalumab (equivalent to 15 mg/kg Q3W) during the
combination therapy and 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) during
monotherapy is included in the current study.

3.4 Discontinuation of Study Intervention
The patient will not receive any further study drug treatment if any of the following occurs:
1. Withdrawal of informed consent to continue the study of drug treatment. Patients can
stop treatment at any time without affecting further treatment.
2. Progressive disease as defined by the RECIST criteria is confirmed by imaging and the
investigator's determination that the patient no longer benefits from the study drug
treatment.
3. Any AE that meets the discontinuation criteria specified in the dose adjustment and
toxicity management guidelines.
4. The investigator or AstraZeneca considered that non-compliance with the study protocol
required discontinuation of the study medication (e.g., refusal to comply with the planned
visit).
5. Hepatic arterial infusion chemotherapy becomes technically infeasible.
6. Pregnancy or planned pregnancy.
3.5 End of study definition
The end of study is defined as the last follow up/contact of the last participant.
The investigator will withdraw all subjects from the study if the study is terminated. If
AstraZeneca judge that the study patient may be at excessive risk due to a clinically significant
finding, the study should be stopped.
4. PATIENT SELECTION
Patients who meet all of the following inclusion criteria and do not meet any exclusion criteria
in screening tests and then observations within 30 days before enrollment will be included in the
study. In this protocol, patients who do not meet the inclusion requirements are regarded as
screening failure, and the enrolled patients are defined as patients who sign informed consent.
4.1 Inclusion criteria
For inclusion in the study patients must fulfill all of the following criteria:
1.
Provided written informed consent to participate in the study before the start of the
study.

2.
Age > 18 years at time of study entry.
3.
Diagnosis of HCC based on the diagnostic criteria for HCC used by the European
Association for the Study of the Liver (EASL).
4.
At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion
(TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic
resonance imaging (MRI) must be performed within 30 days prior to screen.
5.
HCC with PVTT3-4 patients who meet any of the following criteria are considered to
have HCC with PVTT:
a) Biopsy-confirmed HCC. Ultrasound-guided percutaneous tumor biopsy is
performed with a gauge needle.
b) HCC and PVTT confirmed by two image techniques, including contrast-enhanced
ultrasound, dynamic contrast-enhanced computerized tomography and dynamic
contrast-enhanced magnetic resonance imaging.
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7.
Body weight >30 kg.
8.
Disease not amenable to curative surgery or transplantation or patient refuse for
surgery.
9.
No cirrhosis or cirrhotic status of Child-Pugh class A-B7.
10. Adequate normal organ and marrow function as defined below:

Haemoglobin ≥8.5 g/dL

Absolute neutrophil count (ANC) ≥1.5 × 109 /L

Platelet count ≥50 × 109/L

Serum total bilirubin ≤2.0 x institutional upper limit of normal (ULN).

AST (SGOT)/ALT (SGPT) ≤5 x institutional upper limit of normal.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN.

Serum creatinine clearance (CL) ≥30 mL/min or by the Cockcroft-Gault formula
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)
11. 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.
12. Must have a life expectancy of at least 12 weeks.
13. 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).
14. Patients with HBV infection, which is characterized by positive hepatitis B surface
antigen (HBsAg) and/or hepatitis B core antibodies(anti-HBcAb) 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 ≤104 IU/mL) prior to randomization. Patients must remain on antiviral
therapy for the study duration and for 6 months after the last dose of study medication.

Patients who test positive for anti-hepatitis B core (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 randomization. These subjects will be 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.
15. Patients with HCV infection must have management of this disease per local
institutional practice throughout the study. HCV diagnosis is characterized by the
presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon
enrollment.
4.2 Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Evidence of hepatic decompensation including moderate ascites, gastrointestinal
bleeding or hepatic encephalopathy.
2. 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.
3. Known history of human immunodeficiency virus (HIV) or organ allograft. 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]).
4. Known or suspected allergy to the investigational agents or any agent given in
association with this trial.
5. Patients with clinically significant gastrointestinal bleeding within 30 days prior to
study entry or evidence of bleeding diathesis.

6. Known central nervous system tumors including metastatic brain disease.
7. Patients who are pregnant or breastfeeding.
8. History of another primary malignancy except for
a)
Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of IP and of low potential risk for recurrence
b)
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
c)
Adequately treated carcinoma in situ without evidence of disease.
9. Patient who had received anti PD-1, anti PD-L1 or anti CTLA-4 treatment before the
first IP administration.
10. Previous history of HAIC treatment.
11. Previously received systemic anti-cancer therapy for HCC. Any biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-
related conditions (e.g., hormone replacement therapy) is acceptable.
12. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:
a)
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular
injection)
b)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
c)
Steroids as premedication for hypersensitivity reactions.
13. Live attenuated vaccine was inoculated 30 days before the first IP administration. (If
enrolled, patients should not be inoculated live attenuated vaccine during IP treatment
and within 30 days after the last IP administration.)
4.3 Withdrawal of patients from study treatment and/or study
Permanent discontinuation of study treatment
Discontinuation of study treatment, for any reason, does not impact the patient’s participation
in the study. A patient who decides to discontinue IP will always be asked about the reason(s) for
discontinuation and the presence of any AE. The patient should continue attending subsequent
study visits, and data collection should continue according to the study protocol. If the patient
does not agree to continue in-person study visits, a modified follow-up must be arranged to
ensure the collection of endpoints and safety information. This follow-up could be a telephone

contact with the patient, a contact with a relative or treating physician, or information from
medical records. The approach taken should be recorded in the medical records. A patient that
agrees to modified follow-up is not considered to have withdrawn consent or to have withdrawn
from the study.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason,
will be identified as having permanently discontinued treatment. Patients who are permanently
discontinued will enter survival follow-up (see the SoAs).
Patients who permanently discontinue drug for reasons other than objective RECIST disease
progression should continue to have RECIST scans performed Q6W from week0, Q2M from 6
month, Q3-6M from 1 year and depends on investigator’s decision.
If a patient is discontinued for RECIST 1.1-defined progression, then the patient should have
1 additional follow-up scan performed preferably at the next (and no later than the next)
scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD.
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone as
indicated in the SoAs as an alternative.
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the
time the study is completed, such that there is insufficient information to determine the patient’s
status at that time. Patients who refuse to continue participation in the study, including telephone
contact, should be documented as “withdrawal of consent” rather than “lost to follow-up.”
Investigators should document attempts to re-establish contact with missing patients throughout
the study period. If contact with a missing patient is re- established, the patient should not be
considered lost to follow-up and evaluations should resume according to the protocol.
In order to support key end points of OS analyses, the survival status of all patients in the full
analysis and the safety analysis sets should be re-checked, this includes those patients who
withdrew consent or are classified as “lost to follow up.”

•Lost to Follow up – site personnel should check hospital records, the patients’ current
physician, and a publicly available death registry (if available) to obtain a current survival
status. (The applicable CRF modules will be updated.)
•In the event that the patient has actively withdrawn consent to the processing of their
personal data, the survival status of the patient can be obtained by site personnel from
publicly available death registries (if available) where it is possible to do so under
applicable local laws to obtain a current survival status. (The applicable CRF modules will
be updated.)
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 (eg, survival contact
telephone calls)
•Withdrawal to the use of any samples

4.4 Premature Termination of Study/Closure of Center
The investigator has the right to close the study, at any time, although this should occur only
after consultation between involved parties.
If there is a reasonable reason and has been fully informed before the expected suspension, the
investigator can start the closure procedure of the study/center at any time.
The reasons for the closure of the study/center by the investigator/sponsor may include but are
not limited to:
• Lack of patients recruited by investigator.
•The investigator failed to comply with protocol, ethics committee/institutional review
board or local health department requirements, sponsor procedures or the criterions for the
quality control of clinical trial of drugs.
•Suspension of further research intervention.
5. TREATMENT PLAN
5.1 Treatments to be Administered
5.1.1 Investigational Product(s)
Durvalumab
Formulation/packaging/storage
Durvalumab will be supplied by AstraZeneca as a 500 mg vial or 120 mg vial concentrate for
solution
for
infusion.
The
solution
contains
50
mg/mL
durvalumab,
26
mM
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v)
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The label-claim volume is 10
mL. Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from
visible particles.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Any
excursions outside to the intended storage conditions is to be reported. Investigational product
must be kept in original packaging until use to prevent prolonged light exposure.
Preparation of durvalumab doses for administration with an IV bag

The dose of durvalumab for administration must be prepared by the Investigator’s or site’s
designated IP manager using aseptic technique.
Total time from needle puncture of the
durvalumab vial to the start of administration must not exceed:
• 24 hours at 2°C to 8°C (36°F to 46°F)
• 4 hours at room temperature
If the final product is stored at both refrigerated and ambient temperatures, the total time must
not exceed 24 hours. A dose of 1120 mg will be administered during HAIC + durvalumab
treatment using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final
durvalumab concentration ranging from 1 to 15 mg/mL and delivered through an IV
administration set with a 0.2- or 0.22-μm filter. Add 22.4 mL (i.e. 1120 mg) of durvalumab to
the IV bag. The IV bag size should be selected such that the final concentration is within 1 to 15
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
After the last cycle of HAIC, a durvalumab dose of 1500 mg (for participants >30 kg in weight)
will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a
final durvalumab concentration ranging from 1 to 15 mg/mL and delivered through an IV
administration set with a 0.2- or 0.22-μm filter. Add 30 mL (i.e. 1500 mg) of durvalumab to the
IV bag. The IV bag size should be selected such that the final concentration is within 1 to 15
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
If patient weight falls to ≤30 kg during whilst receiving 1500 mg dose, weight-based dosing at
20 mg/kg will be administered using an IV bag size selected such that the final concentration is
within 1 to 15 mg/mL.
Standard infusion time is one hour, however if there are interruptions, the total allowed time
must not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose is administered.
Infusion time does not include the final flush time.

If either preparation time or infusion time exceeds the time limits a new dose must be prepared
from new vials. Durvalumab does not contain preservatives, and any unused portion must be
discarded.
Procedure of HAIC
For HAIC, a micro-catheter was inserted and located in common hepatic artery or proper
branch (feeding artery). An arterial catheter was inserted using an image-guided procedure
through the femoral artery. Firstly, the femoral artery was percutaneously punctured using the
Seldinger technique. Then, the catheter was inserted to the celiac trunk or superior mesenteric
artery for arteriography. When more than one feeding artery of HCC was detected, the smaller
arteries were embolized with gelatin sponge particles. A micro-catheter was inserted through the
arterial catheter and located at the common hepatic artery or proper hepatic arterial branch
(feeding artery). When blood flow into the gastroduodenal artery was confirmed by micro-
catheter angiography, the route was embolized with a coil or micro-coil to prevent reflux of
chemotherapeutic drugs to the stomach and duodenum. The peripheral end of the micro-catheter
was locked with a heparin lock (10 ml, 10,000 units, 1: 1,000 dilution) to prevent clotting of the
catheter. The peripheral part of catheter that exposing to outside of body was covered with
medical sterile gauze and fastened on the skin of thigh using medical rubberized fabric and
bandage. Medication was started within 2 days after catheter insertion. After treatment, catheters
were removed from patient’s body. Catheter insertion was repeatedly performed before every
cycle of treatment. Medication was started within 2 days after catheter insertion. The therapeutic
scheme (See Figure 2) was modified FOLFOX6 including oxaliplatin (130 mg/m2 infusion for 3
hours on day 1), leucovorin (200 mg/m2 from hour 3 to 5 on day 1) and Fluorouracil (400
mg/m2 bolus, and then 2400 mg/m2 continuous infusion 46 hours). All drugs were given by
hepatic arterial infusion.
Figure 2. Treatment schedule of HAIC.

Durvalumab doses
In this study, patients will receive intravenous infusion of 1120 mg durvalumab q3w, starting
treatment no earlier than 3±2 days after the first HAIC treatment and continued until the last
HAIC cycle:
1. The initial dose of durvalumab will be given at least 3±2 days after the first HAIC treatment.
2. Durvalumab monotherapy will begin at least 14 days after the completion of the last cycle
HAIC until progressive disease, intolerable toxicity, withdrawal of informed consent, or
compliance with other discontinuation criteria. When switching from 1120 mg q3w to 1500
mg durvalumab q4w, at least 14 days interval will be allowed between two doses of
durvalumab. See Figure 3.The 14 days interval provides investigator with flexibility to
switch to monotherapy as soon as possible after the last HAIC cycle. If durvalumab
monotherapy is not initiated within the last 7 weeks of HAIC treatment, the AstraZeneca
research team or research physician should be contacted and delayed clinical reasons should
be provided.
3. Patients whose weight falls to 30 kg or below (≤30 kg) whilst receiving 1500 mg durvalumab,
should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W until the
weight improves to >30 kg, at which point the patient should start receiving the fixed dosing
of durvalumab 1500 mg.

Figure 3. HAIC + Durvalumab Combined Therapy Dosing Schedule
Note:
HAIC*: Oxaliplatin 130 mg/m2 for 3 hours on day 1; leucovorin 200 mg/m2 from hour 3 to 5 on
day 1; fluorouracil 400 mg/m2 in bolus, and then 2400 mg/m2 continuous infusion over 46 hours.
Durva#: Patients will receive 1120 mg durvalumab via intravenously infusion q3w during HAIC
treatment.
Durva&: Patients will receive durvalumab monotherapy (1500 mg durvalumab q4w) after the
completion of the last cycle HAIC until progressive disease, intolerable toxicity, withdrawal of
informed consent, or compliance with other discontinuation criteria.
5.1.2 Duration of treatment and criteria for treatment through progression
All treatment will be administered beginning on Day 1 until clinical progression or RECIST 1.1-
defined radiological progression (refer to Appendix 14.2) unless there is unacceptable toxicity,
withdrawal of consent, or another discontinuation criterion is met (Section 4.3).
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined
PD may continue to receive study treatment at the discretion of the Investigator and patient as
long as they are deemed to be receiving clinical benefit. A follow-up scan is to be collected after
the initial RECIST 1.1 defined PD, 4-8 weeks after the prior assessment of PD, and this follow-
up scan is evaluated using the post-progression evaluation criteria outlined. Patients with PD
who continue to receive IP at the discretion of the Investigator and patient can receive treatment
until they are no longer deemed to be receiving clinical benefit, and image acquisitions and
tumor assessments should continue on their regular imaging schedule for the duration of
treatment.

Patients with rapid tumor progression or with symptomatic progression that requires urgent
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor
compression, or spinal cord compression) will not be eligible for continuing durvalumab.
Crossover within the study will not be permitted.
Patients who meet RECIST 1.1-defined PD may undergo retreatment as described below:
Patients who complete the 4-8 dosing cycles of the combination of HAIC and
durvalumab portion of the regimen (with clinical benefit per Investigator judgment),
but subsequently have evidence of RECIST 1.1 defined PD, during the durvalumab
monotherapy portion of the combination regimen may restart treatment with the
combination.
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end
of the 12-month treatment period may restart their assigned treatment (HAIC +
durvalumab combination therapy) with the combination upon evidence of RECIST 1.1
defined PD that occurs during the 12 months follow-up period.
For all patients who are treated through progression and for patients who are restarting HAIC +
durvalumab combination therapy, the Investigator should ensure that:

The patient does not have any significant, unacceptable, or irreversible toxicities that
indicate continuing treatment will not further benefit the patient. The patient may not
have experienced a toxicity that required permanent discontinuation of study treatment.

There is absence of clinical symptoms or signs indicating clinically significant disease
progression accompanied by a decline in ECOG performance status to >1

There is absence of rapid disease progression or threat to vital organs or critical
anatomical sites (eg, central nervous system metastasis, respiratory failure due to tumor
compression, or spinal cord compression) requiring urgent alternative medical
intervention

The patient still fulfills the eligibility criteria for this study (see Section 4.1 and 4.2) with
the exception of inclusion criteria and exclusion criteria (eg, 10 and 11 teams)

Patients who AstraZeneca and the Investigator determine may not continue treatment after
RECIST 1.1-defined PD will be followed up for survival. Patients who have discontinued
treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent
anticancer therapy, will be followed up with tumor assessments until RECIST 1.1-defined PD
plus an additional follow-up scan or until death (whichever comes first) and followed for
survival.
5.2 Dose modification
5.2.1 FOLFOX regimen
If a subject experience several toxicities and there are conflicting recommendations, the
recommended dose adjustment that reduces the dose to the lowest level will be used. Dose
reduction of FOLFOX regimens (to 80% of dose) was allowed in cases of intolerable (grade 3 or
4) drug related toxicities including neutropenia or thrombocytopenia, diarrhoea despite the use of
antidiarrheics, fever, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and
creatinine elevation that did not recover to normal level within one treatment cycle, and
peripheral sensory neuropathy. Dose delays were only allowed within 1 week after the date of a
regularly scheduled treatment. If further dose reduction is required, the subject should be
discontinued from the study. Disease assessment and imaging scan were undertaken according to
the original study protocol, regardless of dose delays.
5.2.2 Durvalumab of dose administration
Patients will be monitored before, during and after the infusion with assessment of vital signs
at the times specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood
pressure) every 30 minutes during the infusion period (including times where infusion rate is
slowed or temporarily stopped).
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at
50% of the initial rate until completion of the infusion. For patients with a ≤Grade 2
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per
institutional standard may be administered at the discretion of the investigator. If the
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The

standard infusion time is one hour, however if there are interruptions during infusion, the total
allowed time from infusion start to completion of infusion should not exceed 8 hours at room
temperature (otherwise requires new infusion preparation). For management of patients who
experience an infusion reaction, please refer to the toxicity and management guidelines (See
Section 8.14.7).
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs
and medical equipment to treat acute anaphylactic reactions must be immediately available, and
study personnel must be trained to recognize and treat anaphylaxis. The study site must have
immediate access to emergency resuscitation teams and equipment in addition to the ability to
admit patients to an intensive care unit if necessary.
For dosing modification and toxicity management guidelines for immune-mediated, infusion-
related, and non-immune-mediated reactions of Durvalumab therapy, see detail in toxicity and
management guidelines for durvalumab.
5.3 Concomitant treatment(s)
Patient should inform the investigator as soon as possible of all drugs taken from the study
screening period to clinical treatment, including the 90 days follow-up period after the last IP
administration.
Any drugs (including over-the-counter, prescription or herbal health products) received by the
patient during the registration period or during the study period, as well as the reason for use, the
date of administration (including the start and end dates), and the administration information
(including dose, unit and frequency) must be recorded.
Patients should not take any drugs, including over-the-counter drugs, without consulting the
investigator.
5.3.1 Drug interactions
To date, there is no data on drug-drug interactions in durvalumab preclinical or clinical studies.
Due to the fact that durvalumab is mAb, i.e. protein drugs, it can be degraded into small
molecular peptides and amino acids, which are excreted through the clearance of kidney and
reticuloendothelial system. Therefore, durvalumab is not expected to induce or inhibit the
cytochrome P450 pathway, a major drug metabolizing enzyme. Therefore, no pharmacokinetic

drug interactions are expected. Durvalumab MoA includes binding to PD-L1 and therefore no
significant pharmacodynamic drug interactions are expected with common combinations. In
addition, appropriate clinical monitoring will be conducted in all planned clinical studies to
assess any potential drug interactions.
5.3.2 Permitted concomitant medications
Table 4. 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 above
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
Additional
HAIC
treatment
according
to
the
specific conditions of the disease.
Permission
after
consulting
the
investigator and sponsor.
Inactivated viruses, such as those in the influenza
vaccine
Permitted
5.3.3 Excluded concomitant medications
Table 5. Prohibited Concomitant Medications
Prohibited medication/class of drug:
Usage:

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.).

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
6. ASSESSMENT OF EFFICACY
6.1 Imaging examination schedule
Within 30 days before enrollment, radiologic examination, which includes chest / abdomen /
pelvic dynamic contrast-enhanced CT / MRI, is needed to evaluate the baseline tumor size and
improve tumor staging. A bone scan should also be obtained if bone metastases are suspected per
standard of care procedures and investigators’ discretion.
During the combined treatment period, subjects will have study visits on Day 1 of every cycle
(every 3 weeks from start of study), At the stage of durvalumab monotherapy, subjects will have
study visits on Day 1 of every cycle (repeated every 4 weeks). Tumor assessment by CT/MRI
will be performed by Q6W from week0, Q2M from 6 month, Q3-6M from 1year and depends on
investigator’s decision.
6.2 Image acquisition and evaluation
All Images (including other hospital scans) will be continuously collected and stored.

6.3 Tumor assessment
The primary efficacy endpoint was one-year overall survival rate in the full-analysis-set (FAS)
population. Progression free survival (PFS) is one of the secondary efficacy endpoints, which is
defined as from time of treatment until disease progression or death according to RECIST 1.1
criteria (refer to Appendix 14.2). Objective response rate (ORR) evaluations will be based on
made by CT/MRI imaging, Q6W from week0, Q2M from 6 month, Q3-6M from 1year and
depends on investigator’s decision.
6.4 Survival tracking
After study drug treatment ends, subjects will be contacted every 2 months to determine
survival status if this was not reached at the time of the primary end point analysis. If the subject
has received any subsequent anti-cancer therapy following end of treatment, details should be
collected. Post study follow up will end at last overall survival (OS) analysis.
If a subject discontinues due to an adverse event or clinical laboratory abnormality, the subject
should be followed-up until the event resolves, the subject stabilized, or 30 days, whichever is
shorter. If a subject die within 30 days of the last dose of study treatment, the SAE
complementary form should be completed in the usual.
6.5 Clinical efficacy evaluation
Quality of Life(QOL) Questionnaire will designed by Investigator, which will be collected
and assessed in this study. During HAIC+Durvalumab treatment, will assessed Q4W, during
durvalumab monotherapy, will be collected every 8 weeks(two treatment cycle).
6.6 Biological sample analysis
6.6.1 Blood sample
Blood samples will not be collected and analysed by any testing institution but only tested in
the study site.
6.6.2 Tissue sample
Tissue Samples at Screening. If available, archival tissue samples will be obtained at baseline
for exploratory research on PD-L1 expression level. A representative FFPE tumor specimen in a
paraffin block is preferred, or approximately 3 slides containing unstained, freshly cut, serial

sections along with an associated pathology report. Samples collected via resection is
preferred. Core-needle biopsy is acceptable. If no available archival tissue sample at baseline, an
optional screening biopsy may be performed. The Informed Consent Form will contain a
separate section that addresses this optional screening biopsy. A separate, specific signature will
be required to document a patient's agreement to undergo optional biopsies.
7. ASSESSMENT OF SAFETY
7.1 Physical examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs).
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
observations and symptomatology. Situations in which physical examination results should be
reported as AEs are described in Section 8.8.
7.2 Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated
according to the SoAs. Body weight is also recorded at each visit along with vital signs.
First infusion of durvalumab
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 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)
•
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.
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.
Vital sign results should be reported as AEs are described in Section 8.8. For all infusion related
AEs, vital signs should be recorded in eCRF.
7.3 Electrocardiogram
Resting 12-lead ECGs will be recorded at screening 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.
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 (eg, 30 minutes) to confirm the
finding.
Situations in which ECG results should be reported as AEs are described in Section 8.8.
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.
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 8.8.
7.4 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 the
SoAs).

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. Pregnancy tests
may be performed at the site using a licensed test (urine or serum pregnancy test). If possible, all
pregnancy outcomes (spontaneous abortion, selective termination of pregnancy, ectopic
pregnancy, normal delivery or congenital malformations) occurring between the first
administration date and 90 days after the last IP administration should be followed up and
recorded. 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 6 (hematology), Table 7 (clinical
chemistry), and Table 8 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface antigen,
hepatitis C antibodies, and HIV antibodies.
Note: HBV positive patients must continue to receive antiviral treatment during the period of
study and within 6 months after the last administration.
The following laboratory variables will be measured:
Table 6. Hematology Laboratory Tests
Hemoglobin
Platelet count
Absolute lymphocyte a
Total white cell count
Absolute neutrophil count a
Note: For coagulation parameters, activated partial thromboplastin time and international
normalized ratio are to be assessed at baseline on Day 0 (unless all screening laboratory
haematology assessments are performed within 3 days prior to Day 0), and as clinically
indicated.

a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by
DM if entered as percentage. Total white cell count therefore has to be provided.
Table 7. Clinical Chemistry (Serum or Plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium
Total bilirubin a
Chloride
Total protein
Creatinine
Urea or blood urea nitrogen, depending on local
practice
Gamma glutamyltransferase b
Thyroid-stimulating hormone e
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 baseline, on Day 0 (unless all screening
laboratory clinical chemistry assessments are performed within 3 days prior to Day 0), and if
clinically indicated.
d Creatinine Clearance will be calculated by data management using Cockcroft-Gault (using
actual body
weight).
e
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be
repeated at day 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

Table 8. Urinalysis Testsf
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Colour and appearance
f Microscopy should be used as appropriate to investigate white blood cells and use the high-
power field for red blood cells
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
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 8.8. Elevated transaminase is usually observed after HAIC
treatment. Therefore, investigator should take it into account when determining the causal
relationship.
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.
7.5 ECOG performance status
ECOG performance status will be assessed at the times specified in the assessment schedules
(see the SoAs) based on the following criteria (refer to Appendix 14.3).
7.6 Child-Pugh classification
The severity of liver cirrhosis is determined by Child-Pugh score, and the results are recorded in
eCRF according to the requirements of SoA. For specific Child-Pugh classification methods,
please refer to Appendix 14.4.

7.7 Gastroscopy
Gastroscopy should be assessed during the whole study, to determine whether patients have
gastrointestinal erosion, ulcers, bleeding, also to evaluate the risk of adverse events like
gastrointestinal bleeding. Gastroscopy should be performed before first HAIC or no later than 2
weeks after first HAIC, and before 5th HAIC or no later than 2 weeks after. During durvalumab
monotherapy, should be performed every 3-6 months.
7.8 Other safety assessments
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing
Modification and Toxicity Management Guidelines (See Section 8.14.7) 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 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.

SpO2

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan

(ii)
Tumor markers: Particular tumor markers which are related to disease
progression.
Additional Clinical chemistry: CRP, LDH
Safety parameters
8. ADVERSE EVENTS
8.1 Adverse Event Definitions
8.1.1 Adverse events
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation patient administered a
pharmaceutical product and which does not necessarily have a causal relationship with this
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the use of a medicinal
product, whether or not considered related to the medicinal product.
An AE includes but is not limited to any clinically significant worsening of a patient’s
pre- existing condition. An abnormal laboratory finding (including ECG finding) that requires an
action or intervention by the investigator, or a finding judged by the investigator to represent a
change beyond the range of normal physiologic fluctuation, should be reported as an AE.
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom,
disease, or other untoward medical event that begins after written informed consent has been
obtained but before the patient has received investigational product.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the
patient being enrolled into the study) for a documented pre-existing condition, that did not
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical
event occurring during the prescheduled elective procedure or routinely scheduled treatment
should be recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.

8.1.2 Adverse drug reaction
An Adverse Drug Reaction (ADR) is an Adverse Event suspected to be causally related to the
medicinal product.
An ADR is a response to a medicinal product which is noxious and unintended. Adverse
reactions may arise from use of the product within or outside the terms of the marketing
authorization or from occupational exposure.
8.1.3 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

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect in offspring of the patient

Is an important medical event that may jeopardize the patient or may require medical
intervention to prevent one of the outcomes listed above.

Medical or scientific judgment should be exercised in deciding whether expedited
reporting is appropriate in this situation. Examples of medically important events are
intensive treatment in an emergency room or at home for allergic bronchospasm,
blood dyscrasias, or convulsions that do not result in hospitalizations; or development
of drug dependency or drug abuse.

Adverse Events (AEs) for malignant tumours reported during a study should
generally be assessed as Serious AEs. If no other seriousness criteria apply, the
‘Important Medical Event’ criterion should be used. In certain situations, however,
medical judgement on an individual event basis should be applied to clarify that the
malignant tumour event should be assessed and reported as a Non-Serious AE. For
example, if the tumour is included as medical history and progression occurs during
the study, but the progression does not change treatment and/or prognosis of the
malignant tumour, the AE may not fulfill the attributes for being assessed as Serious,
although reporting of the progression of the malignant tumor as an AE is valid and

should occur. Also, some types of malignant tumours, which do not spread remotely
after a routine treatment that does not require hospitalization, may be assessed as Non-
Serious; examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer
removed via cone biopsy.

The above instruction applies only when the malignant tumour event in question is a
new malignant tumour (i.e., it is not the tumour for which entry into the study is a
criterion and that is being treated by the IP under study and is not the development of
new or progression of existing metastasis to the tumour under study). Malignant
tumours that – as part of normal, if rare, progression – undergo transformation (e.g.,
Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large B
cell lymphoma) should not be considered a new malignant tumour.
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by
the investigator(s) and communicated to AstraZeneca.
8.1.4 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. An AESI may be
serious or non-serious.
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 include:

Diarrhea / Colitis and intestinal perforation

Pneumonitis / ILD

hepatitis / transaminase increases

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

Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)

Other inflammatory responses that are rare/less frequent with a potential immune-mediated
etiology include, but are not limited to:

Pericarditis

Sarcoidosis

Uveitis

Other events involving the eye and skin

Hematological events

Rheumatological events

Vasculitis

Non-infectious meningitis

Non-infectious encephalitis.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different
underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (e.g. presenting symptoms) can be found in the current version
of the durvalumab Investigator’s Brochure. More specific guidelines for their evaluation and
treatment are described in detail in the Dosing Modification and Toxicity Management
Guidelines (See Section 8.14.7).These guidelines have been prepared by the Sponsor to assist 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.
8.2 Adverse Event Collections
8.2.1 Collection mode
AE and/or SAE will be reported by the patient (or caregiver, agent/legally authorized
representative as appropriate). When collecting AE and/or SAE, open and non-guided oral
questioning should be preferred to avoid bias.
8.2.2 Collection schedule
AEs and SAEs will be actively collected from the time of the patient signing the informed
consent form until the safety follow-up period is completed (90 days after the last dose of
durvalumab). In the survival follow-up period, AEs related to AZ products will be reported
spontaneously by investigators to AZ. If an event that starts post the defined safety follow up

period noted above is considered to be due to a late onset toxicity to study drug then it should be
reported as an AE or SAE as applicable.
After the patient has been permanently withdrawn from the study, there is no obligation for the
investigator to actively report information on new AE or SAEs occurring in former study patients.
However, if an investigator learns of any SAEs, including death, at any time after the patient has
been permanently withdrawn from study, and he/she considers there is a reasonable possibility
that the event is related to study treatment, the investigator should notify the study sponsor.
8.2.3 Follow up and collection
During the course of the study, all AEs and SAEs should be proactively followed up for each
patient for as long as the event is ongoing. Every effort should be made to obtain a resolution for
all events, even if the events continue after the patient has discontinued study drug or the study
has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the
Investigator for as long as medically indicated, but without further recording in specify where
this information will be recorded e.g. eCRF.
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.
8.3 Assessment of severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs
and SAEs. The grading scales found in the National Cancer Institute CTCAE 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
CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer
Therapy Evaluation Program website (http://ctep.cancer.gov).
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 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 8.1.2. 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.
8.4 Recording of adverse events and serious adverse events
The following variables will be collected for each AE:
In addition, the following variables will be collected for SAEs 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 (See Section 8.5)

Description of the SAE
The grading scales found in the 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
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).
8.5 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.”
8.6 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.

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.
8.7 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 specify where this
information will be recorded e.g. 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.
8.8 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.
8.9 Hy’s Law
Not applicable for this study.
8.10 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.
8.11 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.

8.12 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 follows:

Death clearly resulting from disease progression should be reported to the Study
Monitor/Physician at the next monitoring visit and should be documented in the specify
where this information will be recorded e.g. eCRF in the Statement of Death page. It
should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the
AE causing the death must be reported to the Study Monitor/Physician as an SAE within
24 hours. It should also be documented in the Statement of Death page in specify where
this information will be recorded e.g. eCRF.

Deaths with an unknown cause should always be reported as an SAE. It should also be
documented in the Statement of Death page in specify where this information will be
recorded e.g. eCRF.

A post mortem may be helpful in the assessment of the cause of death, and if performed,
a copy of the post-mortem results should be forwarded to AstraZeneca Patient Safety.
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 Statement of Death page. 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.
8.13 Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure,
it is recommended that the patients continue the scheduled site visits and Investigators monitor
the patient’s safety laboratory results prior to and periodically during treatment with durvalumab
in order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity
Management Guidelines (See Section 8.14.7). All data post the final DCO and database closure
will be recorded in the patient notes but, with the exception of SAEs, will not otherwise be
reported for the purposes of this study.

All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days
following the last dose of durvalumab treatment) post the final DCO and database closure must
be reported.
8.14 Safety reporting and medical management
8.14.1 Reporting of Adverse Events
The investigators are responsible for informing the EC and the Regulatory Authority of the
adverse events as per China regulations.
The investigators are also responsible for reporting all SAEs within 24 hours after awareness to
AZ Data Entry site and reporting non-serious ADRs related to Durvalumab to AZ Data Entry
Site within 5 calendar days after awareness. Investigators should report AESIs which is also a
SAE within 24 hours and within 5 calendar days for AESIs of non-serious ADRs (AESIs of
Durvalumab).
For all SAEs and non-serious ADRs (related to Durvalumab)where important or relevant
information is missing, active follow-up is undertaken immediately. Investigators or other site
personnel inform AstraZeneca of any follow-up information on a previously reported SAE/ non-
serious ADR (related to Durvalumab) within the same timeframe as initial reports of when he or
she becomes aware of it.
Contact information of AZ Data Entry Site:
E-mail: AEMailboxClinicalTrialTCS@astrazeneca.com
Fax: +1 302 886 4114
8.14.2 Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received durvalumab.
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca’s designated fax
line: +1 302 886 4114 or email: AEMailboxClinicalTrialTCS@astrazeneca.com if a secure line
is set up.

8.14.2.1 Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should be discontinued
immediately.
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.
8.14.3 Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for
180 days after the last dose of HAIC + durvalumab 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 HAIC + durvalumab 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.
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca’s designated fax
line: +1 302 886 4114 or email: AEMailboxClinicalTrialTCS@astrazeneca.com if a secure line
is set up.
8.14.4 Toxicity management guidelines
Following general guidelines for toxicity management:
1. Use maximum supportive treatment to deal with each toxicity, if applicable, suspend IP
causing toxicity. If symptoms are relieved, consider continuing to administer IP and continuing
supportive treatment. Dosage adjustment is allowed if medically applicable.

2. All dose adjustments should clearly document the reasons and methods.
All toxicities will be graded according to NCI CTCAE, Version5.0.
Durvalumab
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and
non-immune-mediated reactions for durvalumab are provided in the Toxicity Management
Guidelines (see section 14.5).
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic,
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially
immune related.
In addition, there are certain circumstances in which durvalumab should be permanently
discontinued (see section 4.4.)
Following the first dose of IP, subsequent administration of durvalumab can be modified based
on toxicities observed as described in the Dosing Modification and Toxicity Management
Guidelines. These guidelines have been prepared to assist 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 durvalumab monotherapy by the reporting investigator.
FOLFOX regimen
If a subject experience several toxicities and there are conflicting recommendations, the
recommended dose adjustment that reduces the dose to the lowest level will be used. Dose
reduction of FOLFOX regimens (to 80% of dose) was allowed in cases of intolerable (grade 3 or
4) drug related toxicities (see section 5.2.1).

9. DATA COLLECTION AND MANAGEMENT
9.1 Data Collection
For studies using Electronic Data Capture, the designated investigator staff will enter the data
required by the protocol into the eCRF. Investigator site staff will not be given access to the
Electronic Data Capture (EDC) system until they have been trained. Automatic validation
programs check for data discrepancies in the eCRFs and, allow modification or verification of
the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete,
accurate, and that entry and updates are performed in a timely manner. This includes clinical data
from safety assessments.
9.2 Data Management
For studies using eCRFs, the research group will review the data entered by investigational staff
for completeness and accuracy. Electronic data queries stating the nature of the problem and
requesting clarification will be created for discrepancies and missing values and sent to the
investigational site via the Electronic Data Capture system. Designated investigator site staff are
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification
system. Medical history/current medical conditions and AEs will be coded using the Medical
dictionary for regulatory activities terminology.
10. STATISTICAL METHODS AND DATA ANALYSIS
10.1 Statistical and Analytical Plans
10.1.1Analysis Populations
Efficacy and safety analysis will be performed in a full-analysis-set (FAS) population, which
includes all subjects receiving at least one dose of study treatment.

10.1.2 Baseline and Demographic Characteristics
Baseline and demographic characteristics will be summarized by descriptive statistics.
10.1.3 Primary Efficacy analysis
The OS12 will be defined as the Kaplan-Meier estimate of OS at 12 months. OS12 will be
summarized using the Kaplan-Meier method.
10.1.4 Interim analysis
An interim analysis is planned for the evaluation of safety and efficacy:
The objective of IA is to explore the signal of safety and efficacy. The planned data cut off
(DCO) for IA will occur when at least 50% patients enrolled and follow up for 3m. ORR and
safety will be summarized. If results are unfavorable, the trial may be stopped for futility.
10.1.5 Other Efficacy analysis
Objective Response Rate is defined as the number (%) of patients with measurable disease
with at least 1 visit response of CR or PR. Data obtained up until progression or last evaluable
assessment in the absence of progression will be included in the assessment of ORR. However,
any CR or PR which occurred after a further anti-cancer therapy was received will not be
included in the numerator for the ORR calculation (where the FAS will be the denominator).
Progression-free survival is defined as the time from first dose of treatment until the date of
objective disease progression or death (by any cause in the absence of progression) regardless of
whether the patient withdraws from study therapy or receives another anti-cancer therapy prior to
progression. Patients who have not progressed or died at the time of analysis will be censored at
the time of the latest date of assessment from their last evaluable RECIST assessment.
However, if the patient progresses or dies after 2 or more missed visits, the patient will be
censored at the time of the latest evaluable RECIST assessment. If the patient has no evaluable
visits or does not have baseline data, they will be censored at 0 days unless they die within 2
visits of baseline.

Overall survival is defined as the time from the date of first dose of treatment in this study
until death due to any cause. Any subject not known to have died at the time of analysis will be
censored based on the last recorded date on which the subject was known to be alive.
Time-to-event data (PFS, OS) will be summarized using Kaplan-Meier estimates of the
median event time and quartiles together with their 95% Cis, given the maturity of 60%.The
Kaplan-Meier curves will be provided.
10.1.6 Safety analysis
Descriptive summary tables will be presented on all safety parameters. Subjects will be
monitored for adverse events using the NCI-CTCAE version 5.0. Treatment-emergent adverse
events drug-related adverse events, procedure-related, SAE, AESI and safety laboratory
parameters will be summarized CTC grade.
10.1.7 Biomarker analysis
1) Archived tumor biopsy:

patients’ tumor biopsy will be used to test transcriptomic sequencing, the summary the
result to analyzed the relationship between clinical efficacy(OS, PFS, ORR) with
different gene expression and molecular pathways.

PD-L1 testing outcome will be listed individually for each patient and summarized
according to the status (Positive\Negative\Not Evaluable). Clinical efficacy (OS, PFS and
ORR) will be summarized by PD-L1 expression status.
2) Archived/fresh Serum and peripheral blood mononuclear cells(PBMC)

Serum samples from patients will be evaluated by protein detection methods to detect
serum biomarkers related to clinical efficacy.

PBMC samples will be used to detect the phenotypic characteristics of peripheral immune
cells to 0065plore the relationship between clinical efficacy and specific immune cell
subpopulations in peripheral blood.

10.2 Determination of sample size
To determine the appropriate sample size, we used a one-stage binomial design with a one-
sided alpha level of 0.05 and statistical power of 80%. Previous studies have reported a median
OS of approximately 7.6 months in high-risk HCC patients treated with atezolizumab plus
bevacizumab, corresponding to an estimated 1-year OS rate of 35%6,25. We hypothesized that
the combination of hepatic arterial infusion chemotherapy (HAIC) and durvalumab would
improve the 1-year OS rate to 60%. Assuming an anticipated dropout rate of 10%, the target
sample size was set at 30 patients.
11. USE OF DATA AND PUBLICATION
All data and results and all intellectual property rights in the data and results derived from the
study will be the property of the sponsor, who may utilize the data in various ways, such as for
submission to government regulatory authorities or disclosure to other investigators. The
investigator, whilst free to utilize data derived from the study for scientific purposes, must
discuss any publication with the sponsor prior to release and obtain written consent of the
sponsor on the intended publication. The sponsor recognizes the right of the investigator to
publish the results upon completion of the study. However, the investigator must send a draft
manuscript of the publication or abstract to the sponsor thirty days in advance of submission in
order to obtain approval prior to submission of the final version for publication. This will be
reviewed promptly and approval will not be withheld unreasonably. In case of a difference of
opinion between the sponsor and the investigator(s), the contents of the publication will be
discussed in order to find a solution which satisfies both parties.
12. ETHICAL CONSIDERATIONS
12.1 Ethics Committee (EC) or Institutional Review Board (IRB)Ethics and
regulatory review
Documented approval from appropriate independent Ethics Committee(s)/IRBs will be obtained
for all participating centers/countries prior to study start, according to GCP, local laws,
regulations and organizations. When necessary, an extension, amendment or renewal of the
Ethics Committee approval must be obtained and also forwarded to the sponsor. The Ethics

Committees must supply to the sponsor, upon request, a list of the Ethics Committee members
involved in the vote and a statement to confirm that the Ethics Committee is organized and
operates according to GCP and applicable laws and regulations.
12.2 Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation
of this study, are designed to ensure that the sponsor and investigator abide by Good Clinical
Practice Guidelines and under the guiding principles detailed in the Declaration of Helsinki. The
study will also be carried out in keeping with applicable local law(s) and regulation(s). This may
include an inspection by the sponsor representatives and/or Regulatory Authority representatives
at any time. The investigator must agree to the inspection of study-related records by the
Regulatory Authority/sponsor representatives, and must allow direct access to source documents
to the Regulatory Authority/sponsor representatives.
Modifications to the study protocol will not be implemented by either the sponsor or the
investigator without agreement by both parties. However, the investigator may implement a
deviation form, or a change of, the protocol to eliminate an immediate hazard(s) to the trial
subjects without prior EC/IRB/sponsor approval/favorable opinion. As soon as possible, the
implemented deviation or change, the reasons for it and if appropriate the proposed protocol
amendment should be submitted to the EC/IRB/sponsor. Any deviations from the protocol must
be fully explained and documented by the investigator.
12.3 REGULATORY AUTHORITY APPROVALS/AUTHORIZATIONS
Regulatory Authority approvals/authorizations/ notifications, where required, must be in place
and fully documented prior to study start.
12.4 INFORMED CONSENT
A core information and Informed Consent Form will be provided. Prior to the beginning of the
study, the investigator must have the ECs/IRB written approval/favorable opinion of the written
Informed Consent Form and any other written information to be provided to subjects. The

written approval of the EC/IRB together with the approved subject information/Informed
Consent Forms must be filed in the study files.
Written informed consent must be obtained before any study specific procedure takes place.
Participation in the study and date of informed consent given by the subject should be
documented appropriately in the subject’s files.
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14. APPENDICES
14.1 The Barcelona Clinic Liver Cancer (BCLC) staging system
Clinical staging is crucial for risk stratification during cancer management. The BCLC system
are most widely studied and will be assessed at screening for all patients participating in this
study. It includes variables related to tumor stage, liver functional status, physical status and
cancer related symptoms. Only BCLC Stage C HCC patients are eligible for participating in this
study, provided that the patients meet all other eligibility criteria.
Reference: European Association For The Study Of The Liver; European Organisation For
Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of
hepatocellular carcinoma. J Hepatol. 2012 Apr;56(4):908-43. doi: 10.1016/j.jhep.2011.12.001.
14.2 RECIST 1.1 criteria
Complete response is the disappearance of any intratumoral arterial enhancement in all target
lesions; Partial response is at least a 30% decrease in the sum of diameters of viable (contrast
enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the
diameters of target lesions; Progressive disease is 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 the treatment started; Stable disease
is any cases that do not qualify for either partial response or progressive disease.
According to these amendments, progressive disease will also be declared on the appearance
of one or more new lesions, as per RECIST.

A newly detected hepatic nodule will be classified as HCC — and therefore will be declared
as evidence of progression —when its longest diameter is at least 10 mm and the nodule
shows the typical vascular pattern of HCC on dynamic imaging, that is, hypervascularization
in the arterial phase with washout in the portal venous or late venous phase.

Lesions larger than 10 mm that do not show a typical vascular pattern can be diagnosed as
HCC by evidence of at least 1-cm interval growth in subsequent scans.

An individual radiological event will be adjudicated in retrospect as progression at the time
it was first detected by imaging techniques, even if strict criteria were fulfilled only on
subsequent radiological testing.

Finally, for non-enhancing atypical lesions, the conventional RECIST criteria will be
applied.

Reference: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J,
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D,
Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

14.3 ECOG Performance Status Classification
Reference: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T.,
Carbone, P.P. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am
J Clin Onco. 1982; 5:649-655.
14.4 Child–Pugh Classification
Reference: Child CG, Turcotte JG (1964). Surgery and portal hypertension. In: The liver and
portal hypertension. Edited by CG Child. Philadelphia: Saunders:50-64.