A Randomized, Open-label, Multi-center Phase III Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Sponsor: AstraZeneca

Revised Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736) 
and tremelimumab
Study Code
D419CC00002
Edition Number
8.0
Date
17-June-2024
EudraCT Number
2016-005126-11
A Randomized, Open-label, Multi-center Phase III Study of Durvalumab 
and Tremelimumab as First-line Treatment in Patients with advanced
Hepatocellular Carcinoma (HIMALAYA)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
4 (244) 
• Amendment inclusion criteria 10 to indicate HBV DNA detectable level is ≥10 IU/ml 
rather than >10 IU/ml  
• Clarification that only patients with HBV infection (positive HBsAg or detectable HBV 
DNA), must be treated with antiviral therapy to achieve HBV DNA ≤2000 IU/mL prior 
to enrollment, and they must remain on it for the study duration and for 6 months after 
the last dose of study medication.  Patients with hepatitis B core antibodies (anti-HBc 
Ab), but no viral DNA, do not require antiviral treatment.  
• Addition from new protocol template of the inclusion criteria “Must have a life 
expectancy of at least 12 weeks”  
Section 3.2 – Exclusion criteria  
• Amendment to exclusion criteria 12, specifying “clinically meaningful ascites (defined 
as ascites requiring non-pharmacologic intervention eg, paracentesis or escalation in 
pharmacologic intervention to maintain symptomatic control), within 6 months prior to 
the first scheduled dose”, rather than “ascites that require ongoing paracentesis, within 
6 weeks prior to the first scheduled dose to control symptoms.  In addition, in the 
amended exclusion criteria “subjects on stable doses of diuretics for ascites for ≥2 
months are eligible”. 
• Amendment to HBV DNA detectable level from >10 IU/ml to ≥10 IU/ml for exclusion 
criteria 18 
• Rewording of exclusion criteria 18 and 19 to clarify that they are exclusion criteria 
• Qualification for exclusion criteria 22 that a history of, or current, brain metastases will 
constitute an exclusion criteria.  
Section 3.3 – Patient enrollment:  Removal of Interactive Voice Response System as only 
Interactive Web Response System will be used 
Section 3.8 – Restrictions:  Update from new protocol template to the restrictions that 
apply to patients’ contraception, while receiving study drugs, and for the specified times, 
before and after study drug administration  
Section 3.9 – Discontinuation of study drug(s):  Addition from the new protocol template 
of a supplementary condition under which patients will not receive any further study drugs: 
“Clinical progression, ie. Investigator determination that the patient is no longer benefiting 
from treatment with the investigational product (IP), with or without radiological 
progression by RECIST 1.1.” 
Section 3.10.2.1:  Removal of the condition that survival status for patients who are lost to 
follow-up or withdraw consent must be “in the 7 days following data cutoff” 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
6 (244) 
Section 5.1 – Efficacy assessments: Rewording of the text on tumor response to align it 
with the Statistical Analysis Plan and the new protocol template.  In addition, the following 
specific changes were made: 
• While RECIST 1.1 assessments will be performed on CT or MRI, with IV contrast of 
the chest, abdomen, and pelvis, pelvic imaging is only recommended when primary or 
metastatic disease involvement in the pelvic region is likely.   
• During follow-up assessments (Q8W ±1 week for 48 weeks and Q12W ±1 week 
thereafter until confirmed PD), the imaging schedule must be followed regardless of 
any delays in dosing.   
• The text for confirmation of progression guidelines was removed from this section, as 
these guidelines are also presented in Appendix B. 
Section 5.2.1 – Laboratory safety assessments and 5.2.3 - Electrocardiograms:  
Provision that additional safety monitoring for patient receiving sorafenib should be carried 
out as per the label. 
Section 5.4.1 – Collection of PK samples:  The following collection window was added:  
Pre-dose (1 hour) and post-dose (10 minutes post-infusion). 
Section  5.4.1.3 – Collection of samples to measure for the presence of ADAs:  Addition 
of the following: 
• Window for pre-dose sample is 1 hour 
• For some countries, these samples may not be collected depending on their local 
regulatory and ethical requirements. 
Section 5.4.1.4 – Storage and destruction of pharmacokinetic/ADA samples:  Addition 
that PK and ADA samples collected in China will be stored and disposed of according to 
local laws and regulations. 
Section 5.5.1 – Collection of patient samples for analysis of PD-L1 expression: 
• Inclusion that additional archived tissue not intended for PD-L1 testing, and optional 
biopsies obtained at the time of progression or part of clinical care will not be collected 
in China.  Additionally, China study sites will not submit tumor tissue blocks and only 
unstained sections from the tissue block will be submitted for further analysis. 
• Retention of sections of tumor (to meet the FDA requirement for approval of a 
companion diagnostic) can also be kept at the Investigation Use only testing laboratory 
as well as at Ventana.  

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
13 (244) 
Inclusion criteria #13 – added “Note: INR prolongation due to anticoagulants for prophylaxis 
(e.g. atrial fibrillation) in patients without liver cirrhosis could be exception”. 
Section 3.2 Exclusion Criteria 
Exclusion criteria #12 – removed “or escalation in pharmacologic intervention”. 
Exclusion criteria #13 - added clarification for thrombosis -  thrombosis (i.e. thrombosis in 
the main trunk of the portal vein, with or without blood flow) on baseline imaging.   
Exclusion criteria #14 – removed “or assessed as high risk for esophageal variceal by the 
Investigator” 
Exclusion criteria #18 – removed “≥10 IU/ml”.  Clarification added to Appendix I. 
Exclusion criteria #19 – added “inferior vena cava thrombosis”. 
Exclusion criteria #20 – added “Patients with a history of prostate cancer of stage 
≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the 
Investigator are not deemed to require active intervention “. 
Section 3.3 Patient Enrolment and Randomization 
Clarification added to etiology of liver disease – “confirmed” HBV versus “confirmed “HCV 
versus others. 
Updated randomization ratio 
Section 3.9 Discontinuation of Study Drug(s), Section 3.9, Section 5.2.8, Section 6.3.12, 
Section 6.9.1, Section 6.9.3, Section 7.7 
Removal of Appendix F – replaced with reference to Toxicity Management Guidelines 
website https://tmg.azirae.com. Updated appendices lettering accordingly. 
Section 3.10.2.1 Survival status for withdrawn consent and lost to follow-up patients 
Clarified that patients are “potentially” lost to follow-up until the end of the study. 
Table 2 Schedule of assessments for all immunotherapy arms treatment period 
Clarified timeline for C1D1 PRO and tumor collection 
Added row for “randomization” to clarify that this must occur prior to C1D1 
Added “PT” to Coagulation collection 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
15 (244) 
Table 4 Schedule of assessments for patients who discontinue treatment 
Clarification added for collection of PK post discontinuation of IP – in case of a dose delay 
the PK should be collected 3 months from the last dose. 
Removed in appendix I “Either PT or INR can be performed at baseline (screening)”. 
Section 4.1 Screening/enrolment period 
Added clarification for tumor pathology and fibrosis score according to Appendix J 
Added requirement to check eligibility at the date of randomization and if the patient does 
not meet I/E criteria they cannot be randomized.  
Section 5.2.1 Laboratory safety assessments 
Removed the reference to Table 5 and added quantitative HCV RNA as another safety test to 
be performed. 
Table 6 Hematology 
Added total white cell count to hematology with a note for coagulation parameters stating: 
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. 
Added a footnote to absolute lymphocyte count that it should be recorded as an absolute 
count or as a percentage. Percentages will be calculated by DM. 
Table 7 Coagulation 
Add clarification of PT and INR instead of PT or INR in the Coagulation assessments table 
and note. 
Updated the reference to Appendix E for evaluation of Hy’s Law incidents 
Section 5.2.7 Child-Pugh Score 
Clarified that the use of the Child-Pugh score determines the severity of chronic liver 
disease, mainly cirrhosis. 
Table 9 Child-Pugh classification of cirrhosis severity 
Added footnote: For Child-Pugh classification, ascites should be assessed primarily based on 
physical examination. For example, a thin rim of ascites detected only on CT scan would be 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
35 (244) 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be established to monitor data on 
an ongoing basis to ensure the continuing safety of patients enrolled in this study, to ensure 
the integrity of the study, and to oversee the 2 planned interim analyses. The first IDMC 
safety review will occur when approximately 30 patients per arm are randomized or 6 months 
after the first patient is dosed (whichever comes first), and will occur approximately every 6 
months thereafter; the frequency of IDMC review may be adjusted by the IDMC as needed. 
The IDMC will be composed of individuals external to AstraZeneca. An IDMC charter will be 
developed which will specify the Committee’s responsibilities, authorities, and procedures 
along with details of the interim analysis planning, decision-making guidance, and 
dissemination of the results as well as the recommendations and decisions after the interim 
analyses. Formal implementation and communication of IDMC recommendations will be 
managed by the AstraZeneca Executive Committee, which will be unrelated to the 
HIMALAYA project team. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
50 (244) 
1. 
INTRODUCTION  
1.1 
Background and rationale for conducting this study  
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide 
and the second most common cause of cancer death in males (Altekruse et al 2009, Parkin 
et al 2005, Torre et al 2015).  The incidence and prognosis of HCC vary geographically 
largely due to variations in etiological factors such as hepatitis B (HBV) and hepatitis C virus 
(HCV) infection and alcohol use.  While the incidence rate of HCC has historically remained 
very high in HBV endemic regions of eastern Asia, the rates have recently been gradually 
increasing in many other parts of the world including North America, Latin America, and 
Europe (Bosetti et al 2008, Golden-Mason et al 2007, Hashim et al 2016, Ryerson et al 2016), 
possibly related to the higher incidence of cirrhosis due to chronic HCV infection and 
alcoholic/non-alcoholic fatty liver disease (Davila et al 2004, Dunn et al 2004, El-Serag et al 
2003). 
Patients with early-stage and localized HCC with well-preserved liver function can be treated 
with potentially curative options such as surgical resection, liver transplantation, and/or 
radiofrequency ablation (RFA).  Only about 30% of the HCC patients are eligible for curative 
treatments (Llovet 2005), while the rest present with intermediate/advanced stage disease, 
which is usually treated with palliative intent.  Advanced unresectable HCC for which 
liver-directed therapy is not appropriate is usually managed with systemic treatment 
approaches with palliative intent.  However, HCC expresses high levels of multi-drug 
resistance proteins and is inherently chemotherapy resistant (Johnson et al 2013  
Johnson PJ, Qin S, Park JW, Poon R, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as 
first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results 
from the randomized phase III BRISK-FL study. J Clin Oncol 2013; 31:3517-3524. 
Kato et al 2001, Zhu 2006).  Cytotoxic chemotherapy has limited clinical value as first-line 
systemic regimen because of the limited survival benefit and tolerability issues in patients 
with underlying hepatic dysfunction (Zhu 2006). 
Sorafenib is currently accepted as the reference standard systemic therapy for advanced HCC 
based on the demonstrated overall survival (OS) superiority over placebo.  The median 
survival of sorafenib-treated advanced HCC patients is between 6.5 and 10.7 months (Cheng 
et al 2009, Llovet et al 2008).  While sorafenib overall demonstrated a manageable tolerability 
profile in advanced HCC patients, certain adverse events (AEs) such as diarrhea, hand-foot 
skin reaction, and fatigue occurred significantly more in sorafenib-treated patients (Cheng 
et al 2009, Lencioni et al 2014, Llovet et al 2008).  AEs such as hand-foot skin reaction and 
rash, while not life-threatening, are often associated with superimposed complications such as 
infections and pain and can severely limit the activities and the quality of life (QoL) of the 
patients. 
In summary, the currently available therapies have had a positive impact on the survival of 
HCC patients; however, the overall prognosis and QoL remain poor.  HCC, therefore, 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
51 (244) 
represents a significant unmet medical need.  Hence, novel therapies are needed for patients 
with HCC not eligible for locoregional therapy. 
1.1.1 
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). 
Programmed cell death ligand 1 (PD-L1) is a member of the B7 family of ligands that inhibit 
T-cell activity through binding to the programmed cell death (PD-1) receptor (Keir et al 2008) 
and to cluster of differentiation (CD)80 (Butte et al 2007).  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 programmed cell death ligand 2 (PD-L2), (B7-DC, 
CD273) (Okazaki and Honjo 2007).  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 (Qin et al 
2016).  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. 
PD-L1 expression is an adaptive response that helps tumors evade detection and elimination 
by the immune system.  In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is 
constitutively expressed by regulatory T-cells and upregulated on activated T-cells.  
Expression of PD-L1 protein is induced by inflammatory signals that are typically associated 
with an adaptive immune response (eg, interferon gamma [IFNγ]) and can be found on both 
tumor cells (TC) and tumor-infiltrating IC.  The binding of PD-L1 to PD-1 on activated T-
cells delivers an inhibitory signal to the T-cells, preventing them from killing target TC and 
protecting the tumor from immune elimination (Zou and Chen 2008).  PD-L1 may also inhibit 
T-cells through binding to CD80, although the exact mechanism is still not elucidated (Butte 
et al 2007, Paterson et al 2011).   
PD-L1 is expressed with a high frequency in a broad range of cancers, up to 88% in some 
types of cancers.  Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance anti-tumor immune responses in patients with cancer.  Results of 
nonclinical 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 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
52 (244) 
the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
anti-tumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Huz et 
al 2012, Iwai et al 2002, Okazaki and Honjo 2007  
Okazaki T, Honjo T.  PD-1 and PD-1 ligands: from discovery to clinical application.  Int 
Immunol 2007;19(7):813-824. 
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, Qin et al 
2016  
Qin A, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current 
status  of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 2016;9:2567–2578. 
Rizvi et al 2015, Segal et al 2015).  In addition, high mutational burden (eg, in bladder 
carcinoma) (Alexandrov et al 2013) may contribute to the responses seen with immune 
therapy. 
In contrast to PD-L1, CTLA-4 is constitutively expressed by regulatory T-cells and 
upregulated on activated T-cells.  CTLA-4 delivers a negative regulatory signal to T-cells 
upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting cells (FDA 
Guidance for Industry (issued November 2016). Non-Inferiority Clinical Trials to Establish 
Effectiveness. Available from: URL: https://www.fda.gov/media/78504/download. 
Fife and Bluestone 2008).  In addition, blockade of CTLA-4 binding to CD80 and CD86 by 
anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and anti-tumor activity 
in animal models, including killing of established murine solid tumors and induction of 
protective anti-tumor immunity.  Therefore, it is expected that treatment with an anti-CTLA-4 
antibody will lead to increased activation of the human immune system, increasing anti-tumor 
activity in patients with solid tumors. 
Nonclinical data has now been added to with a wealth of clinical data showing that blockade 
of negative regulatory signals to T-cells such as CTLA-4 and PD-L1 has promising clinical 
activity.  There are data from agents in the anti-PD-1/PD-L1 anti-CTLA-4 class showing 
clinical activity in a wide range of tumor types including metastatic melanoma, squamous and 
non-squamous cell non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head 
and neck, and urothelial carcinoma. 
1.1.2 
Durvalumab  
Durvalumab is a human mAb of the immunoglobulin (Ig) G1 kappa subclass that blocks the 
interaction of PD-L1 (but not PD-L2) with PD-1 on T-cells and CD80 (B7.1) on immune 
cells.  It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer 
(MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document.)   

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
65 (244) 
against TC.  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 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 (GI) 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 
hyperthyroidism. 
1.3.2.1 
Durvalumab  
Risks with durvalumab include, but are not limited to, diarrhea, colitis, intestinal perforation 
pneumonitis/ILD, endocrinopathies (hypo- and hyperthyroidism, diabetes mellitus type I, 
hypophysitis, and adrenal insufficiency), hepatitis/increases in transaminases, 
nephritis/increases in creatinine, pancreatitis, increases in amylase and lipase, 
rash/pruritus/dermatitis, 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 durvalmab, always refer to the 
current version of the durvalumab IB. 
In monotherapy clinical studies of durvalumab, AEs (all grades) reported very commonly 
(≥10% 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% of patients experienced an AE that resulted 
in permanent discontinuation of durvalumab, and approximately 6% of patients experienced 
an SAE that was considered to be related to durvalumab by the Investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see 6.9.1). 
The safety profile of the HCC cohort in Study CD-ON-MEDI4736-1108 is consistent with the 
overall safety profile of durvalumab in other indications.  In addition to the above mentioned 
AEs, the study showed a higher percentage of AST/ALT elevation, which would be expected 
in a HCC patient population.  Refer to Section 1.2.1 for additional details. 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
69 (244) 
Tumor assessments, based on RECIST 1.1, will be performed every 8 weeks (Q8W) 
(±1 week) for the first 48 weeks from the date of randomization and then Q12W (±1 week) 
thereafter until RECIST 1.1-defined radiological progression followed by a subsequent scan if 
clinically feasible, evaluated by Confirmation of Radiological Progression criteria (Appendix 
B).  Patients who permanently discontinue study drug(s) for reasons other than PD should 
continue to have radiographic scans performed per their original schedule until confirmed PD 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
71 (244) 
2. 
STUDY OBJECTIVES  
All patients will be evaluated for all endpoints unless otherwise indicated. 
2.1 
Primary objectives  
Primary objective: 
Outcome measure: 
To assess the efficacy of Arm C vs. Arm D (for 
superiority) 
OS 
2.2 
Key Secondary objectives  
Key Secondary objectives: 
Outcome measure: 
To assess the efficacy of Arm A vs. Arm D (for 
non-inferiority)  
OS 
To assess the efficacy of Arm A vs. Arm D (for 
superiority)  
OS 
2.3 
Secondary objectives  
Secondary objectives: 
Outcome measures: 
To assess the efficacy of Arm A vs. Arm D and 
Arm C vs. Arm D 
• 
OS at 18 months (OS18),OS at 24 months 
(OS24) and OS at 36 months (OS36) 
• 
PFS, TTP, ORR, DCR, DCR-16w, DCR-
24w and DoR, according to RECIST 1.1 
using Investigator assessments 
To assess the efficacy of Arm A and Arm C in 
patients with an opportunity for 32 weeks of 
follow-up. 
• 
ORR, BoR, and DoR according to 
RECIST1.1 and mRECIST by Blinded 
Independent Central Review (BICR) 
To assess the efficacy of Arm A vs. Arm D and 
Arm C vs. Arm D by PD-L1 expression 
• 
OS 
• 
PFS, TTP, ORR, DCR, DCR-16w, DCR-
24w and DoR according to RECIST 1.1 
using Investigator assessments 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
75 (244) 
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 or central lab standard) do not require anti-viral therapy prior to enrollment.  
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 or central 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. 
11. 
Patients with HCV infection must have confirmed diagnosis of HCV characterized 
by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment 
(management of this disease is per local institutional practice).  
12. 
At least 1 measurable lesion, not previously irradiated, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, 
which must have a short axis ≥15 mm) with computerized tomography (CT) or 
magnetic resonance imaging (MRI), and that is suitable for accurate repeated 
measurements as per RECIST 1.1 guidelines.  A lesion which progressed after 
previous ablation or TACE could be measurable if it meets these criteria. 
13. 
Adequate organ and marrow function, as defined below.  Criteria “a,” “b,” “c,” and 
“f” cannot be met with transfusions, infusions, or growth factor support 
administered within 14 days of starting the first dose. 
a. Hemoglobin ≥9 g/dL  
b. Absolute neutrophil count ≥1000/µL 
c. Platelet count ≥75000/µL 
d. Total bilirubin (TBL) ≤2.0× upper limit of normal (ULN) 
e. AST and ALT ≤5×ULN 
f. Albumin ≥2.8 g/dL 
g. International normalized ratio (INR) ≤1.6. Note: INR prolongation due to 
anticoagulants for prophylaxis (e.g. atrial fibrillation) in patients without liver 
cirrhosis could be exception. 
h. Calculated creatinine clearance ≥50 mL/minute as determined by 
Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine 
clearance 
14. 
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal as 
described in Section 3.8. 
15. 
Must have a life expectancy of at least 12 weeks 
 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
76 (244) 
3.2 
Exclusion criteria  
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
2. 
Previous study drug(s) assignment in the present study. 
3. 
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an 
interventional study. 
4. 
Have received an investigational product within 28 days prior to the first dose of 
study drug(s). 
5. 
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy 
with the exception of alopecia, vitiligo, and the laboratory values defined in the 
inclusion criteria: 
− 
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Study Physician. 
− 
Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician. 
6. 
Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for 
cancer treatment.  Concurrent use of hormonal therapy for non-cancer-related 
conditions (eg, hormone replacement therapy) is acceptable.  
7. 
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
8. 
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 28 days of the first dose of study drug(s).  
9. 
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of study drug(s).  Note: Local surgery of isolated lesions for palliative 
intent is acceptable. 
10. 
History of allogeneic organ transplantation (eg, liver transplant). 
11. 
History of hepatic encephalopathy within past 12 months or requirement for 
medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if 
used for purposes of hepatic encephalopathy). 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
77 (244) 
12. 
Clinically meaningful ascites, defined as any  ascites requiring non-pharmacologic 
intervention (eg, paracentesis)  to maintain symptomatic control, within 6 months 
prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for 
≥2 months are eligible.  
13. 
Patients with main portal vein thrombosis (i.e. thrombosis in the main trunk of the 
portal vein, with or without blood flow) on baseline imaging.   
14. 
Active or prior documented GI bleeding (eg, esophageal varices or ulcer bleeding) 
within 12 months.   
(Note: For patients with a history of GI bleeding for more than 12 months or 
assessed as high risk for esophageal variceal by the Investigator, adequate 
endoscopic therapy according to institutional standards is required.) 
15. 
Patient currently exhibits symptomatic or uncontrolled hypertension defined as 
diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg.   
16. 
Any condition interfering with swallowing pills, uncontrolled diarrhea, or other 
contraindication to oral therapy. 
17. 
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, 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]).  Patients without active disease in 
the last 5 years are excluded unless discussed with the Study Physician and 
considered appropriate for study participation. 
The following are exceptions to this criterion: 
− 
Patients with vitiligo or alopecia 
− 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement  
− 
Any chronic skin condition that does not require systemic therapy 
− 
Patients with celiac disease controlled by diet alone 
18. 
Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D 
virus (HDV).  HBV positive (presence of HBsAg and/or anti-HBcAb with 
detectable HBV DNA); HCV positive (presence of anti-HCV antibodies); HDV 
positive (presence of anti-HDV antibodies). 
19. 
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
78 (244) 
angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated 
with diarrhea, inferior vena cava thrombosis, or psychiatric illness/social situations 
that would limit compliance with study requirement, substantially increase the risk 
of incurring AEs, or compromise the ability of the patient to give written informed 
consent. 
20. 
History of another primary malignancy except for: 
− 
Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of study drug(s) and of low potential risk for 
recurrence  
− 
Patients with a history of prostate cancer of stage ≤T2cN0M0 without 
biochemical recurrence or progression and who in the opinion of the 
Investigator are not deemed to require active intervention . 
− 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
− 
Adequately treated carcinoma in situ without evidence of disease 
21. 
History of leptomeningeal carcinomatosis. 
22. 
History of, or current, brain metastases or spinal cord compression.  Patients with 
suspected brain metastases at screening should have an MRI (preferred) or CT, each 
preferably with IV contrast of the brain prior to study entry. 
23. 
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and 
HCC. 
24. 
History of active primary immunodeficiency.  
25. 
Active infection including tuberculosis (TB) (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and TB testing in 
line with local practice), or human immunodeficiency virus (positive human 
immunodeficiency virus [HIV] 1/2 antibodies).  
26. 
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of study drug(s).  The following are exceptions to this criterion: 
− 
Intranasal, inhaled, topical steroids, or local steroid injections (eg, 
intra-articular injection) 
− 
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
82 (244) 
3.7 
Methods for unblinding  
Not applicable as this is an open-label study. 
3.8 
Restrictions  
The following restrictions apply while the patient is receiving study drug(s) and for the 
specified times before and after study drug(s) administration: 
1. 
Female patients of childbearing potential 
− 
Females patients of childbearing potential who are not abstinent and intend to 
be sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 1) from the time of screening 
throughout the total duration of the drug treatment and the drug washout period 
(180 days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after the last dose of durvalumab monotherapy).  
Non-sterilized male partners of a female patient of childbearing potential must 
use male condom plus spermicide throughout this period.  Cessation of birth 
control after this point should be discussed with a responsible physician.  
Periodic abstinence, as well as the rhythm and withdrawal methods, are not 
acceptable methods of birth control.  Female patients should also refrain from 
breastfeeding throughout this period. 
2. 
Male patients with a female partner of childbearing potential 
− 
Non-sterilized male patients who are not abstinent and intend to be sexually 
active with a female partner of childbearing potential must use a male condom 
plus spermicide from the time of screening throughout the total duration of the 
drug treatment and the drug washout period (180 days after the last dose of 
durvalumab + tremelimumab combination therapy or 90 days after the last dose 
of durvalumab monotherapy).  However, occasional abstinence, as well as the 
rhythm and withdrawal methods, are not acceptable methods of contraception.  
Male patients should refrain from sperm donation throughout this period. 
− 
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 1).   
Note: Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.  
• 
Women will be considered post-menopausal if they have been amenorrheic for 
12 months without an alternative medical cause.  The following age-specific 
requirements apply:  

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
84 (244) 
Table 1 
Highly effective methods of contraception (<1% failure rate)  
Barrier/intrauterine methods 
Hormonal methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)a 
• 
Implants: etonogestrel-releasing implants 
(eg, Implanon®, Norplan®)  
• 
Intravaginal devices: 
ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)   
• 
Injection: medroxyprogesterone injection 
(eg, Depo-Provera®)  
• 
Combined pill: normal and low-dose 
combined oral contraceptive pill 
• 
Patch: 
norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)  
• 
Minipill: progesterone-based oral 
contraceptive pill using desogestrel 
(Cerazette® is currently the only highly 
effective progesterone-based pill) 
a 
This is also considered a hormonal method. 
All patients  
− 
Patients should not donate blood or blood components while participating in 
this study and through 180 days after receipt of the final dose of the 
durvalumab plus tremelimumab combination therapy or 90 days after receipt of 
the final dose of durvalumab monotherapy or until alternate anticancer therapy 
is started.   
Restrictions relating to concomitant medications are described in Section 7.7. 
3.9 
Discontinuation of study drug(s)  
An individual patient will not receive any further study drug(s) if any of the following occur 
in the patient in question: 
• 
Withdrawal of consent from further treatment with study drug(s).  The patient is, at 
any time, free to discontinue treatment, without prejudice to further treatment.  A 
patient who discontinues treatment is normally expected to continue to participate 
in the study unless they specifically withdraw their consent to further participation 
in any study procedures and assessments (see Section 3.10.2).  
• 
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates 
further dosing. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
86 (244) 
3.10 
Criteria for withdrawal  
3.10.1 
Screen failures  
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not be randomized.  These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (ie, not randomized 
patients).  Patients can be re-screened a single time, but they cannot be re-randomized.  
If a screen failed patient is re-screened, a new E-code must be assigned.  Patients will 
reconfirm their consent to participate in the study by resigning and dating their original 
consent form(s), next to their initial signature and date. 
3.10.2 
Withdrawal of the informed consent  
Patients are free to withdraw from the study at any time (study drug[s] and assessments) 
without prejudice to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any 
further study drug(s) 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 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) 
• 
Use of their study generated data  
• 
Use of any samples (see Section 5.5.6) 
3.10.2.1 Survival status for withdrawn consent and lost to follow-up patients  
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), 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. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
87 (244) 
At the time of OS analyses, the survival status of all patients in the full analysis set (FAS) and 
the safety analysis sets should be re-checked as follows (this includes survival status of 
patients who withdrew consent or are classified as “potentially lost to follow-up):” 
• 
Potentially 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 electronic Case Report Form 
[eCRF] modules will be updated.) 
• 
In the event that the patient has actively withdrawn consent to the processing of his 
or her 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 eCRF modules will be updated.)  
3.11 
Discontinuation of the study  
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings.  In addition, the study may be stopped 
based on the findings of the interim safety analysis conducted by the IDMC (see 
Section 6.10.1). 
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.In terminating the study, AstraZeneca will ensure that 
adequate consideration is given to the protection of the patients interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES  
The procedures for the screening and treatment periods in this study are presented in Table 2 
and Table 3, and the procedures for the follow-up period are presented in Table 4.  Patients 
who continue beyond Cycle 5 (C5) will continue with all C5 assessments until termination of 
treatment (Table 2).  
For all treatment arms: 
• 
Patient-reported outcome (PRO) and tumor efficacy (RECIST 1.1) assessment dates 
will not be affected by dose delays, rechallenge and will remain as originally 
scheduled. 
• 
All other scheduled assessments must be performed relative to the start of the 
dosing cycle, such that all laboratory procedures, etc required for dosing should be 
performed within 3 days prior to dosing. 

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Revised Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419CC00002
Version 8.0
Date 17-June-24
91 (244)
Table 2
Schedule of assessments for all immunotherapy arms treatment period
Screening
Treatment period
Final 
visit
Source
Durvalumab cycle
Week -4 to 
-1
C1
C2
C3
C4
C5 to 
PDa
At time 
of 
confirme
d PD
Day
-28 to -1
1
Window (days)
NA
(+3 days, 
tumor 
assessmen
ts)
(±3 days, tumor assessments and e-PRO assessments ±7 days)
ECOG performance status
X
X
X
X
X
X
X
5.2.6
AE/SAE assessmentn
<-----------------------------------------All visits--------------------------------------------------------->
6.3
Patient follow-up contact/Patient review for safety
On D14 of C1, 2, 3
5.2.5
Study drug(s) administration
Durvalumab 
mg monotherapy
Durvalumab 
mgo
Durvalumab 
mg plus tremelimumab 
mg
 combination therapy
Durvalumab 
mg o,p,q
Tremelimumab 
mg
o,p,q
Durvalumab 
mg plus tremelimumab 
mg
 combination therapy
Durvalumab 
mg o,p,q
Tremelimumab 
mg
o,p,q
ADA sampling
Durvalumab 
mg monotherapy 
Durvalumab ADA sample (pre-dose)
Durvalumab
mg plus tremelimumab 
mg
 combination therapyy
Durvalumab ADA sample (pre-dose)
X
X
5.4
Tremelimumab ADA sample (pre-dose)
X
X
5.4
Durvalumab 
mg plus tremelimumab 
mg
 combination therapy
Durvalumab ADA sample (pre-dose)
Tremelimumab ADA samplew
Other assessments and assays
Vitamin D assessment (serum)
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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
93 (244) 
Table 2  
Schedule of assessments for all immunotherapy arms treatment period  
 
Screening 
Treatment period 
Final 
visit 
Source 
Durvalumab cycle 
Week -4 to 
-1 
C1 
C2 
C3 
C4 
C5 to 
PDa 
At time 
of 
confirme
d PD 
Day 
-28 to -1 
1 
 
 
 
 
Window (days) 
NA 
(+3 days, 
tumor 
assessmen
ts) 
(±3 days, tumor assessments and e-PRO assessments ±7 days) 
 
Archived tumor sample (optional) 
X 
 
 
 
 
 
 
5.5.1 
Fresh tumor biopsy (optional) 
 
 
 
 
 
 
Xt 
5.5.1 
Tumor and disease assessments  
Disease assessment by RECIST 1.1 (CT or MRI)u 
X 
Q8W ±1 week for the first 48 weeks (relative to the date of randomization) and 
then Q12W±1 week thereafter until RECIST 1.1-defined radiological progression 
followed by a subsequent scan if clinically feasible. 
The schedule of Q8W±1 week for first 48 weeks and then Q12W±1 week 
thereafter MUST be followed regardless of any delays in dosing. 
5.1 
a 
Visits continue every 4 weeks. 
b 
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary.  If laboratory, imaging, or pathology 
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 28 days of randomization.  Note: tumor biopsy is optional for China cohort. 
c 
For the first infusion, BP and pulse will be collected from patients prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 
0 minutes), at 30 minutes during the infusion (halfway through infusion), and the end of the infusion (approximately 60 minutes ±5 minutes).  These collection times 
should be followed for each of the durvalumab and the tremelimumab infusions.  For subsequent infusions, BP and pulse should be collected during and post-infusion as 
per institution standard and as clinically indicated. 
d 
Any clinically significant abnormalities detected require triplicate ECG results. 
e 
If screening laboratory assessments (including clinical chemistry, hematology, coagulation)  are performed within 3 days prior to Day 1 (first infusion day), they do not 
need to be repeated at Day 1.  
f 
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.   
g 
If thyroid function, AFP and virology assessment are performed within 14 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1. These 
assessments may be performed more frequently, if clinically indicated. 
h 
Patients who are anti-HBc positive and HBV DNA undetectable (<10UL/ml or under the limit of detection per local or central lab standard) at screening are considered 
as HBV negative. If these patients are stratified to HCV positive or others, they still must be tested for HBV DNA viral load every cycle. In case of HBV 
reactivation (HBV DNA ≥10 IU/ml or above the limit of detection per local or central lab standard), patients must be treated with antiviral therapy, as per institutional 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
103 (244) 
4.1 
Screening/enrollment period  
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening/baseline 
evaluations.  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.  All 
patients will be required to provide consent to supply a sample of their tumor (archived or 
newly acquired biopsy) for entry into this study.  This consent is included in the main patient 
informed consent form (ICF).   
All screening and enrollment procedures will be performed according to the schedule of 
assessments in Table 2 and Table 3.  Demographic data and other characteristics will be 
recorded, including date of birth or age, sex, smoking and alcohol use, and race/ethnicity, 
according to local regulations.  A standard medical and surgical history will be obtained. 
Tumor pathology (including fibrosis score) and tumor stage (Llovet et al 1999 and Benson et 
al 2018) should be collected per Appendix J.  all screening laboratory and imaging results 
must have been obtained within 28 days of randomization. 
Screening/baseline evaluations may be performed over more than 1 visit. 
 
All eligibility criteria must be checked on the date of randomization. If a patient meets 
eligibility criteria during screening, but subsequently becomes ineligible at randomization, the 
patient cannot be randomized. If there are multiple tests for a lab parameter, the one which is 
most recent should be used for the eligibility check. 
4.2 
Treatment period  
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2 and Table 3).  
Whenever ECG, vital signs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, then vital signs, and then blood draws.  
The timing of the first 2 assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the timepoints indicated in Table 2 and Table 3.   
4.3 
Follow-up period  
Patients who are permanently discontinued from further receipt of study drug(s), regardless of 
the reason, will be identified as having permanently discontinued treatment and will enter 
follow-up (Table 4). 
Patients who permanently discontinue drug for reasons other than objective RECIST 1.1 
disease progression should continue to have RECIST 1.1 scans performed Q8W (±1 week) for 
the first 48 weeks relative to the date of randomization and then Q12W (±1 week) thereafter 
until confirmed PD as defined in Table 4. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
104 (244) 
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs, and then blood draws.  The 
timing of the first 2 assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the timepoints indicated in Table 4. 
All patients will be followed for survival until the end of the study.  Following the final 
primary analysis, which will include all study endpoints, the study database may remain open 
for collection of long term follow-up as presented in Table 22 in section 9.3.   
Post final data cutoff 
Patients who continue to receive benefit from their assigned treatment at the final primary 
analysis DCO may continue to receive their assigned treatment for as long as they and their 
physician feel they are gaining clinical benefit.  For patients continuing to receive treatment 
following the final primary analysis DCO, it is recommended that the patients continue the 
scheduled site visits and investigators monitor the patient’s safety laboratory results during 
treatment in order to manage AEs the Long-term follow-up data may be collected post the 
final primary analysis DCO as outlined in section 9.3. 
In the event that a rollover or safety extension study is available following the final primary 
analysis DCO, patients currently receiving treatment with durvalumab (monotherapy or in 
combination with tremelimumab) may be transitioned to such a study, and the current study 
would reach its end.  The rollover or safety extension study would ensure treatment 
continuation with visit assessments per its protocol.  Any patient that would be proposed to 
move to such study would be given a new Informed Consent. 
5. 
STUDY ASSESSMENTS   
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in the 
study protocol and in accordance with the instructions provided. 
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement.  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site. 
The Investigator will record data on the observations, tests, and assessments specified in the 
protocol on the eCRFs provided by AstraZeneca.  The eCRF will be accompanied with 
“Instructions for the Investigator,” which should be followed.  These instructions provide 
guidance for the recording of study data in the eCRF, including how to change data 
incorrectly recorded. 
5.1 
Efficacy assessments  

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
105 (244) 
This study will evaluate the primary endpoint of OS.  Efficacy assessments of PFS, TTP,  
ORR, DCR, DCR-16w, DCR-24w and DoR will be derived (by AstraZeneca) according to 
RECIST 1.1. 
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1 (Appendix B).  It will also be used to determine if, 
and when, a patient has progressed in accordance with RECIST 1.1 and their best objective 
response to study treatment.  RECIST 1.1 assessments will be performed on images from CT 
(preferred) or MRI, each preferably with IV contrast of the chest, abdomen (including liver 
and adrenal glands), and pelvis.  Pelvic imaging is recommended only when primary or 
metastatic disease in the pelvic region is likely.  Additional anatomy should be imaged based 
on signs and symptoms of individual patients at baseline and follow-up. 
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
date of randomization and, ideally, as close as possible to randomization (Table 2 and 
Table 3).  Follow-up assessments will be performed Q8W (±1 week) for the first 48 weeks 
following randomization, and then Q12W (±1 week) thereafter until confirmed PD.  The 
imaging schedule must be followed regardless of any delays in dosing.   
If an unscheduled imaging assessment is performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments as per the standard imaging 
schedule.  If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) 
after the initial assessment of progression, the patient should continue to be followed with 
scheduled imaging until confirmed objective disease progression. 
At each visit, using the information from TLs, non-target lesions (NTLs), and new lesions, 
patients will be programmatically assigned a RECIST 1.1 visit response of complete response 
(CR), PR, stable disease (SD), PD, or not evaluable (NE) depending on the status of their 
disease compared with baseline and previous assessments.  Baseline will be assessed within 
the 28 days prior to randomization.  If a patient has had a tumor assessment that cannot be 
evaluated, then the patient will be assigned a visit response of NE, unless there is objective 
disease progression according to RECIST 1.1 in which case the response will be assigned as 
PD).  Confirmation of progression guidelines are set for the reasons shown in Appendix B.  
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiological progression, the patient should still continue to be followed until confirmed 
radiological objective disease progression. 
Following confirmed progression, patients should continue to be followed up for survival as 
outlined in the follow-up schedules of assessments (Table 4).  In addition, all patients will be 
contacted in the week following data cutoff to confirm survival status. 
Patients in the durvalumab plus tremelimumab combination therapy arms who complete the 
assigned dosing cycle(s) of durvalumab plus tremelimumab, and are benefiting from study 
drug(s) in the Investigator’s opinion, and subsequently have evidence of PD with or without 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
107 (244) 
should be carried out as per the label.  If a patient has completed any safety laboratory tests 
within 3 days before Day 1, they do not need to be repeated at Day 1. 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (dipstick).  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 5 (serum chemistry), Table 6 
(hematology), Table 7 (coagulation), and Table 8 (urinalysis). 
Serum samples will be obtained prior to first dose and will be analyzed for vitamin D values; 
correction may occur as clinically indicated.   
Other safety tests to be performed include : 
• 
Qualitative hepatitis B surface antigen (HBsAg), qualitative hepatitis B e antigen 
(HBeAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-
HBs), hepatitis B e antibody (anti-HBe), hepatitis C antibody (anti-HCV), hepatitis 
D antibody (anti-HDV), and quantitative HBV DNA, quantitative HCV RNA and 
HCV genotype. 
• 
HIV antibodies (as per local standards) 
Note: HBV positive patients must remain on antiviral therapy for the study duration and must 
continue therapy for 6 months after the last dose of study medication. 
Table 5 
Serum chemistry  
Albumin 
Lipaseb 
Alkaline phosphatasea 
Magnesiumc 
ALTa 
Potassium 
Amylaseb 
Sodium 
ASTa 
Total bilirubina 
Bicarbonatec 
Total protein 
Calcium  
TSH 
Chloridec 
Free T3d (reflex) 
Creatinine clearancec 
Free T4d (reflex) 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
108 (244) 
Creatinine  
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferasec 
 
Glucose 
 
Lactate dehydrogenase 
 
a 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is ≥2×upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed.   
c 
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
tests will be performed at screening, on Day 1 (unless screening laboratory assessments are performed 
within 3 days prior to Day 1), and if clinically indicated. 
d 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system. 
ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid-stimulating hormone; 
T3  Triiodothyronine; T4  Thyroxine. 
Table 6 
Hematology  
Absolute neutrophil count 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
 
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 counties 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 
Coagulation  
PT and INR 
aPTT 
 
aPTT  Activated partial thromboplastin time; INR  international normalized ratio; PT  prothrombin time  
Table 8 
Urinalysis  
Bilirubin 
Ketones 
Blood 
pH 
Color and appearance 
Protein 
Glucose 
Specific gravity 
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated. 
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for 
red blood cells.  

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
109 (244) 
If a patient shows an AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law.  These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a Hy’s law case or if any of the individual liver test parameters fulfill any of the 
SAE criteria.   
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 study drug(s) 
(see Table 4). 
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 6.3.7. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study drug(s) 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. 
5.2.2 
Physical examination  
Physical examinations will be performed according to the schedule of assessments (see 
Table 2, Table 3, and Table 4).  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 6.3.6.  
5.2.3 
Electrocardiograms  
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see Table 2 and Table 3).  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. 
Additional safety monitoring for patient receiving sorafenib should be carried out as per the 
label 
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 
prolongation. 
Situations in which ECG results should be reported as AEs are described in Section 6.3.7. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
111 (244) 
5.2.6 
ECOG performance status  
Performance status as determined by the ECOG Scale will be recorded in the eCRF as per the 
schedules in Table 2, Table 3, and Table 4), based on the following: 
0=Fully active; able to carry out all usual activities without restrictions 
1=Restricted in strenuous activity, but ambulatory and able to carry out light work 
or work of a sedentary nature (eg, light housework or office work) 
2=Ambulatory and capable of self-care, but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3=Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4=Completely disabled; unable to carry out any self-care and totally confined to bed 
or chair 
5=Dead 
5.2.7 
Child-Pugh score  
The severity of chronic liver disease, mainly cirrhosis, as determined by the Child-Pugh score 
(Pugh et al 1973), will be recorded in the eCRF as specified in the assessment schedules (see 
Table 2, Table 3, and Table 4). 
The modified Child-Pugh classification of liver disease severity according to the degree of 
ascites, serum concentrations of bilirubin and albumin, prothrombin time, and degree of 
encephalopathy is shown in Table 9.  The severity of cirrhosis is classified as follows: 
• 
Child-Pugh class A (well-compensated disease): score of 5 to 6 
• 
Child-Pugh class B (significant functional compromise): score of 7 to 9 
• 
Child-Pugh class C (decompensated disease): score of 10 to 15 
Table 9 
Child-Pugh classification of cirrhosis severity  
Parameter 
Points assigned 
1 
2 
3 
Ascites * 
Absent 
Slight 
Moderate 
Bilirubin 
<2 mg/dL 
(<34.2 μmol/L) 
2 to 3 mg/dL 
(34.2 to 51.3 μmol/L) 
>3 mg/dL 
(>51.3 μmol/L) 
Albumin 
>3.5 g/dL 
(35 g/L) 
2.8 to 3.5 g/dL 
(28 to 35 g/L) 
<2.8 g/dL 
(28 g/L) 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
125 (244) 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
Further guidance on the definition of a SAE is provided in Appendix A. 
6.3 
Recording of adverse events  
6.3.1 
Time period for collection of adverse events  
AEs and SAEs will be collected from the time of the patient signing the informed consent 
form until the follow-up period is completed (90 days after the last dose of 
durvalumab±tremelimumab or sorafenib).  If an event that starts after 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. 
6.3.2 
Follow-up of unresolved adverse events  
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 will be followed up by 
the Investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.3.3 
Variables  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
Date when the AE started and stopped 
• 
Maximum CTCAE grade reported 
• 
Changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study drug(s) (yes or no) 
• 
Action taken with regard to study drug(s) 
• 
Administration of treatment for the AE 
• 
Outcome 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
126 (244) 
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 
• 
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, as explained in Section 6.3.4 
• 
Description of the SAE 
The grading scales found in the revised NCI CTCAE version 4.03 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 NCI CTCAE version 4.03 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but it is not an SAE unless it meets the criteria 
shown in Section 6.2.  In addition, a stroke that results in only a limited degree of disability 
may be considered a mild stroke, but it would only be considered an SAE if it satisfies the 
criteria shown in Section 6.2. 
6.3.4 
Causality collection  
The Investigator will assess causal relationship between the study drug(s) 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.” 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
127 (244) 
A guide to the interpretation of the causality question is found in Appendix A. 
6.3.5 
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 (ie, 
SAEs that occur prior to the administration of study drug[s]) and treatment-emergent SAEs.  
A protocol-related SAE may occur as a result of a procedure or intervention required during 
the study (eg, 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. 
6.3.6 
Adverse events based on signs and symptoms  
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you 
were last asked?” or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
6.3.7 
Adverse events based on examinations and tests  
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR.  Deteriorations 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 study drug(s). 
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 (eg, 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. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
128 (244) 
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. 
6.3.8 
Hy’s Law  
Cases where a patient shows elevations in liver biochemistry may require further evaluation, 
and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN may need to 
be reported as SAEs.  Appendix E provides further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 
6.3.9 
Disease progression  
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study drug 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. 
6.3.10 
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 study inclusion and have been identified after the 
patient’s enrollment in this study.  New metastatic lesions will be considered progression of 
the malignancy under investigation and should not be reported as a new cancer. 
6.3.11 
Deaths  
All deaths that occur during the 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 
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 the eCRF.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE.  It should also 
be documented in the Statement of Death page in the eCRF.  A postmortem may be 
helpful in the assessment of the cause of death.  If performed, a copy of the 
postmortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
129 (244) 
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug(s) 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(s), then it should also be 
reported as an SAE. 
6.3.12 
Safety data to be collected following the final DCO of the study  
For patients continuing to receive  treatment after final DCO and database closure, it is 
recommended that the patients continue the scheduled site visits, and the Investigators should 
continue to monitor the patient’s safety laboratory results during treatment in order to manage 
AEs.  All data post the final DCO and database closure will be recorded in the patient notes 
but, with the exception of Serious Adverse Events and reports of prenancy, will not otherwise 
be reported for the purposes of this study. If long term survival follow-up is required, all data 
outlined in section 9.3 will be reported directly in the eCRF. 
All SAEs and pregnancy (but not overdose) that occur in patients still receiving study 
treatment (or within the 90 days following the last dose of durvalumab treatment) post the 
final DCO and database closure must be reported as detailed below.  
6.4 
Reporting of serious adverse events  
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s).  All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel should 
inform the appropriate AstraZeneca representatives within 1 day, that is, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, that is, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the Investigators or other site personnel indicate that an AE is serious in the WBDC 
system, an automated email alert is sent to the designated AstraZeneca representative.  If the 
WBDC system is not available, then the Investigator or other study site personnel must report 
an SAE to the appropriate AstraZeneca representative by telephone.  The AstraZeneca 
representative will advise the Investigator/study site personnel how to proceed.   

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
130 (244) 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such. 
 
 
6.5 
Adverse events of special interest  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the study drug(s) and may require close monitoring and rapid 
communication by the Investigator to AstraZeneca.  An AESI may be serious or non-serious.  
The rapid reporting of AESIs will allow ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this study drug(s) 
AESIs for durvalumab and tremelimumab include, but are not limited to, events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants, and/or 
hormone replacement therapy.  These AESIs are being closely monitored in clinical studies 
with durvalumab monotherapy and combination therapy.  An immune-mediated adverse event 
(imAE) is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology.  
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an imAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESIs observed with durvalumab and/or tremelimumab include the following: 
• 
Diarrhea/colitis, and intestinal perforation 
• 
Pneumonitis/ILD 
• 
Hepatitis/transaminase increases 
• 
Endocrinopathies (ie, 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 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
131 (244) 
• 
Myositis/polymyositis 
• 
Neuropathy/neuromuscular toxicity (eg., Guillain-Barré syndrome, myasthenia 
gravis) 
• 
Other inflammatory responses that are rare/less frequent with a potential immune-
mediated etiology comprise, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving eye, skin, haematological and rheumatological events. 
• 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions 
with a different underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab IBs.  More specific guidelines for their 
evaluation and treatment are described in detail in Section 6.9.1.  These guidelines have been 
prepared by AstraZeneca to assist the Investigator in the exercise of his or 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. 
6.6 
Overdose  
6.6.1 
Durvalumab and tremelimumab  
The use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is 
considered to be an overdose.  Currently, there is no specific treatment in the event of 
overdose of durvalumab or tremelimumab, and possible symptoms of overdose are not yet 
established.  
• 
An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the eCRF and in the Overdose eCRF 
module. 
• 
An overdose without associated symptoms will only be reported in the Overdose 
eCRF module. 
If an overdose of an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately or no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply (see 
Section 6.4).  For other overdoses, reporting must occur within 30 days. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
134 (244) 
• 
Errors related to or resulting from IWRS, including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• 
Patient accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Patient failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication 
in open-label studies, even if an AstraZeneca product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel inform the appropriate AstraZeneca representatives within 1 day ie, immediately 
and no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors. 
6.9 
Management of investigational product-related toxicities  
The following general guidance should be followed for management of toxicities: 
• 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned study drug(s) along with 
appropriate continuing supportive care.  If medically appropriate, dose 
modifications are permitted.  
• 
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
All toxicities will be graded according to NCI CTCAE version 4.03.   
6.9.1 
Specific toxicity management and dose modification information - Durvalumab 
and durvalumab plus tremelimumab  
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab monotherapy and durvalumab in 
combination with tremelimumab are provided in the Dosing Modification and Toxicity 
Management Guidelines.  The most current version of these guidelines is to be maintained 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
136 (244) 
1. Uninfected HCC: Interpretation of hepatic laboratory results not confounded by 
underlying viral infection.  Management should focus on ruling out non-imAEs and early 
intervention with steroids and/or other immunosuppressive agents as clinically appropriate 
2. HCV+ or HBV+ HCC: Differential diagnosis for isolated increases in ALT could include 
the following:  
a. Activation of the immune system resulting in increased immune response to HCV or 
HBV manifesting as decreases in viral replication, decreases in HCV viral load, or 
decreases in HBsAg 
b. Changes in immune response to HCV or HBV leading to increased HCV or HBV viral 
replication, increases in HCV viral load, or increases in HBV viral load/HBsAg 
(primarily a hypothetical risk given the mechanism of action of durvalumab and 
tremelimumab) 
c. Non-imAEs unrelated to HCV or HBV 
d. imAEs such as autoimmune hepatitis 
 
Increases in ALT attributable to changes in HCV status do not necessarily require immediate 
immunosuppression. Rather, only in the setting of imAEs would immunosuppression 
(eg, corticosteroids) be considered.  Antiviral therapy may be considered in the setting of an 
ALT increase due to increased HCV viral replication. 
Increases in ALT attributable to changes in HBV viral replication do not necessarily require 
immediate intervention and/or immunosuppression, with the exception of increases in HBV 
viral load.  Increases in HBV viral load suggest onset of resistance to anti-HBV therapy, 
which should precipitate a change in anti-HBV therapy.  Only in the setting of imAEs would 
immunosuppression (eg, corticosteroids) be considered. 
Liver biopsy is recommended soon after the AE is reported as a way to understand the 
underlying pathology and determine the best type of intervention.  Suggested laboratory tests 
to monitor liver status include AST, ALT, TBL, direct bilirubin, albumin, alkaline 
phosphatase (ALP), gamma glutamyltransferase, and INR.  Patients should be 
monitored/evaluated for etiologies (eg, viral hepatitis, disease progression, concomitant 
medications, herbals, over-the-counter medications, and supplements) other than 
immune-related hepatotoxicity before the initiation of dose modifications and 
immunosuppression. 
Treatment modification and management guidelines for hepatotoxicity are presented in the 
Toxicity Management Guidelines. 
6.10 
Study governance and oversight  
6.10.1 
Data Monitoring Committee  
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing 
safety of patients enrolled in this study, to ensure the integrity of the study, and to oversee the 
2 planned interim analyses. The first IDMC safety review will occur when approximately 

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Revised Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419CC00002
Version 8.0
Date 17-June-24
141 (244)
•
Arm D: sorafenib 
mg 
Crossover within the study will not be permitted for any of the treatment arms, except for 
rechallenge in Arm B.  Following amendment 4 patients will be randomized in a 1:1:1 ratio to 
1 of 3 treatment arms: Arm A, Arm C and Arm D.
Durvalumab monotherapy (Arm A)
Patients in Arm A will receive 
mg durvalumab via IV infusion 
 starting on 
until confirmed PD, unacceptable toxicity, or any discontinuation criterion are met (Figure 2).  
(Note: If a patient’s weight decreases to ≤30 kg, the patient should receive weight-based 
dosing of durvalumab 
mg/kg 
 after consultation between the Investigator and the 
Study physician, until the weight increases to >30 kg, at which point the patient should receive 
the fixed dose of durvalumab 
mg 
.) 
Standard infusion time is 1 hour (±5 minutes).  Less than 55 minutes is considered a deviation.  
In the event that there are interruptions during infusion, the total allowed time should not 
exceed 8 hours at room temperature.
Figure 2
Durvalumab monotherapy dosing schedule
Durva Durvalumab; D/C Discontinuation; PD Progressive disease.
Durvalumab 
mg plus tremelimumab 
mg
 combination therapy (Arm B)
Patients in Arm B will receive durvalumab 
mg plus tremelimumab 
mg
 
starting at 
 followed by durvalumab 
mg monotherapy 
starting 
 
after the final infusion of the combination therapy until confirmed PD, unacceptable toxicity, 
or any discontinuation criteria are met (Figure 3).  (Note: If a patient’s weight decreases to 
30 kg or below (≤30 kg), the patient should receive weight-based dosing of durvalumab 
mg/kg 
and tremelimumab
mg/kg 
, after consultation beween The Investigator 
and the Study physician, until the weight increases to >30 kg, at which point the patient 
should receive the original assigned fixed dose of durvalumab 
mg
 with or without 
tremelimumab 
mg 
.)
Tremelimumab will be administered first; the durvalumab infusion will start immediately after 
the end of the tremelimumab infusion.  The standard infusion time is 1 hour (±5 minutes).  
Less than 55 minutes is considered a deviation.  In the event that there are interruptions during 
infusion, the total allowed time should not exceed 8 hours at room temperature.  If there are 
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Revised Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419CC00002
Version 8.0
Date 17-June-24
142 (244)
clinically significant concerns after the first cycle, then, at the discretion of the Investigator, 
all other cycles of durvalumab can be given up to 1 hour after the tremelimumab infusion has 
finished.  
Figure 3
Durvalumab 
mg plus tremelimumab 
 mg
 combination 
therapy dosing schedule (Arm B)
Durva Durvalumab; D/C Discontinuation; PD Progressive disease; Treme Tremelimumab.
Durvalumab 
mg plus tremelimumab 
mg
 combination therapy (Arm C)
Patients in Arm C will receive durvalumab 
mg plus tremelimumab 
mg
 at 
Week 0, followed by durvalumab 
mg monotherapy 
 starting 
 after the first 
and final infusion of the combination therapy until confirmed PD, unacceptable toxicity, or 
any discontinuation criteria are met (Figure 4).  (Note: If a patient’s weight decreases to 30kg 
or below (≤30 kg), the patient should receive weight-based dosing of durvalumab 
mg/kg 
 and tremelimumab mg/kg, after consultation between investigator and study 
physician, until the weight increases to >30 kg, at which point the patient should receive the 
original assigned fixed dose of durvalumab 
mg Q4W with or without tremelimumab 
mg.)
Tremelimumab will be administered first; the durvalumab infusion will start immediately after 
the end of the tremelimumab infusion.  Standard infusion time is 1 hour (±5 minutes).  Less 
than 55 minutes is considered a deviation.  In the event that there are interruptions during 
infusion, the total allowed time should not exceed 8 hours at room temperature.  If there are 
clinically significant concerns after the first cycle, then, at the discretion of the Investigator, 
all other cycles of durvalumab can be given up to 1 hour after the tremelimumab infusion has 
finished.
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Revised Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419CC00002
Version 8.0
Date 17-June-24
143 (244)
Figure 4
Durvalumab 
mg plus tremelimumab 
 mg
 combination 
therapy dosing schedule
Durva Durvalumab; D/C Discontinuation; PD Progressive disease; Treme Tremelimumab.
Sorafenib 
 mg 
 (Arm D)
Patients in the sorafenib arm will receive
mg (
-mg tablets) orally 
 until PD, 
unacceptable toxicity, or any discontinuation criteria are met.  
Dose reductions for the management of adverse drug reactions will be based on the locally 
approved product label for sorafenib.  In countries where sorafenib is not approved, the 
following modification will be followed: sorafenib dose may be reduced to 
mg [
-
mg tablets] orally 
.  If additional dose reduction is required, the sorafenib dose may 
be reduced to a single 
-mg dose 
mg tablets) orally 
7.2.1
Duration of treatment, treatment through disease progression, and rechallenge
Any time during the treatment period, the patients who meet study discontinuation criteria 
(Section 3.9) and the patients with rapid tumor progression or symptomatic progression that 
requires urgent medical intervention (eg, central nervous system metastasis, respiratory failure 
due to tumor compression, spinal cord compression) will not be eligible for continuing study 
treatment.
Crossover within the study arms will not be permitted for any of the treatment arms with the 
exception of rechallenge in Arm B.
7.2.1.1
Treatment through disease progression
Patients in all treatment arms may continue receiving their originally assigned treatment, at 
the Investigator’s discretion, after the first overall time point assessment of PD by 
RECIST 1.1 until PD is confirmed on a follow-up scan evaluated by Confirmation of 
Radiological Progression criteria (Appendix B).  A subsequent scan is required following the 
assessment of PD by RECIST 1.1, preferably at the next scheduled visit and no earlier than 
4 weeks after the previous assessment of PD.
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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
145 (244) 
Rechallenge is permitted only for patients randomized to the durvalumab and tremelimumab 
combination arms. 
7.2.1.3 
Criteria for treatment through progression and for rechallenge  
For all patients who are treated through progression or who are rechallenged with 
tremelimumab in combination with durvalumab, the Investigator should ensure that the 
following criteria are met: 
• 
Progression should not have occurred after confirmed response (CR or PR as 
defined by RECIST 1.1) in the TLs (regardless of the appearance of new lesions); 
ie, the response and progression events both occurred in the TLs during the same 
treatment period.  
• 
No significant, unacceptable, or irreversible toxicities that indicate continuing 
treatment will not further benefit the patient. 
• 
There is absence of clinical symptoms or signs indicating clinically significant 
disease progression accompanied by a decline in World Health Organization 
(WHO)/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. 
• 
All eligibility criteria for this study (see Sections 3.1 and 3.2), with the exception of 
inclusion criteria 5 and 12 and exclusion criterion 23, are met.   
Patients who AstraZeneca and the Investigator determine may not continue treatment after 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 until confirmed disease progression and for survival. 
7.3 
Labeling  
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labeling.  Label 
text will be translated into local language, as required.  Durvalumab  and tremelimumab will 
be provided with either single-panel labels or multi-language booklet labels. 
Label text prepared for durvalumab  will show the product name as “MEDI4736” or 
“durvalumab (MEDI4736)” depending on the agreed product name used in the approved study 
master label document.  All naming conventions are correct during this transitional period. 
7.4 
Storage  

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
147 (244) 
Table 10 
Prohibited concomitant medications  
Prohibited medication/class of drug: 
Usage: 
For all treatment arms 
Any investigational anticancer therapy other 
than those under investigation in this study 
Should not be given concomitantly while the patient 
is on study drug(s) 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study 
Should not be given concomitantly while the patient 
is on study drug(s) 
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 while the patient 
is on study drug(s).  (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable.  Local treatment of isolated lesions, 
excluding TLs, for palliative intent is acceptable [eg, 
by local surgery or radiotherapy].) 
Live attenuated vaccines  
Should not be given through 30 days after the last 
dose of study drug(s) 
For all immunotherapy arms 
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 infusions.  The following are 
allowed exceptions: 
• 
Use of immunosuppressive medications for 
the management of study drug(s)-related 
AEs 
• 
Use in patients with contrast allergies   
• 
Use of inhaled, topical, and intranasal 
corticosteroids 
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 (eg, chronic 
obstructive pulmonary disease, radiation, nausea). 
Drugs with laxative properties and herbal or 
natural remedies for constipation 
Should be used with caution through to 90 days after 
the last dose of tremelimumab during the study 
Sunitinib 
Should not be given concomitantly or through 
90 days after the last dose of tremelimumab (acute 
renal failure has been reported with combination 
therapy of tremelimumab and sunitinib) 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
148 (244) 
Prohibited medication/class of drug: 
Usage: 
EGFR TKIs  
Should not be given concomitantly  
Should be used with caution in the 90 days after 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. 
Herbal and natural remedies, which may have 
immune-modulating effects 
Should not be given concurrently unless agreed by 
AstraZeneca 
AE  Adverse event; CTLA-4  Cytotoxic T-lymphocyte-associated antigen-4; EGFR TKI  Epidermal growth 
factor receptor tyrosine kinase inhibitor; mAb  Monoclonal antibody; PD-1  Programmed cell death-1; 
PD-L1  Programmed cell death ligand 1; TL  target lesion. 
Table 11 
Supportive medications  
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(eg, 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 NTLs, etc]) 
Should be used, when necessary, for all patients 
Inactivated viruses, such as those in the 
influenza vaccine 
Permitted 
NTL  Non-target lesion. 
7.7.1 
Other concomitant treatment  
Other medication other than that described above, which is considered necessary for the 
patients’ safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF. 
7.7.2 
Durvalumab drug-drug interactions  
There is no information to date on drug-drug interactions with durvalumab either nonclinically 
or in patients.  As durvalumab is a mAb and therefore a protein, it will be degraded to small 
peptides and amino acids and will be eliminated by renal and reticuloendothelial clearance.  It 
is, therefore, not expected that durvalumab will induce or inhibit the major drug metabolizing 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
151 (244) 
o using including Brivanib (Johnson 2013), Sunitinib (Cheng 2013), Linifanib 
(Cainap 2014), and Lenvatinib (Kudo 2017). 
8.3 
Definitions of analysis sets  
Definitions of the analysis sets for each outcome variable are provided in Table 12.  
Table 12 
Summary of outcome variables and analysis populations  
Outcome variable 
Populations 
Efficacy data 
 
OS 
FAS (ITT population) 
ORR, BoR, DoR, DCR, DCR-16w, DCR-24w PFS, TTP, 
OS18, OS24, OS36 and PROs 
FAS (ITT population) 
DoR will be based on the subset 
of patients in the full analysis set 
who achieved objective tumor 
response. 
Demography 
FAS set (ITT population) 
PK data 
PK analysis set 
Immunogenicity data 
 
Immunogenicity data 
Listings will be based on safety 
analysis set 
Summaries will be based on 
ADA evaluable set 
Safety data 
 
Exposure 
Safety analysis set 
AEs 
Safety analysis set 
Laboratory measurements 
Safety analysis set 
Vital signs 
Safety analysis set 
AE  Adverse event; BoR Best objective Response; DCR  Disease control rate; DCR-16w  DCR at 16 weeks; 
DCR-24w DCR at 24 weeks; DoR  Duration of response; FAS  full analysis set; ITT  Intent-to-treat; 
ORR  Objective response rate; OS  Overall survival; OS18  Overall survival at 18 months; OS24  Overall 
survival at 24 months; Overall survival at 36 months, PFS  Progression-free survival; 
PK  Pharmacokinetics; PRO  Patient-reported outcome; TTP  Time to progression. 
8.3.1 
Full analysis set  
The FAS will include all randomized patients.  The FAS will be used for all efficacy analyses 
(including PROs).  Treatment arms will be compared on the basis of randomized study 
drug(s), regardless of the study drug(s) actually received.  Patients who were randomized but 
did not subsequently go on to receive study drug(s) are included in the analysis in the 
treatment arm to which they were randomized. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
152 (244) 
8.3.2 
Safety analysis set  
The safety analysis set will consist of all patients who received at least 1 dose of study 
drug(s).  Safety data will not be formally analyzed but summarized using the safety analysis 
set according to the study drug(s) received, that is, erroneously treated patients (eg, those 
randomized to treatment A but actually given treatment B) will be summarized according to 
the study drug(s) they actually received. 
8.3.3 
PK analysis set  
The PK analysis set will include all patients who receive at least 1 dose of study drug(s) per 
the protocol for whom any postdose data are available. 
8.3.4 
ADA evaluable set  
The ADA evaluable set will include all patients who have non-missing baseline ADA and at 
least 1 non-missing post-baseline ADA results. All major ADA analyses will be based on the 
ADA evaluable set. 
8.4 
Outcome measures for analyses  
8.4.1 
Calculation or derivation of efficacy variables  
8.4.1.1 
RECIST 1.1-based endpoints  
Analysis of the secondary endpoints, ORR, DCR, DCR-16w, DCR-24w DoR, TTP, and PFS, 
will be based on the Investigator assessments using RECIST 1.1.   
Blinded Independent Central Review (BICR)  
A BICR of radiological scans will be performed on patients included for the first interim 
analysis, ie, all randomized patients who have had at least 32 weeks of follow-up at the time 
of the interim analysis 1 (IA1) DCO (ie. randomized ≥ 32 weeks prior to IA1 DCO).  
The imaging scans will be reviewed by 2 primary radiologist reviewers using RECIST 1.1.  If 
the overall timepoint assessments differ at any timepoint between the 2 primary reviewers, the 
case will be adjudicated by a third radiologist, who must choose all the overall timepoint 
assessments from the primary reviewer with which he agrees more.  If the overall timepoint 
assessments are identical between the 2 primary reviewers, the timepoint responses from the 
reviewer who completed their assessment of baseline scans first will be used for the analyses. 
For each patient, the BICR will define the overall visit response data (CR, PR, SD, PD, or NE) 
and the relevant scan dates for each time point (ie, for visits where response or progression is 
or is not identified).  
Further details of the BICR will be documented in the Imaging Charter. 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
153 (244) 
Investigator RECIST 1.1-based assessments  
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.  
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments.  Baseline will be assessed within the 28 days prior to randomization.  If a patient 
has had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE, unless there is evidence of progression in which case the response will be 
assigned as PD. 
8.4.1.2 
Primary endpoint, OS  
OS is defined as the time from the date of randomization until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  
Note: Survival calls will be made following the date of data cutoff for the analysis (these 
contacts should generally occur within 7 days of the data cutoff).  If patients are confirmed to 
be alive or if the death date is post the data cutoff date, these patients will be censored at the 
date of data cutoff.  Death dates may be found by checking publicly available death registries. 
8.4.1.3 
Secondary endpoints  
Objective response rate  
ORR (per RECIST 1.1 as assessed by the Investigator) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR.  Data obtained up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR.  Patients who go off treatment without progression, receive a subsequent therapy, and 
then respond will not be included as responders in the ORR.   
Duration of response  
DoR (per RECIST 1.1 as assessed by the Investigator) will be defined as the time from the 
date of first documented response until the first date of documented progression or death in 
the absence of disease progression (ie, date of PFS event or censoring – date of first response 
+1).  The end of response should coincide with the date of progression or death from any 
cause used for the RECIST 1.1 PFS endpoint.  
DoR will not be defined for those patients who do not have documented response. 
Disease control rate  
DCR (per RECIST 1.1 as assessed by the Investigator) is defined as the rate of best objective 
response of either CR, PR, or SD according to RECIST 1.1. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
165 (244) 
alpha level will be spent on all OS analyses.  The primary objective of OS will be tested (H1: 
Arm C vs. Arm D) with 4.9% for this comparison.  
Since two analyses of OS are planned (Interim Analysis, Final Analysis), the Lan DeMets 
approach (Lan and DeMets 1983)  that approximates the O’Brien and Fleming spending 
function will be used to maintain an overall 2-sided 4.9% type I error across the two planned 
analyses of OS (Interim and Final) for the primary comparison (H1: Arm C vs. Arm D)   
If 78% of the target OS events for H1 (ie. 404/515) are available at the time of the interim 
analysis, the 2-sided significance levels to be applied for the interim and final OS analyses 
would be and 0.0222 and 0.0425, respectively.  Strong control of the type 1 error will be 
applied testing endpoints as outlined in the MTP (Figure 5, further details in the SAP). 
 
 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
166 (244) 
Figure 5    
Multiple testing procedure for controlling the type 1 error  
 
 
8.5.2 
 Analysis of the primary variable(s)   
8.5.2.1 
Overall survival  
The primary analysis is to compare OS for Arm C vs. Arm D (for superiority) in the FAS 
(ITT) analysis set.  
The primary OS endpoint will be analyzed using a stratified log-rank test adjusting for 
etiology of liver disease (Confirmed HBV versus confirmed HCV versus others), ECOG (0 
versus 1), and macro-vascular invasion (yes versus no). The effect of Arm C vs. Arm D will 
be estimated by the HR together with its corresponding 95% CI and p-value. 
The key secondary analyses are to compare OS for Arm A vs. Arm D (for non-inferiority, 
then superiority) in the FAS (ITT) analysis set.  
The comparison of OS for Arm C vs. Arm A in the FAS (ITT) analysis set is a secondary 
analysis.  

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
168 (244) 
8.5.3 
Analysis of the secondary variable(s)  
8.5.3.1 
Progression-free survival  
Analysis of PFS (per RECIST 1.1 using Investigator assessments) will be performed to 
compare Arm A vs. Arm D and Arm C vs. Arm D as well as to compare Arm C vs. Arm A 
using the same methodology as for OS. 
8.5.3.2 
Time to progression  
Analysis of TTP will be performed to compare Arm A vs. Arm D and Arm C vs. Arm D as 
well as to compare Arm C vs. Arm A using a stratified log-rank test as described for OS. 
8.5.3.3 
Objective response rate  
At IA1, only descriptive summaries of ORR including exact 95% CIs will be presented for 
each treatment arm (Arm A and Arm C).  The analysis set will include all randomized patients 
who have had the opportunity for at least 32 weeks of follow-up at the time of the IA1 data 
cutoff (ie, randomized ≥32 weeks prior to IA1 DCO).  ORR results will be presented by 
Investigator assessment (using RECIST1.1) and BICR (using RECIST1.1 and mRECIST).  
At the final analysis, the ORR (per RECIST 1.1 using Investigator assessments) will be 
compared between Arm A vs. Arm D and Arm C vs. Arm D as well as to compare Arm C vs. 
Arm A.  Logistic regression models adjusting for the same factors as the primary endpoint 
(etiology of liver disease, ECOG, and macro-vascular invasion) will be fitted.  The results of 
the analysis will be presented in terms of an odds ratio together with its associated 95% CI and 
p-value.  This analysis will be performed in the FAS (ITT) analysis set.  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  Overall visit response data will be listed for all patients (ie, the FAS).  For 
each treatment arm, best objective response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE).  No formal statistical analyses are planned for BoR. 
8.5.3.4 
Disease control rate  
The DCR, DCR-16w and DCR-24w based on Investigator assessments per RECIST 1.1 will 
be summarized (ie, number of patients [%]) per treatment arm. 
8.5.3.5 
Duration of response  
Descriptive data will be provided for the DoR based on Investigator assessments per RECIST 
1.1 in responding patients, including the associated Kaplan-Meier curves (without any formal 
comparison of treatment arms or p-value attached).  This analysis will be performed in the 
FAS (ITT) analysis set. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
172 (244) 
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors.  Forest 
plots will be performed. 
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of OS. 
Cox proportional hazards modeling will be employed to assess the effect of covariates on the 
HR estimate (Cox 1972).  A model will be constructed containing treatment and the 
stratification factors to ensure that any output from the Cox modeling is likely to be consistent 
with the results of the stratified log-rank test. 
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985). 
Additionally, for each subgroup, the HR for Arm C vs. Arm D and 95% CI will be calculated 
from a Cox proportional hazards model with treatment as the only covariate.  These will be 
presented on a forest plot including the HR and 95% CI.   
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analyzed.  In 
this case, only descriptive summaries will be provided. 
8.5.6.2 
Subgroup analyses for secondary endpoints  
Analyses described in Section 8.5.3 will be performed comparing PFS, ORR, TTP, DoR, 
DCR, DCR-16w and DCR-24w, between Arm C vs. Arm D in the following subgroups: 
• 
PD-L1 expression (high versus low) 
• 
Etiology of liver disease (confirmed HBV versus confirmed HCV versus others) 
8.5.7 
Safety data  
Safety and tolerability data will be presented by treatment arm using the safety population. 
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient.  The number and percentage of 
patients experiencing each AE will be summarized by treatment arm and CTCAE grade.  
Additionally, data presentations of the rate of AEs per person-years at risk may be produced.  
Any safety summaries examining rechallenge with tremelimumab may be produced separately 
as described in the SAP. 
Other safety data will be assessed in terms of serum chemistry, hematology, vital signs, and 
ECGs.  Exposure to study drug(s), time on study, dose delays (all arms), and dose reductions 

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9.2.1 
Source data  
Refer to the Clinical Study Agreement (CSA) for location of source data. 
Source data are any data generated as a result of the patient’s inclusion in the study (including 
run-in and/or follow-up related to the study) and include all related medical examinations and 
other records. 
9.2.2 
Study agreements  
The Principal Investigator at each/the center should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of the Clinical Study Protocol 
shall prevail with respect to the conduct of the study and the treatment of patients, and in all 
other respects, not relating to study conduct or treatment of patients, the terms of the CSA 
shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before patients are enrolled. 
9.2.3 
Archiving of study documents  
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study  
The study will remain open until the last patients’ treatment discontinuation. 
The study is expected to start in Q4 2017 and to end by Q4 2021 (final primary analysis).  
Long-term follow-up data may be collected in eCRFs post final primary analysis for 
approximately 5 years, as outlined in Table 22. 
Long-term follow-up: Subjects continuing treatment should be followed for below 
assessments Q4W (+/-1 week). Subjects who have discontinued from treatment should be 
followed for below assessments Q8W (+/-1 week). All SAEs and reports of pregnancy 
experienced by patients whilst receiving treatment or within 90 days of treatment 
discontinuing must continue to be reported to the Sponsor within the usual timelines (ie, 
immediately, or no later than 24 hours of when the site become aware of the SAE) directly in 
the EDC.  If long-term follow-up is collected post final primary analysis, then the end of study 
is defined as the last visit of the last patient in the study. 
 
 
 
 

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Table 22. Schedule of study assessment and relevant eCRF pages to be completed during 
long-term follow-up 
 
Assessment 
Relevant eCRF page 
Informed Consent 
CONSENT 
Survival assessent 
SURVIVE 
Durvalumab, tremelimumab, 
Sorafenib exposure (applicable 
only for patients continuing 
treatment post final analysis) 
EX, EX1, EX2, EX3, EX4 
Discontinuation (only for patients 
continuing treatment post final 
analysis) 
DOSDISC 
Statement of death 
DEATH 
Termination 
DS 
Subsequent anti-cancer therapy 
CAPRX1, CAPRXR2 
Pregnancy 
PREG 
All SAEs experienced by patients 
whilst receiving treatment or 
within 90 days of treatment 
discontinuing. 
If SAE is reported then all data 
relevant to the SAE (e.g.  
concomitant medications, 
laboratory data, dosing data, new 
medical or surgical history) 
should be submitted as part of the 
SAE report. 
 
SAE 
 

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The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with durvalumab plus tremelimumab combination therapy. 
9.4 
Data management by AstraZeneca  
Data management will be performed by a chosen vendor according to the Data Management 
Plan.   
The data collected through designated third party sources will be obtained and reconciled 
against study data. 
AEs and medical/surgical history will be classified according to the terminology of the latest 
version of the MedDRA.  Medications will be classified according to the WHO Drug 
Dictionary.  All coding will be performed by the chosen vendor. 
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
When all data have been coded, validated, signed, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added, and the final database will be locked.   
Limited data collection may continue after the final primary analysis database lock per 
section  9.3. 
Serious adverse event reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.  
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
 
 

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Version 8.0 
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10. 
ETHICAL AND REGULATORY REQUIREMENTS  
10.1 
Ethical conduct of the study  
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
10.2 
Subject data protection  
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, or general physician, unless required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the patient.  In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient.  For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also, Regulatory Authorities may 
require access to the relevant files, although the patient’s medical information and the genetic 
files would remain physically separate. 
10.3 
Ethics and regulatory review  
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients.  The Investigator 
will ensure the distribution of these documents to the applicable EC/IRB, and to the study site 
staff. 
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study.  
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the EC annually. 
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national Regulatory Authority or a notification to the 
national Regulatory Authority is done, according to local regulations. 

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AstraZeneca will handle the distribution of any of these documents to the national Regulatory 
Authorities. 
AstraZeneca will provide Regulatory Authorities, EC/IRBs, and Principal Investigators with 
safety updates/reports according to local requirements. 
Each Principal Investigator, if applicable as per local requirements, is responsible for 
providing the EC/IRB with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the IP.  AstraZeneca will provide this information to the 
Principal Investigator so that he or she can meet these reporting requirements. 
 
10.4 
Informed consent  
The Principal Investigator(s) at each center will: 
• 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk, and benefit of the study 
• 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
• 
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• 
Ensure a copy of the signed ICF is given to the patient 
• 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC 
10.5 
Changes to the protocol and informed consent form  
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (Revised Clinical Study Protocol). 

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The amendment is to be approved by the relevant IRB/EC and, if applicable, also the national 
Regulatory Authority, before implementation.  Local requirements are to be followed for 
revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to the IRB/EC, see Section 10.3. 
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
IRB/EC are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/EC. 
10.6 
Audits and inspections  
Authorized representatives of AstraZeneca, a Regulatory Authority, or an EC may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to check if data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the center. 

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Study Code D419CC00002 
Version 8.0 
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11. 
LIST OF REFERENCES  
Aaronson et al 1993  
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76. 
Abou-Alfa et al 2006  
Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of 
sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 
2006;24(26):4293-300. 
Adnane et al 2006  
Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43-9006, Nexavar), a 
dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases 
VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2006;407:597-612. 
Alexandrov et al 2013  
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature 2013;500:415-21. 
Altekruse et al 2009  
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, 
and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009 
20;27(9):1485-91. 
Antonio et al 2016  
Antonio S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety and 
antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a 
multicentre, phase 1b study. Lancet Oncol 2016;17(3):299-308. 
Basch et al 2009  
Basch E, Jia X, Heller G, Barz A, Sit L, Fruscione M, et al. Adverse symptom event reporting 
by patients vs clinicians: relationship with clinical outcomes. J Natl Cancer Inst 
2009;101:1624-32. 
Benson et al 2018  
Benson AB, D’Angelica MI, Abbott DE, Abrams TA, Alberts SR, et al. NCCN Clinical 
Practice Guidelines in Oncology: Hepatobiliary Cancers. National Comprehensive Cancer 
Network 2018; version 2, pages 40-44. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf  (account registration 
needed). 

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Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
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Version 8.0 
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Study Code D419CC00002 
Version 8.0 
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Date 17-June-24 
 
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Appendix A 
Additional Safety Information: Further guidance on the 
definition of a serious adverse event (SAE) 
Life threatening 
“Life-threatening” means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death.  “Life-threatening” does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious adverse event (SAE), 
although the reasons for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions 
and/or surgical operations planned before or during a study are not considered AEs if the 
illness or disease existed before the patient was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
• 
Simply stopping the suspect drug does not mean that it is an important medical 
event; medical judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring intravenous (IV) 
hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
A guide to interpreting the causality question 
When making an assessment of causality, consider the following factors when deciding if 
there is a “reasonable possibility” that an AE may have been caused by the drug. 

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• 
Time course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship. 
In difficult cases, other factors could be considered such as the following: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case.  The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as “not related.” 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 

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Appendix B 
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors) 
Introduction 
This Appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for this study with regard to Investigator 
assessment of tumor burden including protocol-specific requirements for this study.  
Additional special guidance is provided for determination of confirmation of radiological 
progression. 
Definitions of measurable, non-measurable, target and non-target lesions  
Measurable: 
A lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes which must have short axis1diameter of ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements. 
Non-measurable: 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2). 
• 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination (manual palpation) that is not 
measurable by CT or MRI. 
• 
Previously irradiated lesions3  
• 
Brain metastasis 
Special cases: 
• 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable. 
 
1 The short axis is defined as the longest axis perpendicular to long axis 
2 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as non-target lesions (NTLs). 
3 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment. 

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• 
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected over cystic lesions as Target Lesions 
(TLs). 
Target Lesions 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.  Lymph nodes, in any location (local/regional and distant), are collectively 
considered as a single organ, with a maximum of 2 lymph nodes as TLs.  A bilateral organ 
(eg, adrenal glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each 
considered as a single organ. 
Tumor lesions selected for fresh screening biopsy should not be selected as Target Lesions, 
unless imaging occurred at least ~2 weeks after biopsy, allowing time for healing. 
Non-Target Lesions (NTLs):  
Additional measurable lesions not recorded as TLs and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline. 
Imaging Modalities  
A summary of the methods of assessment (imaging modalities) to be used for RECIST 1.1 
assessment of Target Lesions, Non-Target Lesions, and New Lesions is provided in Table 17. 
Table 17 
Summary of methods of assessment  
Target Lesions  
Non-Target Lesions 
New Lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Plain X-ray 
Chest X-ray 
CT (preferred) 
MRI 
Plain X-ray 
Chest X-ray 
Bone scan 
FDG-PET/CT 
CT   computed tomography; FDG-PET/CT  18F-fluoro-deoxyglucose positron emission tomography/CT; 
MRI  magnetic resonance imaging.  
CT and MRI  
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
non-target lesion (NTL), and identification of any New Lesions.   
It is recommended that CT examinations of the chest and abdomen (including the entire liver 
and both adrenal glands) will be used to assess tumour burden at baseline and follow-up visits. 

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Any other areas of disease involvement (eg, pelvis, brain) should be additionally imaged 
based on the signs and symptoms of individual patients.  In patients who are sensitive to 
intravenous CT contrast, a non-contrast CT examination of the chest and an MRI with 
intravenous MRI contrast of the abdomen is appropriate.  In patients with severely 
compromised renal function a non-contrast CT examination of the chest and abdomen is 
appropriate.  For brain lesion assessment, MRI with IV contrast is the preferred method over 
IV contrast-enhanced CT.  It is strongly recommended to maintain use of the same imaging 
modality (CT or MRI), acquisition protocol, facility and scanner across all imaging time 
points per patient. 
Clinical examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST assessments. Tumors identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans. 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions. 
Plain X-ray  
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions.   
Ultrasound  
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may 
not provide an accurate assessment of true tumor size.  Tumors identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 
Tumor markers  
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1. 
Histology and Cytology 
Histology on tumor biopsy samples will not be used as part of the tumor response assessment 
as per RECIST 1.1.   
Results of cytological examination for the neoplastic origin of any effusion (e.g. ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 

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used as part of the tumor response assessment in this study. An effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be 
considered to be disease progression due to New Lesions or progression of NTLs, 
respectively. 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.   
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  New lesions may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 
observed equivocal hot-spot on a bone scan which cannot be verified with correlative imaging 
(CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that timepoint.  
FDG-PET/CT 
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new lesions, according to the 
following algorithm:  New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake4 not present on baseline or prior FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no 
baseline or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI scans 
then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to verify new lesions. 
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST 1.1 tumor assessments.  Caution that this is not recommended 
because the PET portion of the CT introduces additional (PET) data that may bias an 
Investigator if it is not routinely or serially performed. 
Tumor response evaluation  
Schedule of evaluation 
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including the entire liver and both adrenal glands) must be used at each subsequent 
 
4 A positive FDG-PET scan lesion should be reported only when an uptake (e.g. SUV) greater than twice that of 
the surrounding tissue or liver is observed. 

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follow-up assessment.  Additional imaging may be performed based on the signs and 
symptoms of the patient, eg, new lesions at follow-up. 
Baseline assessments should be performed no more than 28 days before the date of 
randomization, and ideally should be performed as close as possible to the date of 
randomization.  Efficacy by RECIST 1.1 for all patients will be assessed according to the 
schedules of assessment.  If an unscheduled assessment is performed, and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled imaging visits.   
Target lesions 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline.  Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters. 
Special cases: 
• 
For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis diameter.   
• 
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan. 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If 
a lesion appears in the same location on a subsequent scan, it will be recorded as a 
New Lesion. 
• 
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts.   
• 
If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s). 

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• 
If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm. 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion.   
• 
When a TL has had any intervention eg, definitive radiotherapy, embolization, 
surgery, etc.  during the study, the size of the TL should still be provided where 
possible and the intervention recorded in the RECIST case report form. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL. 

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Table 18 
Evaluation of target lesions  
Complete response (CR) 
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis 
diameter to <10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters 
Stable disease (SD) 
Neither sufficient decrease in sum of diameters to qualify for PR 
nor sufficient increase to qualify for PD 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – this 
includes the baseline sum if that is the smallest on study.  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm from nadir. 
Not evaluable (NE) 
Only relevant if any of the TLs at follow-up were not assessed or 
NE (eg missing anatomy) or had a lesion intervention at this visit.  
Note: if the sum of diameters meets the progressive disease 
criteria, progressive disease overrides NE as a TL response 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion. 
Non-target lesions  
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (Table 
19). 
Table 19 
Evaluation of non-target lesions  
Complete response (CR) 
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of one or more NTL. 
Progression (PD) 
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy. 

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Table 19 
Evaluation of non-target lesions  
Not evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met. 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion. 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to qualify for unequivocal progression status. 
New lesions 
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.  The finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor.  If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should 
be continued until the previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
Symptomatic deterioration 
Symptomatic (clinical) deterioration is not a descriptor of an objective response: it is a reason 
for stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective radiological evidence of disease progression at that time should continue to undergo 
tumor assessments where clinically feasible. 
Evaluation of overall visit response 
The overall visit response will be derived using the algorithm shown in Table 20. 

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CCI

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Version 8.0 
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• 
When scans are evaluated by Investigator and by BICR, additional scans can reduce 
informative censoring by Investigator assessments (if the Investigator assesses PD 
but collects no follow-up scans, and the BICR reviewer does not identify RECIST 
PD among the available scans, then this patient would be censored for PFS by 
BICR). 
Confirmation of Radiological Progression Criteria: 
An immediate prior RECIST 1.1-defined radiological PD would be considered confirmed if 
any of the following criteria are met in the subsequent follow-up scan (acquired preferably at 
the next regularly scheduled imaging visit but no sooner than 4 weeks after the RECIST 1.1-
defined PD scan): 
• 
≥20% increase in the sum diameters of TLs compared with the nadir at 
2 consecutive visits, each with an absolute increase of at least 5 mm in sum of 
diameters compared to nadir (as per RECIST 1.1 definition) 
• 
and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint (as per RECIST 1.1 definition) 
• 
and/or significant progression (worsening) of pre-existing new lesions at the 
follow-up scan timepoint compared with the immediate prior timepoint (unique 
definition) 
and/or additional (brand) new unequivocal lesions at the follow-up scan timepoint (as per 
RECIST 1.1 definition) 
NOTE: In order to have confirmed radiological  progression, there should be two consecutive 
assessments meeting the PD definition: the first PD by RECIST 1.1 and the second PD using 
the confirmation of radiological progression criteria (above). If the first assessment fulfilling 
the PD definition by RECIST 1.1 is not confirmed, in the absence of significant clinical 
deterioration, then the patient may continue with assessments until the next PD by RECIST 
1.1, which will also require a follow-up scan evaluated using the Confirmation of Radiological 
Progression criteria.  If the first PD (by RECIST 1.1) is not confirmed by the immediate 
next scan, then the Investigator should not change the PD assessment of the first scan. 
Central Review 
All images will be collected, quality checked, and stored centrally by an Imaging CRO 
appointed by AstraZeneca.  Guidelines for image acquisition, storage at the investigative site as 
source data, and transfer to the imaging CRO will be provided in a separate document.  The 
management of patients will be based solely upon the results of the RECIST 1.1 and 
confirmation of radiological progression assessments conducted by the Investigator. 
Further details of the BICR will be documented in the Independent Review Charter, (also 
referred to as ‘Imaging Charter’). 

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Specifications for radiological imaging 
These notes are recommendations for use in clinical studies.  The use of standardized 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken. 
If specified, all images will be collected, quality checked and stored centrally by the imaging 
CRO appointed by AstraZeneca.  Guidelines for image acquisition, anonymization, storage at 
the investigative site as source data and transfer to the imaging CRO will be provided in a 
separate document. The management of patients will be based solely upon the local 
assessments conducted by the Investigator. 
Also if specified, further details of the Blinded Independent Central Review (BICR) will be 
documented in the Independent Review Charter (also referred to as the ‘Imaging Charter’). 
CT Scan 
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous 
throughout all the anatomic region of interest. 
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients.  Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points.  This will enable better 
consistency not only of tumour measurements but also identification of new disease. 
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning.  Typically, most abdominal imaging is performed during the portal venous phase 
and (optimally) about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given 
patient.  It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered as NE from that 

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point forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality.  Oral contrast is recommended to help visualise 
and differentiate structures in the abdomen.  
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic (chest) examination 
without contrast and abdominal (and pelvis) MRI with contrast.  If MRI cannot be performed 
then CT without i.v. contrast is an option for the thorax and abdomen (and pelvis) 
examination. For brain imaging, MRI with IV contrast is the preferred method. 
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5mm contiguous slice thickness and this guideline presumes a minimum 5 mm 
thickness in recommendations for measurable lesion definition.  Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm.  If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans. 
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TL should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion. 
MRI Scan 
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis (and other anatomies e.g. neck) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed.  The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimised for the specific body part being imaged as well as the scanner utilised.  CT of the 
chest is typically recommended over MRI due to significant motion artifacts (heart, major 
blood vessels, breathing) associated with MRI. It is beyond the scope of this appendix to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts and 
diseases.  Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques if possible. 
For these reasons, CT is the imaging modality of choice. 

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References 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 

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Appendix C 
International Airline Transportation Association 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes, the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B, or Exempt.  There 
is no direct relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening disease, or fatal disease 
in otherwise healthy humans or animals.  Examples of Category A pathogens are ebola, Lassa 
fever virus: 
• 
Are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Examples of Category B pathogens include hepatitis A, B, C, D, and 
E viruses as well as human immunodeficiency virus types 1 and 2.  They are assigned the 
following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
They are to be packed in accordance with UN3373 and IATA 650. 
Exempt includes all other materials with minimal risk of containing pathogens. 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging. 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content. 
• 
IATA-compliant courier and packaging materials should be used for packing and 
transportation, and packing should be done by an IATA-certified person, as 
applicable. 
• 
Samples routinely transported by road or rail are patient to local regulations, which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
210 (244) 
Appendix E 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed to identify and appropriately report cases 
of Hy’s law (HL).  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.   
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in the 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug-induced liver injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
Definitions 
Potential Hy’s Law 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).  
Hy’s Law 
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, for example, elevated ALP 
indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of potential Hy’s Law cases 
To identify cases of PHL, it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• 
ALT ≥3 × ULN 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
211 (244) 
• 
AST ≥3 × ULN 
• 
TBL ≥2 × ULN 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met; where this is the case, the Investigator will do the following: 
• 
Notify the AstraZeneca representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory 
• 
Complete the appropriate unscheduled laboratory eCRF module(s) with the original 
local laboratory test result 
When the identification criteria are met from central or local laboratory results, the 
Investigator will, without delay, do the following: 
• 
Determine whether the patient meets PHL criteria (see definitions within this 
Appendix) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results) 
The Investigator will, without delay, review each new laboratory report and, if the 
identification criteria are met, will do the following: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the patient meets PHL criteria (see definitions within this 
Appendix) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory eCRF 
Follow-up 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria, the Investigator will do the following: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria, the Investigator will do the following: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
drug(s)  
• 
Notify the AstraZeneca representative who will then inform the central Study Team 

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
212 (244) 
The Study Physician contacts the Investigator, to provide guidance as well as discuss and 
agree on an approach for the study patient’s follow-up and the continuous review of data.  
Subsequent to this contact, the Investigator will do the following: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels or as long as medically 
indicated 
• 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  This includes deciding which the tests 
available in the HL laboratory kit should be used.  
• 
Complete the 3 Liver eCRF Modules as information becomes available 
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
Review and assessment of Potential Hy’s Law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF 
accordingly and follow the AstraZeneca standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP, 
• 
Report an SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes.  

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
213 (244) 
− 
The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term “Potential Hy’s Law”) applying serious criteria and 
causality assessment as per above. 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review, amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined. 
Actions required for repeat episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study drug(s) and has already 
met PHL criteria at a previous on-study treatment visit. 
The requirement to conduct follow-up review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following questions: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, for example, chronic or progressing malignant 
disease or severe infection or liver disease, or did the patient meet PHL criteria 
prior to starting study drug(s)and at his or her first on-study treatment visit  
If no, follow the process described in Potential Hy’s Law criteria metsection of this Appendix. 
If yes, determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met. 
• 
If there is no significant change, no action is required. 
• 
If there is a significant change, follow the process described in Potential Hy’s Law 
criteria met section of this Appendix  

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
214 (244) 
A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL), in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty. 
References 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing 
clinical evaluation. Available from: URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf. 

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Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
225 (244) 
PGIC 
  

Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) and tremelimumab  
Study Code D419CC00002 
Version 8.0 
Date 17-June-24 
 
226 (244) 
Appendix I 
Hepatitis stratification 
Patients will be stratified to the HBV positive cohort if they test positive for HBsAg or have 
occult HBV infection (postivie anti-HBc with detectable HBV DNA) (Table 21).   
Patients Subjects will be stratified to the HCV positive cohort if they test positive for HCV or 
have a history of HCV infection  
 
 

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Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
228 (244) 
 
 
Appendix J  
T, N, M, Fibrosis scoring, & BCLC 
Table 1. Definition for T,N,M according to AJCC TNM staging for HCC (8th ed.) 
Primary tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Solitary tumor ≤2 cm, or >2 cm without vascular invasion 
T1a Solitary tumor ≤2 cm 
T1b Solitary tumor >2 cm without vascular invasion 
T2 
Solitary tumor >2 cm with vascular invasion, or multiple tumors, none >5 cm 
T3 
Multiple tumors, at least one of which is >5 cm 
T4 
Single tumor or tumors of any size involving a major branch of the portal vein 
or hepatic vein, or tumor(s) with direct invasion of adjacent organs other than 
the gallbladder or with perforation of visceral peritoneum 
Regional lymph nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
Distant metastasis (M) 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
Table 2. AJCC Prognostic Groups 
Stage 
T 
N 
M 
IA 
T1a 
N0 
M0 
IB 
T1b 
N0 
M0 
II 
T2 
N0 
M0 
IIIA 
T3 
N0 
M0 
IIIB 
T4 
N0 
M0 
IVA 
Any T 
N1 
M0 
IVB 
Any T 
Any N 
M1 
 
 
 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
229 (244) 
 
Fibrosis Score  
The fibrosis score as defined by Ishak is recommended by NCCN guideline because of its 
prognostic value in overall survival. This scoring system uses a 0-6 scale. 
F0: Fibrosis score 0-4 (none to moderate fibrosis) 
F1: Fibrosis score 5-6 (severe fibrosis or cirrhosis) 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
230 (244) 
 
BCLC
 
(Llovett et all 1999.) 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
231 (244) 
 
 
Appendix K 
Country Specific Requirements 
K1  
France specific changes 
Reason for Addendum: 
Requested by the French Competent Authority (ANSM) during assessment of the CTA. 
Centres affected by the Addendum : 
All French centres 
Changed text is indicated in bold italics underligned, where applicable. Deleted text is 
indicated as scored through. 
 
Section of protocol affected: 
3.1 Inclusion criteria 
Previous text: 
7. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional 
therapy) or stage C. 
 
Revised text : 
 
7. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) 
or stage C. The inclusion of a Stage B patients not eligible for locoregional therapy should be 
discussed and agreed upon in a Multidisciplinary Consultative Meeting. 
 
 
Section of protocol affected : 
 
3.2 Exclusion criteria 
 
Previous text: 
 
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, ILD, serious chronic GI conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially 
increase the risk of incurring AEs, or compromise the ability of the patient to give written 
informed consent. 
 
 
 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
232 (244) 
 
Revised text: 
 
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, ILD, serious chronic GI conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially 
increase the risk of incurring AEs, or compromise the ability of the patient to give written 
informed consent. 
Note: For subjects who have or may develop prolongation of QTC, close monitoring with on-
treatment electrocardiograms and electrolytes should be performed as per Nexavar SmPC 
(see Appendix) and/or local institutional guidelines. 
 
 
Section of protocol affected : 
 
4. STUDY PLAN AND TIMING OF PROCEDURES - Table 3 
 
 

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Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
236 (244) 
 
 
Section of protocol affected: 
Appendix J 
Previous text : 
No previous text. 
Revised text: 
Appendix J       Nexavar® (sorafenib) Summary of Product Characteristics 
 
Please refer to http://base-donnees-publique.medicaments.gouv.fr, to access 
the current version of the Nexavar® (sorafenib) Summary of Product 
Characteristics. 
 
Section of protocol affected: 
Appendix K 
Previous text : 
No previous text. 
Revised text: 
Appendix K         List of drugs known to prolong the QTc interval 
 
Please refer to https://www.crediblemeds.org for a list of drugs known to prolong the QTc 
interval. 
 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
237 (244) 
 
K2  
Germany Specific Changes  
 
Reason for Addendum: 
Requested by the German regulatory authority (PEI) during assessment of the CTA. 
Centres affected by the Addendum : 
All German centres 
Changed text is indicated in bold italics underligned, where applicable. Deleted text is 
indicated as scored through. 
 
Section of protocol affected: 
3.2 Exclusion criteria 
Previous text: 
7. 
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab plus tremelimumab combination therapy.  Not 
engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the 
total duration of the treatment and washout periods is an acceptable practice. 
Revised text : 
29. 
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab plus tremelimumab combination therapy.  For 
sorafenib criteria on birth control, refer to the approved label in your country. 
Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for 
the total duration of the treatment and washout periods is an acceptable practice.  
 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
238 (244) 
 
Section of protocol affected: 
3.4 Procedures for handling incorrectly enrolled or randomized patients 
Previous text: 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study drug(s).  There can be no exceptions to this rule.  Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria, must not be 
randomized or initiated on treatment and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented. 
Revised text: 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study drug(s).  There can be no exceptions to this rule.  Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria, must not be 
randomized or initiated on treatment and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment taking into consideration the benefit/risk of study continuation for that patient. 
The AstraZeneca Study Physician must ensure all decisions are appropriately documented. In 
situations where an agreement cannot be reached, the patient should have their study 
therapy stopped and be withdrawn from the study. 
 
 
 

Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
239 (244) 
 
Section of protocol affected: 
7.2 Dose and treatment regimens 
 Previous text: 
Durvalumab 
 mg plus tremelimumab 
 mg
 combination therapy (Arm 3) 
Patients in Arm 3 will receive durvalumab 
 mg plus tremelimumab 
 mg
 at 
Week 0, followed by durvalumab 
 mg monotherapy 
 starting 4 weeks after the first 
and final infusion of the combination therapy until confirmed PD, unacceptable toxicity, or 
any discontinuation criteria are met (Figure 4).  (N.B.  If a patient’s weight decreases to 
≤30 kg, the patient should receive weight-based dosing of durvalumab 
 mg/kg 
 and 
tremelimumab mg/kg, until the weight increases to >30 kg, at which point the patient should 
receive the original assigned fixed dose of durvalumab 
 mg/kg 
 with or without 
tremelimumab 
 mg.) 
Revised text: 
Durvalumab 
 mg plus tremelimumab 
 mg
combination therapy (Arm 3) 
Patients in Arm 3 will receive durvalumab 
 mg plus tremelimumab 
 mg
at 
Week 0, followed by durvalumab 
 mg monotherapy 
 starting 4 weeks after the first 
and final infusion of the combination therapy until confirmed PD, unacceptable toxicity, or 
any discontinuation criteria are met (Figure 4).  Patients in Arm 3 will receive durvalumab 
mg plus tremelimumab 
mg
 at Week 0, followed by durvalumab 
 mg 
monotherapy 
 after the first and final infusion of the combination 
therapy until confirmed PD, unacceptable toxicity, or any discontinuation criteria are met 
(Figure 4).  (N.B.  If a patient’s weight decreases to ≤30 kg, the patient should receive weight-
based dosing of durvalumab 
 mg/kg 
 and tremelimumab mg/kg, until the weight 
increases to >30 kg, at which point the patient should receive the original assigned fixed dose 
of durvalumab 
 mg/kg 
 with or without tremelimumab 
 mg.)
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Study Protocol - Addendum 
Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
240 (244) 
 
Appendix L 
Regulatory, Ethical, and Study Oversight Considerations 
L1  
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
- Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and CIOMS International Ethical Guidelines. 
- Applicable ICH GCP Guidelines. 
- Applicable laws and regulations. 
• 
The protocol, revised protocol, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca. 
• 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR 312.120, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
For all studies except those utilising medical devices investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations. 
• 
An investigator who receives an investigator safety report describing an SAE or other 

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Date: 17-June-24 
241 (244) 
 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and any related documents and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
- A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
- AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If EU 
Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter details of 
serious breaches into the EMA CTIS. It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS. 
• 
The investigator should have a process in place to ensure that: 
- The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach. 
- A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca. 
 
 

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Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
242 (244) 
 
 
L2  
Data Protection 
• 
Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca will contain the identifier only; participant 
names or any information, which would make the participant identifiable, will not be 
transferred. 
• 
The participant must be informed that their personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
• 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 
The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information.  
• 
The participant must be informed that in some cases their data may be pseudonymised. 
The GDPR defines pseudonymisation as the processing of personal data in such a way 
that the personal data can no longer be attributed to a specific individual without the use 
of additional information, provided that such additional information is kept separately and 
protected by technical and organisational measures to ensure that the personal data are not 
attributed to an identified or identifiable natural person. 
 
Unless previously specified, the biomarker data will have unknown clinical significance and 
AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third-party, unless required to do so by law. 
The participant’s samples will not be used for any purpose other than those described in the 
study protocol. 
 
L3  
Committee Structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators. 

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Drug Substance Durvalumab (MEDI4736) and tremelimumab 
Study Code D419CC00002 
Version: 8.0 
Date: 17-June-24 
243 (244) 
 
 
L4  
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plan(s). 
• 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the [Monitoring Plan(s)] [contracts]. 
• 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs). 
 
 

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Version: 8.0 
Date: 17-June-24 
244 (244) 
 
Study monitors will perform ongoing source data verification as per the Monitoring Plan(s) to 
confirm that data entered into the eCRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca GRAD Scheme. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca. 
 
L5  
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
Definition of what constitutes source data and its origin can be found in source data 
acknowledgement or monitoring guidelines. All information in original records and 
certified copies of original records of clinical findings, observations, or other activities in 
a clinical study necessary for the reconstruction and evaluation of the study are defined as 
source documents. Source data are contained in source documents (original records or 
certified copies). 

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