A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab Administered as Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Subjects With Advanced Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: MedImmune LLC

MedImmune                                                                                                 Protocol D4190C00022 Amendment 6
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A Study of Safety, Tolerability, and Clinical Activity of 
Durvalumab and Tremelimumab Administered as 
Monotherapy, or Durvalumab in Combination with 
Tremelimumab or Bevacizumab in Subjects with 
Advanced Hepatocellular Carcinoma
Sponsor Protocol Number: D4190C00022
Application Number:
BB-IND number 125409
Investigational Products:
Durvalumab (MEDI4736), Tremelimumab, Bevacizumab
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC
 Gaithersburg, MD 20878, USA
(Japan) AstraZeneca K.K., 
Osaka 530-0011, Japan
Medical Monitors:
 AstraZeneca
Phone: 
Contract Research
Organization:
ICON Clinical Research Limited
Protocol History, Date:
Original Protocol, 09Apr2015
Amendment 1, 20Aug2015
Amendment 2, 30Mar2016
Amendment 3, 20Jul2017
Amendment 4, 19Dec2017
Amendment 5, 26Nov2018
                                                Amendment 6, 04Jan2019
33'
33'
33'
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PROTOCOL SYNOPSIS
TITLE
A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab Administered as 
Monotherapy, or Durvalumab in combination with Tremelimumab or Bevacizumab in Subjects with 
Advanced Hepatocellular Carcinoma.
HYPOTHESIS
Durvalumab and tremelimumab as monotherapy, and durvalumab in combination with tremelimumab or
bevacizumab can be administered to subjects with advanced hepatocellular carcinoma (HCC) with adequate 
safety, tolerability, and efficacy.
OBJECTIVES
Primary Objectives
1.
To assess the safety and tolerability of durvalumab and tremelimumab administered as monotherapy,
and durvalumab in combination with tremelimumab or bevacizumab to subjects with advanced HCC.
Secondary Objectives
1.
To evaluate the efficacy of durvalumab and tremelimumab administered as monotherapy, and 
durvalumab in combination with bevacizumab or tremelimumab in subjects with advanced HCC.
2.
To evaluate the relationship between candidate biomarkers (eg, programmed cell death ligand 1 [PD-L1] 
expression in the tumor microenvironment) and measures of clinical outcome of durvalumab and 
tremelimumab administered as monotherapy, and durvalumab in combination with tremelimumab or
bevacizumab in subjects with advanced HCC.
Exploratory Objectives
STUDY ENDPOINTS
Primary Endpoints 
1.
Adverse events (AEs), serious adverse events (SAEs), discontinuation of investigational product(s) due 
to toxicity, and changes from baseline in laboratory parameters (including liver and viral laboratory 
tests), electrocardiograms (ECG), and vital signs.
Secondary Endpoints
1.
Objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of 
response (DoR), time to progression (TTP), and progression-free survival (PFS) based on investigator 
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assessments and Blinded Independent Central Review (BICR) according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1, and overall survival (OS).
2.
AEs, SAEs, discontinuation of investigational product(s) due to toxicity, and changes from baseline in 
laboratory parameters (including liver and viral laboratory tests), ECG, and vital signs in three distinct 
HCC populations: uninfected, HBV+, and HCV+.
3.
PD-L1 expression within the tumor microenvironment.
Exploratory Endpoints
STUDY DESIGN AND TREATMENT REGIMENS
This is a multicenter, open-label, stratified, study designed to evaluate the safety, tolerability, and clinical 
activity of durvalumab and tremelimumab administered as monotherapy, and durvalumab in combination 
with tremelimumab or bevacizumab, in subjects with advanced HCC. Approximately 655 subjects will be 
screened to enroll approximately 456 subjects globally, including approximately 12 subjects in Part 1A, 
approximately 24 subjects in Part 1B, approximately 108 subjects in Part 2A, approximately 12 subjects in 
Part 2B, approximately 200 subjects in Part 3, and approximately 100 subjects in Part 4. 
The study will comprise 6 parts, as described below. Subjects in Part 1A, Part 1B, and Part 2A will receive 
weight-based dosing regimens of durvalumab and tremelimumab either as monotherapy or as combination 
therapy. Subjects in Part 2B and Part 3 will receive fixed dosing regimens of durvalumab and tremelimumab 
either as monotherapy or as combination therapy. Subjects in Part 4 will receive weight-based dosing 
regimen of durvalumab and bevacizumab in combination therapy. 
Following protocol amendment 5, enrollment of Part 3 Arm A will be closed. Patients who have been 
randomized to Arm A before this protocol amendment, can continue on assigned study treatment 
(provided the investigator and patient think it is in the best interests of the patient) until confirmed PD 
or any other discontinuation criteria as described in section 4.1.6 is met. If a patient has not completed
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or started all 4 doses of tremelimumab, the patient may either continue to complete the full schedule or 
continue with durvalumab monotherapy only.
2L = second line; 1L = first line; HBV+ = hepatitis B virus positive; HCC = hepatocellular carcinoma; HCV+ = hepatitis 
C virus positive; D = Durvalumab; T = tremelimumab; B = Bevacizumab
Part 1A: Safety Run-in with Durvalumab and Tremelimumab Combination Therapy. 
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant of, or refused 
sorafenib-based therapy will be enrolled in Part 1A using a risk-based, staggered approach. 
•
Stage 1: Approximately 6 subjects with advanced uninfected or HCV+ HCC will be enrolled. Subjects 
will be administered the durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy every 4 
weeks (Q4W) for 4 doses followed by durvalumab 20 mg/kg monotherapy Q4W until confirmed PD or 
any other discontinuation criteria as described in Section 4.1.6 is met. If the frequency of AEs meeting 
dose-limiting toxicity (DLT) criteria is ≥ 33% for a given viral status/type, then lower dose cohorts in 
that specific subpopulation may be explored depending on the type and severity of the toxicities seen at 
this combination dose.
•
Stage 2:
◦
HBV+ Cohort: Enrollment of 6 additional subjects with advanced HBV+ HCC may start after the 
first 3 subjects in Stage 1 have been observed on study for at least 4 weeks. Subjects will be 
administered durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy Q4W for 4 
doses followed by durvalumab 20 mg/kg monotherapy Q4W until confirmed PD or any other 
discontinuation criteria as described in Section 4.1.6 is met. If the frequency of AEs meeting DLT 
criteria is ≥ 33%, then Dose Level -1 (ie, durvalumab 15 mg/kg and tremelimumab 1 mg/kg 
combination therapy Q4W followed by durvalumab 15 mg/kg monotherapy Q4W until confirmed 
PD or any other discontinuation criteria as described in Section 4.1.6 is met) may be explored 
depending on the type and severity of the toxicities seen at this combination dose.
◦
Dose for HBV+ HCC Subjects Administered the durvalumab and Tremelimumab Combination:
durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy Q4W for 4 doses followed 
by durvalumab 20 mg/kg monotherapy Q4W will be the dose evaluated for HBV+ subjects in Part 
1B and Part 2A if the following criteria are met: (1) all 6 subjects have been observed for at least 
4 weeks and the DLT frequency is < 33% (ie, < 2 of 6 subjects); AND (2) at least 3 of the 6 subjects 
have been observed for 6 weeks. If the DLT frequency for the Stage 2 cohort is ≥33% (ie, ≥2 of 6 
subjects), then Dose Level -1 (ie, durvalumab 15 mg/kg and tremelimumab 1 mg/kg combination 
therapy Q4W for 4 doses followed by durvalumab 15 mg/kg monotherapy Q4W until confirmed PD 
or any other discontinuation criteria as described in Section 4.1.6 is met) will be the dose evaluated 
for HBV+ subjects in Part 1B and Part 2A assuming the DLT frequency at Dose Level -1 is < 33%. 

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Part 1B: Efficacy Gating Cohort for Durvalumab and Tremelimumab Combination Therapy.
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant of, or refused 
sorafenib-based therapy will be enrolled in Part 1B.
Approximately 24 subjects (uninfected, HBV infected, or HCV infected) will be enrolled in an efficacy 
gating cohort to determine if there is sufficient evidence of clinical activity to warrant opening enrollment to 
Part 2. Refer to Section 4.8.7 for details regarding the definition of sufficient evidence. Subjects will be 
administered the durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy Q4W for 4 doses 
followed by durvalumab 20 mg/kg monotherapy Q4W until confirmed PD or any other discontinuation 
criteria as described in Section 4.1.6 is met. After approximately 12 of the 24 subjects have been enrolled, 
enrollment of subjects who have progressed on or are intolerant to sorafenib may be paused in favor of 
subjects who have refused sorafenib to ensure a minimum enrollment of 12 subjects who have refused 
sorafenib in Part 1 (A and B). The total number of subjects with a specific viral status may be restricted in 
this cohort to ensure that all types of patients have an opportunity to enroll. For example, as enrollment 
proceeds if emerging data indicate that the majority of patients enrolling are all HBV infected, enrollment of 
this specific viral type of HCC may be paused to allow other types of subjects (uninfected and HCV infected) 
to enroll.
If during Part 1B of the study, ≥ 33% of subjects with a specific viral status type discontinue therapy for 
treatment-related toxicity, enrollment for that specific viral status type may be paused and study data will be 
reviewed to determine whether additional monitoring, alternate dose levels, or treatment schedules should be 
evaluated prior to further enrollment of subjects with that specific viral status type.
Part 2A: Randomized Arms Evaluating Durvalumab and Tremelimumab Combination Therapy, 
Durvalumab Monotherapy, and Tremelimumab Monotherapy. Immunotherapy-naive subjects with 
advanced HCC who have progressed on, are intolerant of, or refused sorafenib-based therapy, will be 
stratified based on viral status (uninfected, HCV infected, or HBV infected) and PD-L1 expression (positive, 
negative, or non-evaluable). 
•
Subjects may not enroll into any arm of Part 2A until sufficient evidence, as specified in Section 4.8.7 
(in Part 1A and Part 1B), is observed.
•
Subjects will be randomized 1:1:1 within each stratum to 1 of the 3 treatment arms with approximately 
36 subjects (approximately 12 subjects/viral status type) per treatment arm:
◦
Arm A: durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy Q4W for 4 doses 
followed by durvalumab 20 mg/kg monotherapy Q4W until confirmed PD or any other 
discontinuation criteria as described in Section 4.1.6 is met 
◦
Arm B: durvalumab 20mg/kg monotherapy Q4W until confirmed PD or any other discontinuation 
criteria as described in Section 4.1.6 is met 
◦
Arm C: Tremelimumab 10 mg/kg monotherapy Q4W for 7 doses followed by every 12 weeks 
(Q12W) until confirmed PD or any other discontinuation criteria as described in Section 4.1.6 is 
met
If during Part 2A of the study, ≥ 33% of subjects with a specific viral status type within a given arm 
discontinue therapy for treatment-related toxicity, enrollment for that specific viral status type may be paused 
and study data will be reviewed to determine whether additional monitoring, alternate dose levels, or 
treatment schedules should be evaluated prior to further enrollment of subjects with that specific viral status 
type. Enrollment into any arm of Part 2A may be discontinued at the discretion of the sponsor should 
emerging clinical or nonclinical data suggest that continued treatment may not be beneficial to a given arm.
All subjects in Part 1A, Part 1B, and Part 2A will be evaluated for efficacy as specified in the protocol, and 
their disease status primarily analyzed according to RECIST v1.1. All subjects will be followed for survival 
until the end of study as defined in section 6.3. For biomarker analysis, subjects will be required to have a 
fresh tumor tissue biopsy at screening, an optional post-dose biopsy, and an optional biopsy at disease 
progression. Collection of noncancerous liver tissue at screening should also be attempted if it can be done 
safely (as judged by the investigator) during the same procedure in which the fresh tumor tissue biopsy is 
obtained. Evaluation of PD-L1 expression status will be done in real-time while the study is ongoing.

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Part 2B: Safety Run-in for Additional Treatment Regimen of Durvalumab and Tremelimumab 
Combination Therapy. Immunotherapy-naive subjects with advanced HCC who have progressed on, are 
intolerant to, or have refused sorafenib-based therapy will be enrolled in Part 2B. 
Approximately 6 to 12 subjects will be enrolled into Arm D evaluating a single higher dose of tremelimumab 
in combination with durvalumab: 
◦
Arm D: durvalumab 1500 mg and tremelimumab 300 mg combination therapy for 1 dose followed 
by durvalumab 1500 mg monotherapy Q4W until confirmed PD or any other discontinuation 
criteria as described in Section 4.1.6 is met
A safety evaluation will be performed once 6 safety evaluable subjects have completed 4 weeks of 
follow-up. A safety evaluable subject is defined as a subject who has received at least 1 dose of study drug 
and completed at least 4 weeks of follow-up or discontinued treatment prior to the completion of 4 weeks of 
follow-up due to an adverse event. 
Enrollment into Part 2B may be discontinued at the discretion of the sponsor should emerging clinical or 
nonclinical data suggest that continued treatment may not be beneficial. 
For biomarker analysis, all subjects in Part 2B will be required to have a newly acquired (fresh or acquired 
within 3 months, preferred) or archival (< 3 years) tissue sample at screening, an optional post-dose biopsy, 
and an optional biopsy at disease progression.
Part 3: Randomized Arms Evaluating Durvalumab and Tremelimumab Combination Therapy, 
Durvalumab Monotherapy, and Tremelimumab Monotherapy. Immunotherapy-naive subjects with 
advanced HCC who have progressed on, are intolerant to, or have refused sorafenib or another approved 
VEGFR TKI-based therapy will be stratified based on viral status (uninfected, HCV infected, or HBV 
infected) and sorafenib/VEGFR TKI treatment (refusers or all others). 
•
Subjects may not enroll into any arm of Part 3 until enrollment in Part 2A and Part 2B has been 
completed and the safety evaluation of the first 6 subjects in Part 2B has been completed. 
•
Subjects will be randomized at a ratio of 2:1:2 into 1 of up to 3 treatment arms with approximately 
64 subjects in each of the durvalumab monotherapy or combination treatment arm (B and D) and 
approximately 32 subjects in the tremelimumab monotherapy treatment arm (Arm C). No prerequisite 
number of subjects for viral status is set for any arms in Part 3:
◦
Arm A (recruitment closed following protocol amendment 5): durvalumab 1500 mg and 
tremelimumab 75 mg combination therapy Q4W for 4 doses followed by durvalumab 1500 mg 
monotherapy Q4W until confirmed PD or any other discontinuation criteria as described in Section 
4.1.6 is met. Following protocol amendment 5, enrollment into Arm A of Part 3 will close.  Patients 
randomized to this arm before protocol amendment 5 can continue on assigned study treatment 
(provided the investigator and patient think it is in the best interests of the patient) until confirmed 
PD or any other discontinuation criteria as described in Section 4.1.6 is met.  If a patient has not 
completed or started all 4 doses of tremelimumab, the patient may either continue to complete the 
full schedule or continue with durvalumab monotherapy only.
◦
Arm B: durvalumab 1500 mg monotherapy Q4W until confirmed PD or any other discontinuation 
criteria as described in Section 4.1.6 is met
◦
Arm C: Tremelimumab 750 mg monotherapy Q4W for 7 doses followed by Q12W until confirmed 
PD or any other discontinuation criteria as described in Section 4.1.6 is met 
◦
Arm D: durvalumab 1500 mg and tremelimumab 300 mg combination therapy for 1 dose followed 
by durvalumab 1500 mg monotherapy Q4W until confirmed PD or any other discontinuation 
criteria as described in Section 4.1.6 is met
All subjects in Part 3 will be evaluated for safety and efficacy as specified in the protocol, and their disease 
status will be primarily analyzed according to RECIST v1.1. An interim analysis will occur after 
approximately 10 subjects per treatment arm in Part 3 have completed 4 weeks of follow-up as described in 
Section 4.8.7. All subjects will be followed for survival until the end of study. 
For biomarker analysis, subjects will be required to have a newly acquired (fresh or acquired 
within 3 months, preferred) or archival (≤3 years) tissue sample at screening, an optional post-dose biopsy, 
and an optional biopsy at disease progression.

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Enrollment into any arm of Part 3 may be discontinued at the discretion of the sponsor should emerging 
clinical or nonclinical data suggest that continued treatment may not be beneficial in a given arm. 
Part 4: Single Arm Evaluating Durvalumab with Bevacizumab in Combination. Subjects with advanced 
HCC who have not received any prior systemic therapy can be enrolled into Part 4. Approximately 100 
subjects will be enrolled into a single arm in Part 4 to evaluate the safety and efficacy of durvalumab in 
combination with bevacizumab:  
◦
durvalumab 15 mg/kg (1120 mg) and bevacizumab 15 mg/kg combination therapy Q3W until 
confirmed PD or any other discontinuation criteria as described in Section 4.1.6 is met
An interim analysis will occur after approximately 100 subjects in Part 4 have had the opportunity for 18
weeks of follow-up. Another interim analysis will occur after approximately 100 subjects in Part 4 have had 
the opportunity for 36 weeks of follow-up.
All subjects will be followed for survival until the end of study as per section 6.3.
TARGET SUBJECT POPULATION
Subjects will be male or female, ≥ 18 years of age (all countries except Japan) or ≥ 20 years of age (Japan 
only), with a diagnosis of advanced HCC confirmed pathologically or by noninvasive imaging methods and, 
have preserved liver function (Child-Pugh Score class A). 
Subjects in Part 1 to Part 3 must be immunotherapy-naive and have either progressed on, are intolerant to, or 
have refused treatment with sorafenib/other VEGFR TKI. Subjects in Part 4 must not have received any prior 
systemic therapy for HCC.
STATISTICAL METHODS
Sample Size and Power Calculations
The sample sizes for Part 1A were determined empirically and are consistent with those used in clinical 
studies to evaluate the safety of a proposed administered dose in a new patient population. There is a 47% to 
91% probability of observing an AE from 6 subjects if the true incidence rate is 10% to 33%. 
For Part 1B, approximately 24 subjects will be enrolled. For the combined sample size of approximately 
36 subjects for Part 1A and Part 1B, there is an 84% to 98% probability of observing at least one AE if the 
true incidence rate is 5% to 10%. The sample size of 36 subjects is chosen to obtain a preliminary assessment 
of antitumor activity. Table 1 provides the estimated ORR and the 95% confidence interval (CI) based on the 
exact probability method for a range of possible responses out of 36 subjects. The preliminary assessment of 
antitumor activity will help determine if there is sufficient evidence of clinical efficacy to warrant continued 
enrollment of subjects in Part 2.
Table 1. Estimated ORR and 95 Percent CI Out of 36 Subjects
Number (%) of 
Responses
2 
(5.6)
4 
(11.1)
6 
(16.7)
8 
(22.2)
10 
(27.8)
12 
(33.3)
14 
(38.9)
Lower limit of 95% CI
0.7%
3.1%
6.4%
10.1%
14.2%
18.6%
23.1%
Upper limit of 95% CI
18.7%
26.1%
32.8%
39.2%
45.2%
50.9%
56.5%
Part 2A dose expansion analysis cohort will include the approximately 108 subjects who are enrolled as a 
part of the global recruitment. The subjects will be stratified in a 1:1:1 ratio based on viral status (HBV vs 
HCV vs uninfected) and PD-L1 status and assigned randomly within each stratum in a 1:1:1 ratio to 1 of the 
3 treatment arms (Arms A, B, and C). With 12 subjects (per viral status cohort) treated with durvalumab or 
tremelimumab monotherapy respectively, there is a 72% to 86% probability of observing at least 1 AE from 
12 subjects if the true incidence rate is 10% to 15%. 
Part 2B is a safety cohort for the evaluation of durvalumab in combination with a higher single-dose of 
tremelimumab (Arm D) in which approximately 6 to 12 subjects will be enrolled. 
Part 3 is a dose-expansion cohort in which approximately 200 subjects. Following protocol amendment 5, 
subjects in Part 3 will be assigned randomly at a ratio of 2:1:2 to 1 of 3 treatment arms (Arms B, C, or D). 
There is a 96% probability of observing at least 1 AE from 64 subjects if the true incidence rate is 5%. 
To evaluate the efficacy in terms of ORR of durvalumab and tremelimumab administered as monotherapy 
and in combination to subjects with advanced HCC, data from Part 2 and Part 3 will be analyzed for each 
part separately and for both parts combined. If the true ORR is 20% in the combination therapy of 

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durvalumab 1500 mg and tremelimumab 75 mg Q4W for 4 doses (or durvalumab 20 mg/kg and 
tremelimumab 1 mg/kg combination therapy Q4W for 4 doses), a sample size of 100 subjects will provide at 
least 95% power to test the hypothesis that ORR is greater than 7% at a 0.05 significance level. 
Part 4 is a single arm cohort to evaluate the safety and efficacy of durvalumab in combination with 
bevacizumab in which approximately 100 subjects will be enrolled. The primary efficacy endpoint is ORR 
assessed by BICR according to RECIST 1.1. If the true ORR is 32%, a sample size of 100 subjects will 
provide at least 83% power to test the hypothesis that ORR is greater than 18.8% (Kudo et al 2018) at a 0.05 
(2-sided) significance level.
During the course of the study, subjects’ tumor samples will be analyzed for PD-L1 expression and the 
prevalence of PD-L1-positive expression for this population will be evaluated. 
Analysis Timing
An interim analysis will occur after approximately 10 subjects per treatment arm in Part 3 have completed 
4 weeks of follow-up. The objective of this interim analysis is to assess futility and safety of the 
monotherapy arms (Arms B and C) and safety of the additional durvalumab and tremelimumab combination 
therapy arm (Arm D).
For Part 4, an interim analysis will occur after approximately 100 subjects have had the opportunity for 18 
weeks of follow-up. Another interim analysis will occur after approximately 100 subjects in Part 4 have had 
the opportunity for 36 weeks of follow-up. The main objective of this interim analysis is to assess the safety 
and efficacy of durvalumab in combination with bevacizumab. The primary efficacy endpoint is ORR 
assessed by BICR according to RECIST 1.1.
Additional interim analyses with the same aims may be performed to support the ongoing PIII development 
for Parts 1-3. No formal adjustments will be made to the significance level used for testing. 
The final analysis for this study, which will include all study endpoints, will be performed 12 months after
the first dose to the last patient in the study. 
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and database closure 
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 study durvalumab treatment following the final DCO and 
database closure, it is recommended that the patients continue the scheduled site visits and investigators 
monitor the patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab toxicity management guidelines.
In the event that a roll-over or safety extension study is available at the time of the final DCO and database 
closure, patients currently receiving treatment with durvalumab (in Parts 1-3) may be transitioned to such a 
study, and the current study would reach its end. The roll-over or safety extension study would ensure 
treatment continuation with visits assessment per its protocol. Any patient that would be proposed to move to 
such study would be given a new Informed Consent.
Efficacy
Efficacy data will be analyzed on the Response Evaluable Population, which will include all treated subjects 
who have a baseline tumor assessment and measurable disease at baseline. Summaries and analyses will be 
performed for each part separately and for Part 2 and Part 3 combined. Efficacy data will be presented by 
treatment arm.
The efficacy endpoints of ORR and DCR will be estimated based on their 2-sided 95% CIs using an exact 
probability method. DCR at 24 weeks will be estimated along with its 2-sided 95% exact CI.
Time-to-event endpoints, including TTR, DoR, TTP, PFS, and OS, will be analyzed using the Kaplan-Meier 
method. The median of each time-to-event endpoint and its 95% CI will be estimated based on the Kaplan-
Meier curves. Only subjects with an objective response (best overall response of complete or partial 
response) will be included in the analysis of DoR. The landmark 6-month PFS rate, 6-month TTP, and 1-year 
OS rate will be estimated based on the Kaplan-Meier curves along with their 95% CIs. Primary analysis of 
all tumor assessment-related endpoints will be based on BICR assessments according to RECIST v1.1. 
Sensitivity analysis of these endpoints will be performed using investigator assessments according to 
RECIST v1.1. 

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Tumor samples (archival and/or from fresh biopsies) will be analyzed to determine the expression level of 
selected immune-related pathways (eg, PD-L1 protein expression as determined by immunohistochemistry) 
that may predict increased frequency of response or longer disease stabilization. 
 
 
 
 
Safety
Safety summaries will be performed for each part separately and for Part 2 and Part 3 combined. Safety data 
will be presented by treatment arm.
Safety data will include AEs, SAEs, discontinuation of investigational product due to toxicity, and changes 
from baseline in laboratory parameters (including liver and viral labs), ECGs, and vital signs. These data will 
be summarized by treatment arm for each viral status cohort (HBV vs HCV vs uninfected) in the As-treated 
Population.
The number and percentage of subjects reporting treatment-emergent AEs will be summarized overall and by 
the worst National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.03 grade, system organ class, and preferred term. Similarly, the number and percentage of subjects 
reporting treatment-emergent SAEs and treatment-emergent AE/SAEs considered related to investigational 
product(s) will be summarized. Laboratory abnormalities will be graded according to the NCI CTCAE v4.03, 
if applicable. Frequencies of maximum observed grade will be presented for each laboratory parameter as 
well as the rates of subjects with Grade 3-4 toxicities. A shift table, presenting the 2-way frequency 
tabulation for baseline and post-baseline grade at scheduled time of evaluation as well as the maximum post-
baseline grade, will be provided for clinical laboratory tests.
Other Analyses
 
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ......................................................................................................2
LIST OF ABBREVIATIONS..............................................................................................16
1
INTRODUCTION ....................................................................................................19
1.1
Disease Background........................................................................................19
1.1.1Cancer and Immune Function..................................................................19
1.1.2Immune-checkpoint Inhibition.................................................................19
1.2
Durvalumab and Tremelimumab and VEGF Inhibitors Background................20
1.2.1Durvalumab Background.........................................................................20
1.2.2Tremelimumab Background ....................................................................20
1.2.3VEGF Inhibitors Background..................................................................20
1.3
Summary of Nonclinical Experience ...............................................................21
1.4
Summary of Clinical Experience.....................................................................21
1.4.1Durvalumab Clinical Experience .............................................................21
1.4.2Tremelimumab Clinical Experience.........................................................24
1.4.3Clinical Experience with Durvalumab and Tremelimumab 
Combination ..........................................................................26
1.4.3.1
Clinical Experience with Durvalumab and Tremelimumab 
Combination Therapy Regimens (Study 
D4190C00006) ........................................................28
1.4.3.2
Clinical and PK Data for Combination Regimen of 
Durvalumab with Single Dose Schedule of 
Tremelimumab.........................................................38
1.4.4Clinical Experience with Other Inhibitors of the PD-1/PD-L1 Pathway 
in Subjects with HCC.............................................................38
1.4.5Clinical Experience with Durvalumab and VEGF Inhibitors with HCC ...38
1.5
Rationale for Conducting the Study.................................................................39
1.5.1Benefit-risk Evaluation............................................................................40
1.6
Research Hypothesis.......................................................................................43
2
OBJECTIVES AND ENDPOINTS ...........................................................................43
2.1
Objectives.......................................................................................................43
2.1.1Primary Objectives..................................................................................43
2.1.2Secondary Objectives..............................................................................43
2.1.3Exploratory Objectives............................................................................44
2.2
Study Endpoints..............................................................................................44
2.2.1Primary Endpoints...................................................................................44
2.2.2Secondary Endpoints...............................................................................44
2.2.3Exploratory Endpoints.............................................................................45
3
STUDY DESIGN......................................................................................................45

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3.1
Description of the Study..................................................................................45
3.1.1Overview ..............................................................................................45
3.1.2Treatment Regimen.................................................................................52
3.1.2.1
Duration of Treatment and Criteria for Treatment Through 
Progression and for Retreatment...............................57
3.1.2.2
Dose-limiting Toxicity...........................................................59
3.1.3Management of Study Medication Related Toxicities..............................60
3.1.3.1
Management of Hepatotoxicity ..............................................62
3.2
Study Design and Dose Rationale ...................................................................63
3.2.1Dose Rationale ........................................................................................63
3.2.2Rationale for Study Population................................................................67
3.2.3Rationale for Endpoints...........................................................................69
3.2.4Rationale for Interim Analysis Criteria ....................................................72
4
MATERIALS AND METHODS...............................................................................73
4.1
Subjects ..........................................................................................................73
4.1.1Number of Subjects.................................................................................73
4.1.2Inclusion Criteria.....................................................................................73
4.1.3Exclusion Criteria....................................................................................76
4.1.4Subject Enrollment and Randomization...................................................79
4.1.5Withdrawal from the Study......................................................................80
4.1.5.1
Survival Status for Withdrawn Consent and Lost to Follow-
Up Patients...............................................................80
4.1.6Discontinuation of Investigational Product ..............................................81
4.1.7Replacement of Subjects .........................................................................81
4.1.8Withdrawal of Informed Consent for Data and Biological Samples .........82
4.2
Schedule of Study Procedures.........................................................................83
4.2.1Enrollment/Screening Period...................................................................83
4.2.2Treatment Period.....................................................................................85
4.2.3Follow-up Period.....................................................................................99
4.3
Description of Study Procedures ...................................................................103
4.3.1Efficacy………. ....................................................................................103
4.3.1.1
Evaluation of Response by Response Evaluation Criteria in 
Solid Tumors .........................................................106
4.3.1.2
 
......................................................................110
4.3.2Tissue Biopsies .....................................................................................110
4.3.2.1
Fresh Tissue Biopsies...........................................................110
4.3.2.2
Archival Tumor Samples......................................................111
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4.3.3Medical History, Physical Examination, Electrocardiogram, ECOG 
Performance Status, Child-Pugh Score, and Vital Signs .......111
4.3.3.1
Medical History and Physical Examination ..........................111
4.3.3.2
Electrocardiograms ..............................................................111
4.3.3.3
ECOG Performance Status...................................................112
4.3.3.4
Child-Pugh Score.................................................................112
4.3.3.5
Vital Signs ...........................................................................113
4.3.4Clinical Laboratory Tests ......................................................................113
4.3.5
..........................................115
4.3.6
..........................................116
4.3.7
..........................................116
4.3.8Estimate of Volume of Blood to Be Collected .......................................117
4.4
Study Suspension or Termination..................................................................118
4.5
Investigational Products................................................................................119
4.5.1Identity of Investigational Product(s).....................................................119
4.5.1.1
Dose Calculation..................................................................119
4.5.1.2
Investigational Product Dose Preparation .............................121
4.5.1.3
Investigational Product Inspection........................................124
4.5.1.4
Treatment Administration ....................................................124
4.5.1.5
Monitoring of Dose Administration......................................125
4.5.1.6
Reporting Product Complaints .............................................126
4.5.2Additional Study Medications ...............................................................126
4.5.3Labeling
............................................................................................126
4.5.4Storage
............................................................................................126
4.5.5Treatment Compliance ..........................................................................126
4.5.6Accountability.......................................................................................127
4.6
Treatment Assignment and Blinding .............................................................127
4.6.1Methods for Assigning Treatment Groups .............................................127
4.6.2Methods for Ensuring Blinding..............................................................128
4.7
Restrictions During the Study and Concomitant Treatment(s) .......................128
4.7.1Permitted Concomitant Medications......................................................128
4.7.2Prohibited Concomitant Medications.....................................................128
4.8
Statistical Evaluation.....................................................................................129
4.8.1General Considerations .........................................................................129
4.8.2Sample Size and Power Calculations .....................................................129
4.8.3Efficacy
............................................................................................132
4.8.3.1
Efficacy Endpoint Definitions..............................................132
4.8.3.2
Analysis of Efficacy.............................................................133
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4.8.4Safety……….. ......................................................................................134
4.8.4.1
Analysis of Adverse Events..................................................134
4.8.4.2
Analysis of Clinical Laboratory Parameters..........................134
4.8.4.3
Analysis of Vital Signs.........................................................134
4.8.4.4
Analysis of Electrocardiograms............................................135
4.8.4.5
Analysis of ECOG Performance Status ................................135
4.8.5
................................................135
4.8.5.1
..............................................135
4.8.5.2
..............................................135
4.8.6
.......................................136
4.8.7Interim Analysis....................................................................................136
5
ASSESSMENT OF SAFETY..................................................................................138
5.1
Definition of Adverse Events ........................................................................138
5.2
Definition of Serious Adverse Events............................................................139
5.3
Definition of Adverse Events of Special Interest ...........................................140
5.3.1Infusion-related Reactions.....................................................................141
5.3.2Hypersensitivity Reactions ....................................................................141
5.4
Recording of Adverse Events........................................................................142
5.4.1Time Period for Collection of Adverse Events.......................................142
5.4.2Follow-up of Unresolved Adverse Events..............................................143
5.4.3Deaths………........................................................................................143
5.4.4Safety Data to be Collected following the Final DCO of the Study........143
5.5
Reporting of Serious Adverse Events ............................................................144
5.6
Other Events Requiring Immediate Reporting ...............................................144
5.6.1Overdose……….. .................................................................................144
5.6.2Hepatic Function Abnormality ..............................................................145
5.6.3Pregnancy ............................................................................................146
5.6.4Medication Error...................................................................................147
6
STUDY AND DATA MANAGEMENT .................................................................148
6.1
Training of Study Site Personnel...................................................................148
6.2
Monitoring of the Study................................................................................148
6.2.1Source Data...........................................................................................149
6.2.2Study Agreements .................................................................................149
6.2.3Archiving of Study Documents..............................................................149
6.3
Study Timetable and End of Study................................................................149
6.4
Data Management .........................................................................................150
6.5
Medical Monitor Coverage............................................................................150
7
ETHICAL AND REGULATORY REQUIREMENTS............................................151
&&,
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7.1
Ethical Conduct of the Study.........................................................................151
7.2
Subject Data Protection.................................................................................151
7.3
Ethics and Regulatory Review.......................................................................151
7.4
Informed Consent..........................................................................................153
7.5
Changes to the Protocol and Informed Consent Form....................................153
7.6
Audits and Inspections ..................................................................................154
8
REFERENCES .......................................................................................................155
9
CHANGES TO THE PROTOCOL..........................................................................162
9.1
Protocol Amendment 1 .................................................................................162
9.2
Protocol Amendment 2 .................................................................................165
9.3
Protocol Amendment 3 .................................................................................167
9.4
Protocol Amendment 4 .................................................................................171
9.5
Protocol Amendment 5 .................................................................................173
9.6
Protocol Amendment 6 .................................................................................173
10
APPENDICES ........................................................................................................175
10.1
Appendix 1 Signatures ..................................................................................175
10.2
178
10.3
Appendix 3 Additional Safety Guidance .......................................................180
10.4
Appendix 4 National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis...........................................................................................183
10.5
Appendix 5 Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluations of Hy’s Law .............................................................184
10.6
Appendix 6 Hepatitis B Stratification Guidance ............................................188
LIST OF IN-TEXT TABLES
Table 1.4.1-1
Overview of Ongoing Clinical Studies of durvalumab in Which 
Subjects Have Been Treated .............................................................22
Table 1.4.3-1
Number of Subjects Treated by Cohort (Study D4190C00006).........27
Table 1.4.3-2
Number of Subjects in the Q4W Cohorts with Treatment-related 
Adverse Events (All Grades), As-treated Population, Study 
D4190C00006 ..................................................................................29
Table 1.4.3-3
Number of Subjects in the Q2W Cohorts with Treatment-related 
Adverse Events (All Grades), As-treated Population, Study 
D4190C00006 ..................................................................................32
Table 1.4.3-4
Rate Summary of All Adverse Events in the Q4W Cohorts, As-treated 
Population, Study D4190C00006......................................................34
Table 1.4.3-5
Rate Summary of All Adverse Events in the Q2W Cohorts, As-treated 
Population, Study D4190C00006......................................................36
Table 3.1.2-1
Treatment and Regimens ..................................................................52
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Table 4.1.2-1
Highly Effective Methods of Contraception......................................76
Table 4.2.1-1
Schedule of Screening/Baseline Procedures......................................83
Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 
1-3 ONLY ........................................................................................86
Table 4.2.2-3
Schedule of Treatment Period Study Procedures Weeks 1 to 25 –
PART 4 ONLY.................................................................................90
Table 4.2.2-2
Schedule of Treatment Period Study Procedures Week 29 to End of 
Study - Parts 1-3 ONLY ...................................................................94
Table 4.2.2-4
Schedule of Treatment Period Study Procedures Week 28 to End of 
Study – PART 4 ONLY....................................................................97
Table 4.2.3-1
Schedule of End of Treatment and Follow-up Procedures ...............100
Table 4.3.1.1-1
Evaluation of Overall Response at a Single Timepoint by RECIST 
V1.1 ...............................................................................................108
Table 4.3.3.3-1
Eastern Cooperative Oncology Group Performance Status..............112
Table 4.3.3.4-1
Child-Pugh Classification of Cirrhosis Severity ..............................113
Table 4.5.1-1
Identification of Investigational Products........................................119
Table 4.8.2-1
Estimated Objective Response Rate and 95 Percent Confidence 
Interval Out of 36 Subjects .............................................................130
Table 4.8.7-1
Probabilities of Different Scenarios for Different True Response 
Rates...............................................................................................137
LIST OF IN-TEXT FIGURES 
Figure 3.1.1-1
Study Flow Diagram.........................................................................46
Figure 3.1.2-1
Durvalumab and Tremelimumab Combination Therapy Treatment 
Schedule...........................................................................................54
Figure 3.1.2-2
Durvalumab Monotherapy Treatment Schedule ................................55
Figure 3.1.2-3
Tremelimumab Monotherapy Treatment Schedule............................56
Figure 3.1.2-4
Durvalumab and Tremelimumab Combination Therapy Treatment 
Schedule...........................................................................................56
Figure 3.1.2-5
Durvalumab and Bevacizumab Combination Therapy Treatment 
Schedule...........................................................................................57

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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration-time curve
BICR
Blinded Independent Central Review
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
Cmax
Maximum observed plasma drug concentration
CNS
central nervous system
CR
complete response
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4
D5W
5% dextrose in water
DC
disease control
DCR
disease control rate
DCR-12w
disease control rate at 12 weeks
DEHP
bis (2-ethylhexyl) phthalate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FAAN
Food Allergy and Anaphylaxis Network
Fc
fragment crystallizable 
FDG
18F-Fluoro-deoxyglucose 
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography
GCP
Good Clinical Practice
HBc
hepatitis B core
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
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Abbreviation or 
Specialized Term
Definition
HCV
hepatitis C virus
HDV
hepatitis D virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgE
immunoglobulin E
IgG
immunoglobulin G
IHC
immunohistochemistry
IL
interleukin
ILD
interstitial lung disease
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
irCR
immune-related complete response
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IV
intravenous(ly)
IXRS
interactive response system
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCA
non-compartmental analysis
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID
National Institute of Allergy and Infectious Diseases
NK
natural killer
NSCLC
non-small-cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PFS
progression-free survival
PR
partial response
PT
prothrombin
&&,
&&,
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Abbreviation or 
Specialized Term
Definition
PVC
polyvinyl chloride
Q2W
every 2 weeks
Q4W
every 4 weeks
Q12W
every 12 weeks
QTcB
QT corrected using Bazett’s formula
QTcF
QT corrected using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SID
subject identification
sPD-L1
soluble programmed cell death ligand 1
TIL
tumor-infiltrating lymphocyte
TNF
tumor necrosis factor
TSH
thyroid stimulating hormone
TTP
time to progression
TTR
time to response
ULN
upper limit of normal
US/USA
United States
w/v
weight per volume

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1
INTRODUCTION
1.1
Disease Background
1.1.1
Cancer and Immune Function
The importance of the immune system in cancer development and progression has been 
recognized during the past decade (Hanahan and Weinberg, 2000). Failure of immune 
surveillance of preneoplastic lesions and micrometastases is a key step in cancer 
development. Chronically immunosuppressed individuals show higher rates of cancer. This 
observation led to the hypothesis that sporadic cancers among immune-competent individuals 
are likely to be minimally immunogenic, allowing for passive escape from immune 
surveillance. Recent data suggest that this may be an oversimplification. Some sporadic 
tumors are highly immunogenic, but actively suppress the local immune environment 
through production of immunosuppressive cytokines (Shields et al, 2010). As such, the local 
tumor environment is likely a highly dynamic environment where most tumors grow and 
metastasize through adaptive responses that modulate antitumor immunity.
The complexity and redundancy of the immune system offers multiple targets that may be 
manipulated to maximize the body’s inherent immune response to a tumor. Immune response 
may be augmented by directly stimulating effector cells, indirectly stimulating effectors by 
augmenting antigen presentation activity or costimulation, or by suppressing 
immunosuppressive factors, cells, or messages (Monti et al, 2005).
1.1.2
Immune-checkpoint Inhibition
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types 
of cancers (Gooden et al, 2011). Most tumors show infiltration by TILs, but tumors modulate 
the local microenvironment through expression of inhibitory molecules. Engagement of TIL 
cell-surface receptors with these inhibitory ligands leads to a dysfunctional immune response, 
causes T-cell exhaustion, and facilitates tumor progression (Baitsch et al, 2012; 
Crespo et al 2013). Novel monoclonal antibodies (mAbs) that block these inhibitory 
receptors have shown significant clinical activity across a number of tumor types 
(Wolchok et al, 2009; Hodi et al, 2010; Robert et al, 2011; Brahmer et al, 2010; 
Topalian et al, 2012). Specifically, blockade of immune-checkpoint inhibitors such as 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), 
and programmed cell death ligand 1 (PD-L1) have shown clinical activity not only in 
conventionally immune-responsive tumors such as melanoma and renal cell carcinoma but 
also in non-small-cell lung cancer (NSCLC; Brahmer et al, 2010; Brahmer et al, 2012; 
Topalian et al, 2012; Gordon et al, 2013), prostate cancer (Harzstark and Small, 2010; 

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Slovin et al, 2013), pancreatic cancer (Royal et al, 2010), mesothelioma (Calabrò et al, 2013), 
and other solid tumors (Brahmer et al, 2010; Brahmer et al, 2012; Gordon et al, 2013).
1.2
Durvalumab and Tremelimumab and VEGF Inhibitors Background
Durvalumab and tremelimumab are briefly described below. Refer to the current 
Investigator’s Brochures (IBs) for details. Background information on bevacizumab is 
provided in local prescribing information.
1.2.1
Durvalumab Background
Durvalumab is a human immunoglobulin G (IgG)1 kappa mAb directed against human 
PD-L1. Durvalumab is expressed in Chinese hamster ovary cells and has an overall 
molecular weight of approximately 149 kDa. Durvalumab selectively binds human PD-L1 
with high affinity and blocks its ability to bind to PD-1 and cluster of differentiation (CD)80. 
The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to the complement component 
C1q and the Fc gamma receptors responsible for mediating antibody-dependent 
cell-mediated cytotoxicity (ADCC; Oganesyan et al, 2008).
1.2.2
Tremelimumab Background
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb being investigated as a cancer 
immunotherapeutic agent. Tremelimumab is expressed in NS0 (murine myeloma) cells and 
has an overall molecular weight of approximately 149 kDa. Tremelimumab is specific for 
human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks 
the inhibitory effect of CTLA-4, and therefore enhances T-cell activation. Tremelimumab 
shows minimal specific binding to Fc receptors, does not induce natural killer (NK) ADCC 
activity, and does not deliver inhibitory signals following plate-bound aggregation.
1.2.3
VEGF Inhibitors Background
Vascular Endothelial Growth Factor (VEGF) is an important regulator of tumor angiogenesis 
and promotes the proliferation, survival, and migration of endothelial cells and induces 
microvascular permeability (Ferrara 2002). VEGF has been shown to play a role in the 
development and spread of HCC (Kaseb et al 2009). Additional evidence suggests that the 
combination of PD-L1 inhibition with vascular endothelial growth factor (VEGF) inhibition 
may result in synergistic activity and improved clinical benefit (Barsoum et al 2014, Voron et 
al 2015, Yasuda et al 2013). Preliminary data from an ongoing Phase Ib study testing 
atezolizumab (a PD-L1 inhibitor) and bevacizumab therapy as first-line treatment in patients 

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1.3
Summary of Nonclinical Experience
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1.4
Summary of Clinical Experience
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1.4.1
Durvalumab Clinical Experience
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current durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics.
Table 1.4.1-1
Overview of Ongoing Clinical Studies of Durvalumab in 
Which Subjects Have Been Treated
Study Number
Phase
Study Population
Treatment Regimen
Monotherapy Studies 
CD-ON- durvalumab -1108 
1/2
Advanced solid tumors 
including HCC
durvalumab Q2W or Q3W
D4190C00002
1
Advanced solid tumors
durvalumab Q2W or Q3W
D4190C00007
1
MDS
durvalumab Q2W
D4190C00003/ ATLANTIC
2
NSCLC
durvalumab Q2W
D4190C00001/PACIFIC
3
NSCLC
durvalumab Q2W or placebo Q2W
Combination Therapy Studies
CD-ON- durvalumab -1161
1
Melanoma
durvalumab Q2W + trametinib BID ± 
dabrafenib QD
D4190C00006
1b
NSCLC
durvalumab Q2W or Q4W + 
tremelimumab Q4W
D791PC00001
1
NSCLC
durvalumab Q2W + gefitinib daily
D6020C00001
1
Advanced malignancies
durvalumab Q2W + MEDI0680 
(AMP-514) Q2W or Q4W
LUD2013-003a
1
Advanced solid tumors
durvalumab Q2W + tremelimumab 
Q4W
BID = twice daily; HCC = hepatocellular carcinoma; MDS = myelodysplastic syndrome; NSCLC = non-
small-cell lung cancer; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks; QD = once 
daily.
a
All studies in this table are sponsored by AstraZeneca/MedImmune, except LUD2013-003.
Data from Study CD-ON-durvalumab-1108 (durvalumab monotherapy) are presented below. 
Refer to Section 1.4.3 for data from Study D4190C00006 (durvalumab in combination with 
tremelimumab) and to the durvalumab IB for the most recent detailed description of all 
studies.
Study CD-ON-durvalumab-1108
Study CD-ON-durvalumab-1108 is a Phase 1, first-time-in-human, multicenter, open-label, 
dose-escalation, and dose-expansion study to determine the maximum tolerated dose (MTD) 
or optimal biologic dose, safety, pharmacokinetics (PK), immunogenicity, and antitumor 
activity of durvalumab in adult subjects with advanced solid tumors refractory to standard 
therapy or for which no standard therapy exists. As of 21Aug2014, 408 subjects across 
8 tumor types (NSCLC, squamous cell carcinoma of the head and neck, pancreatic 
adenocarcinoma, uveal melanoma, cutaneous melanoma, gastroesophageal cancer, 

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triple-negative breast cancer, and hepatocellular carcinoma [HCC (n = 21); hepatitis B virus 
(HBV) or hepatitis C virus (HCV) positive]) have received durvalumab 10 mg/kg every 
2 weeks (Q2W) for a median of 6 doses (Segal et al, 2014).
Overall, durvalumab 10 mg/kg Q2W was well tolerated in this subject population 
(Segal et al, 2014). Adverse events (AEs), regardless of severity or causality, were reported 
in 372 of 408 subjects (91%). A total of 170 subjects (42%) reported ≥ Grade 3 AEs; these 
events were considered to be treatment related in 30 subjects (7%). The most common 
treatment-related AE, regardless of severity, was fatigue (16%); ≥ Grade 3 fatigue occurred 
in 2% of subjects. Other select treatment-related AEs of interest (all grades) were vomiting, 
diarrhea, rash (6% each); pruritus dyspnea (4% each); pyrexia, hypothyroidism, increased 
alanine transaminase (ALT), increased aspartate transaminase (AST; 3% each); abdominal 
pain, hyperthyroidism (2% each), and hyperglycemia, pneumonitis, peripheral neuropathy 
(1% each). No treatment-related colitis of any grade, and no ≥ Grade 3 pneumonitis were 
reported. Five subjects (1%) reported AEs that resulted in discontinuation of investigational 
product. No treatment-related AEs resulted in death. Overall, AEs were manageable and 
generally reversible with treatment interruption, discontinuation, and/or steroids. The safety 
profile of durvalumab 10 mg/kg Q2W was similar across all tumor types.
Partial efficacy data are available as of 21Aug2014 (Segal et al, 2014). In this study, 352 of 
408 subjects treated with durvalumab 10 mg/kg Q2W were evaluable for response analysis, 
which included subjects who had at least 12 weeks of follow-up as of the data cutoff date, 
measurable disease at baseline, and at least 1 follow-up scan (included discontinuations due 
to progressive disease [PD] or death prior to first follow-up scan). Early (5 weeks) and 
durable (56+ weeks) activity were observed across multiple tumor types. Disease control rate 
(DCR) at 12 weeks (DCR-12w) was 33% (115/352 subjects) and objective response rate 
(ORR) was 10% (36/352 subjects) across the 8 tumor types. Greater DCR-12w (47% vs 
28%) and ORR (22% vs 5%) were observed in subjects with PD-L1-positive versus 
PD-L1-negative tumors. Responses are ongoing in 92% of subjects (33/36) with an objective 
response (OR).
A total of 21 advanced stage HCC subjects, including 4 HBV+ and 5 HCV+ subjects, 
received durvalumab monotherapy (10 mg/kg Q2W; Segal et al, 2014). As of the 21Aug2014 
data cutoff, the safety profile of the HCC cohort appears similar to all other tumor type 
cohorts. Thirteen subjects (62%) experienced any treatment-related AE, 2 subjects (10%) 
experienced a Grade 3 or higher treatment-related AEs, and 1 subject (5%) experienced a 
treatment-related serious adverse event (SAE). There were no reported AEs leading to 

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discontinuation of investigational product or death. In addition, of the 19 evaluable subjects, 
4 (21%) demonstrated prolonged stable disease (SD; ≥ 3 months) while there were no ORs.
As of 01May2014, PK data were available for 38 subjects in the dose-escalation (n = 26) and 
dose-expansion (n = 12) phases following dosing with durvalumab 0.1 to 10 mg/kg Q2W or 
15 mg/kg every 3 weeks. durvalumab monotherapy exhibited nonlinear (dose-dependent) 
PK. The area under the concentration-time curve (AUC) from 0 to 14 days increased in a 
greater than dose-proportional manner over the dose range of 0.1 to 15 mg/kg and 
approached linearity at ≥ 3 mg/kg, suggesting that the nonlinear PK of durvalumab is likely 
due to saturable target-mediated clearance. Of the 220 subjects for whom antidrug antibody 
(ADA) data were available, 5 were detected ADA positive, with an impact on 
PK/pharmacodynamics reported in 1 subject.
1.4.2
Tremelimumab Clinical Experience
Refer to the current tremelimumab IB for the most recent detailed description of all studies.
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cut-
off date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of the 
tremelimumab clinical development program. Of these studies, 13 have been completed and 
9 are ongoing. Tremelimumab has been administered as monotherapy to 973 subjects (not 
including 497 subjects who have been treated in the blinded Phase 2b study, D4880C00003 
[DETERMINE]) participating in 10 of the 22 clinical studies, 2 of which are ongoing. In 
addition, 208 subjects with a variety of tumor types have received tremelimumab in 
combination with other anticancer agents in 12 of the 22 sponsored clinical studies, 7 of 
which are ongoing.
Update: To date tremelimumab has been given to more than 1500 patients as part of ongoing 
studies either as monotherapy or in combination with other anticancer agents. Refer to the 
current tremelimumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics.
Across the clinical development program for tremelimumab a pattern of efficacy has 
emerged, also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to 
be consistent across tumor types for this class of agents. Response rates to anti-CTLA-4 
antibodies are generally low, approximately 10%. However, in subjects who respond, the 
responses are generally durable, lasting months to years even in subjects with aggressive 
tumors, such as, refractory metastatic melanoma. Some subjects may have had progression of 
their disease early during treatment, with delayed tumor response or disease stabilization. 

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Tremelimumab has been tested in a Phase 3 study for advanced melanoma. Although the 
study failed to demonstrate improved overall survival (OS; primary endpoint) following a 
prespecified interim futility analysis, the final analysis showed a median OS of 12.6 months 
in the tremelimumab arm and 10.7 months in the dacarbazine/temozolomide arm (hazard 
ratio = 1.1416, p = 0.1272). The ongoing Phase 2b study in recurrent pleural or peritoneal 
malignant mesothelioma is testing an alternative dosing schedule of tremelimumab with a 
dose of 10 mg/kg every 4 weeks (Q4W) to maximize exposure to tremelimumab while 
managing safety according to the established anti-CTLA-4 AE management guidelines. The 
10 mg/kg Q4W regimen is also being tested in an ongoing Phase 2 investigator-sponsored 
study in malignant mesothelioma (NCT01655888).
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following 
intravenous (IV) infusion. The estimate of clearance, volume of distribution at steady state, 
and terminal-phase half-life is 0.132 mL/hour/kg, 81.2 mL/kg, and 22.1 days, respectively. 
These values are consistent with those of natural IgG2. 
The profile of AEs and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target. To 
date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo 
that seems to be confined to subjects with melanoma). As of the data cutoff date of 
12Nov2014 (for all studies except D4190C00006 that has a cutoff date of 04Dec2014), AEs 
(all grades, regardless of causality) reported in > 10% of subjects in the completed and 
rollover tremelimumab monotherapy studies (N = 973, integrated data) were diarrhea 
(45.3%), fatigue (37.5%), nausea (32.5%), rash (28.8%), pruritus (27.3%), decreased appetite 
(22.8%), vomiting (22.5%), pyrexia (15.3%), cough (15.0%), constipation (14.4%), 
abdominal pain (13.9%), headache (13.8%), dyspnea (12.4%), and decreased weight 
(10.2%). Based on integrated data from completed studies of tremelimumab in combination 
with other agents (N = 116), AEs (all grades, regardless of causality) reported in > 15% of 
subjects were diarrhea (54.3%); nausea (40.5%); fatigue (38.8%); rash (35.3%); pruritus, 
decreased appetite (30.2% each); vomiting (27.6%); pyrexia (26.7%); influenza like illness 
(20.7%); arthralgia (19.8%); constipation (19.0%); thrombocytopenia, injection site reaction 
(18.1% each); and increased aspartate aminotransferase (15.5%). Most of these events 
occurred at a higher rate with tremelimumab plus sunitinib than with other combinations. The 
events of diarrhea, rash, and pruritus are considered as identified risks. Acute renal failure 
was reported in subjects who received the combination of tremelimumab and sunitinib; 
however, acute renal failure has not been an expected AE for single-agent tremelimumab. 
The incidence and/or severity of many of the AEs observed following administration of 

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tremelimumab can be reduced by adherence to current immune-related toxicity management 
guidelines.
Tremelimumab at a dose of 15 mg/kg IV every 90 days has been administered to 20 subjects 
with HCV+ HCC (43% Child-Pugh class B; Sangro et al, 2013). Overall, tremelimumab was 
well tolerated; no subjects received systemic steroids and there were no treatment-related 
deaths. Transient increases in transaminases were observed after the first dose in more than 
half of the subjects and 45% of the cases had increases to Grade 3 or higher without 
simultaneous decline in liver function. Seventeen subjects were evaluable for response with 
confirmed partial responses (PRs) observed in 3 subjects (17.6%).
In another Phase I/II study, 32 advanced HCC (Child-Pugh class A/B7) patients were treated 
with tremelimumab at 2 dose levels (3.5 and 10 mg/kg IV Q4W) in combination with 
subtotal ablation (RFA/TACE) during Week 6 of treatment (Duffy et al 2016). Safety 
evaluation showed no clear trend in AEs across the cohorts utilizing different doses of 
tremelimumab. No DLT was encountered on the study. The most common Grade 3 or 
Grade 4 toxicities were AST elevation (21%), ALT elevation (9%), and hyperbilirubinemia 
(9%). There were no episodes of Grade 3 or Grade 4 diarrhea, colitis, or pneumonitis. Of 19 
patients evaluable for response outside of the areas treated directly with TACE/RFA, 5 
(26.3%) achieved confirmed partial response (PR).
1.4.3
Clinical Experience with Durvalumab and Tremelimumab 
Combination
Refer to the current durvalumab and tremelimumab IBs for the most recent detailed 
descriptions of all studies with durvalumab and tremelimumab combination therapy.
!
Update: To date more than 3000 patients have received the combination using a 
number of doses and dosing schedules.
Study D4190C00006 is a multicenter, open-label, dose-escalation, and dose-expansion study 
of durvalumab in combination with tremelimumab to evaluate the safety, tolerability, PK, 
immunogenicity, and antitumor activity of durvalumab in combination with tremelimumab in 
adult subjects with advanced NSCLC.
The safety, efficacy and PK/pharmacodynamics of the combination were explored using the 
modified zone-based design (Huang et al, 2007). The zone based design allowed for the 
comparison of multiple combinations of doses at the same time. 
The schedules used in this study were:

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•
For durvalumab:
◦
Q4W dosing schedule - durvalumab was administered Q4W for 13 doses.
◦
Q2W dosing schedule - durvalumab was administered Q2W for 26 doses. 
•
For tremelimumab combined in both schedules of durvalumab
◦
Tremelimumab was administered Q4W for 6 doses and every 12 weeks (Q12W) for 
3 doses; Dose 7 is given at 4 weeks from Dose 6 and Dose 8 is given at 12 weeks 
from Dose 7.
As of 27Jan2015, a total of 74 subjects with advanced NSCLC have been treated in 
Study D4190C00006 (Table 1.4.3-1) in 10 combination dose cohorts. This included subjects 
with tumors that were both PD-L1 positive and negative. Subjects have received between 
1 and 9 doses of tremelimumab and between 1 and 13 doses of durvalumab. The greater 
number of durvalumab doses is due to the inclusion of both schedules of durvalumab Q4W 
dosing schedule and Q2W. Fifty-eight of these subjects were in the durvalumab Q4W dosing 
schedule and 16 subjects were in the Q2W dosing schedule.
Table 1.4.3-1
Number of Subjects Treated by Cohort (Study 
D4190C00006)
Cohort
Durvalumab Dose 
(mg/kg)
Tremelimumab Dose 
(mg/kg)
Subjects Treated
Dosing Schedule                  Q4W (every 4 weeks)                      Q4W 
1a
3
1
3
2a
10
1
3
3a
15
1
12
3b
10
3
3
4
20
1
11
4a
15
3
11
5
15
10
9
5a
20
3
6
Q4W Total
58
Dosing Schedule                 Q2W (every 2 weeks)                      Q4W 
8
10
1
6
9
10
3
10
Q2W Total
16
Overall Total
74

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1.4.3.1
Clinical Experience with Durvalumab and Tremelimumab Combination 
Therapy Regimens (Study D4190C00006)
Safety
Refer to the current durvalumab and tremelimumab IBs for the most recent detailed 
description of the safety for all studies with durvalumab and tremelimumab combination 
therapy.
Overall, 62 (83.8%) of the 74 subjects reported an AE regardless of causality. The most 
frequently (10 or more subjects) reported AEs were fatigue (37.8%; 28 subjects); diarrhea 
(32.4%; 24 subjects); amylase increased and pruritus (16.2%; 12 subjects); decreased 
appetite, dyspnea, nausea, and rash (14.9%; 11 subjects each), and headache and pyrexia 
(13.5%; 10 subjects). 
Twenty of the 62 subjects who experienced AEs regardless of causality had events that were 
Grade 1 or 2 in severity. Forty-two of the 62 subjects reported ≥Grade 3 events. The most 
frequently reported ≥Grade 3 events (in 3 or more subjects) were diarrhea (7 subjects); 
colitis (6 subjects); increased lipase (4 subjects); and anemia, increased ALT, increased AST, 
dehydration, and pneumonitis (3 subjects each).
Fifty of the 74 subjects reported a treatment-related AE. The most frequently reported 
treatment-related AEs were fatigue (24.3%; 18 subjects); diarrhea (21.6%; 16 subjects); 
increased ALT (13.5%; 10 subjects); pruritus (12.2%; 9 subjects); and rash (10.8%; 
8 subjects). Twenty-four of the 50 subjects who experienced treatment-related AEs reported 
Grade 1 or 2 events only. Twenty-six of the 50 subjects reported ≥Grade 3 events. The most 
frequently reported treatment-related ≥Grade 3 events (in 3 or more subjects) were colitis 
and diarrhea (6 subjects each), increased lipase (4 subjects), and increased ALT, increased 
AST, and pneumonitis (3 subjects). 
Q4W Cohorts
For the Q4W cohorts, 43 (74.1%) of 58 subjects reported treatment-related AEs (Table 1.4.3-
2). The most frequently reported (5 or more subjects) treatment-related AEs were fatigue 
(16 subjects), diarrhea (14 subjects), increased amylase (10 subjects), increased ALT, 
increased lipase, pruritus, and rash (7 subjects each), colitis (6 subjects), and increased AST 
and decreased appetite (5 subjects each).

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Table 1.4.3-2
Number of Subjects in the Q4W Cohorts with Treatment-related Adverse Events (All Grades), 
As-treated Population, Study D4190C00006
System Organ Class/Preferred Term 
(MedDRA V17.1)
M3/T1
(N = 3)
n (%)
M10/T1
(N = 3)
n (%)
M10/T3
(N = 3)
n (%)
M15/T1
(N = 12)
n (%)
M15/T3
(N = 11)
n (%)
M15/T10
(N = 9)
n (%)
M20/T1
(N = 11)
n (%)
M20/T3
(N = 6)
n (%)
Total
(N = 58)
n (%)
Total subjects reporting 1 or more 
events
1 (33.3)
3 (100)
3 (100)
7 (58.3)
9 (81.8)
8 (88.9)
7 (63.6)
5 (83.3)
43 (74.1)
Endocrine Disorders
0
2 (66.7)
1 (33.3)
0
1 (9.1)
0
0
1 (16.7)
5 (8.6)
Hypothyroidism
0
1 (33.3)
1 (33.3)
0
1 (9.1)
0
0
0
3 (5.2)
Gastrointestinal Disorders
0
2 (66.7)
2 (66.7)
4 (33.3)
5 (45.5)
4 (44.4)
2 (18.2)
3 (50.0)
22 (37.9)
Abdominal pain
0
0
1 (33.3)
1 (8.3)
2 (18.2)
0
0
0
4 (6.9)
Colitis
0
0
1 (33.3)
1 (8.3)
1 (9.1)
1 (11.1)
1 (9.1)
1 (16.7)
6 (10.3)
Diarrhoea
0
0
2 (66.7)
3 (25.0)
4 (36.4)
2 (22.2)
0
3 (50.0)
14 (24.1)
Dyspepsia
0
1 (33.3)
0
0
0
0
1 (9.1)
1 (16.7)
3 (5.2)
Nausea
0
1 (33.3)
0
2 (16.7)
0
0
0
1 (16.7)
4 (6.9)
Vomiting
0
1 (33.3)
0
1 (8.3)
0
0
0
2 (33.3)
4 (6.9)
General Disorders and Administration 
Site Conditions
0
1 (33.3)
0
5 (41.7)
4 (36.4)
4 (44.4)
1 (9.1)
3 (50.0)
18 (31.0)
Fatigue
0
1 (33.3)
0
5 (41.7)
4 (36.4)
4 (44.4)
0
2 (33.3)
16 (27.6)
Pyrexia
0
0
0
2 (16.7)
0
0
1 (9.1)
0
3 (5.2)
Investigations
1 (33.3)
2 (66.7)
1 (33.3)
4 (33.3)
0
4 (44.4)
3 (27.3)
4 (66.7)
19 (32.8)
Alanine aminotransferase increased
0
1 (33.3)
1 (33.3)
2 (16.7)
0
0
1 (9.1)
2 (33.3)
7 (12.1)
Amylase increased
1 (33.3)
0
1 (33.3)
3 (25.0)
0
2 (22.2)
1 (9.1)
2 (33.3)
10 (17.2)
Aspartate aminotransferase 
increased
0
1 (33.3)
0
1 (8.3)
0
0
1 (9.1)
2 (33.3)
5 (8.6)
Blood thyroid stimulating hormone 
decreased
0
0
0
0
0
2 (22.2)
0
2 (33.3)
4 (6.9)
Blood thyroid stimulating hormone 
increased
0
0
0
0
0
1 (11.1)
1 (9.1)
1 (16.7)
3 (5.2)

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Table 1.4.3-2
Number of Subjects in the Q4W Cohorts with Treatment-related Adverse Events (All Grades), 
As-treated Population, Study D4190C00006
System Organ Class/Preferred Term 
(MedDRA V17.1)
M3/T1
(N = 3)
n (%)
M10/T1
(N = 3)
n (%)
M10/T3
(N = 3)
n (%)
M15/T1
(N = 12)
n (%)
M15/T3
(N = 11)
n (%)
M15/T10
(N = 9)
n (%)
M20/T1
(N = 11)
n (%)
M20/T3
(N = 6)
n (%)
Total
(N = 58)
n (%)
Gamma-glutamyltransferase 
increased
0
0
0
1 (8.3)
0
0
0
2 (33.3)
3 (5.2)
Lipase increased
0
0
0
3 (25.0)
0
1 (11.1)
1 (9.1)
2 (33.3)
7 (12.1)
Thyroxine free decreased
0
0
0
0
0
0
1 (9.1)
2 (33.3)
3 (5.2)
Metabolism and Nutrition Disorders
0
2 (66.7)
1 (33.3)
2 (16.7)
0
1 (11.1)
1 (9.1)
0
7 (12.1)
Decreased appetite
0
1 (33.3)
0
2 (16.7)
0
1 (11.1)
1 (9.1)
0
5 (8.6)
Musculoskeletal and Connective Tissue 
Disorders
0
2 (66.7)
1 (33.3)
4 (33.3)
3 (27.3)
1 (11.1)
0
1 (16.7)
12 (20.7)
Arthralgia
0
0
1 (33.3)
2 (16.7)
0
0
0
0
3 (5.2)
Myalgia
0
1 (33.3)
1 (33.3)
0
1 (9.1)
1 (11.1)
0
0
4 (6.9)
Respiratory, Thoracic and Mediastinal 
Disorders
0
0
0
0
2 (18.2)
2 (22.2)
1 (9.1)
0
5 (8.6)
Pneumonitis
0
0
0
0
2 (18.2)
2 (22.2)
0
0
4 (6.9)
Skin and Subcutaneous Tissue Disorders
0
1 (33.3)
2 (66.7)
1 (8.3)
5 (45.5)
5 (55.6)
1 (9.1)
2 (33.3)
17 (29.3)
Dry skin
0
0
0
0
0
2 (22.2)
0
1 (16.7)
3 (5.2)
Pruritus
0
0
1 (33.3)
0
2 (18.2)
2 (22.2)
1 (9.1)
1 (16.7)
7 (12.1)
Rash
0
0
1 (33.3)
1 (8.3)
3 (27.3)
1 (11.1)
1 (9.1)
0
7 (12.1)
MedDRA = Medical Dictionary for Regulatory Activities; M(x)/T(y) = durvalumab (x) mg/kg and tremelimumab (y) mg/kg; Q4W = every 4 weeks.

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Q2W Cohorts
Seven (43.8%) of 16 subjects in the Q2W cohorts experienced treatment-related AEs 
(Table 1.4.3-3). Colitis, diarrhea, fatigue, and pruritus were each reported in 2 subjects. All 
other events were reported in a single subject only. For most AEs, the incidence was higher 
in the durvalumab 10 mg/kg and tremelimumab 3 mg/kg group than the durvalumab 10 
mg/kg and tremelimumab 1 mg/kg group.

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Table 1.4.3-3
Number of Subjects in the Q2W Cohorts with Treatment-related Adverse Events (All 
Grades), As-treated Population, Study D4190C00006
System Organ Class/Preferred Term (MedDRA V17.1)
M10/T1 (N = 6)
n (%)
M10/T3 (N = 10)
n (%)
Total (N = 16)
n (%)
Total subjects reporting 1 or more events
1 (16.7)
6 (60.0)
7 (43.8)
Ear and Labyrinth Disorders
0
1 (10.0)
1 (6.3)
Tinnitus
0
1 (10.0)
1 (6.3)
Endocrine Disorders
0
1 (10.0)
1 (6.3)
Hyperthyroidism
0
1 (10.0)
1 (6.3)
Gastrointestinal Disorders
0
3 (30.0)
3 (18.8)
Colitis
0
2 (20.0)
2 (12.5)
Diarrhoea
0
2 (20.0)
2 (12.5)
General Disorders and Administration Site Conditions
1 (16.7)
1 (10.0)
2 (12.5)
Fatigue
1 (16.7)
1 (10.0)
2 (12.5)
Metabolism and Nutrition Disorders
0
1 (10.0)
1 (6.3)
Decreased appetite
0
1 (10.0)
1 (6.3)
Respiratory, Thoracic and Mediastinal Disorders
0
1 (10.0)
1 (6.3)
Pneumonitis
0
1 (10.0)
1 (6.3)
Skin and Subcutaneous Tissue Disorders
1 (16.7)
3 (30.0)
4 (25.0)
Pruritus
1 (16.7)
1 (10.0)
2 (12.5)
Rash 
0
1 (10.0)
1 (6.3)
Rash maculo-papular
0
1 (10.0)
1 (6.3)
MedDRA = Medical Dictionary for Regulatory Activities; M(x)/T(y) = durvalumab (x) mg/kg and tremelimumab (y) mg/kg; Q2W = every 2 weeks.

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Safety Comparison of Durvalumab 15 mg/kg Q4W, 20 mg/kg Q4W, and 10 
mg/kg Q2W Cohorts with Varying Doses of Tremelimumab
Both durvalumab and tremelimumab as monotherapy have a distinct safety profile in 
comparison to the combination of durvalumab and tremelimumab. 
In regards to durvalumab monotherapy as of 21Aug2014, 408 subjects have received 
durvalumab 10 mg/kg Q2W. AEs (all grades, regardless of causality) were reported in 372 of 
408 subjects (91%). A total of 170 subjects (42%) reported ≥ Grade 3 AEs; these events were 
considered to be treatment related in 30 subjects (7%). The most common treatment-related 
AE, regardless of severity, was fatigue (16%); ≥ Grade 3 fatigue occurred in 2% of subjects. 
In regards to tremelimumab monotherapy as of the data cutoff date of 12Nov2014, AEs were 
considered to be treatment related in 770 of 973 subjects (79.1%). A total of 485 subjects 
(49.8%) reported treatment related ≥ Grade 3 AEs. The most frequent treatment-related AEs 
(in > 5% of subjects) were diarrhea (41.2%), rash (27.2%), pruritus (25.1%), fatigue (23.8%), 
nausea (21.9%), vomiting (13.5%), decreased appetite (11.3%), headache (7.2%), pyrexia 
(7.0%), abdominal pain (6.7%), and colitis (5.5%).
In the cohort of durvalumab 15 mg/kg Q4W in combination with varying doses of 
tremelimumab (1 mg/kg [n = 12], 3 mg/kg [n = 11], and 10 mg/kg [n = 9]), the percentage of 
subjects who reported at least 1 treatment-related AE or treatment-related AE resulting in 
discontinuation of investigational product was numerically lower when durvalumab 15 
mg/kg Q4W was combined with tremelimumab 1 mg/kg versus higher tremelimumab doses 
(3 and 10 mg/kg; Table 1.4.3-4). Specifically, the durvalumab 15 mg/kg Q4W and 
tremelimumab 1 mg/kg cohort had a lower frequency of immune-mediated toxicities such as 
colitis and pneumonitis (Table 1.4.3-2). 
Similarly, the percentage of subjects who reported treatment-related AEs, ≥ Grade 3 
treatment-related events, or related AEs leading to discontinuation of investigational product 
was lower when durvalumab 20 mg/kg Q4W was combined with tremelimumab 1 mg/kg 
(n = 11) versus tremelimumab 3 mg/kg (n = 6)(Table 1.4.3-4). The clinical summary of the 
cohort treated with durvalumab 20 mg/kg Q4W and tremelimumab 3 mg/kg regimen is 
presented in Section 1.4.3.

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Table 1.4.3-4
Rate Summary of All Adverse Events in the Q4W Cohorts, As-treated Population, Study 
D4190C00006
Adverse Event Outcome
(MedDRA V17.1)
M3/T1
(N = 3)
n (%)
M10/T1
(N = 3)
n (%)
M10/T3
(N = 3)
n (%)
M15/T1
(N = 12)
n (%)
M15/T3
(N = 11)
n (%)
M15/T10
(N = 9)
n (%)
M20/T1
(N = 11)
n (%)
M20/T3
(N = 6)
n (%)
Total
(N = 58)
n (%)
1 or more event
3 (100)
3 (100)
3 (100)
12 (100)
11 (100)
9 (100)
7 (63.6)
6 (100)
54 (93.1)
1 or more Grade 3 event
0
2 (66.7)
3 (100)
9 (75.0)
5 (45.5)
7 (77.8)
3 (27.3)
6 (100)
35 (60.3)
1 or more Grade 4 event
0
1 (33.3)
1 (33.3)
1 (8.3)
0
0
1 (9.1)
1 (16.7)
5 (8.6)
1 or more serious event
1 (33.3)
2 (66.7)
2 (66.7)
7 (58.3)
7 (63.6)
7 (77.8)
2 (18.2)
6 (100)
34 (58.6)
1 or more event leading to 
discontinuation of study drug
1 (33.3)
1 (33.3)
2 (66.7)
2 (16.7)
5 (45.5)
3 (33.3)
0
5 (83.3)
19 (32.8)
Death
0
1 (33.3)
0
1 (8.3)
2 (18.2)
0
0
2 (33.3)
6 (10.3)
1 or more related event
1 (33.3)
3 (100)
3 (100)
7 (58.3)
9 (81.8)
8 (88.9)
7 (63.6)
5 (83.3)
43 (74.1)
1 or more ≥Grade 3 related event
0
2 (66.7)
2 (66.7)
5 (41.7)
4 (36.4)
4 (44.4)
2 (18.2)
5 (83.3)
24 (41.4)
1 or more related serious event
0
1 (33.3)
2 (66.7)
3 (25.0)
5 (45.5)
4 (44.4)
2 (18.2)
5 (83.3)
22 (37.9)
1 or more related event leading to 
discontinuation of study drug
0
1 (33.3)
2 (66.7)
1 (8.3)
4 (36.4)
3 (33.3)
0
4 (66.7)
15 (25.9)
Death related to study drug
0
1 (33.3)
0
0
0
0
0
1 (16.7)
2 (3.4)
MedDRA = Medical Dictionary for Regulatory Activities; M(x)/T(y) = durvalumab (x) mg/kg and tremelimumab (y) mg/kg; Q4W = every 4 weeks.

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The overall pattern and frequency of AEs noted in the durvalumab 10 mg/kg Q2W cohorts 
(Table 1.4.3-5) were similar to those seen in the Q4W cohorts. As noted above, a numerical 
increase in the percentage of subjects with previous mentioned types of AEs was observed in 
combination cohorts that included 3 mg/kg tremelimumab relative to 1 mg/kg tremelimumab 
(Table 1.4.3-3).

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Table 1.4.3-5
Rate Summary of All Adverse Events in the Q2W Cohorts, As-treated Population, Study 
D4190C00006
Adverse Event Outcome
(MedDRA V17.1)
M10/T1 (N = 6)
n (%)
M10/T3 (N = 10)
n (%)
Total (N = 16)
n (%)
1 or more event
2 (33.3)
6 (60.0)
8 (50.0)
1 or more Grade 3 event
2 (33.3)
4 (40.0)
6 (37.5)
1 or more Grade 4 event
0
0
0
1 or more serious event
1 (16.7)
5 (50.0)
6 (37.5)
1 or more event leading to 
discontinuation of study drug
1 (16.7)
1 (10.0)
2 (12.5)
Death
1 (16.7)
1 (10.0)
2 (12.5)
1 or more related event
1 (16.7)
6 (60.0)
7 (43.8)
1 or more ≥Grade 3 related event
0
2 (20.0)
2 (12.5)
1 or more related serious event
0
4 (40.0)
4 (25.0)
1 or more related event leading to 
discontinuation of study drug
0
1 (10.0)
1 (6.3)
Death related to study drug
0
0
0
MedDRA = Medical Dictionary for Regulatory Activities; M(x)/T(y) = durvalumab (x) mg/kg and tremelimumab (y) mg/kg; Q2W = every 2 weeks.

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In summary, safety data in NSCLC patients from the 15 or 20 mg/kg durvalumab Q4W 
combination cohorts in Study D4190C0006 demonstrated a numerical increase in the 
frequency of treatment-related AEs and related AEs leading to discontinuation of 
investigational product with increasing doses of tremelimumab. In addition, the frequency of 
select immune-mediated toxicities was lower with 1 mg/kg tremelimumab. The overall safety 
profile for the durvalumab Q4W and Q2W cohorts appeared similar. The safety profile for 20 
mg/kg durvalumab Q4W in combination with 1 mg/kg tremelimumab appeared comparable 
to the safety profile for 15 mg/kg durvalumab Q4W in combination with 1 mg/kg 
tremelimumab. 
Summary of PK, Pharmacodynamic, and ADA Data
Refer to the current durvalumab and tremelimumab IBs for the most recent detailed 
descriptions of PK, pharmacodynamic, and ADA data in all studies with durvalumab and 
tremelimumab combination therapy.
PK (n = 55), ADA (n = 60), and soluble PD-L1 (sPD-L1; n = 69) data were collected from 
10 cohorts following durvalumab Q4W or Q2W regimens. An approximately dose-
proportional increase in PK exposure (maximum plasma concentration and area under the 
plasma drug concentration-time curve from time 0 to Day 28 post-dose) of both durvalumab 
and tremelimumab was observed over the dose range of 3 to 20 mg/kg durvalumab Q4W or 
Q2W and 1 to 10 mg/kg tremelimumab Q4W.
Four of 60 subjects were ADA positive for anti- durvalumab antibodies post treatment. One 
of 53 subjects was ADA positive for anti-tremelimumab antibodies post treatment. No clear 
relationship between ADA and the dose of either durvalumab or tremelimumab was 
observed. No obvious association between ADA and safety or efficacy was observed. 
Target engagement for durvalumab was assessed using suppression of free sPD-L1 in serum. 
Following treatment with the durvalumab and tremelimumab combination, complete sPD-L1 
suppression (surrogate for PD-L1 targeting) was observed in almost all subjects over the dose 
range of 3 to 20 mg/kg durvalumab Q4W or Q2W. Two subjects (1 subject at 10 mg/kg 
durvalumab Q4W + 1 mg/kg tremelimumab Q4W and 1 subject at 15 mg/kg durvalumab
Q4W + 1 mg/kg tremelimumab Q4W) showed partial sPD-L1 suppression at some visits 
followed by complete suppression after repeated dosing. One subject who received 15 mg/kg 
durvalumab Q4W + 10 mg/kg tremelimumab Q4W showed partial suppression on Day 29 
and was ADA positive with an impact on PK. No clear dose-dependent changes in sPD-L1 
were identified over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W. There was 
evidence of augmented pharmacodynamic activity, most notably CD8 T cell proliferation, 

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relative to durvalumab monotherapy even with combination doses containing 1 mg/kg 
tremelimumab.
1.4.3.2
Clinical and PK Data for Combination Regimen of Durvalumab with Single 
Dose Schedule of Tremelimumab
The supporting data for this regimen are based on PK and pharmacodynamic data of doses of 
greater than 1 mg/kg from Study D4190C00006. As presented above, approximately dose-
proportional increases in PK exposure and activation/proliferation markers were noted with 
increasing doses of tremelimumab (1, 3, and 10 mg/kg). Higher Cmax of tremelimumab was 
related to a higher maximum pharmacodynamic effect in the NSCLC patient population. 
Based on simulation of pharmacokinetic data, the Cmax (78 μg/mL) post single dose 
administration of tremelimumab 4 mg/kg is approximately 4-fold higher than the predicted 
Cmax (19 μg/mL) post the first dose of tremelimumab 1 mg/kg, and is 3-fold higher than the 
predicted Cmax (25 μg/mL) post the fourth dose of tremelimumab 1 mg/kg in a Q4W × 4 
doses setting. Taken together, the above evidence suggests that the combination dose of 
durvalumab with a single dose of tremelimumab 4 mg/kg may provide a higher 
pharmacodynamic effect when compared with durvalumab with 4 doses of tremelimumab 
1 mg/kg.
1.4.4
Clinical Experience with Other Inhibitors of the PD-1/PD-L1 Pathway 
in Subjects with HCC
Nivolumab is a fully human anti-PD1 mAb that has been administered to 47 subjects with 
advanced HCC (n = 24 uninfected; n = 12 HCV positive; n = 11 HBV positive; 
El-Khoueiry et al, 2015) not amenable to curative resection at doses ranging from 0.1 to 
10 mg/kg Q2W (monotherapy dose for melanoma and NSCLC is 3 mg/kg; OPDIVO, 2015). 
The patient population enrolled in the nivolumab study is similar to the predicted patient 
population for this study with 68% of subjects having a history of prior sorafenib exposure. 
The most common (frequency ≥15%) treatment-related AEs were increased AST, increased 
lipase, rash, increased ALT, and increased amylase, with 4% (2/47) of subjects discontinuing 
because of an AE. The ORR was 19% (8/42) with 2 subjects experiencing complete 
responses (CRs).
1.4.5
Clinical Experience with Durvalumab and VEGF Inhibitors with HCC
Bevacizumab, a mAb targeting VEGF, is approved by the FDA for the treatment of several 
types of cancer, including colorectal cancer, non-small cell lung cancer, glioblastoma, renal 
cell carcinoma, cervical cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer.

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A Phase II trial evaluating the clinical and biologic effects of bevacizumab in advanced
hepatocellular carcinoma (Siegel et al 2008) included 46 patients, of whom 6 had objective 
responses (13%; 95% CI: 3% to 23%), and 65% were progression free at 6 months. Median 
PFS time was 6.9 months (95% CI: 6.5 to 9.1 months); OS rate was 53% at 1 year, 28% at 2 
years, and 23% at 3 years. Grade 3 to 4 AEs included hypertension (15%) and thrombosis 
(6%, including 4% with arterial thrombosis). Safety results showed a Grade 3 or higher 
haemorrhage occurred in 11% of patients, including 1 fatal variceal bleed.
Additional evidence suggests that the combination of PD-L1 inhibition with VEGF inhibition 
may result in synergistic activity and improved clinical benefit (Barsoum et al 2014, Voron et 
al 2015, Yasuda et al 2013). In a recent Phase Ib study, atezolizumab (a PD-L1 inhibitor) and 
bevacizumab therapy as first-line treatment in patients with HCC showed promising clinical 
activity, with an ORR of 65% (Stein et al 2018). Another Phase Ib study, pembrolizumab (a 
PD-1 inhibitor) and lenvatinib therapy in patients with advanced HCC showed an ORR of 
46% (6 out of 13 patients; Ikeda et al 2018). These data indicate further evaluation of 
durvalumab therapy in combination with VEGF inhibitor therapy in patients with HCC 
concurrent with administration of TACE is warranted.
1.5
Rationale for Conducting the Study
HCC is the third-leading cause of cancer death worldwide (Parkin et al, 2005; 
Altekruse et al, 2009). The current treatment paradigm for HCC utilizes multimodality 
therapy, including surgical resection, liver transplantation and/or local regional therapies 
such as radiofrequency ablation with curative intent in early-stage disease. Unfortunately, 
those patients who do not qualify for curative treatment have limited treatments options, 
which primarily include bland transarterial embolization, transarterial embolization with 
chemo or radioactive particles, or systemic therapy with sorafenib. In the noncurative setting, 
sorafenib is the only option that has been shown to extend survival (median OS, 10.7 months 
for sorafenib vs 7.9 months for placebo). However, its benefit is primarily limited to those 
patients with well-preserved liver function (Child-Pugh class A; Llovet et al, 2008; 
Pressiani et al, 2013). Recently, regorafenib and nivolumab have been approved as second 
line therapy for advanced HCC in some countries/areas. Regorafenib has been shown to 
extend survival (median OS, 10.6 months for regorafenib vs 7.8 months for placebo) in 
second-line HCC patients (Bruix et al, 2017). Nivolumab has been shown encouraging 
response rate of 14% in patients with or without previous sorafenib and the responses are 
durable (El-Khoueiry et al, 2017).  However, with these new treatment options, the overall 
outcome of patients with advanced HCC are still poor. Therefore, HCC represents a 
significant unmet medical need.

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1.5.1
Benefit-risk Evaluation
Emerging data demonstrate encouraging clinical activity with durvalumab and tremelimumab 
in HCC. In the ongoing Study CD-ON- durvalumab -1108, durvalumab monotherapy 
prolonged SD (≥ 3 months) in 4 of 19 evaluable subjects (21%) with advanced HCC. In 
addition, evaluation of single-agent tremelimumab administered with a suboptimal dosing 
schedule (15 mg/kg every 90 days) in subjects with HCV-associated HCC demonstrated an 
ORR of 18% (3 of 17 subjects; Sangro et al, 2013). These data combined with emerging 
clinical data from other mAb inhibitors of the PD-1/PD-L1 pathway (nivolumab with ORR 
of 19% [8/42]; El-Khoueiry et al, 2015), as well as nonclinical and clinical data suggesting 
improved anticancer activity with the durvalumab 20 mg/kg and tremelimumab 1 mg/kg 
combination as compared to either agent alone, make a compelling case for evaluation of this 
combination in HCC (Antonia et al 2016). 
Bioanalytical data evaluating increasing dose levels of tremelimumab (1, 3, 10 mg/kg) in 
NSCLC patient population shows a dose-proportional monotonic increase in 
pharmacodynamic activity, suggesting that a higher dose of tremelimumab may result in 
higher antitumor activity. Studies evaluating tremelimumab either as a single agent or in 
combination with TACE/ablation in HCC population have used doses higher than 1 mg/kg 
Q4W of tremelimumab (15 mg/kg every 90 days as monotherapy and 3.5 or 10 mg/kg Q4W 
in combination with TACE/ablation) and have demonstrated a high response rate of 18% and 
26%, respectively (Sangro et al 2013 and Duffy et al 2016). These data suggest that a higher 
dose of tremelimumab in combination with durvalumab may provide better efficacy in HCC 
population. Additionally, as described in Section 1.4.3.2, a single high dose of tremelimumab 
may provide a higher peak pharmacodynamic effect when compared with multiple lower 
doses while potentially avoiding the toxicity that may be associated with repeated dosing of 
tremelimumab. Taken together, these data support the evaluation of a higher dose of 
tremelimumab as a single-dose in combination with durvalumab.
Potential risks are associated with durvalumab and tremelimumab given their mechanism of 
action and data from studies of relevant or similar therapies. The frequency and/or severity of 
immune-related adverse events (irAEs) may be increased when these 2 drugs are 
administered in combination as compared to their monotherapy safety profiles. It is also 
possible that the higher doses of tremelimumab in combination with durvalumab may be 
associated with a higher rate and/or severity of irAEs when compared to the standard 
durvalumab plus tremelimumab combination regimen. For durvalumab monotherapy, the 
identified risks include pneumonitis, increased ALT/AST, hepatitis, diarrhea, colitis, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypopituitarism, type 1 diabetes 

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mellitus, increased blood creatinine, nephritis, rash, pruritus, dermatitis, and infusion-related 
reaction. Important potential risks are immune-mediated reactions such as pancreatitis 
(including elevated amylase and lipase); hypophysitis/hypopituitarism; 
neuropathy/neuromuscular toxicity (eg, myasthenia gravis and Guillain-Barré syndrome); 
other rare events such as myocarditis, pericarditis, and uveitis; hypersensitivity reactions 
(including anaphylaxis and allergic reaction, cytokine release syndrome, and immune 
complex disease); and serious infections. For tremelimumab, identified risks include 
diarrhea, nausea, fatigue, rash, pruritus, decreased appetite, vomiting, pyrexia, influenza-like 
illness, arthralgia, constipation, thrombocytopenia, injection site reaction, and increased
AST. Important potential risks are immune-mediated reactions such as hepatitis, including 
autoimmune hepatitis and increased serum ALT and AST; respiratory tract events, including 
pneumonitis and interstitial lung disease (ILD); nervous system events, including 
encephalitis, peripheral motor and sensory neuropathies, proximal muscle weakness, and 
Guillain-Barré syndrome; cytopenias, including thrombocytopenia, anemia, and neutropenia; 
renal failure, acute kidney injury, nephritis and nephrotic syndrome, including autoimmune 
nephritis, and electrolyte abnormalities; autoimmune diseases, including autoimmune 
arthritis, Sjogren’s syndrome, giant cell temporal arteritis, and ulcerative colitis; 
hyperglycemia, including diabetes mellitus; infusion reactions and acute immunoglobulin E 
(IgE)-mediated allergic reactions; dehydration; nausea; vomiting; pyrexia; and hypokalemia. 
Several strategies have been incorporated in the study protocol to mitigate these risks 
(Section 3.1.3).
Hepatocellular carcinoma subjects with HBV infection may be at an increased risk for 
complications from an immune-modulatory anticancer therapy. While patients with 
HBV and HCV, in the absence of HCC, experience hepatic flares (defined minimally by 
ALT > 5 × ULN), the precipitating factors, incidence, and outcome vary significantly 
between the 2 populations. Hepatitis B virus flares can be precipitated by a variety of agents 
(steroids, rituximab, anti-tumor necrosis factor [TNF] agents, and highly active 
antiretroviral therapy) and can lead to liver decompensation, fulminant hepatic 
failure, and death, particularly if viral replication is not suppressed by antiviral medications 
(Chang and Liaw, 2014; Perrillo et al, 2015). In contrast, HCV flares are much less 
common and do not lead to liver decompensation, fulminant hepatic failure, or death 
(Sagnelli et al, 2014). For those subjects with HCC in the setting of HBV or HCV, 
additional data from monotherapy administration of durvalumab (Section 1.4.1), 
tremelimumab (Section 1.4.2), and nivolumab (Section 1.4.4) provide reassurance with 
regards to the safety risk of these 2 agents in this clinical setting. 

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An understanding of the potential difference in benefit-risk analysis for the different HCC 
populations has influenced the study design in several ways: 
1. Inclusion of a safety run-in evaluation of the combination of durvalumab 20 mg/kg with 
tremelimumab 1 mg/kg x 4 doses in a limited number of subjects in each viral population 
(uninfected, HCV, and HBV) prior to exposure of a larger number of subjects in the 
randomized portion of the study.
2. Risk-based staggered assessment of the combination of durvalumab 20 mg/kg with 
tremelimumab 1 mg/kg x 4 doses (in the safety run-in portion of the study) in subjects 
(uninfected and HCV+) who might have a better benefit-risk profile as compared to those 
whose safety risk could be higher (HBV+).
3. Potential for evaluation of Dose Level -1 in HBV+ subjects if the combination regimen of 
durvalumab 20 mg/kg with tremelimumab 1 mg/kg x 4 doses is not tolerated as assessed 
by prospectively defined parameters. 
4. Collection of noncancerous liver tissue at screening to help guide management of any 
hepatotoxic AEs is also requested if it can be done safely (as judged by the investigator)
during the same procedure in which the tumor tissue biopsy is obtained.
5. Specific hepatotoxicity guidelines and eligibility criteria developed in cooperation with 
hepatologists specializing in HBV and HCV infection.
6. Requirement for all subjects with HBV infection to be on antiviral medications for 
adequate viral suppression.
7. Inclusion of a safety run-in evaluation of durvalumab in combination with a higher single 
dose of tremelimumab in Part 2B in a limited number of subjects prior to exposure of a 
larger number of subjects in the randomized portion (Part 3) of the study.
Bevacizumab has been approved by the FDA for the treatment of several types of cancers, 
although it is not currently approved for the treatment of HCC. Several studies are currently 
underway in evaluating the combination of bevacizumab (VEGF inhibitor) with 
atezolizumab (PD-L1 inhibitor) in patients with a variety of tumor types, including HCC. 
NCT02715531 is an ongoing, open-label, Phase Ib study of the safety and efficacy of 
atezolizumab (a PD-L1 inhibitor) and bevacizumab in patients with solid tumors, including 1 
arm in patients with metastatic or advanced HCC with no prior treatment. As of the data 
cutoff (October 24, 2017), 26 pts were evaluable for safety. Treatment-related all grade AEs 
occurred in 21 patients (81%). Treatment-related Grade 3-4 AEs were seen in 9 patients 
(35%), most commonly hypertension (n=5 patients [19%]). No grade 5 AEs were observed. 
Two patients (8%) experienced 3 treatment-related Grade 3 SAEs (autoimmune encephalitis, 
mental status change, and intra-abdominal haemorrhage). Immune-related AEs requiring 
corticosteroid treatment occurred in 3 patients (12%). The combination of atezo + bev is safe 
and well tolerated; no new safety signals were identified beyond the established safety profile 
for each agent. As of the data cutoff (11 January 2018), 23 patients had a median of 10.3 

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months of follow up (range: 3.5 to 17.3 months). The confirmed ORR was 61% based on 
Investigator assessment and 65% based on independent review. Disease control was 
maintained for ≥6 months in 65% of all patients and 70% of responders (Stein et al 2018).
The preliminary safety of durvalumab in combination with bevacizumab has been established 
in NCT02802098 (unpublished data) and NCT02336165. In NCT02336165, in patients with 
bevacizumab-refractory, recurrent glioblastoma, durvalumab combined with continuing 
bevacizumab therapy was shown to be well tolerated (Reardon et al 2017).
Preclinical as well as recent clinical data support the synergistic antitumor effect of PD-L1 
inhibition combined with VEGF inhibition. The preliminary safety data has been established 
and is generally well tolerated. Therefore, the overall benefit/risk assessment supports the 
proposed study to evaluate the efficacy and safety of durvalumab in combined with a 
VEGFR inhibitor in advanced HCC.
1.6
Research Hypothesis
Durvalumab and tremelimumab as monotherapy, and durvalumab in combination with 
tremelimumab or bevacizumab can be administered to subjects with advanced HCC with 
adequate safety, tolerability, and efficacy. 
2
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objectives
1. To assess the safety and tolerability of durvalumab and tremelimumab administered as 
monotherapy, and durvalumab in combination with tremelimumab or bevacizumab in
subjects with advanced HCC. 
2.1.2
Secondary Objectives
1. To evaluate the efficacy of durvalumab and tremelimumab administered as monotherapy,
and durvalumab in combination with tremelimumab or bevacizumab in subjects with 
advanced HCC.
2. To evaluate the relationship between candidate biomarkers (eg, PD-L1 expression in the 
tumor microenvironment) and measures of clinical outcome of durvalumab and 
tremelimumab administered as monotherapy, and durvalumab in combination with 
tremelimumab or bevacizumab in subjects with advanced HCC.

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2.1.3
Exploratory Objectives
2.2
Study Endpoints
2.2.1
Primary Endpoints
1. AEs, SAEs, discontinuation of investigational product(s) due to toxicity, and changes 
from baseline in laboratory parameters (including liver and viral laboratory tests), 
electrocardiograms (ECG), and vital signs.
2.2.2
Secondary Endpoints
1. Objective response rate (ORR), disease control rate (DCR), time to response (TTR), 
duration of response (DoR), time to progression (TTP), and progression-free survival 
(PFS) based on investigator assessments and Blinded Independent Central Review 
(BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
(Eisenhauer et al, 2009), and overall survival (OS).
2. AEs, SAEs, discontinuation of investigational product(s) due to toxicity, and changes 
from baseline in laboratory parameters (including liver and viral laboratory tests), ECG, 
and vital signs in 3 distinct HCC populations: uninfected, HBV+, and HCV+.
3. PD-L1 expression within the tumor microenvironment.
&&,

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2.2.3
Exploratory Endpoints
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a multicenter, open-label, stratified, study designed to evaluate the safety, tolerability, 
and clinical activity of durvalumab and tremelimumab administered as monotherapy, and 
durvalumab in combination with tremelimumab or bevacizumab in subjects with advanced 
HCC. The study will comprise of 6 parts described below and illustrated in Figure 3.1.1-1. 
Approximately 655 subjects will be screened to enroll approximately 456 subjects globally, 
including approximately 12 subjects in Part 1A, approximately 24 subjects in Part 1B, 
approximately 108 subjects in Part 2A, approximately 12 subjects in Part 2B, approximately 
200 subjects in Part 3, and approximately 100 subjects in Part 4.
Following protocol amendment 5, enrollment into Part 3 Arm A will be closed. Patients 
who have been randomized to Arm A before this protocol amendment, can continue on 
assigned study treatment (provided the investigator and patient think it is in the best 
&&,

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interests of the patient) until confirmed PD or any other discontinuation criteria as 
described in section 4.1.6 is met. If a patient has not completed or started all 4 doses of 
tremelimumab, the patient may either continue to complete the full schedule or 
continue with durvalumab monotherapy only.
Figure 3.1.1-1
Study Flow Diagram
2L = second line; 1L = first line; HBV+ = hepatitis B virus positive; HCC = hepatocellular carcinoma; HCV+ = 
hepatitis C virus positive; D = durvalumab; T = tremelimumab; B = Bevacizumab
Part 1A: Safety Run-in with Durvalumab and Tremelimumab Combination 
Therapy
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant 
of, or refused sorafenib-based therapy will be enrolled in Part 1A using a risk-based 
staggered approach. 
•
Stage 1: Approximately 6 subjects with advanced uninfected or HCV+ HCC will be 
enrolled (rationale for excluding HBV+ HCC subjects is explained in Section 1.4.4). 
Subjects will be administered the durvalumab 20 mg/kg and tremelimumab 1 mg/kg 
combination therapy Q4W for 4 doses followed by durvalumab 20 mg/kg monotherapy 
Q4W until confirmed PD or any other discontinuation criteria as described in 
Section 4.1.6 is met. If the frequency of AEs meeting DLT criteria is ≥ 33% for a given 
viral status/type, then lower dose cohorts in that specific subpopulation may be explored 
depending on the type and severity of the toxicities seen at this combination dose.
•
Stage 2:

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◦
HBV+ Cohort: Enrollment of 6 additional subjects with advanced HBV+ HCC may 
start after the first 3 subjects in Stage 1 have been observed on study for at least 4 
weeks. Subjects will be administered durvalumab 20 mg/kg and tremelimumab 
1 mg/kg combination therapy Q4W for 4 doses followed by durvalumab 20 mg/kg 
monotherapy Q4W until confirmed PD or any other discontinuation criteria as 
described in Section 4.1.6 is met. If the frequency of AEs meeting DLT criteria is ≥ 
33%, then Dose Level -1 (ie, durvalumab 15 mg/kg and tremelimumab 1 mg/kg 
combination therapy Q4W followed by durvalumab 15 mg/kg monotherapy Q4W 
until confirmed PD or any other discontinuation criteria as described in Section 4.1.6
is met) may be explored depending on the type and severity of the toxicities seen at 
this combination dose. 
◦
Dose for HBV+ HCC Subjects Administered the Durvalumab and Tremelimumab 
Combination: durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy 
Q4W for 4 doses followed by durvalumab 20 mg/kg monotherapy Q4W will be the 
dose evaluated for HBV+ subjects in Part 1B and Part 2A if the following criteria are 
met: (1) all 6 subjects have been observed for at least 4 weeks and the DLT frequency 
is < 33% (ie, < 2 of 6 subjects); AND (2) at least 3 of the 6 subjects have been 
observed for 6 weeks. If the DLT frequency for the Stage 2 is ≥ 33% (ie, ≥2 of 6 
subjects), then Dose Level -1 (ie, durvalumab 15 mg/kg and tremelimumab 1 mg/kg 
combination therapy Q4W for 4 doses followed by durvalumab 15 mg/kg 
monotherapy Q4W until confirmed PD or any other discontinuation criteria as 
described in Section 4.1.6 is met) will be the dose evaluated for HBV+ subjects in 
Part 1B and Part 2A assuming the DLT frequency at Dose Level -1 is < 33%.
Part 1B: Efficacy Gating Cohort for Durvalumab and Tremelimumab 
Combination Therapy
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant 
of, or refused sorafenib-based therapy will be enrolled in Part 1B.
Approximately 24 subjects (uninfected, HBV infected, or HCV infected) will be enrolled in 
an efficacy gating cohort to determine if there is sufficient evidence of clinical activity to 
warrant opening enrollment to Part 2. Refer to Section 4.8.7 for details regarding the 
definition of sufficient evidence. Subjects will be administered durvalumab 20 mg/kg and 
tremelimumab 1 mg/kg combination therapy Q4W for 4 doses followed by durvalumab
20 mg/kg monotherapy Q4W until confirmed PD or any other discontinuation criteria as 
described in Section 4.1.6 is met. After approximately 12 of the 24 subjects have been 
enrolled, enrollment of subjects who have progressed on or are intolerant to sorafenib may be
paused in favor of subjects who have refused sorafenib to ensure a minimum enrollment of 
12 subjects who have refused sorafenib in Part 1 (A and B). The total number of subjects 
with a specific viral status may be restricted in this cohort to ensure that all types of patients 
have an opportunity to enroll. For example, as enrollment proceeds if emerging data indicate 

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that the majority of patients enrolling are all HBV infected, enrollment of this specific viral 
type of HCC may be paused to allow other types of subjects (uninfected and HCV infected) 
to enroll.
If during Part 1B of the study, ≥ 33% of subjects with a specific viral status type discontinue 
therapy for treatment-related toxicity, enrollment for that specific viral status type may be 
paused and study data will be reviewed to determine whether additional monitoring, alternate 
dose levels, or treatment schedules should be evaluated prior to further enrollment of subjects 
with that specific viral status type. 
Part 2A: Randomized Arms Evaluating Durvalumab and Tremelimumab 
Combination Therapy, Durvalumab Monotherapy, and Tremelimumab 
Monotherapy
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant 
of, or refused sorafenib-based therapy, will be stratified based on viral status (uninfected, 
HCV infected, or HBV infected) and PD-L1 expression (positive, negative, or non-
evaluable).
•
Subjects may not enroll into any arm of Part 2A until sufficient evidence, as specified in 
Section 4.8.7 (in Part 1A and Part 1B), is observed 
•
Subjects will be randomized 1:1:1 within each stratum to 1 of the 3 treatment arms with 
approximately 36 subjects (approximately 12 subjects/viral status type) per treatment 
arm:
◦
Arm A: Durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy 
Q4W for 4 doses followed by durvalumab 20 mg/kg monotherapy Q4W until 
confirmed PD or any other discontinuation criteria as described in Section 4.1.6 is 
met
◦
Arm B: Durvalumab 20 mg/kg monotherapy Q4W until confirmed PD or any other 
discontinuation criteria as described in Section 4.1.6 is met 
◦
Arm C: Tremelimumab 10 mg/kg monotherapy Q4W for 7 doses followed by every 
12 weeks (Q12W) until confirmed PD or any other discontinuation criteria as 
described in Section 4.1.6 is met
If during Part 2A of the study, ≥ 33% of subjects with a specific viral status type within a 
given arm discontinue therapy for treatment-related toxicity, enrollment for that specific viral 
status type may be paused and study data will be reviewed to determine whether additional 
monitoring, alternate dose levels, or treatment schedules should be evaluated prior to further 
enrollment of subjects with that specific viral status type. Enrollment into any arm of Part 2A 

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may be discontinued at the discretion of the sponsor should emerging clinical or nonclinical 
data suggest that continued treatment may not be beneficial to a given arm.
All subjects in Part 1A, Part 1B, and Part 2A will be evaluated for efficacy, as specified in 
the protocol (Section 4.2), and their disease status primarily analyzed according to RECIST 
v1.1. All subjects will be followed for survival until the end of study, as defined in section 
6.3. For biomarker analysis, subjects will be required to have a fresh tumor tissue biopsy at 
screening, an optional post-dose biopsy, and an optional biopsy at disease progression. 
Collection of noncancerous liver tissue at screening should also be attempted if it can be 
done safely (as judged by the investigator) during the same procedure in which the fresh 
tumor tissue biopsy is obtained. Evaluation of PD-L1 expression status will be done in real-
time while the study is ongoing.
Part 2B: Safety Run-in for Additional Treatment Regimen of Durvalumab and 
Tremelimumab Combination Therapy
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant 
to, or have refused sorafenib-based therapy will be enrolled in Part 2B. 
Approximately 6 to 12 subjects will be enrolled into Arm D evaluating a single higher dose 
of tremelimumab in combination with durvalumab:
◦
Arm D: durvalumab 1500 mg and tremelimumab 300 mg combination therapy for 
1 dose followed by durvalumab 1500 mg monotherapy Q4W until confirmed PD or 
any other discontinuation criteria as described in Section 4.1.6 is met
A safety evaluation will be performed once 6 safety evaluable subjects have completed 4 
weeks of follow-up. A safety evaluable subject is defined as a subject who has received at 
least 1 dose of study drug and completed at least 4 weeks of follow-up or discontinued 
treatment prior to the completion of 4 weeks of follow-up due to an adverse event. 
Enrollment into Part 2B may be discontinued at the discretion of the sponsor should 
emerging clinical or nonclinical data suggest that continued treatment may not be beneficial. 
For biomarker analysis, all subjects in Part 2B will be required to have a newly acquired 
(fresh or acquired within 3 months, preferred) or archival (< 3 years) tissue sample at 
screening, an optional post-dost biopsy, and an optional biopsy at disease progression. 

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Part 3: Randomized Arms Evaluating Durvalumab and Tremelimumab 
Combination Therapy, Durvalumab Monotherapy, and Tremelimumab 
Monotherapy
Immunotherapy-naive subjects with advanced HCC who have progressed on, are intolerant 
to, or have refused sorafenib-based therapy will be stratified based on viral status 
(uninfected, HCV infected, or HBV infected) and sorafenib-based therapy (refusers or all 
others). Subjects will be stratified to the HCV positive cohort if they test positive for HCV or 
have a history of HCV infection. 
•
Subjects may not enroll into any arm of Part 3 until enrollment in Part 2A and Part 2B 
has been completed and the safety evaluation of the first 6 subjects in Part 2B is 
completed.
•
Subjects will be randomized at a ratio of 2:1:2 into 1 of up to 3 treatment arms with 
approximately 64 subjects in each of the durvalumab monotherapy or combination 
treatment arms (Arms B and D) and approximately 32 subjects in the tremelimumab 
monotherapy treatment arm (Arm C). No prerequisite number of subjects for viral status 
is set for any arm in Part 3: 
◦
Arm A (recruitment closed following protocol amendment 5): durvalumab 1500 mg 
and tremelimumab 75 mg combination therapy Q4W for 4 doses followed by 
durvalumab 1500 mg monotherapy Q4W until confirmed PD or any other 
discontinuation criteria as described in Section 4.1.6 is met. Following protocol 
amendment 5, enrollment into Part 3 Arm A will be closed. Patients who have been 
randomized to Arm A before this protocol amendment, can continue on assigned 
study treatment (provided the investigator and patient think it is in the best interests of 
the patient) until confirmed PD or any other discontinuation criteria as described in 
Section 4.1.6 is met.  If a patient has not completed or started all 4 doses of 
tremelimumab, the patient may either continue to complete the full schedule, or 
continue with durvalumab monotherapy only.
◦
Arm B: durvalumab 1500 mg monotherapy Q4W until confirmed PD or any other 
discontinuation criteria as described in Section 4.1.6 is met
◦
Arm C: Tremelimumab 750 mg monotherapy Q4W for 7 doses followed by Q12W 
until confirmed PD or any other discontinuation criteria as described in Section 4.1.6
is met

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◦
Arm D: durvalumab 1500 mg and tremelimumab 300 mg combination therapy for 
1 dose followed by durvalumab 1500 mg monotherapy Q4W until confirmed PD or 
any other discontinuation criteria as described in Section 4.1.6 is met
All subjects in Part 3 will be evaluated for safety and efficacy as specified in the protocol, 
and their disease status will be primarily analyzed according to RECIST v1.1. An interim 
analysis will occur after approximately 10 subjects per treatment arm in Part 3 have 
completed 4 weeks of follow-up as described in Section 4.8.7. All subjects will be followed 
for survival until the end of study as defined in section 6.3. 
For biomarker analysis, subjects will be required to have a newly acquired (fresh or acquired 
within 3 months, preferred) or archival (< 3 years) tissue sample at screening, an optional 
post-dost biopsy, and an optional biopsy at disease progression. 
Enrollment into any arm of Part 3 may be discontinued at the discretion of the sponsor should 
emerging clinical or nonclinical data suggest that continued treatment may not be beneficial 
in a given arm. 
The endpoints to be measured in this study are described in Section 2.2.
Part 4: Single Arm Evaluating Durvalumab with Bevacizumab in Combination. 
Subjects with advanced HCC who have not received any prior systemic therapy can be 
enrolled into Part 4. Approximately 100 subjects will be enrolled into a single arm in Part 4 
to evaluate the safety and efficacy of durvalumab in combination with bevacizumab:  
◦
Durvalumab 15mg/kg (1120 mg) and bevacizumab 15 mg/kg combination therapy 
Q3W until confirmed PD or any other discontinuation criteria as described in Section 
4.1.6 is met
All subjects in Part 4 will be evaluated for safety and efficacy as specified in the protocol, 
and their disease status will be primarily analyzed according to RECIST 1.1. An interim 
analysis will occur after approximately 100 subjects in Part 4 have had the opportunity for 18 
weeks of follow-up. Another interim analysis will occur after approximately 100 subjects in 
Part 4 have had the opportunity for 36 weeks of follow-up.
All subjects will be followed for survival until the end of study as per section 6.3.

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For biomarker analysis, subjects will be required to have a newly acquired (fresh or acquired 
within 3 months, preferred) or archival (< 3 years) tissue sample at screening.
3.1.2
Treatment Regimen
Subjects in Part 1A, Part 1B, and Part 2A will receive weight-based dosing regimens of 
durvalumab and tremelimumab either as monotherapy or as combination therapy. Subjects in 
Part 2B and Part 3 will receive a fixed dosing regimen of durvalumab and tremelimumab 
either as monotherapy or as combination therapy as described in Table 3.1.2-1.
Table 3.1.2-1
Treatment and Regimens
Study Part
Dosing Regimen
Part 1A and Part 1B
Combination therapy
(see Figure 3.1.2-1)
Durvalumab 20 mg/kg (or 15 mg/kg for Dose Level -1, if needed) in 
combination with tremelimumab 1 mg/kg Q4W for 4 doses. After 
completion of the combination therapy, subjects will receive durvalumab
monotherapy at 20 mg/kg Q4W until any of the discontinuation criteria in 
Section 4.1.6 are met. The first durvalumab monotherapy dose at 20 mg/kg 
Q4W will be given 4 weeks after the final dose of durvalumab and 
tremelimumab combination therapy. Subjects who progress on durvalumab
monotherapy may be retreated with the durvalumab and tremelimumab 
combination as described in Section 3.1.2.1.
Part 2A
Arm A
Combination therapy
(see Figure 3.1.2-1)
Durvalumab 20 mg/kg (or 15 mg/kg for Dose Level -1, if needed) in 
combination with tremelimumab 1 mg/kg Q4W for 4 doses. After 
completion of the combination therapy, subjects will receive durvalumab
monotherapy at 20 mg/kg Q4W until any of the discontinuation criteria in 
Section 4.1.6 are met. The first durvalumab monotherapy dose at 20 mg/kg 
Q4W will be given 4 weeks after the final dose of durvalumab and 
tremelimumab combination therapy. Subjects who progress on durvalumab
monotherapy may be retreated with the durvalumab and tremelimumab 
combination as described in Section 3.1.2.1.
Arm B
Durvalumab monotherapy
(see Figure 3.1.2-2)
Durvalumab monotherapy at 20 mg/kg Q4W until any of the 
discontinuation criteria in Section 4.1.6 are met.
Arm C
Tremelimumab monotherapy
(see Figure 3.1.2-3)
Tremelimumab monotherapy at 10 mg/kg, Q4W for 7 doses and then every 
12 weeks until any of the discontinuation criteria in Section 4.1.6are met.
Part 2B
Arm D
Combination therapy
(see Figure 3.1.2-4)
Durvalumab 1500 mg in combination with tremelimumab 300 mg for 
1 dose. After completion of the combination therapy, subjects will receive 
durvalumab monotherapy at 1500 mg Q4W until any of the discontinuation 
criteria in Section 4.1.6 are met. The first durvalumab monotherapy dose at 
1500 mg Q4W will be given 4 weeks after the final dose of durvalumab
and tremelimumab combination therapy. Subjects who progress on 
durvalumab monotherapy may be retreated with the durvalumab and 
tremelimumab combination as described in Section 3.1.2.1.

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Table 3.1.2-1
Treatment and Regimens
Study Part
Dosing Regimen
Part 3
Arm A (recruitment closed 
following protocol 
amendment 5)
Combination therapy
(see Figure 3.1.2-1)
Durvalumab 1500 mg in combination with tremelimumab 75 mg Q4W for 
4 doses. After completion of the combination therapy, subjects will receive 
durvalumab monotherapy at 1500 mg Q4W until any of the discontinuation 
criteria in Section 4.1.6 are met. The first durvalumab monotherapy dose at 
1500 mg Q4W will be given 4 weeks after the final dose of durvalumab 
and tremelimumab combination therapy. Subjects who progress on 
durvalumab monotherapy may be retreated with the durvalumab and 
tremelimumab combination as described in Section 3.1.2.1.
Following protocol amendment 5, enrollment into Part 3 Arm A will be 
closed. Patients who have been randomized to Arm A before this 
protocol amendment, can continue on assigned study treatment 
(provided the investigator and patient think it is in the best interests of 
the patient) until confirmed PD or any other discontinuation criteria as 
described in Section 4.1.6 is met. If a patient has not completed or started
all 4 doses of tremelimumab, the patient may either continue to complete 
the full schedule, or continue with durvalumab monotherapy only.
Arm B
Durvalumab monotherapy
(see Figure 3.1.2-2)
Durvalumab monotherapy at 1500 mg Q4W until any of the 
discontinuation criteria in Section 4.1.6 are met.
Arm C
Tremelimumab monotherapy
(see Figure 3.1.2-3)
Tremelimumab monotherapy at 750 mg, Q4W for 7 doses and then every 
12 weeks until any of the discontinuation criteria in Section 4.1.6 are met
Arm D
Combination therapy
(see Figure 3.1.2-4)
Durvalumab 1500 mg in combination with tremelimumab 300 mg for 
1 dose. After completion of the combination therapy, subjects will receive 
durvalumab monotherapy at 1500 mg Q4W until any of the discontinuation 
criteria in Section 4.1.6 are met. The first durvalumab monotherapy dose at 
1500 mg Q4W will be given 4 weeks after the final dose of durvalumab
and tremelimumab combination therapy. Subjects who progress on 
durvalumab monotherapy may be retreated with the durvalumab and 
tremelimumab combination as described in Section 3.1.2.1.
Part 4 
Combination Therapy
(see Figure 3.1.2-5)
Durvalumab 15mg/kg (1120 mg) in combination with Bevacizumab 15 
mg/kg Q3W until any of the discontinuation criteria in Section 4.1.6 are 
met. Subjects who progress on this combination therapy may not be 
retreated.
Q4W = every 4 weeks, Q12W = every 12 weeks, Q3W = every 3 weeks 
The treatment regimen for durvalumab and tremelimumab combination therapy for Part 1A, 
Part 1B, and Part 2A Arm A is illustrated in Figure 3.1.2-1 below. 

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Figure 3.1.2-1
Durvalumab and Tremelimumab Combination Therapy 
Treatment Schedule 
Q4W = every 4 weeks.
The treatment regimen for durvalumab monotherapy (Part 2A Arm B and Part 3 Arm B) is 
illustrated in Figure 3.1.2-2.

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Figure 3.1.2-2
Durvalumab Monotherapy Treatment Schedule
Q4W = every 4 weeks.
The treatment regimen for tremelimumab monotherapy (Part 2A Arm C and Part 3 Arm C) is 
illustrated in Figure 3.1.2-3.

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Figure 3.1.2-3
Tremelimumab Monotherapy Treatment Schedule
Q4W = every 4 weeks: Q12W = every 12 weeks.
The treatment regimen for durvalumab and tremelimumab combination therapy for Part 2B 
Arm D and Part 3 Arm D is shown in Figure 3.1.2-4.
Figure 3.1.2-4
Durvalumab and Tremelimumab Combination Therapy 
Treatment Schedule 

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Figure 3.1.2-5
Durvalumab and Bevacizumab Combination Therapy 
Treatment Schedule 
Q4W = every 4 weeks.
Q3W = every 3 weeks. 
3.1.2.1
Duration of Treatment and Criteria for Treatment Through Progression 
and for Retreatment
All treatment will be administered beginning on Day 1 unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met (Section 4.1.6). 
Treatment through progression is permitted for subjects with durvalumab and bevacizumab 
combination in Part 4. However, only durvalumab can be continued through progression 
while bevacizumab should be discontinued at initial radiological progression. Re-treatment is 
not permitted for subjects in Part 4.
Subjects with rapid tumor progression (based on investigator opinion) or with symptomatic 
progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumor compression, or spinal cord compression) will not be eligible 
for continuing durvalumab and tremelimumab combination therapy. 
For all subjects who are treated through progression, the investigator should ensure subjects 
do not have any significant, unacceptable or irreversible toxicities that indicate continuing or 
restarting treatment would not further benefit the subjects. 
Subjects enrolled in the durvalumab and tremelimumab combination therapy arms meeting 
the retreatment criteria below will follow the same treatment guidelines followed during the 

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original treatment period, including the same dose and frequency of treatments and the same 
schedule of assessments. Subjects who meet the criteria for retreatment for their respective 
treatment arm may only receive retreatment once. Crossover within the study is not 
permitted, except for patients in Part 3 Arm A, who can be retreated with the durvalumab 
1500mg + tremelimumab 300mg x 1 dose, with prior approval from the AstraZeneca Study 
Physician.
Subjects randomized to any durvalumab and tremelimumab combination therapy arm may 
undergo retreatment as described below:
•
Subjects who complete the specified dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per investigator judgment), 
but subsequently have evidence of PD during the durvalumab portion of the combination 
regimen, with or without confirmation according to investigator assessments using 
RECIST v1.1, may restart treatment with the combination.
For all subjects who are treated through progression and for subjects who are restarting 
durvalumab and tremelimumab combination therapy, the investigator should ensure that
1. The subject does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the subject.
2. The subject does not meet any of the investigational product discontinuation criteria 
(Section 4.1.6).
3. There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in World Health Organization/Eastern Cooperative 
Oncology Group (WHO/ECOG) performance status to >1.
4. There is absence of rapid PD 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.
5. The subject still fulfills the eligibility criteria for this study (Section 4.1.2 and 4.1.3) with 
the exception of inclusion criteria 4, 9, and 10 and exclusion criteria 5 and 17. Subjects 
must also agree to re-consent to restart durvalumab and tremelimumab combination 
therapy and treatment through progression.  
6. The subject has not used additional immunosuppression other than corticosteroids for the 
management of an AE, has not experienced recurrence of an AE if re-challenged, and 
does not currently require maintenance doses > 10 mg prednisone or equivalent per day.
Subjects in the immunotherapy arms will not be permitted to continue immunotherapy if 
progression occurs after confirmed response (CR or PR as defined by investigator 
assessments using RECIST v1.1) to immunotherapy treatment in the target lesions 

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(regardless of the appearance of new lesions), ie, the response and progression events both 
occurred in the target lesions while receiving immunotherapy during the same period. 
Subjects who the sponsor and the investigator determine may not continue treatment after PD 
will be followed up for survival. Subjects 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. 
3.1.2.2
Dose-limiting Toxicity
A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs during 
the first 4 weeks of treatment, including:
•
Any Grade 4 irAE
•
Any Grade 3 colitis
•
Any Grade 3 noninfectious pneumonitis irrespective of duration
•
Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days of the 
initiation of maximal supportive care
•
Any other Grade 3 irAE (excluding colitis or pneumonitis), that does not downgrade to 
Grade 2 within 7 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 
14 days
•
Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN
•
AST or ALT > 3 × ULN with concurrent increase in total bilirubin > 2 × ULN without 
evidence of cholestasis or alternative explanations, eg, viral hepatitis, disease progression 
in the liver, etc (Hy’s Law)
•
Any ≥ Grade 3 non-irAE, except for the exclusions listed below
The definition excludes the following conditions: 
•
Grade 3 fatigue lasting ≤ 7 days
•
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic
•
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes) 
•
Concurrent vitiligo or alopecia of any AE grade
•
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management

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•
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 7 days. Grade 3 or Grade 4 febrile neutropenia will be 
a DLT regardless of duration or reversibility
•
Grade 3 or 4 lymphopenia
•
Isolated Grade 3 thrombocytopenia that is not associated with clinically significant 
bleeding and does not require medical intervention 
•
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days
•
Isolated Grade 3 amylase or lipase abnormalities that are not associated with clinical 
signs/symptoms or findings on imaging consistent with pancreatitis
Immune-related AEs are defined as events of immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of clinical abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT.
An AE not listed above may be defined as a DLT after a consultation with the sponsor and 
investigators, based on the emerging safety profile.
DLT is only applicable for Part 1. 
3.1.3
Management of Study Medication 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 IP 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 National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.03. When in doubt, the investigator should 
consult with the medical monitor. If the investigator has any question in regards to an AE 
being an irAE, the investigator should immediately contact the medical monitor. 

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Specific toxicity management and dose modification for durvalumab and 
tremelimumab 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell 
activation and proliferation, the occurrence of irAEs that are either overlapping or greater 
than each of these drugs when used as monotherapy is possible. Potential irAEs may be 
similar to those seen with the use of ipilimumab, nivolumab, or the combination thereof and 
may include immune-mediated enterocolitis, dermatitis, pneumonitis, hepatitis 
(hepatotoxicity), neurotoxicity, and endocrinopathies (Hodi et al, 2010; Brahmer et al, 2012; 
Topalian et al, 2012; Wolchok et al, 2013). Subjects should be monitored for signs and 
symptoms of irAEs in any organ. In the absence of an alternate etiology (eg, infection, HBV 
or HCV hepatic flare, or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, pneumonitis, dermatitis, hepatitis, neurotoxicity, pancreatitis, 
cytopenias, and endocrinopathies. 
Treatment modifications will not be required for AEs that are clearly not attributed to 
durvalumab or tremelimumab (such as an accident) or for laboratory abnormalities that are 
not deemed to be clinically significant. Dose reductions of durvalumab or tremelimumab are 
not permitted. Guidelines for the management of immune-mediated reactions, infusion-
related reactions, and non-immune-mediated reactions for durvalumab and tremelimumab 
monotherapy and durvalumab + tremelimumab combination therapy are provided in the 
Dosing Modification and Toxicity Management Guidelines. The most current version of 
these guidelines is to be maintained within the Site Master File. In addition, a version of the 
current Dosing Modifications and Toxicity Management Guidelines is available through the 
following link: https://tmg.azirae.com. Please contact your clinical trial associate for 
information on how to gain access to this website. Hepatotoxicity management guidelines are 
provided below.      
Specific toxicity management and dose modification for bevacizumab
Subjects receiving durvalumab and bevacizumab combination therapy who, in the opinion of 
the investigator, have an AE attributed to bevacizumab that meets interruption or 
discontinuation criteria for bevacizumab, may continue durvalumab dosing regimen as 
scheduled. However, if an AE is attributed to durvalumab and meets the interruption or 
discontinuation criteria for durvalumab, both durvalumab and bevacizumab should be 
interrupted or discontinued according to toxicity management guideline. For management of 
toxicities due to bevacizumab, please refer to the local approved regulatory prescribing 
information for bevacizumab or manage in accordance with institutional guidelines.

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3.1.3.1
Management of Hepatotoxicity
Management of hepatotoxicity should take into consideration the viral status of the subject as 
well as the type of toxicity observed. In general, while both ALT and AST will be monitored, 
ALT is considered to be more liver-specific; therefore, changes in ALT should be the 
primary driver for dose modification and management decisions. In addition, isolated 
increases in ALT without other signs of hepatotoxicity (such as fever, hyperbilirubinemia, 
and worsening ascites), which have been observed in subjects treated with tremelimumab 
monotherapy (Sangro et al, 2013), should be considered to be of a different risk-benefit 
profile than increases in ALT associated with other signs of hepatotoxicity.
General guiding principles for select subject populations:
1. Uninfected HCC: Interpretation of hepatic laboratory results not confounded by 
underlying viral infection. Management should focus on ruling out non-immune-related 
AEs 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: 
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-irAEs unrelated to HCV or HBV
d. irAEs 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 irAEs 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 irAEs would 
immunosuppression (eg, corticosteroids) be considered.

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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, total bilirubin, direct bilirubin, albumin, alkaline 
phosphatase, gamma-glutamyltransferase, and international normalized ratio. Subjects should 
be monitored/evaluated for etiologies (eg, viral hepatitis, disease progression, concomitant 
medications, herbals, over-the-counter medications, supplements) other than immune-related 
hepatotoxicity before the initiation of dose modifications and immunosuppression.
3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
Durvalumab Monotherapy (20 mg/kg)
The dose and schedule for durvalumab monotherapy (20 mg/kg Q4W) were selected based 
on 2 sets of data: (1) the safety analysis of doses administered in Study CD ON 
durvalumab-1108 (a Phase 1/2 study to evaluate the safety, tolerability, and PK of 
durvalumab given as monotherapy in subjects with advanced solid tumors [see Section 
1.4.1]); and (2) PK profile simulations described above indicating that durvalumab 
administered using a 10 mg/kg Q2W schedule and 20 mg/kg Q4W schedule are predicted to 
have similar PK profiles.
Tremelimumab Monotherapy (10 mg/kg)
The dose and schedule for tremelimumab monotherapy (10 mg/kg Q4W for 7 doses and then 
Q12W until any of the criteria outlined in Section 4.1.6 are met) is currently being evaluated 
in Study D4880C00003, an ongoing double-blind, randomized, global Phase 2b study in 
subjects with mesothelioma (NCT01843374).
Durvalumab 20 mg/kg (or 1500 mg fixed dose) in Combination with 
Tremelimumab 1 mg/kg (or 75 mg fixed dose) x 4 doses
The dose and schedule for 20 mg/kg durvalumab Q4W and 1 mg/kg tremelimumab Q4W 
was selected based on PK, pharmacodynamics, safety and efficacy data from Study 
D4190C0006, as described in Section 1.4.3. The goal of dose selection was to identify an 
optimal dose of durvalumab that would yield sustained target suppression, optimize synergy 
of the combination, while maintaining the balance of safety in combination with 
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The observed PK exposures of both durvalumab and tremelimumab following combination 
therapy were consistent with respective monotherapy data, indicating no PK interaction 
between these 2 agents. A low incidence of ADA was observed with no obvious association 
with dose and safety. Following treatment with the durvalumab and tremelimumab 
combination in all cohorts, complete sPD-L1 suppression (surrogate for PD-L1 targeting) 
was observed in all but 3 subjects who received durvalumab at doses of 10 and 15 mg/kg 
Q4W. Complete sPD-L1 suppression was maintained in all subjects receiving 20 mg/kg 
Q4W durvalumab. Based on PK/pharmacodynamics (monotherapy and combination) and 
preliminary efficacy data (from combination), durvalumab doses of 3 and 10 mg/kg Q4W 
combination cohorts were excluded from further development. Pharmacokinetic simulations 
indicated that a similar AUC at steady state (4 weeks) was expected following both 10 mg/kg 
Q2W and 20 mg/kg Q4W durvalumab regimens; given the similar AUC and overlapping 
exposure, both regimens are expected to have a similar safety and efficacy profiles. Cohorts 
were narrowed to 15 mg/kg Q4W and 20 mg/kg Q4W of durvalumab.
Monotonic increases in pharmacodynamic activity best illustrated by T-cell proliferation 
(Ki67) were observed with increasing doses of tremelimumab relative to the activity 
observed in subjects treated with durvalumab monotherapy. There was evidence of 
augmented Ki67 activity in CD4 and CD8 T cells relative to durvalumab monotherapy with 
combination doses containing 1 mg/kg and higher tremelimumab and with doses of 15 or 
20 mg/kg durvalumab in combination with 1 mg/kg tremelimumab. 
Safety data from the 15 and 20 mg/kg durvalumab Q4W cohorts demonstrated a numerical 
increase in the frequency of treatment-related AEs and AEs leading to discontinuation of 
investigational product with increasing doses (> 1 mg/kg) of tremelimumab. 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not 
appear to have a qualitative change with increasing doses of tremelimumab. The 15 and 
20 mg/kg durvalumab Q4W cohorts demonstrated ORs at all doses of tremelimumab, and 
increasing doses of tremelimumab did not provide deeper or more rapid responses in some 
tumor types such as NSCLC or urothelial cancer. A pharmacodynamic analysis demonstrated 
that the peak change (%) from baseline of CD4+Ki67+ T cells was significantly increased by 
increasing doses of tremelimumab from 1 to 10 mg/kg in patients with NSCLC who received 
durvalumab and tremelimumab combination therapy (Study D4190C00006). Therefore, the 
optimal dose of tremelimumab at 1 mg/kg and higher based on PK/pharmacodynamics, 
safety, and preliminary clinical activity should be investigated. 

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To achieve optimal receptor occupancy with an acceptable safety profile, the dose of 
durvalumab 20 mg/kg Q4W was selected. The combination of 20 mg/kg durvalumab Q4W 
and 1 mg/kg tremelimumab Q4W has been chosen in Part 2A because it provided the optimal 
balance between PK/pharmacodynamics, safety, and clinical activity. 
Due to the potential for increased toxicity that is associated with repeated dosing of 
tremelimumab in combination with durvalumab in comparison to durvalumab or 
tremelimumab monotherapy, and as maximal tumor shrinkage was observed during the first 
8 to 16 weeks in the majority of subjects, the combination will consist of 4 monthly 
tremelimumab doses of 1 mg/kg in combination with durvalumab in Part 2A.
In conclusion, the selected dose and schedule of the combination therapy for Part 2A 
weight-based dosing regimen is 20 mg/kg durvalumab and 1 mg/kg tremelimumab Q4W for 
4 doses, followed by 20 mg/kg durvalumab monotherapy Q4W. For Part 3 of this study, a 
fixed dose equivalent of the above dose (1500 mg durvalumab and 75 mg tremelimumab 
Q4W for 4 doses, followed by 1500mg durvalumab monotherapy Q4W) will be used. The 
justification for using the fixed dose regimen of durvalumab and tremelimumab is provided 
below. 
Durvalumab 1500 mg in Combination with Tremelimumab 300 mg x 1 dose 
The PK/pharmacodynamic data supporting a single high dose of tremelimumab in 
combination with durvalumab are presented in Section 1.4.3.2. The 4 mg/kg × 1 dose of 
tremelimumab, while maintaining a similar overall exposure, has a 3- to 4-fold higher Cmax
compared with the 1 mg/kg × 4 doses of tremelimumab. Therefore, this single administration 
of the higher dose of tremelimumab may have the potential for better antitumor activity while 
potentially avoiding the cumulative toxicity associated with repeated dosing of the 1 mg/kg 
tremelimumab. This hypothesis will be tested by evaluating the safety and preliminary 
efficacy on this regimen in the current study. The justification for using the fixed dose 
equivalent of durvalumab and tremelimumab combination regimen is provided below. 
Rationale for Utilizing a Fixed Dose Regimen of Durvalumab in Combination 
with Tremelimumab
A population PK model was developed for durvalumab using monotherapy data from a 
Phase 1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid 
tumors). Similarly, a population PK model was developed for tremelimumab using data from 

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Phase 1 through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic 
melanoma) (Wang et al 2014). 
Population PK analysis indicated only minor impact of body weight on the PK of 
durvalumab and also tremelimumab (coefficient of ≤ 0.5). The weight-based versus fixed 
dosing (based on median body weight of ~75 kg) regimens of both durvalumab and 
tremelimumab were compared using predicted PK concentrations (5th, median, and 95th 
percentiles) using a population PK model. A total of 1000 patients were simulated using 
body weight distribution of 40 kg to 120 kg. Simulation results demonstrate that body 
weight-based versus fixed dosing regimens of both durvalumab and tremelimumab yield 
similar median steady-state PK concentrations with slightly less overall between-subject 
variability. 
Similar findings have been reported by others (Ng et al, 2006, Wang et al, 2009, Zhang et al, 
2012, Narwal et al, 2013). Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies (Wang et al, 2009). In addition, they investigated 18 therapeutic 
proteins and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-subject variability in PK/pharmacodynamic parameters 
(Zhang et al, 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body weight of 
75 kg, a fixed dose of 1500 mg durvalumab (equivalent to 20 mg/kg) and a fixed dose of 75 
and 300 mg tremelimumab (equivalent to 1 and 4 mg/kg) is included in the current study.
In conclusion, the selected doses and schedules of the combination therapy for fixed dosing 
regimens are 1500 mg durvalumab and 75 mg tremelimumab Q4W for 4 doses, followed by 
1500 mg durvalumab monotherapy Q4W and 1500 mg durvalumab and 300 mg 
tremelimumab for 1 dose, followed by 1500 mg durvalumab monotherapy Q4W.
Dose Rationale for Bevacizumab
The dose regimen for bevacizumab in this study (ie, bevacizumab 15 mg/kg) is consistent 
with the regimen that has been approved by the FDA for treatment of several types of cancers 
and with the dose of bevacizumab used in combination with atezolimumab evaluated in 
patients with HCC, which showed promising early efficacy and acceptable tolerability (Stein 
et al 2018).

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Dose Rationale for Durvalumab in Combination with Bevacizumab
The proposed dosing regimen of durvalumab 1120 mg Q3W is aligned with the fixed doing 
of durvalumab 1500 mg Q4W, which is supported by efficacy and safety as well as 
tolerability data in ongoing and prior durvalumab clinical studies. To conform to the 
bevacizumab schedule in the study, we propose to use standard durvalumab dose and ratio at 
a Q3W dosing interval, rather than the standard Q4W schedule.
The safety of a Q3W dosing schedule in combination with chemotherapy has been explored 
in the Study D419SC00001 (refer to the current durvalumab IB for more information), where 
tremelimumab is administered at 75 mg in combination with 1120 mg durvalumab Q3W 
followed by 1120 mg durvalumab Q3W. The combination has been declared tolerable and 
manageable. The 1120 mg dose of durvalumab is the Q3W equivalent of the standard 
1500mg Q4W dose.
Based on available PK data from Study 1108 with doses ranging from 0.1 to 10 mg/kg Q2W 
and 15 mg/kg Q3W (dose-escalation), 10 mg/kg Q2W (dose expansion), and 20 mg/kg Q4W 
(dose-exploration), similar overall exposure is expected following both 15mg/kg Q3W and 
20 mg/kg Q4W regimens.  Population PK analysis indicated only minor impact of body 
weight on the PK of durvalumab (coefficient of ≤0.5). Based on average body weight of 75 
kg, a fixed dose of 1120 mg Q3W durvalumab is included in the current study.
The weight-based dosing of durvalumab of 15 mg/kg is applied if a patient’s weight falls to 
30 kg or below to maintain similar median steady state PK concentrations in comparison with 
fixed dosing regimen.
3.2.2
Rationale for Study Population
The proposed study population, comprising adult subjects with advanced HCC, represents a 
high unmet medical need. This tumor indication, described below, presents an opportunity 
for novel treatment approaches that may lead to improved clinical outcomes.
Globally, HCC is the third-leading cause of cancer death (Parkin et al, 2005; 
Altekruse et al, 2009). The incidence of HCC in males is more than twice (2.4) that of 
females (Parkin et al, 2005; Miamen et al, 2012). Approximately 80% of the global HCC 
burden is accounted for in the high-incidence (> 20 per 100,000) regions of East Asia and 
sub-Saharan Africa, with 55% occurring in China alone (Parkin et al, 2005). However, even 
in the low-incidence (< 5 per 100,000) regions of North America and Europe, the incidence 
of HCC is increasing (El-Serag, 2012). In the United States (US) alone, HCC incidence rates 

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have more than tripled in the past 30 years (Miamen et al, 2012). The global variation in 
HCC incidence reflects geographic differences in risk factors, particularly chronic infections 
with HBV and HCV (Montalto et al, 2002; Llovet et al, 2003). Worldwide, it is estimated 
that HBV is responsible for 50% to 80% of HCC cases, while HCV is responsible for 10% to 
25% of cases (Block et al, 2003; Anthony, 2001). In the Asia-Pacific region where HBV is 
endemic, an estimated 70% of HCC patients have chronic HBV infections and 20% have 
chronic HCV infections. These rates are approximately reversed in non-HBV endemic areas 
such as North America, Europe, and Japan, where HCV and alcoholic cirrhosis are 
considered the main risk factors (Llovet et al, 2003).
Treatment options for HCC depend on a number of factors including resectability, liver 
function, and patient performance status. Current treatment options include resection and 
transplantation, ablative therapy, and systemic therapy. However, upon initial diagnosis, only 
20% of HCC patients with advanced disease are considered eligible for surgical resection 
(Kantar Health, 2013). As a result, HCC patients face a poor prognosis with a median OS of 
less than 1 year (Frenette and Gish, 2012), and less than 10% of patients are expected to 
survive 5 years after initial diagnosis (Kantar Health, 2013). Since 2007, sorafenib has been 
the global standard of care systemic therapy for advanced HCC after demonstrating a modest 
increase in median OS from 7.9 to 10.7 months when compared to placebo in a Phase 3 
clinical study (Llovet et al, 2008). In addition, the benefit of sorafenib is primarily limited to 
those patients whose liver function is well preserved (Child-Pugh class A; Llovet et al, 2008; 
Pressiani et al, 2013). For those patients whose disease progresses on, or who are intolerant 
to sorafenib, there are no other standard of care options. Therefore, it appears a significant 
unmet need exists for new and improved systemic therapies in HCC 
(Villanueva and Llovet, 2011).
Clinical evidence suggests HCC may be particularly susceptible to immunotherapy. HCC has 
shown the highest rate of spontaneous regression among all tumors through what is believed 
to be an antitumor immune response mechanism (Oquinena et al, 2009). Objective tumor 
responses have previously been reported following adoptive immunotherapy with dendritic 
cells pulsed with tumor lysate (Palmer et al, 2009) and lymphokine-activated killer cells 
combined with recombinant interleukin (IL)-2 (Takayama et al, 2000). In addition, 
overexpression of PD-L1 in HCC patient samples was found to be significantly associated 
with tumor aggressiveness and postoperative recurrence (Gao et al, 2009). Similarly, PD-L1 
expression on tumor-infiltrating monocytes increased with disease progression and was 
associated with high mortality and reduced survival in HCC patients (Kuang et al, 2009). In a 
study of HBV-infected HCC patients, upregulation of circulating and intratumoral PD-1 and 
PD-L1 expression was found to promote CD8+ T-cell apoptosis and postoperative recurrence 

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(Shi et al, 2011). Furthermore, the 2 leading causes of HCC, HBV and HCV infection, have 
also been shown to upregulate the PD-L1/PD-1 pathway as a mechanism to evade antiviral 
immunity (Peng et al, 2008; Golden-Mason et al, 2007). 
In addition, clinical experience exists with both durvalumab monotherapy (10 mg/kg Q2W) 
and nivolumab (El-Khoueiry et al, 2015) in advanced stage HCC patients, including those 
with HBV or HCV infection. In Study CD-ON- durvalumab-1108, 4 of the 19 evaluable 
(21%) HCC subjects treated at the recommended durvalumab monotherapy dose 
demonstrated prolonged SD (≥ 3 months), while 8 of 42 (19%) treated with nivolumab 
demonstrated either partial or complete responses (El-Khoueiry et al, 2015). In addition, 
tremelimumab (15 mg/kg every 90 days) has previously been explored in HCC patients 
(n = 20) with chronic HCV and demonstrated a manageable safety profile as well as 
antitumor and antiviral effects (Sangro et al, 2013). No AEs required systemic steroids for 
management and 3 of 17 evaluable subjects (17.6%) demonstrated PR. The antitumor and 
antiviral effects of dual blockade of CTLA-4 and PD-L1 have yet to be explored in patients 
with advanced HCC with or without an underlying chronic viral infection. The current study 
provides a novel opportunity to test this combination in populations with high unmet need.
3.2.3
Rationale for Endpoints
Primary Endpoint: Safety
Although safety of the recommended Phase 2 dose (RP2D) for the durvalumab and 
tremelimumab combination was established in subjects with NSCLC, the safety profile of the 
combination in the NSCLC population is not directly generalizable to subjects with HCC. 
Based on the eligibility criteria for subjects with NSCLC treated with the durvalumab and 
tremelimumab combination, these subjects will not have HBV or HCV infections, or 
cirrhosis with compromised liver function/reserve. Therefore, careful risk-based exploration 
of the dose using sequential enrollment in a “safety run-in” in the HCC subject population is 
appropriate. In addition, a thorough understanding of the safety profile through monitoring 
and analysis of AEs, SAEs, ECGs, laboratory values (including liver and virology 
measurements), vital signs, and histologic information from biopsies of fresh tumor tissue 
and noncancerous liver tissue has been incorporated into assessments throughout the study.
Secondary Endpoints
Efficacy
The gold standard measurement of efficacy in an oncology Phase III study is OS. Given that 
the median OS of subjects with HCC treated with sorafenib is 10.7 months, it is expected that 

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subjects enrolled in this trial (progressed on, intolerant of, or refused sorafenib) will have an 
even shorter median OS. Therefore, additional efficacy endpoints of TTP, DoR, DCR, ORR, 
and PFS will be evaluated to support OS. 
Candidate Biomarkers
Identification of a predictive biomarker could optimize the risk-to-benefit ratio for an 
immunotherapy combination, which has been associated with life-threatening toxicities. 
Given that durvalumab is a PD-L1 antagonist, understanding how the expression of the drug 
target correlates with tumor response is critical. 
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
&&,

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3.2.4
Rationale for Interim Analysis Criteria 
The goal of the interim analysis following completion of Part 1 enrollment is to determine if 
the durvalumab and tremelimumab combination has an appropriate benefit-risk ratio 
compared with either durvalumab or tremelimumab monotherapies. Given that the 
combination is expected to have a less desirable safety profile compared with the 
monotherapies, the combination must offer increased benefit compared with the 
monotherapies to adequately balance this risk. Therefore, the clinically “interesting” ORR 
has been set to ≥ 20% which is greater than the ORR observed for durvalumab monotherapy 
(5.7%; see durvalumab IB) or tremelimumab monotherapy (17.6%; Sangro et al, 2013). This 
ORR is also substantially greater than the ORR observed for sorafenib (2%; Llovet et al, 
2008), the only approved agent for the treatment of HCC.
&&,

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A subsequent interim analysis will be performed to assess futility and safety of the 
monotherapy arms (Arms B and C) and safety of the additional durvalumab and 
tremelimumab combination therapy arm (Arm D). The futility criteria as described in Section 
4.8.7 for the monotherapy arms (Arms B and C) was chosen such that the risk of falsely 
stopping an effective treatment is < 5%.
For Part 4, an interim analysis will occur after approximately 100 subjects have had the 
opportunity for 18 weeks of follow-up. Another interim analysis will occur after 
approximately 100 subjects in Part 4 have had the opportunity for 36 weeks of follow-up.
The main objective of this interim analysis is to assess the safety and efficacy of durvalumab
in combination with bevacizumab. The primary efficacy endpoint is ORR assessed by BICR 
according to RECIST 1.1. 
Additional interim analyses based on similar objectives may be performed to support the 
ongoing Phase III HCC development for Parts 1-3. No formal adjustments will be made to 
the significance level used for testing. The details of each analysis will be described in the 
SAP prior to database lock for any interim analysis.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Approximately 12 subjects in Part 1A, approximately 24 subjects in Part 1B, approximately 
108 subjects in Part 2A, approximately 12 subjects in Part 2B, approximately 200 subjects in 
Part 3, and approximately 100 subjects in Part 4 will be enrolled globally. 
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male or female subjects; age ≥ 18 years (all countries except Japan) or ≥ 20 years (Japan 
only) at the time of screening. 
2. Written informed consent and any locally required authorization, Health Insurance and 
Portability and Accountability Act in the US, European Union Data Privacy Directive in 
the European Union obtained from the subject/legal representative prior to performing 
any protocol-related procedures, including screening evaluations. 
3. Confirmed HCC based on histopathological findings from tumor tissues. Advanced HCC 
with diagnosis confirmed pathologically or with noninvasive methods (as described 
below).

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a.
Noninvasive methods: focal lesion > 1 cm with arterial hypervascularity and 
venous or delayed phase washout on a 4 phase multi-detector computed 
tomography (CT) or dynamic contrast enhanced magnetic resonance imaging (MRI; 
Bruix and Sherman, 2011).
4. Immunotherapy-naive and have either progressed on, are intolerant to, or refused
treatment with sorafenib or another approved VEGFR TKI. 
Part 4 only: Must not have received prior systemic therapy for HCC.
5. Child-Pugh Score class A.
6. ECOG performance status of 0 or 1.
7. Patients with HBV infection [as characterized by positive hepatitis B surface antigen 
(HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA 
(≥10 IU/ml)] must be treated with antiviral therapy, as per institutional practice, to ensure 
adequate viral suppression (HBV DNA ≤ 2000 IU/mL) prior to enrollment. Patients must 
remain on antiviral therapy for the study duration and for 6 months after the last dose of 
study medication. Patients who test positive for antiHBc with undetectable HBV DNA 
(<10 IU/ml) 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). 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.
8. 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).
9. At least 1 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 computed tomography (CT) or magnetic resonance imaging (MRI) and that is 
suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Subjects in 
Part 1A, Part 1B, or Part 2A must consent to pretreatment biopsies of tumor. Subjects in 
Part 2B, Part 3 and Part 4 must provide a newly acquired (fresh or acquired within 3 
months, preferred) or archival (< 3 years) tumor sample. 
10. Consent to provide a newly acquired or archival tumor tissue (< 3 years) for correlative 
biomarker studies. 
11. 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 ≥ 1,000/μL
c.
Platelet count ≥75000/μL
d. Total bilirubin (TBL) ≤ 2.0 × ULN (Upper Limit of Normal)
e.
AST and ALT ≤ 5 × ULN 
f.
Albumin ≥ 2.8 g/dL
g. International Normalized Ratio ≤ 1.6

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h. Calculated creatinine clearance ≥50 mL/minute as determined by Cockcroft-Gault 
(using actual body weight) or 24-hour urine creatinine clearance
i.
Part 4 only: Proteinuria < 2+. For patients with proteinuria ≥ 2+, further assessment 
of 24-hour proteinuria should be < 1 gram.
12. Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use a highly effective method of contraception (Table 4.1.2-1) from the time 
of screening, and must agree to continue using such precautions for 90 days (durvalumab 
and tremelimumab monotherapy) or 180 days (durvalumab combined with 
tremelimumab) after the final dose of investigational product(s). Male partners of a 
female subject must use male condom plus spermicide (or male condom in countries 
where spermicides are not approved or available) throughout these periods. Cessation of 
contraception after this point should be discussed with a responsible physician. Not 
engaging in sexual activity for the total duration of the study and the drug washout period 
is an acceptable practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. Female subjects should 
refrain from breastfeeding throughout these periods.
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or those who are not postmenopausal (defined as 12 months with no 
menses without an alternative medical cause). The following age-specific 
requirements apply to the definition of postmenopausal:
i.
Females < 50 years of age would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle stimulating hormone 
levels in the postmenopausal range for the institution.
ii. Females ≥ 50 years of age will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced oophorectomy with last menses 
> 1 year ago, had chemotherapy-induced menopause with > 1 year interval since 
last menses, or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).
b. Highly effective methods of contraception are described in Table 4.1.2-1. A highly 
effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or 
without spermicide; non-copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of 
action [excluding Cerazette®/desogestrel which is considered highly effective]; and 
triphasic combined oral contraceptive pills); not all of these methods are approved or 
available in Japan (see Table 4.1.2-1).
13. Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use a highly effective method of contraception (see 
Table 4.1.2-1) from Day 1 through 90 days (durvalumab and tremelimumab 
monotherapy) or 180 days (durvalumab combined with tremelimumab) after receipt of 

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the final dose of investigational product(s). Not engaging in sexual activity for the total 
duration of the study and the drug washout period is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male subjects should refrain from sperm donation throughout 
these periods. Female partners of a male subject must use a highly effective method of 
contraception throughout these periods.
14. Body weight >30kg
15. Must have a life expectancy of at least 12 weeks
Table 4.1.2-1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
•
Etonogestrel implants (eg, Implanon® or 
Norplant®) b
•
Intravaginal device (eg, ethinylestradiol and 
etonogestrel)
•
Medroxyprogesterone injection (eg, Depo-
Provera®)  b
•
Normal and low dose combined oral contraceptive 
pill
•
Norelgestromin/ethinylestradiol transdermal 
system b
•
Cerazette® (desogestrel) b
Note: A highly effective method of contraception is defined as one that results in a low failure rate (ie, < 1% per 
year) when used consistently and correctly.
a
This is also considered a hormonal method.
b
This hormonal method is not approved or available in Japan.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. 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).
2. 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).
3. Clinically meaningful ascites defined as 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. 

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4. Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal 
vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral 
to the primarily involved lobe (or both)).
5. Prior exposure to immunotherapy, including, but not limited to, other anti-CTLA-4, 
anti-PD-1, or anti-PD-L1 mAbs.
6. Known allergy or hypersensitivity to study drug formulations.
7. Requires ongoing therapeutic anti-coagulation or anti-platelet therapy; the subject must 
be off either therapy for at least 7 days prior to the first dose of investigational product. 
Low-dose aspirin for cardiac prophylaxis/protection is permitted per local institutional 
standards.
8. Active or prior documented autoimmune or inflammatory disorders including 
inflammatory bowel disease (eg, colitis, Crohn’s disease), diverticulitis, celiac disease, 
systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangitis); 
myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc. The 
following are exceptions to this criterion: 
a) Subjects with vitiligo or alopecia. 
b) Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.
c) Subjects with psoriasis or eczema not requiring systemic treatment.
9. Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated 
with diarrhea within the past 3 years prior to the start of treatment.
10. 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 HIV 1/2 antibodies).
11. Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus 
(HDV).  HBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis 
B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10IU/ml)]; HCV positive 
(presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies).
12. Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study or the follow-up period of an interventional study.
13. Receipt of any conventional or investigational anticancer therapy not otherwise specified 
above within 28 days prior to the first dose of durvalumab or tremelimumab.
14. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for 
cancer treatment with the exception of subjects on adjuvant endocrine therapy for 
≥5 years for a history of breast cancer. Concurrent use of hormones for noncancer-
related conditions (eg, insulin for diabetes and hormone replacement therapy) is 
acceptable. In addition, local treatment (eg, by local surgery or radiotherapy) of isolated 
lesions for palliative intent is acceptable with prior consultation and in agreement with 
the medical monitor.
15. Any toxicity from prior therapy which has not completely resolved to baseline at the time 
of consent. Subjects with NCI CTCAE v4.03 Grade 1 or 2 toxicities that are deemed 
stable or irreversible can be enrolled on a case-by-case basis with prior consultation and 
agreement with the medical monitor.

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16. Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of IP. The following are exceptions to this criterion:
-
Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection).
-
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent.
-
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
17. History of primary immunodeficiency or solid organ transplantation.
18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of investigational 
products (Note: Subjects, if enrolled, should not receive live vaccine during the study and 
30 days after the last dose of investigational product[s]). Vaccination with a killed 
vaccine is permitted at any time with consultation with the medical monitor.
19. 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 (Durvalumab) monotherapy or 180 
days after the last dose of durvalumab plus tremelimumab or bevacizumab 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.
20. Major surgery (as defined by the investigator) within 28 days prior to first dose of IP or 
still recovering from prior surgery. Local procedures (eg, core needle biopsy, and prostate 
biopsy) are allowed if completed at least 3 days prior to the administration of the first 
dose of study treatment. 
21. History of leptomeningeal carcinomatosis
22. Other invasive malignancy within 2 years except for noninvasive malignancies such as 
cervical carcinoma in situ, in situ prostate cancer, nonmelanomatous carcinoma of the 
skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured.
23. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension (defined as systolic 
blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 90 mmHg, with or without 
antihypertensive medication), unstable angina pectoris, cardiac arrhythmia, vena cava 
thrombosis, active peptic ulcer disease or gastritis, or psychiatric illness/social situations
that would limit compliance with study requirement, substantially increase risk of 
incurring AEs from IP, or compromise the ability of the subject to give written informed 
consent.
24. Any condition that, in the opinion of the investigator or sponsor, would interfere with 
evaluation of the investigational products or interpretation of subject safety or study 
results. 
25. Subjects who are involuntarily incarcerated or are unable to willingly provide consent or 
are unable to comply with the protocol procedures.
26. 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.
Additional Exclusion Criteria Specific to Part 4 Only 

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27. Clinically significant (eg, active) cardiovascular disease, including:
-
Myocardial infarction or unstable angina within ≤6 months of randomization
-
New York Heart Association Grade≥ 2 congestive heart failure
-
Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled 
atrial fibrillation are eligible), or any clinically significant abnormal finding on resting 
ECG
-
Peripheral vascular disease Grade ≥3 (eg, symptomatic and interfering with activities 
of daily living requiring repair or revision)
-
Previous cerebrovascular accident, transient ischemic attack, or sub-arachnoids 
hemorrhage within 6 months prior to randomization
28. Known hereditary predisposition to bleeding or thrombosis; History of arterioembolic 
event including a stroke or myocardial infarction 
29. Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions 
healing by secondary intention with no evidence of facial dehiscence or infection are 
eligible but require wound examinations every 3 weeks.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive response system [IXRS]), and the screening 
evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The SID 
number will be used to identify the subject during the screening process and throughout study 
participation. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
receive investigational products. There can be no exceptions to this rule. Subjects who are 
screening failures should 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 

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documented, and that the potential benefit:risk profile remains positive for the patient.
If sites want to re-screen a screen failed patient, sites should discuss with study physician 
first. Patients may be rescreened a single time, but they may not be re-randomized. If a 
screen failed patient is re-screened, a new subject number must be assigned.
Refer to Section 4.6.1 for assignment of treatment groups.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. If the subject is 
willing, the subject will be seen and assessed by the investigator. AEs will be followed up. If 
a subject withdraws from further participation in the study, then no further study visits or 
data collection should take place.
4.1.5.1
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 6.3), 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.
In order to support key end points of PFS and OS analyses, the survival status of all patients 
in the full analysis and the safety analysis sets should be re-checked, this includes those 
patients who withdrew consent or are classified as “lost to follow up.”    
!
Lost to Follow up – site personnel should check hospital records, the patients’ 
current physician, and a publicly available death registry (if available) to obtain a 
current survival status.
!
In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available death registries (if available) where it is possible 
to do so under applicable local laws to obtain a current survival status.

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4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product(s) if any of the 
following occur in the subject in question:
1. Withdrawal of consent from further participation in the study
2. Lost to follow-up
3. An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
4. Any AE that meets criteria for discontinuation as defined in Section 3.1.3 and in the 
Dosing Modification and Toxicity Management Guidelines. In the opinion of 
investigator, if the AE is attributed to bevacizumab, only bevacizumab should be 
discontinued. If the AE is attributed to durvalumab, both durvalumab and bevacizumab 
should be discontinued.
5. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational product(s) might constitute a 
safety risk
6. Pregnancy or intent to become pregnant
7. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
8. Initiation of alternative anticancer therapy including another investigational agent
9. Confirmed PD and subject not eligible for retreatment. [Note: subjects with confirmed 
PD who, in the investigator’s opinion, continue to receive benefit from their assigned 
treatment and meet the criteria for treatment through progression may continue to receive 
their assigned therapy after discussion with study physician.]
Subjects who are permanently discontinued from receiving investigational product(s) 
regardless of the reason (withdrawal of consent from further treatment, due to an AE, other), 
will be identified as having permanently discontinued treatment and will be followed for 
protocol-specified assessments including follow-up of any AEs unless consent is withdrawn 
specifically from further study participation; the subject is lost to follow-up. 
All subjects will be followed for survival until the end of the study. Subjects who decline to 
return to the site for evaluations should be contacted by phone every 3 months to assess for 
survival unless consent is withdrawn.
4.1.7
Replacement of Subjects
Subjects in Part 1A who do not remain on study for the 4-week observation period will be 
replaced. Subjects in Part 1B, Part 2A, and Part 2B of the study may be replaced if they 
discontinue prior to receiving the first dose of study medication. Subjects randomized in 
Part 3 and Part 4 will not be replaced.

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4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number linked to the SID number but will not be labeled with personal 
identifiers such as the subject’s name. If the subject withdraws consent for participating in 
the genetic research or future research, the sponsor will locate the subject’s sample and 
destroy it. Genetic research refers to the analysis of germline DNA in the blood and does not 
include assessment of mutations specific for the tumor that are part of the main study. The 
coding of samples and results is to ensure that these research results are kept confidential by 
keeping the subject’s identity and these results separate. 
If the subject consents to have his/her sample(s) used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. 
 
 
 
 Samples obtained for future use will not 
be subject to any unknown, experimental research that is not related to the objectives of this 
study and that is not specified in the protocol. Subjects will not be asked to provide samples 
for future research that are not requested as part of the conduct of the main study. 
 
 
 The subject’s samples 
will not be kept for more than 25 years after the end of the study in which they were 
collected. If the subject chooses not to allow his/her study samples to be used for genetic 
research or future research, the samples will be destroyed by the sponsor once they are no 
longer required for the main study.
&&,
&&,

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If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s samples have 
already been used for research, the sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed.
4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
If sites want to re-screen a screen failed patient, sites should discuss with study physician 
first. Patients may be rescreened a single time, but they may not be re-randomized. If a 
screen failed patient is re-screened, a new subject number must be assigned.
Table 4.2.1-1 shows all procedures to be conducted at the screening visit. 
Table 4.2.1-1
Schedule of Screening/Baseline Procedures 
Procedure
Screening/Baseline
Days -14 to -1
Written informed consent/assignment of SID number a
X
Verify eligibility criteria
X
Tumor and disease assessments
History of prior cancer treatment
X
Disease assessment by investigator assessments using RECIST v1.1 (CT or MRI) a
including appropriate tumor markers (eg, 
X
BCLC classification
X
Study procedures and examinations
Demographics (including age, sex, race, ethnicity) and alcohol use
X
Medical history
X
Assessment of Child-Pugh Score
X
Physical examination, including height, weight
X
ECOG performance status
X
12-lead ECG b
X
Vital signs (temperature, BP, respiratory rate, heart rate, pulse oximetry)
X
Assessment of AEs/SAEs (related to study/baseline procedures)
X
Concomitant medications
X
Laboratory tests
Serum chemistry (Section 4.3.4)
X
&&,

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Table 4.2.1-1
Schedule of Screening/Baseline Procedures 
Procedure
Screening/Baseline
Days -14 to -1
Hematology (Section 4.3.4)
X
Coagulation (PT, INR)
X
Thyroid function tests (TSH, free T3, and free T4)
X
Urinalysis
X
Markers of menopause for females who require laboratory testing per inclusion 
criterion #12, Section 4.1.2
X
Serum pregnancy test (for women of childbearing age)
X
Subjects with known diagnosis of hepatitis B: qualitative HBsAg, qualitative 
HBeAg, anti-HBc, anti-HBs, anti-HBe, quantitative HBV DNA, anti-HCV, and anti-
HDV
X
Subjects with known diagnosis of hepatitis C: HCV RNA, HCV genotype c, anti-
HCV, qualitative HBsAg, and anti-HBc 
X
Subjects without known diagnosis of hepatitis B or C: HCV RNA, anti-HCV, 
qualitative HBsAg, quantitative HBV DNA, anti-HBc, and anti-HBs
X
HIV
X
Vitamin D
X
Other laboratory tests and assays
Archival tumor sample (if available)
X
Fresh tumor tissue biopsy a,d
X
Fresh noncancerous liver tissue biopsy a,d,e
X
AE = adverse event; 
 anti-HBc = hepatitis B core antibody; anti-HBe = hepatitis B e 
antibody; anti-HBs = hepatitis B surface antibody; BP = blood pressure; CT = computed tomography; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = 
hepatitis C virus; HDV = hepatitis D virus; HIV = human immunodeficiency virus; INR = international 
normalized ratio; 
 MRI = magnetic resonance imaging; 
 
 PT = prothrombin; RECIST = Response Evaluation Criteria in Solid Tumors; 
 SAE = serious adverse event; SID = subject identification; T3 = triiodothyronine; T4
= thyroxine; TSH = thyroid-stimulating hormone.
a
Informed consent, disease assessments, and collection of fresh biopsy samples can be performed from 
Days -28 to -1; informed consent must be obtained prior to the subject undergoing any screening 
procedures; however, if laboratory or imaging procedures were performed for alternate reasons prior to 
signing consent, these can be used for screening purposes with consent of the patient. However, all 
screening laboratory and imaging results must have been obtained within 28 days of randomization. 
Subjects enrolled in Part 2B or Part 3 are required to submit a newly acquired (fresh or acquired 
within 3 months, preferred) or archival (< 3 years) tumor sample.
b
ECGs should be obtained after the subject has been in a supine position for 5 minutes and recorded while 
the subject remains in that position.
c
Only for subjects without a known genotype at screening.
&&,
&&,
&&,
&&,
&&,

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Table 4.2.1-1
Schedule of Screening/Baseline Procedures 
Procedure
Screening/Baseline
Days -14 to -1
d
Collection of noncancerous liver tissue at screening is also requested if it can be done safely (as judged 
by the investigator) during the same procedure in which the fresh tumor tissue biopsy is obtained.
e
 
 
 
 
f
Part 4 only: flow cytometry will not be collected for patients enrolled into Part 4.
4.2.2
Treatment Period
Procedures to be conducted during the treatment period are presented in Table 4.2.2-1 for 
Weeks 1 to 25 and in Table 4.2.2- for Week 29 through end of treatment. At study visits 
when subjects do not receive investigational product(s), all of the pre-treatment assessments 
will be performed.
The timing of ECGs and vital sign assessments should be such that it allows the blood draw 
 to occur at the exact nominal time. All samples are collected pre-dose 
unless otherwise indicated. If a subject undergoes retreatment with the combination of 
durvalumab and tremelimumab, the timing and type of assessments “resets” to Week 1, 
Day 1. 
 
 
&&,
&&,
&&,

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Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 1-3 ONLY
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W3
D1
± 1D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Randomization/enrollment
X
Tumor and disease assessments
Disease assessment by RECIST v1.1(CT or MRI) a 
X
X
X
Tumor markers 
X c
X
X
X
X
X
X
X
X
X
X
X
X
Fresh tumor biopsy (optional) b
X 
Study procedures and examinations
Physical examination
X c
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of Child-Pugh Score
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X c
X
X
X
12-lead ECG d
As clinically indicated
Vital signs e
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests 
Serum chemistry (see Section 4.3.4 for a list of 
tests)
X c
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (see Section 4.3.4 for a list of tests)
X c
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, INR)
X c
X
X
X
X
X
X
X
X
X
X
X
X
and qualitative HBeAg f, anti-HBe g (HBV+ 
subjects only) 
X h, c
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid function tests (TSH, free T3, free T4)
X c
X
X
X
X
X
X
Urinalysis
X c
X
X
X
X
X
X
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
87 of 188
Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 1-3 ONLY
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W3
D1
± 1D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Urine or serum pregnancy test (for females of 
childbearing potential)
X c
X
X
X
X
X
X
 
  
Other laboratory tests and assays
 
 
 
 
 
 
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
88 of 188
Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 1-3 ONLY
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W3
D1
± 1D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Investigational product(s) administration
Durvalumab administration
(monotherapy and combination therapy) n
X
X
X
X
X
X
X
Tremelimumab administration (as monotherapy) n
X
X
X
X
X
X
X
Tremelimumab administration (combination 
therapy, Tx4)
X
X
X
X
Tremelimumab administration (combination 
therapy, Tx1)
X
AE = adverse event; 
 anti-HBe = hepatitis B e antibody; CT = computed tomography; D = day; 
 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; HBeAg = hepatitis B e antigen; 
 
 INR = international normalized ratio; 
 MRI = magnetic 
resonance imaging; 
 PT = prothrombin; RECIST = Response Evaluation Criteria in Solid 
Tumors; RNA = ribonucleic acid; SAE = serious adverse event; T = tremelimumab; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab /tremelimumab unless otherwise 
indicated. On nontreatment days, all of the pre-treatment assessments will be performed. 
Note:
 
a
Disease assessments should occur ± 7 days of visit. Imaging of the chest and abdomen (head and neck, and pelvic scans are optional unless disease is 
known to be present at these sites at baseline) will be performed. Imaging of hepatic tumors should be collected in the hepatic arterial, portal venous, and 
delayed phases following IV contrast administration. Subjects who meet the criteria for retreatment will have disease assessments performed at the same 
schedule as the original treatment period.
b
Post-dose noncancerous liver tissue biopsies are not required.
c
If assessments are performed within 3 days prior to Dose 1, they do not need to be repeated.
d
Any clinically significant abnormalities detected require triplicate ECG results.
e
Vital signs (temperature, blood pressure, pulse rate, pulse oximetry, and respiratory rate) will be measured on durvalumab and tremelimumab 
(monotherapy and combination) treatment days. Vital signs will be measured within 30 minutes prior to the start of infusion for all subjects in all 
treatment arms. For subjects receiving either durvalumab or tremelimumab as monotherapy (Arms B and C of Part 2A and Arms B and C of Part 3, or 
&&,
&&,
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
89 of 188
Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 1-3 ONLY
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W3
D1
± 1D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
combination arms after the last dose of tremelimumab), vital signs will be measured every 15 minutes (± 5 minutes) during the infusion (eg, 15-, 30-, and 
45-minute collection times), at EOI (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post EOI. For subjects receiving combination treatment 
(Part 1A; Part 1B; Arm A of Part 2A; Part 2B; and Arms A and D of Part 3 prior to last dose of tremelimumab), vital signs will be measured every 
15 minutes (± 5 minutes) during the infusion of tremelimumab, at EOI of tremelimumab (+ 5 minutes), and at 30 and 60 minutes post EOI of 
tremelimumab (immediately prior to the start of the durvalumab infusion). For subjects receiving combination treatment, vital signs will also be measured 
every 15 minutes (± 5 minutes) during the infusion of durvalumab, at EOI durvalumab (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post EOI of 
durvalumab. For the first day of administration of investigational product, an additional 2-hour (± 15 minutes) post EOI period of observation will be 
required following the 60 minutes (± 5 minutes) post EOI assessment of vital signs for all arms. For subjects receiving combination treatment, this will 
occur following the 60 minutes (± 5 minutes) post EOI assessment of vital signs of durvalumab. For subsequent doses, the additional 2-hour observation 
period will not be required unless clinically indicated (eg, subject experiences an infusion reaction).
f
Only required if test was positive at baseline.
g
Only required if subject is HBeAg positive at baseline.
h
i
 
 
j
 
 
k
 
l
 
m
 
n
See Section 4.5.1.4 for description of investigational product administration. 
o
p
 
&&,
&&,
&&,
&&,
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
90 of 188
Table 4.2.2-1
Schedule of Treatment Period Study Procedures Weeks 1 to 25 - Parts 1-3 ONLY
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W3
D1
± 1D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
 
q
 
 
r
Table 4.2.2-2
Schedule of Treatment Period Study Procedures Weeks 1 to 25 – PART 4 
ONLY  
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W4
D1
± 1D
W7
D1
± 3D
W10
D1
± 3D
W13
D1
± 3D
W16
D1
± 3D
W19
D1
± 3D
W22
D1
± 3D
W25
D1
± 3D
Randomization/enrollment
X
Tumor and disease assessments
Disease assessment by RECIST v1.1(CT or MRI) a 
X
X
Tumor markers 
X c
X
X
X
X
X
X
X
X
Study procedures and examinations
Physical examination
X c
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Assessment of Child-Pugh Score
X
X
X
X
X
X
X
X
X
ECOG performance status
X c
X
X
X
X
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
91 of 188
Table 4.2.2-2
Schedule of Treatment Period Study Procedures Weeks 1 to 25 – PART 4 
ONLY  
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W4
D1
± 1D
W7
D1
± 3D
W10
D1
± 3D
W13
D1
± 3D
W16
D1
± 3D
W19
D1
± 3D
W22
D1
± 3D
W25
D1
± 3D
12-lead ECG d
As clinically indicated
Vital signs e
X
X
X
X
X
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Laboratory tests 
Serum chemistry (see Section 4.3.4 for a list of tests)
X c
X
X
X
X
X
X
X
X
Hematology (see Section 4.3.4 for a list of tests)
X c
X
X
X
X
X
X
X
X
Coagulation (PT, INR)
X c
X
X
X
X
X
X
X
X
 and qualitative HBeAg f, anti-HBe g 
(HBV+ subjects only) 
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid function tests (TSH, free T3, free T4)
X c
X
X
X
X
X
X
X
X
Urinalysisk
X c
X
X
X
X
X
X
X
X
Urine or serum pregnancy test (for females of childbearing 
potential)
X c
X
X
X
X
X
X
X
X
Other laboratory tests and assays
&&,
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
92 of 188
Table 4.2.2-2
Schedule of Treatment Period Study Procedures Weeks 1 to 25 – PART 4 
ONLY  
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W4
D1
± 1D
W7
D1
± 3D
W10
D1
± 3D
W13
D1
± 3D
W16
D1
± 3D
W19
D1
± 3D
W22
D1
± 3D
W25
D1
± 3D
Durvalumab and bevacizumab administration i
X
X
X
X
X
X
X
X
X
AE = adverse event; 
 anti-HBe = hepatitis B e antibody; CT = computed tomography; D = day; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; HBeAg 
= hepatitis B e antigen; 
 INR = international normalized ratio; 
 MRI = magnetic resonance imaging; 
 
 PT = prothrombin; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; 
SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab 
/bevacizumab unless otherwise indicated. On nontreatment days, all of the pre-treatment assessments will be performed. 
a
Disease assessments should occur ± 7 days of visit. Imaging of the chest and abdomen (head and neck, and pelvic scans are 
optional unless disease is known to be present at these sites at baseline) will be performed. Imaging of hepatic tumors should 
be collected in the hepatic arterial, portal venous, and delayed phases following IV contrast administration. Subjects who meet 
the criteria for retreatment will have disease assessments performed at the same schedule as the original treatment period.
b
If assessments are performed within 3 days prior to Dose 1, they do not need to be repeated.
c
Any clinically significant abnormalities detected require triplicate ECG results.
d
Vital signs (temperature, blood pressure, pulse rate, pulse oximetry, and respiratory rate) will be measured within 30 minutes 
prior to the start of infusion. BP and pulse will be measured every 15 minutes (± 5 minutes) during the infusion of 
bevacizumab, at EOI of bevacizumab (+ 5 minutes), and at 30 and 60 minutes post EOI of bevacizumab (immediately prior to 
the start of the durvalumab infusion). BP and pulse will also be measured every 15 minutes (± 5 minutes) during the infusion 
of durvalumab, at EOI durvalumab (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post EOI of durvalumab. For the first 
day of administration of investigational products, an additional 2-hour (± 15 minutes) post EOI period of observation will be 
required, i.e. total 3-hour observation after EOI of durvalumab. For subsequent doses, the additional 2-hour observation 
period will not be required unless clinically indicated (eg, subject experiences an infusion reaction).
&&,
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
93 of 188
Table 4.2.2-2
Schedule of Treatment Period Study Procedures Weeks 1 to 25 – PART 4 
ONLY  
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W4
D1
± 1D
W7
D1
± 3D
W10
D1
± 3D
W13
D1
± 3D
W16
D1
± 3D
W19
D1
± 3D
W22
D1
± 3D
W25
D1
± 3D
e
Only required if test was positive at baseline.
f
Only required if subject is HBeAg positive at baseline.
g
 
 
h
See Section 4.5.1.4 for description of investigational product administration. 
i
 
 
 
j
Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
94 of 188
Table 4.2.2-3
Schedule of Treatment Period Study Procedures Week 29 to End of Study - Parts 1-3 
ONLY 
Study Period
Treatment Period: Week 29 to End of Study
Week/Day
W29
D1 ± 3D
W33
D1 ± 3D
W37
D1 ± 3D
W41
D1 ± 3D
W45
D1 ± 3D
W49
D1 ± 3D
Continua-
tion
Tumor and disease assessments
Disease assessment by RECIST v1.1 (CT or MRI) a
X
X
X
Q8W
Tumor markers 
X
X
X
X
X
X
Q4W
Study procedures and examinations
Physical examination 
X
X
X
X
X
X
Q4W
Assessment of Child-Pugh Score
X
X
X
X
X
X
Q4W
ECOG performance status
X
X
X
Q8W
Vital signs (durvalumab monotherapy) b
X
X
X
X
X
X
Q4W
Vital signs (tremelimumab monotherapy and combination therapy) b
X
X
X
X
X
X
Q4W
Assessment of AEs/SAEs (durvalumab monotherapy)
X
X
X
X
X
X
Q4W
Assessment of AEs/SAEs (tremelimumab monotherapy and 
combination therapy)
X
X
X
X
X
X
Q4W
Concomitant medications (durvalumab monotherapy)
X
X
X
X
X
X
Q4W
Concomitant medications (tremelimumab monotherapy and 
combination therapy)
X
X
X
X
X
X
Q4W
Laboratory tests
Serum chemistry (durvalumab monotherapy; see Section 4.3.4 for a list 
of tests)
X
X
X
X
X
X
Q4W
Serum chemistry (tremelimumab monotherapy and combination 
therapy; see Section 4.3.4 for a list of tests)
X
X
X
X
X
X
Q4W
Hematology (durvalumab monotherapy; see Section 4.3.4 for a list of 
tests)
X
X
X
X
X
X
Q4W
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
95 of 188
Table 4.2.2-3
Schedule of Treatment Period Study Procedures Week 29 to End of Study - Parts 1-3 
ONLY 
Study Period
Treatment Period: Week 29 to End of Study
Week/Day
W29
D1 ± 3D
W33
D1 ± 3D
W37
D1 ± 3D
W41
D1 ± 3D
W45
D1 ± 3D
W49
D1 ± 3D
Continua-
tion
Hematology (tremelimumab monotherapy and combination therapy; see 
Section 4.3.4 for a list of tests)
X
X
X
X
X
X
Q4W
Coagulation (PT, INR) (durvalumab monotherapy)
X
X
X
X
X
X
Q4W
Coagulation (PT, INR) (tremelimumab monotherapy and combination 
therapy)
X
X
X
X
X
X
Q4W
 qualitative HBeAg c, 
anti-HBe d (HBV+ subjects only) 
X
X
X
X
X
X
Q4W
X
X
X
X
X
X
Q4W
Thyroid function tests (TSH, free T3, free T4)
X
X
X
X
X
X
Q4W
Urinalysis
X
X
X
X
X
X
Q4W
Urine or serum pregnancy test (for females of childbearing potential)
X
X
X
X
X
X
Q4W
Investigational product(s) administration
Durvalumab administration (monotherapy and combination therapy)
X
X
X
X
X
X
Q4W
Tremelimumab administration (as monotherapy)
X
X
Q12W
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
96 of 188
AE = adverse event; 
 anti-HBe = hepatitis B e antibody; CT = computed tomography; D = day; DNA = deoxyribonucleic acid; 
ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; HBeAg = hepatitis B e antigen; 
 
 INR = international normalized ratio; MRI = magnetic resonance imaging; 
 PT = 
prothrombin; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = 
ribonucleic acid; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab /tremelimumab unless otherwise 
indicated. 
a
Disease assessments should occur ± 7 days of visit. Imaging of the chest and abdomen (head and neck, and pelvic scans are optional unless disease 
is known to be present at these sites at baseline) will be performed. Imaging of hepatic tumors should be collected in the hepatic arterial, portal 
venous, and delayed phases following IV contrast administration. Subjects who meet the criteria for retreatment will have disease assessments 
performed at the same schedule as the original treatment period.
b
Vital signs (temperature, blood pressure, pulse rate, pulse oximetry, and respiratory rate) will be measured on durvalumab and tremelimumab
(monotherapy and combination) treatment days. Vital signs will be measured within 30 minutes prior to the start of infusion for all subjects in all 
treatment arms. For subjects receiving either durvalumab or tremelimumab as monotherapy (Arms B and C of Part 2A and Arms B and C of Part 3 
or combination arms after the last dose of tremelimumab), vital signs will be measured every 15 minutes (± 5 minutes) during the infusion (eg, 15-, 
30-, and 45-minute collection times), at EOI (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post EOI. For subjects receiving combination 
treatment (Part 1A; Part 1B; Arm A of Part 2A; Part 2B; and Arms A and D of Part 3 prior to last dose of tremelimumab), vital signs will be 
measured every 15 minutes (± 5 minutes) during the infusion of tremelimumab, at EOI of tremelimumab (+ 5 minutes), and at 30 and 60 minutes 
post EOI of tremelimumab (immediately prior to the start of the durvalumab infusion). For subjects receiving combination treatment, vital signs will 
also be measured every 15 minutes (± 5 minutes) during the infusion of durvalumab, at EOI durvalumab (+ 5 minutes), and at 30 and 60 minutes (± 
5 minutes) post EOI of durvalumab. For subsequent doses, the additional 2-hour observation period will not be required unless clinically indicated 
(eg, subject experiences an infusion reaction).
c
Only required if test was positive at baseline.
d
Only required if subject is HBeAg positive at baseline.
e
f
 
 
&&,
&&,
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
97 of 188
Table 4.2.2-4
Schedule of Treatment Period Study Procedures Week 28 to 
End of Study – PART 4 ONLY 
Study Period
Treatment Period: Week 28 to End of Study
Week/Day
W28
D1 ± 3D
W31
D1 ± 3D
W34
D1 ± 3D
W37
D1 ± 3D
W40
D1 ± 3D
W43
D1 ± 3D
W46
D1 ± 3D
Continuation
Tumor and disease assessments
Disease assessment by RECIST v1.1 (CT or MRI) a
X
X
X
Q9W
Tumor markers 
X
X
X
X
X
X
X
Q3W
Study procedures and examinations
Physical examination 
X
X
X
X
X
X
X
Q3W
Weight
X
X
X
X
X
X
X
Q3W
Assessment of Child-Pugh Score
X
X
X
X
X
X
X
Q3W
ECOG performance status
X
X
X
Q6W
Vital signs b
X
X
X
X
X
X
X
Q3W
Assessment of AEs/SAEs
X
X
X
X
X
X
X
Q3W
Concomitant medications
X
X
X
X
X
X
X
Q3W
Laboratory tests
Serum chemistry (see Section 4.3.4 for a list of tests)
X
X
X
X
X
X
X
Q3W
Hematology (see Section 4.3.4 for a list of tests)
X
X
X
X
X
X
X
Q3W
Coagulation (PT, INR)
X
X
X
X
X
X
X
Q3W
qualitative HBeAg c, anti-
HBe d (HBV+ subjects only) 
X
X
X
X
X
X
X
Q3W
X
X
X
X
X
X
X
Q3W
Thyroid function tests (TSH, free T3, free T4)
X
X
X
X
X
X
X
Q3W
Urinalysis
X
X
X
X
X
X
X
Q3W
Urine or serum pregnancy test (for females of 
childbearing potential)
X
X
X
X
X
X
X
Q3W
Investigational product(s) administration
Durvalumab and Bevacizumab administration
X
X
X
X
X
X
X
Q3W
&&,
&&,
&&,

MedImmune
Protocol D4190C00022 Amendment 6
Durvalumab
04Jan2019; Final
CONFIDENTIAL AND PROPRIETARY
98 of 188
AE = adverse event; 
 anti-HBe = hepatitis B e antibody; CT = computed tomography; D = 
day; 
 ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; HBeAg = 
hepatitis B e antigen; 
 INR = international normalized ratio; MRI = 
magnetic resonance imaging; 
 PT = prothrombin; Q4W = every 4 weeks; Q8W = every 8 
weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; 
SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of 
durvalumab/bevacizumab unless otherwise indicated. 
a
Disease assessments should occur ± 7 days of visit. Imaging of the chest and abdomen (head and neck, and 
pelvic scans are optional unless disease is known to be present at these sites at baseline) will be performed. 
Imaging of hepatic tumors should be collected in the hepatic arterial, portal venous, and delayed phases 
following IV contrast administration. Subjects who meet the criteria for retreatment will have disease 
assessments performed at the same schedule as the original treatment period.
b
Vital signs (temperature, blood pressure, pulse rate, pulse oximetry, and respiratory rate) will be measured on 
durvalumab and bevacizumab treatment days. Vital signs will be measured within 30 minutes prior to the start of 
infusion for all subjects in all treatment arms. Vital signs will be measured every 15 minutes (± 5 minutes) during 
the infusion of bevacizumab, at EOI of bevacizumab (+ 5 minutes), and at 30 and 60 minutes post EOI of 
bevacizumab (immediately prior to the start of the durvalumab infusion). Vital signs will also be measured every 
15 minutes (± 5 minutes) during the infusion of durvalumab, at EOI durvalumab (+ 5 minutes), and at 30 and 60 
minutes (± 5 minutes) post EOI of durvalumab. For subsequent doses, the additional 2-hour observation period 
will not be required unless clinically indicated (eg, subject experiences an infusion reaction).
c
Only required if test was positive at baseline.
d
Only required if subject is HBeAg positive at baseline.
e
 
 
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4.2.3
Follow-up Period
Table 4.2.3-1 shows all procedures to be conducted during the end of treatment visit and 
follow-up period. Subjects will complete the end of treatment visit at the time the decision is 
made to discontinue treatment.
All subjects are to complete the end of treatment visit, all follow-up visits and be contacted 
for survival status in accordance with the Schedule of Study Procedures. However, if a 
subject discontinues from treatment and moves onto alternative anticancer treatment, the 
follow-up visits will no longer be required; however, survival follow-up assessments would 
be required as indicated in the Schedule of Study Procedures unless the subject withdraws 
consent for further survival follow-up. Survival follow-up will continue until the end of study 
as defined in Section 6.3.

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Table 4.2.3-1
Schedule of End of Treatment and Follow-up Procedures 
Study Period
EOT
Follow-up Period
Procedure / Study Day or Month
Day 30 
Post-last 
Dose ± 
3 Days
Day 60 
Post-last 
Dose ± 
3 Days
Day 90 
Post-last 
Dose ± 
7 Days
Q3M After 
Day 90 Post-last 
Dose up to Month 
12 Post-last Dose 
± 7 Days
Q6M After 
Month 12 Post-
last Dose ± 
14 Days
Disease assessments
Disease assessment by RECIST v1.1 (CT or MRI) a
X
X
X
X
Tumor markers 
X
X
X
X
X
X
Fresh tumor biopsy
X b
Collect information regarding subsequent anticancer therapy
X
X
X
X
X
Survival status
X
X
X
X
X
Study procedures and examinations
Physical examination
X
X
X
X
Assessment of Child-Pugh Score
X
X
X
X
ECOG performance status
X
X
X
Vital signs (temperature, blood pressure, pulse rate, pulse 
oximetry, and respiratory rate)
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
Concomitant medications
X
X
X
X
Laboratory tests
Serum chemistry (see Section 4.3.4 for a list of tests)
X
X
X
X
Hematology (see Section 4.3.4 for a list of tests)
X
X
X
X
Coagulation (PT, INR)
X
X
X
X
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Table 4.2.3-1
Schedule of End of Treatment and Follow-up Procedures 
Study Period
EOT
Follow-up Period
Procedure / Study Day or Month
Day 30 
Post-last 
Dose ± 
3 Days
Day 60 
Post-last 
Dose ± 
3 Days
Day 90 
Post-last 
Dose ± 
7 Days
Q3M After 
Day 90 Post-last 
Dose up to Month 
12 Post-last Dose 
± 7 Days
Q6M After 
Month 12 Post-
last Dose ± 
14 Days
 qualitative 
HBeAg c, and anti-HBe d (HBV+ subjects only)  
X
X
X
X
X
X
X
X
Thyroid function tests (TSH, free T3, free T4)
X
X
X
X
Urinalysis
X
X
X
X
Urine or serum pregnancy test (for women of childbearing 
potential)
X
AE = adverse event; 
 anti-HBe = hepatitis B e antibody; CT = computed tomography; 
 ECOG = 
Eastern Cooperative Oncology Group; EOT = end of treatment; HBeAg = hepatitis B e antigen; 
 
 INR = international normalized ratio; MRI = magnetic resonance imaging; PD = progressive disease; 
 
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Table 4.2.3-1
Schedule of End of Treatment and Follow-up Procedures 
Study Period
EOT
Follow-up Period
Procedure / Study Day or Month
Day 30 
Post-last 
Dose ± 
3 Days
Day 60 
Post-last 
Dose ± 
3 Days
Day 90 
Post-last 
Dose ± 
7 Days
Q3M After 
Day 90 Post-last 
Dose up to Month 
12 Post-last Dose 
± 7 Days
Q6M After 
Month 12 Post-
last Dose ± 
14 Days
PT = prothrombin; Q3M = every 3 months; Q6M = every 6 months; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; 
SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
a
Imaging of the chest and abdomen (head and neck, and pelvic scans are optional unless disease is known to be present at these sites at baseline) will be 
performed. Imaging of hepatic tumors should be collected in the hepatic arterial, portal venous, and delayed phases following IV contrast administration. 
Disease assessment will not be performed if EOT is for PD.
b
Optional tumor biopsy collected once upon confirmed PD.
c
Only required if test was positive at baseline.
d
Only required if subject is HBeAg positive at baseline.
e
 
 
 
 
 
 
f
The 90-day post-last dose of tremelimumab will be drawn at Week 25 Day 1 for subjects who complete all 4 cycles of tremelimumab dosing in 
combination with durvalumab. For subjects enrolled in Arm D of Part 2B and Arm D of Part 3 who receive only 1 dose of tremelimumab, the blood 
sample collected on Week 13 Day 1 will serve as the 90-day post-last dose sample for tremelimumab subjects who receive only 1 dose of tremelimumab 
in combination with durvalumab. Subjects who complete beyond 25 weeks of treatment will not be required to provide an additional 90-day post-last dose 
blood sample collection for tremelimumab during the designated follow-up period. 
g
h
 
 
i
 
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4.3
Description of Study Procedures
4.3.1
Efficacy……….
Tumor assessments will be based on investigator and BICR assessments according to 
RECIST v1.1 (Eisenhauer et al, 2009) and will be performed according to the schedule 
presented in Section 4.2. All subjects will be followed for survival according to the schedule 
in Table 4.2.3-1 through the end of the study as defined in section 6.3. 
All original images used for RECIST tumor assessments, including unscheduled visit scans, 
are to be stored on digital hard media (e.g., CDs) at the Investigative site as source 
documents. Guidelines for image acquisition, de-identification, and transfer to an Imaging 
Contract Research Organization (CRO) appointed by AstraZeneca will be provided in a 
separate document by the imaging CRO. All images will be collected, quality checked, and 
stored centrally by the Imaging CRO. Images will be used for Blinded Independent Central 
Review (BICR) of tumors by RECIST 1.1 for Part 1, Part 2, and Part 3 patients, and will be 
retained for a potential future BICR by RECIST 1.1 for Part 4. The management of patients 
will be based in part on the results of the RECIST 1.1 assessments conducted by the 
Investigator.
Tumor assessments should include the following evaluations: physical examination 
(palpation) and CT or MRI scan of the chest and abdomen (head and neck, and pelvic scans 
are optional unless disease is known to be present at these sites at baseline). The choice of 
imaging for hepatic tumors should follow local institutional practice, eg, 3-phase CT or 
multiphase MRI. The same method is preferred for all subsequent tumor assessments.
Tumor markers specific for the disease under study (eg, 
 should be collected (at a 
minimum) as outlined in Section 4.2.
If the subject has known CNS metastases, a brain MRI with IV contrast is required at 
screening and at each post baseline assessment. If a subject becomes neurologically 
symptomatic during treatment outside of the setting where the subject has known CNS 
metastases, a brain MRI with IV contrast is required. 
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Tumor Evaluations
CT scan with contrast of the chest and abdomen (head and neck, and pelvis 
optional)
•
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm.
•
Head and neck, and pelvis scans are optional unless disease is known to be present at 
these sites at baseline. 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 tumor 
measurements but also identification of new disease.
•
CT images of hepatic tumors should be collected in the hepatic arterial, portal venous, 
and delayed phases following IV contrast administration.
•
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study, then the recommended methods are as follows: CT thoracic (chest) 
examination without contrast and abdominal (and pelvis) MRI with contrast. If an MRI 
cannot be performed, then CT without IV contrast is an option for the thorax and 
abdomen (and pelvis) examination. For brain imaging, MRI with IV contrast is the 
preferred method. 
MRI scans
•
MRI of the chest and abdomen (head and neck, and pelvic scans are optional unless 
disease is known to be present at these sites at baseline) is acceptable for measurement of 
lesions provided that the same anatomical plane is used for serial assessments. If 
possible, the same imaging device should be used for serial evaluations. MRI scans of 
hepatic tumors should be performed in the precontrast, hepatic arterial, portal venous, and 
delayed phases.
•
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 other anatomies such as head and neck and pelvis) 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 optimized for the specific body part being 
imaged as well as the scanner utilized. CT of the chest is typically recommended over 
MRI due to significant motion artifacts (eg, heart, major blood vessels, breathing) 
associated with MRI. It is beyond the scope of this protocol to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Body scans should 
be performed with breath-hold scanning techniques if possible. 

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Isotopic bone scans (scintigraphy)
•
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, 
or X-ray at baseline should be recorded as a non-target lesion 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 lesion at follow-up visits. New lesions will be recorded where a positive 
hot-spot that was not present on the baseline bone scan assessment is identified on a bone 
scan performed at any time during the study. The investigator should consider the 
positive hot-spot to be a significant new site of malignant disease and represent true 
disease progression in order to record the new lesion. Confirmation by CT, MRI, and X-
ray is recommended where bone scan findings are equivocal. 
FDG-PET scan for RECIST v1.1 new lesions
•
18F-Fluoro-deoxyglucose positron emission tomography (FDG-PET)/CTs may be used as 
a method for identifying new RECIST v1.1 lesions, according to the following algorithm: 
new lesions will be recorded where there is positive 18F-Fluoro-deoxyglucose (FDG) 
uptake not present on baseline 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 FDG-PET scan 
available, and no evidence of new lesions on CT/MRI then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol, or clinically indicated in 
order to confirm new lesions.
•
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT 
are of limited use in anatomically-based efficacy assessments. It is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CTs for tumor 
measurements by RECIST v1.1. In exceptional situations, if a site can document that the 
CT performed as part of PET/CT examination is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT, then the CT portion of the PET/CT can be used 
for RECIST measurements. However, 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. 
Physical examination
•
Lesions detected by physical examination (palpation) will only be considered as 
non-target lesions if superficial, eg, skin nodules and palpable lymph nodes. 
Documentation by color photography including ruler is recommended for estimating the 
size of skin lesions.
Measurability of Tumor Lesions
Tumor lesions will be categorized as follows:

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•
Measurable Lesions - Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
◦
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm)
◦
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT/MRI scan (CT/MRI 
scan slice thickness recommended to be no greater than 5 mm)
•
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions 
(or sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm in short axis). Lesions considered truly 
nonmeasurable include the following: leptomeningeal disease, ascites, pleural/pericardial 
effusion, and inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
•
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs should be identified as target 
lesions. It is encouraged to prioritize selection of up to 2 arterial enhancing liver lesions 
over non-enhancing liver lesions as target lesions. Lymph nodes are collectively 
considered as a single organ. Bilateral organs (eg, adrenal glands) are considered as a 
single organ. Mutilobular or segmented organs (eg, liver) are considered as a single 
organ. 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.
•
Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item on the electronic case report form (eCRF; eg, “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”).
4.3.1.1
Evaluation of Response by Response Evaluation Criteria in Solid Tumors 
Tumor response will be assessed by RECIST v1.1. All images, including unscheduled visit 
scans, will be collected on an ongoing basis and sent to the sponsor-appointed Contract 
Research Organization for quality control review and storage. A BICR of the images will be 
performed for part 1, part 2 and part 3 patients (the centralized storage of images from Part 4 
will be retained for a potential future BICR). Results of these independent reviews will not be 
communicated to the investigators, and the management of subjects will be based solely upon 
the results of the RECIST v1.1 assessment conducted by the investigator. 
Evaluation of Target Lesions
•
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes). 

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•
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more 
new lesions may be considered progression.)
•
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions
•
Complete Response - Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm in short 
axis). 
•
Non-complete Response/Non-progressive Disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.
•
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in nonmeasurable disease comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from “trace” to “large,” an increase in lymphangitic disease from localized to 
widespread.
Appearance of New Lesions
The appearance of unequivocal new lesions is considered PD according to RECIST v1.1. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinical 
deterioration, subjects may continue to receive study treatment until confirmed PD as defined 
below.
Evaluation of Overall Response
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no 
less than 4 weeks from the date of first documentation. If the next protocol scheduled scan is 
due within 2 weeks after the confirmatory scan was obtained, the protocol-scheduled scan 
does not need to be done. For subjects who are clinically stable, treatment will continue 
between the initial assessment of PD and an immediate subsequent scan with PD 

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(confirmation of immediate prior PD) (which is not required by RECIST v1.1; see below). 
These subjects may continue to receive durvalumab in combination with tremelimumab 
beyond confirmed PD (see below) and if investigators consider that subjects continue to 
receive benefit from treatment. In the absence of clinical deterioration, such modifications to 
the RECIST criteria may discourage the early discontinuation of durvalumab in combination 
with tremelimumab and provide a more complete evaluation of durvalumab in combination 
with tremelimumab antitumor activity than would be seen with conventional response 
criteria.
Table 4.3.1.1-1 provides overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions.
Table 4.3.1.1-1
Evaluation of Overall Response at a Single Timepoint by 
RECIST V1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response
No
Complete response
No target lesion a
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response/
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response /
non-progressive disease
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes or No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
RECIST = Response Evaluation Criteria in Solid Tumors.
a
Defined as no target lesions at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.

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Confirmation of Progression
Confirmed objective PD refers to either of the following scenarios: 1) clinical 
progression/deterioration confirmed by a radiological scan if clinically feasible or 2) in the 
absence of significant clinical deterioration, radiologic PD by RECIST v1.1 followed by a 
second radiologic confirmation scan with an assessment of PD according to the specific 
confirmation of progression criteria listed below. RECIST v1.1 modified for confirmation of 
progression refers to scenario 2 above. The confirmatory scan should occur at the next 
scheduled imaging visit and no earlier than 4 weeks following the date of the immediate prior 
assessment of PD according to RECIST v1.1. 
Immediate prior radiologic progression would be considered confirmed if any of the 
following criteria are met in the confirmatory scan:
•
≥20% increase in the sum of the diameters of target lesions compared with the nadir at 
2 consecutive visits, with an absolute increase of at least 5 mm in the sum of the 
diameters compared with the nadir
•
and/or significant progression (worsening) of non-target lesions and/or of pre-existing 
new lesions at the immediate subsequent (“confirmatory”) scan timepoint compared with 
the immediate prior timepoint 
•
and/or additional new unequivocal lesions at the immediate subsequent (“confirmatory”) 
scan timepoint
Note: In order to have confirmed objective PD, there should be 2 consecutive assessments of 
PD; the first PD should be assessed by RECIST v1.1, and the second PD should be assessed 
using the confirmation of progression criteria listed above. If the first PD by RECIST v1.1 is 
not confirmed, assessments should continue until the next PD by RECIST v1.1, which, in 
turn, will need its own immediate subsequent confirmation scan. 
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression. If the 
confirmation scan confirms progression, then the date of the prior scan with PD should be 
declared as the date of progression. If the first assessment of PD is not confirmed by the 
immediate subsequent scan, the investigator should not change the PD assessment of 
the prior scan. 
If a subject discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, the subject should still continue to be followed until confirmed 
objective disease progression. 

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If progression is not confirmed, in the absence of significant clinical deterioration, the subject 
should continue study drug and on-treatment assessments until the next assessment of PD, 
which will also require a follow-up confirmation scan. 
4.3.1.2
 
4.3.2
Tissue Biopsies
4.3.2.1
Fresh Tissue Biopsies
Fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely 
accessible as determined by the investigator and are not obtained from sites that require 
significant risk procedures, which include, but are not limited to, biopsies of the brain, lung, 
mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach 
or bowel wall [refer to the definition of a significant risk device under §812.3(m) in the 
Investigational Device Exemptions regulation (21 CFR 812)].
At baseline, fresh tumor tissue biopsies will be attempted prior to administration of the first 
dose of investigational product(s) for all subjects in Part 1A, Part 1B, and Part 2A. For 
subjects in Part 2B and Part 3, newly acquired (fresh or acquired within 3 months, preferred) 
or archival (< 3 years) tumor samples will be required. Noncancerous liver tissue biopsies 
should also be attempted if they can be done safely (as judged by the investigator) during the 
same procedure in which the pretreatment fresh tumor tissue biopsies are obtained.
In addition, fresh tumor biopsies (noncancerous liver tissue is NOT required) will be 
obtained on Week 5 Day 1 (± 3 days) (optional) and upon confirmed PD (optional) if 
clinically feasible (ie, repeat biopsy does not pose unacceptable medical risk to a subject as 
determined by the investigator). Additional biopsies may also be performed if clinically 
indicated (eg, for mixed responses). For subjects requiring serial image-guided core needle 
tumor biopsy, those biopsies will be performed according to institutional practice.
If clinically practical, at each fresh tumor biopsy timepoint, subjects will undergo 4 core 
biopsies, but a minimum of at least 1 core biopsy is required. The first and third (if available) 
core biopsies will be placed in formalin and processed for formalin-fixed, paraffin-embedded 
blocks, while the second and fourth core biopsies (if available) will be immediately frozen in 
liquid nitrogen or equivalent method and then stored at -80°C (-112°F). In exceptional cases, 
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excisional or punch biopsies are permitted and may be substituted for the required minimum 
of 1 core biopsy if sufficiently large (4 mm or greater in diameter). 
Baseline noncancerous liver tissue biopsies are requested to provide information regarding 
the histological status of the liver prior to administration of investigational product(s). If 
clinically feasible at the same procedure in which pretreatment fresh tumor tissue biopsies 
are obtained, subjects should undergo biopsy of noncancerous liver tissue per individual 
institutional standards. The noncancerous liver tissue biopsy will be processed per local 
institutional standards.
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by 
MedImmune. Core (tumor) biopsies may be used for correlative studies such as IHC, tumor 
DNA analysis (non-germline), RNA analysis, proteomic/protein analysis, and 
immunodiversity. Additional details for sample collection, processing, storage, and shipment 
will be provided in the Laboratory Manual.
4.3.2.2
Archival Tumor Samples
If possible, initial and subsequent archival tumor tissue should be provided. Archival tumor 
samples must be formalin fixed and embedded in paraffin blocks for IHC and additional 
correlative markers (eg, tumor DNA analysis [non-germline], RNA analysis, and 
immunodiversity). When an archival tumor block cannot be provided for this study, then 
only freshly cut sections should be provided as described in the Laboratory Manual.
4.3.3
Medical History, Physical Examination, Electrocardiogram, ECOG 
Performance Status, Child-Pugh Score, and Vital Signs
4.3.3.1
Medical History and Physical Examination
Physical examinations will be performed according to institutional guidelines on study days 
noted in Section 4.2, and will include assessments of weight; and height (at screening only).
Findings from medical history (obtained at screening) and physical examination shall be 
given a baseline grade and recorded as AEs in the eCRF. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the prestudy grade or below.
4.3.3.2
Electrocardiograms
ECGs (12-lead) will be recorded at screening and as clinically indicated throughout the study 
as noted in Section 4.2. ECGs should be obtained after the subject has been in a supine 
position for 5 minutes and recorded while the subject remains in that position. In case of 

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clinically significant ECG abnormalities, including a QT interval corrected using Fridericia’s 
formula (QTcF) value > 470 milliseconds, 2 additional 12-lead ECGs should be obtained 
over a brief period (eg, 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 5.1.
The same recorder will be used for each subject at each timepoint, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparations should be thorough and electrode positions should be according to standard 
12-lead ECG placement.
In this study lead V2 will be analyzed and reported as primary. Lead V5 will be analyzed, for 
all visits, as backup for the individual where analysis in lead V2 is not deemed possible for 
pre-dose or significant parts of whole visits or whole visits.
The following variables will be reported: heart rate, PR, RR, QRS and QT intervals from the 
primary lead of the digital 12-lead ECG.
4.3.3.3
ECOG Performance Status
Performance status as determined by the ECOG scale (Oken et al, 1982; Table 4.3.3.3-1) will 
be recorded in the eCRF per the schedule in Section 4.2.
Table 4.3.3.3-1
Eastern Cooperative Oncology Group Performance Status
Grade 
Performance Status Criteria
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all 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. Cannot carry on any self-care. Totally confined to bed or chair 
5
Dead
4.3.3.4
Child-Pugh Score
Cirrhosis severity as determined by the Child-Pugh score (Pugh et al, 1973) will be recorded 
in the eCRF per the schedule in Section 4.2. 

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Table 4.3.3.4-1 shows 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. 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 4.3.3.4-1
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)
Prothrombin time
Seconds over control
< 4
4 to 6
> 6
INR
< 1.7
1.7 to 2.3
> 2.3
Encephalopathy
None
Grade 1 to 2
Grade 3 to 4
INR = international normalized ratio.
*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 but not detectable on physical examination by the 
treating investigator would be assigned to “Absent, 1 point” per standard clinical practice. However, if 
radiological findings are substantially inconsistent with physical examination, the ascites should be re-assessed 
carefully to confirm appropriate Child-Pugh classification for ascites.
4.3.3.5
Vital Signs
Vital signs (temperature, blood pressure [BP], pulse rate, pulse oximetry, and respiratory 
rate) will be measured on study days noted in Section 4.2. 
4.3.4
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. If the subject has completed any safety 
laboratory tests within 72 hours before Week 1 Day 1, they will not need to be repeated.

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Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed according to the schedules of 
procedures in Section 4.2:
Serum Chemistry
•
Calcium
•
Lipase
•
Chloride
•
Gamma glutamyl transferase 
•
Magnesium
•
Lactic dehydrogenase
•
Potassium
•
Uric acid
•
Sodium
•
Creatinine
•
Bicarbonate (not required in countries where this is 
not standard)
•
Blood urea nitrogen
•
AST
•
Glucose
•
ALT
•
Albumin
•
Alkaline phosphatase (ALP)
•
Total protein
•
Total bilirubin
•
Triglycerides
•
Direct bilirubin
•
Cholesterol
•
Amylase
•
Thyroid stimulating hormone, free thyroxine (T4), 
free triiodothyronine (T3)
Note for serum chemistries: Tests for AST, ALT, ALP, direct bilirubin, and total bilirubin must be conducted 
concurrently and assessed concurrently.

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Hematology
•
White blood cell count with differential
•
Activated partial thromboplastin time 
•
Hemoglobin
•
Platelet count 
•
Prothrombin time/international normalized ratio
•
Fibrinogen 
Coagulation
•
Prothrombin (PT)
•
INR 
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein
Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin 
•
Serum beta-human chorionic gonadotropin
Other Safety Tests
•
HBsAg, HBeAg, hepatitis B core antibody, hepatitis B surface antibody, hepatitis B e antibody, IgM 
hepatitis B core antibody, hepatitis C antibody, hepatitis D antibody, hepatitis B DNA, hepatitis C RNA
•
Human immunodeficiency virus antibodies
Other Tests
•
(only as outlined in Section 4)
•
Vitamin D (to be collected and held for later testing)
4.3.5
 
 
 
 
&&,
&&,
&&,

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4.3.6
 
 
 
 
 
 
4.3.7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
&&,
&&,
&&,
&&,

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4.3.8
Estimate of Volume of Blood to Be Collected
A total of approximately 51 mL of blood will be collected during the 14-day screening period 
for all screening tests performed in subjects without a known diagnosis of either HBV or 
HCV infection. No more than approximately 51 mL of blood will be drawn at any one 
protocol visit during treatment of this subpopulation of subjects. 
For subjects with a known diagnosis of either HCV or HBV, approximately 51 and 52 each 
subgroup, respectively. No more than approximately 54 mL of blood will be drawn at any 
one protocol visit during treatment for both the HCV positive and HBV positive subjects, 
with the highest blood draws occurring on 
 collection days.  At all other treatment visits 
no more than approximately 39 mL of blood is expected to be drawn for any subject. All tests 
&&,
&&,

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performed at the end of treatment visit will draw no more than approximately 25 mL of blood 
for all subjects. During the follow-up period, no more than approximately 38 mL of blood 
will be collected at any one follow-up visit in any of the subpopulations. The total volume to 
be collected will depend on the length of subject participation in the study as well as to which 
investigational treatment arm of study they are enrolled.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study (or site) at any 
time. The reasons for temporarily suspending or terminating the study may include but are 
not limited to the following: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects
2. Subject enrollment is unsatisfactory
3. Noncompliance that might significantly jeopardize the validity or integrity of the study
4. Enrollment into Part 2 may be discontinued at the discretion of the sponsor should 
emerging clinical or nonclinical data suggest that continued treatment may not be 
beneficial to a given treatment
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. The investigator may initiate study-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 

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authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1) 
using designated distribution centers.
Table 4.5.1-1
Identification of Investigational Products 
Investigational Product
Manufacturer
Concentration and Formulation as Supplied
Durvalumab
MedImmune
Supplied as a vialed liquid solution containing 500 mg 
(nominal) durvalumab per vial. The solution contains 
50 mg/mL durvalumab, 26 mM histidine/histidine HCl, 
275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, 
at pH 6.0
Tremelimumab
MedImmune
Formulated at a nominal concentration of 20 mg/mL in 
20 mM histidine/histidine HCl, 222 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
EDTA, pH 5.5.
Bevacizumab
Roche
400-mg vial solution for infusion 25 mg/mL. 
EDTA = ethylenediaminetetraacetic acid; HCl = hydrochloride; w/v = weight per volume.
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially available 
0.9% (weight per volume [w/v]) saline or 5% dextrose in water (D5W) will be supplied by 
each site. Upon completion of the study, copies of investigational product accountability 
records will be returned to MedImmune. All unused investigational product will be returned 
to a MedImmune-authorized depot or disposed of upon authorization by MedImmune 
according to the investigational site policy. All investigational products should be kept in a 
secure and dry place.
4.5.1.1
Dose Calculation
The dose will be calculated using the subject’s Week 1 Day 1 weight for subjects enrolled in 
Part 1A, Part 1B, and Part 2A, and Part 4. Dose adjustments for each dose are only needed 

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for greater than 10% change in weight. Dosing day weight may be used for dose calculations 
instead of weight at Week 1 Day 1 per institutional standard.
For fixed-dose regimens: If a patient’s weight falls to 30kg or below (≤30 kg), then the 
patient should receive weight-based dosing equivalent to dosing specified below, after 
consultation between the investigator and/or study physician, until the weight improves to 
above 30 kg (>30 kg), at which point the patient should start receiving the original assigned 
fixed
!
Arm A, B, and D: durvalumab 1500 mg (20 mg/kg if weight ≤30 kg)
!
Arm A: Tremelimumab 75 mg (1 mg/kg if weight ≤30 kg)
!
Arm C: Tremelimumab 750 mg (10 mg/kg if weight ≤30 kg)
!
Arm D: Tremelimumab 300 mg: Not applicable
!
Part 4: durvalumab 1120 mg (15mg/kg if weight ≤30 kg)
!
Part 4: bevacizumab 15mg/kg
Durvalumab
The volume of durvalumab (in mL) to add to the IV bag is calculated as follows: 
Dose (mL) = [subject weight (kg) × durvalumab dose level (mg/kg)]
50 mg/mL
Or for fixed dose:
Dose (mL) = durvalumab dose level (mg)
50 mg/mL
where 50 mg/mL is durvalumab concentration.
The corresponding volume of durvalumab should be rounded to the nearest tenth mL 
(0.1 mL). If no institutional standard on dose calculations exists, then dose adjustments for 
each cycle are only needed for a greater than 10% change in weight.
Tremelimumab
The dose will be calculated using the following formula:
Dose (mL) = [subject weight (kg) × tremelimumab dose level (mg/kg)]
20 mg/mL

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Or for fixed dose:
Dose (mL) = tremelimumab dose level (mg)
20 mg/mL
where 20 mg/mL is tremelimumab concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL 
(0.1 mL). If no institutional standard on dose calculations exists, then dose adjustments for 
each cycle are only needed for a greater than 10% change in weight.
Bevacizumab
The dose will be calculated using the following formula:
Dose (mL) = [subject weight (kg) × bevacizumab dose level (mg/kg)]
25 mg/mL
where 25 mg/mL is bevacizumab concentration.
4.5.1.2
Investigational Product Dose Preparation
Durvalumab
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine 
hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it 
has a pH of 6.0.  The nominal fill volume is 10.0 mL.  Investigational product vials are stored 
at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
secondary packaging until use to prevent excessive light exposure.
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:
!
24 hours at 2°C to 8°C (36°F to 46°F) or
!
4 hours at room temperature

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Select the IXRS-assigned number of vials of investigational product required to prepare the 
subject’s dose. The dose will be administered using an IV bag containing 0.9% 
weight/volume (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration
ranging from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2 μm 
or 0.22 μm  filter.  Patient weight at baseline should be used for dosing calculations unless 
there is a ≥10% change in weight.  Dosing day weight can be used for dosing calculations 
instead of baseline weight per institutional standard.  The calculated volume of durvalumab is 
added to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 20 mg/mL. The bag is mixed by gentle inversion to ensure homogeneity of the 
dose in the bag. Note for a fixed dose of 1500 mg, patient weight should be >30 kg.
Standard infusion time is one hour, however if there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. Durvalumab does not contain preservatives, and any unused 
portion must be discarded. 
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400 mg vial solution for infusion after 
dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine-
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate and 0.02% 
(w/v) polysorbate 80; it has a pH of 5.5. The nominal fill volume is 20.0 mL.  Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product 
should be kept in secondary packaging until use to prevent excessive light exposure.
Product preparation of tremelimumab for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to start of administration should not exceed

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!
24 hours at 2°C to 8°C (36°F to 46°F) or
!
4 hours at room temperature
Select the IXRS-assigned number of vials of investigational product required to prepare the 
subject’s dose. The dose will be administered using an IV bag containing 0.9% (w/v) saline, 
with a final tremelimumab concentration ranging from 0.1 mg/mL to 10 mg/mL, and 
delivered through an IV administration set with a 0.2 μm or 0.22 μm  filter.  
Patient weight at baseline should be used for dosing calculations unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.  The volume of tremelimumab is added to the IV 
bag. The IV bag size should be selected such that the final concentration is within 0.10 to 10 
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. Note 
for a fixed dose of 75 mg, patient weight should be >30 kg.
Standard infusion time is one hour, however if there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials.  Tremelimumab does not contain preservatives, and any unused 
portion must be discarded.  
Bevacizumab
Bevacizumab 15 mg/kg should be administered according to bevacizumab prescribing 
information and clinical practice. The total in-use storage time from needle puncture of 
bevacizumab vial to the start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If the in-use storage time exceeds 
these limits, a new dose must be prepared from new vials. Bevacizumab does not contain 
preservatives, and any unused portion must be discarded.

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The necessary amount of bevacizumab should be withdrawn and diluted to the required 
administration volume with sodium chloride 9 mg/mL (0.9%) solution for injection. The 
concentration of the final bevacizumab solution should be kept within the range of 1.4 to 
16.5 mg/mL. In the majority of the occasions, the necessary amount of bevacizumab can be 
diluted with 0.9% sodium chloride solution for injection to a total volume of 100 mL.
4.5.1.3
Investigational Product Inspection
Investigational products will be supplied to the site in vials in coded kits. Each kit has a 
unique number that is printed on all labels within the kit (ie, the outer carton label and the 
label of each vial within the carton). Each vial selected for dose preparation should be 
inspected. If there are any defects noted with the investigational product(s), the investigator 
and site monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.6) for further instructions.
If there are any defects noted with the investigational products, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.6) for further instructions.
4.5.1.4
Treatment Administration
The first day of dosing is considered Day 1. The duration of durvalumab administration will 
be 1 hour (± 15 minutes) in duration. The IV infusion of tremelimumab will be 1 hour 
(± 15 minutes) in duration. 
For durvalumab and tremelimumab combination therapy, tremelimumab will be administered 
first. durvalumab infusion will start 1 hour (± 15 minutes) after the end of the tremelimumab 
infusion.
Bevacizumab 15 mg/kg should be administered according to bevacizumab prescribing 
information and clinical practice. The initial bevacizumab dose should be delivered over 90 
minutes as an IV infusion. If the first infusion is well tolerated, the second infusion may be 
administered over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent 
infusions may be administered over 30 minutes. It should not be administered as an IV push 
or bolus. The bevacizumab infusion should start approximately 1 hour (maximum 2 hours) 
after the end of the Durvalumab infusion.

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4.5.1.5
Monitoring of Dose Administration
Subjects will be monitored prior to, during, and after infusion of durvalumab, tremelimumab 
and bevacizumab. Vital signs (temperature, BP, pulse rate, pulse oximetry, and respiratory 
rate) will be measured on durvalumab and tremelimumab (monotherapy and combination), 
and durvalumab with bevacizumab combination treatment days as specified in Section 4.2.2.
In the event of ≤ Grade 2 infusion-related reaction, the infusion rate of durvalumab and 
tremelimumab may be decreased by 50% or temporarily interrupted until resolution of the 
event (up to 4 hours) and re-initiated at 50% of the initial rate until completion of the 
infusion. In subjects experiencing ≤ Grade 2 infusion-related reaction, subsequent infusions 
may be administered at 50% of the initial rate.
Primary prophylaxis against infusion-related reactions is not permitted during this study in 
order to avoid obscuring a potential safety signal and to enable a future assessment regarding 
whether premedications should be required for all subjects in future studies. However, at the 
discretion of the investigator, secondary prophylaxis (ie, prevention of infusion-related 
reaction following initial episode) is appropriate and will be permitted. Acetaminophen 
and/or an antihistamine (eg, diphenhydramine) or equivalent medications per institutional 
standard may be administered per institutional standard at the discretion of the investigator. If 
the infusion-related reaction is Grade 3 or higher in severity, treatment with durvalumab and 
tremelimumab will be discontinued.
As with any mAb, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
All dosing visits are initially scheduled based on the date of Week 1 Day 1 dosing. Future 
dosing visits can be recalibrated based on actual dosing dates when necessary.
Subjects are to receive durvalumab monotherapy, durvalumab and tremelimumab 
combination therapy,  tremelimumab monotherapy, or durvalumab with bevacizumab 
combination therapy doses within a 3-day visit window (unless dosing needs to be held for 
toxicity reasons). If the subject experiences a related toxicity, the management guidelines 
provided in Section 3.1.3 and the Dosing Modification and Toxicity Management Guidelines 
should be followed.

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4.5.1.6
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department/AstraZeneca Japan representative (Japan only) 
by the site with further notification to the site monitor. All defects will be communicated to 
MedImmune/AstraZeneca Japan (Japan only) and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints (except Japan):
Email:
Phone:
Fax:
Mail:
MedImmune, LLC
Attn: Product Complaint Department
Gaithersburg, MD 20878, USA
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into 
local languages, as required (except Japan). For Japan, details are specified in the document 
explaining reconstitution and other handling procedures for the investigational products.
4.5.4
Storage
Store durvalumab, tremelimumab and bevacizumab at 2°C to 8°C (36°F to 46°F). Do not 
freeze.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
33'
33'

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4.5.6
Accountability
For all countries except Japan, the investigator’s or site’s designated investigational product 
manager is required to maintain accurate investigational product accountability records. 
Upon completion of the study, copies of investigational product accountability records will 
be returned to MedImmune. All unused investigational product will be returned to a 
MedImmune-authorized depot or disposed of upon authorization by MedImmune.
For Japan, investigational product provided for this study will be used only as directed in the 
study protocol. The Investigational Product Storage Manager is responsible for managing 
investigational product from receipt by the study site until the return or destruction of all 
unused investigational product to the MedImmune representative.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for assignment of investigational product. A subject is considered 
enrolled into the study when the investigator notifies the IXRS that the subject meets 
eligibility criteria and the IXRS provides the assignment of investigational product to the 
subject.
Subjects in Part 2A of the study will be stratified based on viral status (HBV vs HCV vs 
uninfected) and PD-L1 expression (positive, negative, or non-evaluable) and assigned 
randomly 1:1:1 within each stratum to 1 of the 3 treatment arms (Arms A, B, and C) 
according to a randomization schedule. Subjects in Part 2B will be assigned to Arm D. 
Subjects in Part 3 will be stratified based on viral status (uninfected, HCV infected, or HBV 
infected) and TKI-based therapy (refusers or all others) and assigned randomly in a ratio of 
2:2:1:2 to 1 of up to 4 treatment arms (Arms A, B, C, and D). Following protocol amendment 
5, subjects in Part 3 will be assigned randomly in a ratio of 2:1:2 to 1 of up to 3 treatment 
arms (Arms B, C, and D). The randomization code will be produced by an independent 
statistician who is not part of study team. The IXRS will manage the number of HBV, HCV, 
uninfected, PD-L1-positive, and PD-L1-negative subjects randomized. Once approximately 
36 subjects for one viral status cohort have been randomized into Part 2A, the IXRS will not 
allow enrollment of additional subjects for that viral status cohort. 
The time between randomization/enrollment and the initiation of treatment should be as short 
as possible and no more than 1 business day. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately.

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4.6.2
Methods for Ensuring Blinding
This is an open-label study.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 4.7.2. Best 
supportive care (including antibiotics, nutritional support, correction of metabolic disorders, 
optimal symptom control and pain management [including palliative radiotherapy to non-
target lesions after discussion with the medical monitor, etc]) should be used when necessary 
for all subjects. Inactivated viruses, such as those in the influenza vaccine are permitted. 
4.7.2
Prohibited Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following medications are considered exclusionary during the study. The sponsor must
be notified if a subject receives any of these during the study.
1. Any investigational anticancer therapy other than those under investigation in this study 
2. Monoclonal antibodies (mAbs) against CTLA-4, PD-1, or PD-L1 (other than those under 
investigation in this study)
3. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy after 
consultation with the medical monitor), immunotherapy, biologic or hormonal therapy for 
cancer treatment. Concurrent use of hormones for noncancer-related conditions (eg, 
insulin for diabetes and hormone replacement therapy) is acceptable. Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy])
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled, topical, intranasal corticosteroids or local steroid injections 

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(eg, intra-articular injection) is permitted. Temporary uses of corticosteroids for 
concurrent illnesses if clinically indicated and considered to be essential for the 
management of non-immunotherapy related events experienced by the patient (eg, food 
allergies, CT scan contrast hypersensitivity, chronic obstructive pulmonary disease, 
radiation, nausea, etc) are acceptable upon discussion with the medical monitor
5. Live attenuated vaccines during the study through 30 days after the last dose of 
investigational product
6. Drugs with laxative properties and herbal and natural remedies for constipation should be 
used with caution through 90 days after last dose of tremelimumab. 
7. Herbal and natural remedies which may have immune-modulating effects should not be 
given concomitantly unless agreed by the Sponsor.
8. Part 4 only: Any anticoagulants and anti-platelet agents (Low molecular heparin is 
permitted).
9. Sunitinib should not be given concomitantly or through 90 days after the last dose of 
tremelimumab.
10. EGFR TKIs should not be given concomitantly and should be used with caution in the 90 
days post last dose of durvalumab. Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of transaminase increases (with 1st 
generation EGFR TKIs) has been reported when durvalumab has been given 
concomitantly.
4.8
Statistical Evaluation
4.8.1
General Considerations
For the purpose of generating the clinical study report, the final analysis for this study, which 
will include all study endpoints, will be performed 12 months after the first dose to the last 
patient in the study. The study populations are defined as follows:
•
As-treated Population is defined as subjects who receive any dose of either 
investigational product(s). 
•
Response Evaluable Population is defined as all treated subjects who have a baseline 
tumor assessment and have measurable disease at baseline.
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics. Additional details of statistical 
analyses will be described in the statistical analysis plan (SAP).
4.8.2
Sample Size and Power Calculations
The study consists of 5 parts. Part 1A is a safety run-in with initial enrollment of 6 uninfected 
or HCV+ subjects and staggered enrollment of 6 to 12 additional subjects 

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(3+3 dose-escalation design) with HBV+ disease as outlined above. The sample sizes for 
Part 1A were determined empirically and are consistent with those used in clinical studies to 
evaluate the safety of a proposed administered dose in a new patient population. There is a 
47% to 91% probability of observing an AE from 6 subjects if the true incidence rate is 10% 
to 33%. 
For Part 1B, approximately 24 subjects will be enrolled. For the combined sample size of 
approximately 36 subjects for Part 1A and Part 1B, there is an 84% to 98% probability of 
observing at least one AE if the true incidence rate is 5% to 10%. The sample size of 
36 subjects is chosen to obtain a preliminary assessment of antitumor activity. Table 4.8.2-1
provides the estimated ORR and the 95% confidence interval (CI) based on the exact 
probability method for a range of possible responses out of 36 subjects. The preliminary 
assessment of antitumor activity will help determine if there is sufficient evidence of clinical 
efficacy to warrant continued enrollment of subjects in Part 2.
Table 4.8.2-1
Estimated Objective Response Rate and 95 Percent 
Confidence Interval Out of 36 Subjects
Number (%) of Responses
2 (5.6)
4 (11.1)
6 (16.7)
8 (22.2)
10 (27.8)
12 (33.3)
14 (38.9)
Lower limit of 95% CI
0.7%
3.1%
6.4%
10.1%
14.2%
18.6%
23.1%
Upper limit of 95% CI
18.7%
26.1%
32.8%
39.2%
45.2%
50.9%
56.5%
CI = confidence interval.
Part 2A dose-expansion analysis cohort will include the approximately 108 subjects who are 
enrolled as a part of the global recruitment. The subjects will be stratified in a 1:1:1 ratio 
based on viral status (HBV vs HCV vs uninfected) and PD-L1 status, and assigned randomly 
within each stratum in a 1:1:1 ratio to 1 of the 3 treatment arms (Arms A, B, and C). With 
12 subjects (per viral status cohort) treated with durvalumab or tremelimumab monotherapy 
respectively, there is a 72% to 86% probability of observing at least 1 AE from 12 subjects if 
the true incidence rate is 10% to 15%. Details of the China-specific analysis will be specified 
in the China supplementary SAP and China-specific amendment.
Part 2B is a safety cohort for the evaluation of durvalumab in combination with a higher 
single-dose of tremelimumab (Arm D) in which approximately 6 to 12 subjects will be 
enrolled. 
Part 3 is a dose-expansion cohort in which approximately 200 subjects will be randomized in 
a 2:2:1:2 ratio to 1 of up to 4 treatment arms (Arms, A, B, C, and D). Following protocol 
amendment 5, subjects in Part 3 will be assigned randomly at a ratio of 2:1:2 into 1 of 3 
treatment arms (Arms B, C, and D). There is a 96% probability of observing at least 1 AE 

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from 64 subjects if the true incidence rate is 5%. To evaluate the efficacy in terms of ORR of 
durvalumab and tremelimumab administered as monotherapy and in combination to subjects 
with advanced HCC, data from Part 2 and Part 3 will be analyzed for each part separately and 
for both parts combined. If the true ORR is 20% in the combination therapy of durvalumab
1500 mg and tremelimumab 75 mg Q4W for 4 doses (or durvalumab 20 mg/kg and 
tremelimumab 1 mg/kg combination therapy Q4W for 4 doses), a sample size of 100 subjects 
will provide at least 95% power to test the hypothesis that ORR is greater than 7% at a 0.05 
significance level
Part 4 is a single arm cohort to evaluate safety and efficacy of durvalumab in combination 
with bevacizumab. The primary efficacy endpoint is ORR assessed by BICR according to 
RECIST 1.1.If the true ORR is 32%, a sample size of 100 subjects will provide at least 83% 
power to test the hypothesis that ORR is greater than 18.8% (Kudo et al 2018) at a 0.05 (2-
sided) significance level. Other hypothesized ORRs and corresponding power values are 
given in the table below.
Power Calculations to detect difference between True 
ORR  versus Control ORR=18.8%, n=100
ORR
30%
31%
32%
33%
34%
35%
Power
70%
77%
83%
88%
92%
94%
Based on Exact Binominal Test, Alpha = 0.05 (2 sided)
With 100 patients, the precision of the estimation of ORR in the overall study population will 
be within:
• +/- 8% if the ORR is 10% (i.e. 95% CI 4.9%, 17.6%)
• +/- 9% if the ORR is 15% (i.e. 95% CI 8.6%, 23.5%)
• +/-11% if the ORR is 35% (i.e. 95% CI 25.7%, 45.2%)
There is a 99% probability of observing at least 1 AE from 100 subjects if the true incidence 
rate is 5%.
To evaluate the efficacy in terms of ORR of durvalumab and tremelimumab administered as 
monotherapy and in combination to subjects with advanced HCC, data from Part 2 and Part 3 
will be analyzed for each part separately and for both parts combined. If the true ORR is 20% 
in the combination therapy of durvalumab 1500 mg and tremelimumab 75 mg Q4W for 
4 doses (or durvalumab 20 mg/kg and tremelimumab 1 mg/kg combination therapy Q4W for 
4 doses), a sample size of 100 subjects will provide at least 95% power to test the hypothesis 
that ORR is greater than 7% at a 0.05 significance level. 

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During the course of the study, subjects’ tumor samples (archival and/or from fresh biopsies) 
will be analyzed for PD-L1 expression and the prevalence of PD-L1-positive expression for 
this population will be evaluated. 
4.8.3
Efficacy
Primary analysis of response-related endpoints and corresponding time-to-event endpoints 
will be based on BICR assessments (for at least part 1 patients) according to RECIST v1.1. 
Sensitivity analysis of these endpoints will be performed using investigator assessments 
according to RECIST v1.1.
4.8.3.1
Efficacy Endpoint Definitions
The definitions of the efficacy endpoints and associated analyses are described below. 
Details will be provided in the SAP.
•
Objective response rate is defined as the rate of best overall response of CR or PR 
according to RECIST v1.1. The best overall response is defined as the best response (in 
the order of CR, PR, SD, PD, and not evaluable) among all overall responses recorded 
from the start of treatment until progression (per RECIST v1.1), or the last evaluable 
disease assessment in the absence of PD prior to the initiation of subsequent anticancer 
therapy or the discontinuation from the study, whichever occurs first. The best overall 
response of CR or PR must be confirmed, which means a response of CR/PR is recorded 
at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit when the 
response was first observed with no evidence of progression between the initial and 
CR/PR confirmation visit.
•
Progression-free survival is defined as the time from the date of first dosing to the first 
documentation of radiographic disease progression (per RECIST v1.1) or death due to 
any cause, whichever occurs first. Subjects who are alive with no documented PD by the 
data cutoff date for PFS analysis will be censored at the date of their last evaluable 
disease assessment.
•
Time to disease progression is defined as the time from the date of first dosing to the 
first documentation of radiographic disease progression (per RECIST v1.1). Subjects 
with no documented PD by the data cutoff date for TTP analysis will be censored at the 
date of their last evaluable disease assessment.
•
Time to response is defined as the time from the first dose of investigational product to 
the first documentation of a subsequently confirmed objective response. Only subjects who 
have achieved objective response (confirmed CR or confirmed PR) will be evaluated for 
TTR.
•
Duration of response is defined for responders as the period from the first 
documentation of objective response to the first documented disease progression (per 
RECIST v1.1) or death from any cause, whichever occurs first. For subjects who are 

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alive and no documented PD at the time of data cutoff for analysis, DoR will be censored 
at the last evaluable disease assessment date.
•
Disease control rate is defined as the rate of best overall response of CR, PR or SD 
according to RECIST v1.1. Disease control rate at 24 weeks is defined as the rate of best 
overall response of CR, PR or having SD with duration of SD lasting 24 weeks.
•
Overall survival is defined as the time from the date of first dosing until death due to 
any cause. If there is no death reported for a subject by the data cut-off date for overall 
survival analysis, OS will be censored at the last known alive date. If the last known date 
alive is after the data cutoff date for the OS analysis, the last known date alive will be 
truncated at the data cutoff date.
4.8.3.2
Analysis of Efficacy
Efficacy data will be analyzed on the Response Evaluable Population, which will include all 
treated subjects who have a baseline tumor assessment and measureable disease at baseline. 
Summaries and analyses will be performed for each part separately and for Part 2 and Part 3 
combined. Efficacy data will be presented by treatment arm. 
The efficacy endpoints of ORR and DCR will be estimated based on their 2-sided 95% CIs 
using an exact probability method. DCR at 24 weeks will be estimated along with its 2-sided 
95% exact CI. 
Time-to-event endpoints, including DoR, TTR, TTP, PFS, and OS, will be analyzed using 
the Kaplan-Meier method. The median of each time-to-event endpoint and its 95% CI will be 
estimated based on the Kaplan-Meier curves. Only subjects with an OR (best overall 
response of complete response or partial response) will be included in the analysis of DoR. 
The landmark 6-month PFS, 6-month TTP, and 1-year OS rates will be estimated based on 
Kaplan-Meier curves along with their 95% CIs. 
Tumor samples (archival and/or from fresh biopsies) will be analyzed to determine the 
expression level of selected immune-related pathways (eg, PD-L1 protein expression as 
determined by IHC) that may predict increased frequency of response or longer disease 
stabilization. 
 
 
 
 
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4.8.4
Safety………..
Safety summaries will be performed for each part separately and for Part 2 and Part 3 
combined. Safety data will be presented by treatment arm. 
The safety data will include AEs, SAEs, discontinuation of investigational product due to 
toxicity, and changes from baseline in laboratory parameters (including liver and viral labs), 
ECGs, and vital signs. These data will be summarized by treatment arm for each viral status 
cohort (HBV vs HCV vs uninfected) in the As-treated Population.
4.8.4.1
Analysis of Adverse Events
The number and percentage of subjects reporting treatment-emergent AEs will be 
summarized overall and by the worst NCI CTCAE grade, system organ class, and preferred 
term. Similarly, the number and percentage of subjects reporting treatment-emergent SAEs 
and treatment-emergent AE/SAEs considered related to investigational product will be 
summarized. At each level of subject summarization, a subject will be counted once using the 
highest grade and level of causality if one or more occurrences of the same system organ 
class/preferred term is reported. AEs will be graded according to the NCI CTCAE v4.03 and 
coded using the Medical Dictionary for Regulatory Activities.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Laboratory abnormalities will be graded according to the NCI CTCAE v4.03, if applicable. 
Frequencies of maximum observed grade will be presented for each laboratory parameter as 
well as the rates of subjects with Grade 3-4 toxicities. A shift table, presenting the 2-way 
frequency tabulation for baseline and post-baseline grade at scheduled time of evaluation as 
well as the worst post-baseline grade, will be provided for clinical laboratory tests.
4.8.4.3
Analysis of Vital Signs
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment arm including end of treatment 
visit as well as for the maximum and minimum post-baseline values.
&&,

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4.8.4.4
Analysis of Electrocardiograms
Electrocardiogram parameters (PR, RR, QRS, QT, QT corrected using Bazett’s formula 
[QTcB], and QTcF) will be summarized using descriptive statistics for actual values and for 
changes from baseline by treatment arm by scheduled time of evaluation including end of 
treatment visit as well as for the maximum post-baseline values. The QTcF will be 
considered as the primary correction method to assess subject cardiac safety.
The notable ECG interval values in maximum absolute QTcF and QTcB intervals 
(new ∀450 milliseconds, new > 480 milliseconds, new > 500 milliseconds) and the 
maximum absolute uncorrected QT intervals (new ∀500 milliseconds) over all post-baseline 
evaluations, as well as in QTcF and QTcB maximum changes from baseline (∀30 and 
∀60 milliseconds) over all post-baseline evaluations will be summarized by treatment. 
“New” means the category of the QTc abnormality was not present at baseline and became 
present at least one post-baseline ECG assessment.
4.8.4.5
Analysis of ECOG Performance Status
Descriptive statistics will be provided for the ECOG performance status assessments and 
changes from baseline by scheduled time of evaluation and by treatment arm including end 
of treatment visit.
4.8.5
4.8.5.1
 
 
 
 
 
 
 
4.8.5.2
 
 
 
 
&&,
&&,
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4.8.6
 
 
 
 
 
 
 
 
4.8.7
Interim Analysis
An interim analysis is planned to occur when Part 1A and Part 1B are fully enrolled and 
subjects have been followed for at least 16 weeks. The purpose of the interim analysis is to 
determine whether there is sufficient evidence to open Part 2 enrollment. As described in 
Section 3.2.4, the clinically “interesting” ORR is ≥ 20%. Therefore, if the probability of ORR 
≥ 20% is < 20%, then enrollment in Part 2 will not proceed; if the probability of ORR ≥ 20% 
is > 80%, then Part 2 will open for enrollment. The probability is computed based on 
Bayesian approach. Under the rule, based on 36 subjects, including 12 subjects from Part 1A 
and 24 subjects from Part 1B, if ≤ 4 responses (confirmed PR or better) out of the 36 subjects 
are observed, then enrollment in Part 2 will be terminated, and if ≥9 responses (confirmed 
PR or better) out of the 36 subjects are observed then enrollment will begin in Part 2. If the 
number of responses is 5, 6, 7 or 8 out of 36 subjects, then all available data (AEs, SAEs, 
duration of response, DCR, changes in 
 etc) will be evaluated by the sponsor and 
investigators to determine if the benefit-risk profile supports enrollment of Part 2. The 
&&,
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probabilities of different scenarios for different true response rates can be found in 
Table 4.8.7-1.
Table 4.8.7-1
Probabilities of Different Scenarios for Different True 
Response Rates
True 
Response Rate
Probability of Terminating 
Enrollment
Probability of Continuing 
Enrollment
Probability of Further 
Evaluation
0.05
97%
0%
3%
0.10
71%
1%
28%
0.15
36%
8%
56%
0.20
13%
28%
59%
0.25
3%
56%
40%
0.30
1%
80%
20%
0.35
0%
93%
7%
Another interim analysis will occur after approximately 10 subjects per treatment arm in Part 
3 have completed 4 weeks of follow-up. All available data from Part 2 and Part 3 will be 
included in the analysis. The goal of this interim analysis is to potentially terminate 1 or more 
of the 2 monotherapy arms (Arms B and C) for futility or safety and the additional 
durvalumab and tremelimumab combination therapy arm (Arm D) for safety.  The 
monotherapy arms will be terminated for futility if no confirmed complete or partial response 
is observed in the treated subjects. This criterion was chosen given that a monotherapy is 
considered effective if the true ORR is at least 10%. If the true response rate is 10%, the 
probability of stopping a treatment arm based on 36 subjects is 2%. A monotherapy is 
considered effective if the true ORR is at least 10%, which is greater than the ORR observed 
for sorafenib (2%, Llovet et al, 2008).
For Part 4, an interim analysis will occur after approximately 100 subjects have had the 
opportunity for 18 weeks of follow-up. Another interim analysis will occur after 
approximately 100 subjects in Part 4 have had the opportunity for 36 weeks of follow-up. 
The main objective of this interim analysis is to assess the safety and efficacy of durvalumab
in combination with bevacizumab. The primary efficacy endpoint is ORR assessed by BICR 
according to RECIST 1.1.
Additional interim analyses based on similar objectives may be performed to support the 
ongoing Phase III HCC development (in Part 1-3). No formal adjustments will be made to 
the significance level used for testing. The details of each analysis will be described in the 
SAP prior to database lock for any interim analysis.

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In addition, recruitment may be stopped in any arm if emerging data (safety and/or efficacy) 
suggest that it will no longer be developed. This may include data from other ongoing trials.
The final analysis for this study, which will include all study endpoints, will be performed 12 
months after the first dose to the last patient in the study.
  
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. The term disease progression should not be reported as an AE or 
SAE, however, medically significant individual events and/or laboratory abnormalities 
associated with disease progression (see definition of disease progression below) that fulfill 
the AE or SAE definition should be reported. An abnormal laboratory finding (including 
ECG finding) that requires medical intervention by the investigator, or a finding judged by 
the investigator as medically significant should be reported as an AE. If clinical sequelae are 
associated with a laboratory abnormality, the diagnosis or medical condition should be 
reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, 
urine red blood cell increased). 
AEs may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been
obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 

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worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
Adverse Events Associated with Disease Progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product 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 a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. Death clearly resulting from disease 
progression should NOT be reported as an SAE (see reporting guidelines in Section 5.5).
New Cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should NOT be reported as a new cancer.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse.

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5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the investigational product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or nonserious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.
The AESIs for durvalumab ± tremelimumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants and/or 
hormone replacement therapy. These AESIs are being closely monitored in clinical studies 
with durvalumab monotherapy and combination therapy. An irAE is defined as an AE 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 irAE diagnosis. Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the irAE. 
If the investigator has any questions in regards to an AE being an irAE, the investigator 
should promptly contact the study physician/medical monitor.
AESIs observed with durvalumab ± tremelimumab include:
•
Diarrhea/Colitis and intestinal perforation
•
Pneumonitis/ILD
•
Hepatitis/transaminase increases 
•
Neuropathy/neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
•
Endocrinopathies (ie, events of hypophysitis, hypopituitarism, adrenal insufficiency, 
hyperthyroidism, hypothyroidism, and type 1 diabetes mellitus)
•
Rash/Dermatitis
•
Nephritis/blood creatinine increases
•
Pancreatitis/serum lipase and  amylase increases
•
Myocarditis
•
Myositis / Polymyositis

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•
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events.
In addition, infusion-related reactions (Section 5.3.1) and hypersensitivity /anaphylactic 
reactions (Section 5.3.2) with a different underlying pharmacological aetiology are also 
considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab Investigator’s Brochures. More specific 
guidelines for their evaluation and treatment are described in detail in Section 3.1.3
(hepatotoxicity) and in the Dosing Modification and Toxicity Management Guidelines. These 
guidelines have been prepared by the sponsor to assist the investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the investigational product/study regimen by the reporting 
investigator.
For management of toxicities due to bevacizumab, please refer to the local approved 
regulatory prescribing information or manage in accordance with institutional guidelines.
5.3.1
Infusion-related Reactions
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to the 
sponsor and are defined, for the purpose of this protocol, as all AEs occurring from the start 
of the study treatment infusion up to 48 hours after the infusion start time. Guidelines for 
management of infusion-related reactions are provided in the Dosing Modification and 
Toxicity Management Guidelines. 
5.3.2
Hypersensitivity Reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al, 2012). As with the administration of any 
foreign protein and/or other biologic agents, reactions following the infusion of mAbs can be 
caused by various mechanisms, including acute anaphylactic (IgE-mediated) and 
anaphylactoid reactions against the mAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness.

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Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic mAbs delivered through IV 
infusion. These reactions are less common following subsequent exposures. Unlike infusion-
related reactions, anaphylaxis is a rare event, usually occurring after subsequent exposure to 
an antigen, and it is most commonly accompanied by severe systemic skin and/or mucosal 
reactions. The investigator is advised to carefully examine symptoms of adverse reactions 
observed during or shortly after exposure to durvalumab and tremelimumab, and consider the 
above mentioned facts prior to making a final diagnosis. Reactions occurring at the time of or 
shortly after subsequent infusions of investigational product are to be judged by the 
investigator at his/her own discretion. For the investigator’s convenience and in order to 
facilitate consistency in judgments a copy of the National Institute of Allergy and Infectious 
Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) guidance for 
anaphylaxis diagnosis is provided in Appendix 4 National Institute of Allergy and Infectious 
Diseases and Food Allergy and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic 
reaction) and infusion-related reactions are outlined in the Dosing Modification and Toxicity 
Management Guidelines.
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to the sponsor (see 
Section 5.5). See Section 5.2 for the definition of SAEs and Appendix 3 Additional Safety 
Guidance for guidelines for assessment of severity and relationship. If an AE evolves into a 
condition that meets the regulatory definition of “serious,” it will be reported on the SAE 
eCRF.
5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from the time of the patient signing the informed consent 
form through 90 days after the last dose of durvalumab and tremelimumab. If an event that 
starts post the defined safety follow up period noted above is considered to be due to a late 
onset toxicity to study drug then it should be reported as an AE or SAE as applicable.

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5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. 
5.4.3
Deaths……….
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
•
Death clearly the result of disease progression or a complication of disease progression 
should be reported at the next visit and documented in the eCRF but should not be 
reported as an SAE.
•
Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
may be helpful in the assessment of the cause of death, and if performed a copy of the 
post-mortem results should be forwarded to the sponsor representative within the usual 
timeframes (refer to Section 5.5 for additional information).
Deaths occurring after the protocol defined safety follow up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow up period and the 
event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE.
5.4.4
Safety Data to be Collected following the Final DCO of the Study
For patients continuing to receive durvalumab treatment after final DCO and database 
closure, it is recommended that the patients continue the scheduled site visits and 
investigators monitor the patient’s safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab
toxicity management guidelines. All data post the final DCO and database closure will be 
recorded in the patient notes but, with the exception of Serious Adverse Events, will not 
otherwise be reported for the purposes of this study.

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All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure 
must be reported as detailed in Section 5.5. 
5.5
Reporting of Serious Adverse Events
All SAEs must be reported, regardless of whether or not they are considered causally related 
to the investigational product or study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the course of the study, investigators or other site personnel must 
inform the appropriate sponsor representative(s) within 24 hours of when he or she becomes 
aware of it.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor Patient Safety data entry site within 24 
hours of initial receipt of fatal and life-threatening events and within 5 calendar days of 
initial receipt of all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up should be undertaken immediately. Investigators or other site personnel should 
inform the appropriate sponsor representative(s) of any follow-up information on a 
previously reported SAE within 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the electronic data capture system is not available, the investigator or other study site 
personnel reports an SAE to the appropriate sponsor representative(s) by telephone. The 
sponsor representative will advise the investigator/study site personnel how to proceed.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose………..
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IBs, unless otherwise specified in this protocol.
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

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•
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel should inform the appropriate sponsor 
representative(s) within 24 hours of when he or she becomes aware of it. Overdose does not 
automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be reported as an SAE 
(see Section 5.4 and Section 5.5 for additional information). MedImmune does not 
recommend specific treatment for an overdose. The investigator will use clinical judgment to 
treat any overdose.
5.6.2
Hepatic Function Abnormality
Adverse events of hepatic function abnormality of special interest to the sponsor are defined 
as any increase in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin 
to greater than 2 × ULN (ie, Hy’s Law cases). Concurrent findings are those that derive from 
a single blood draw or from separate blood draws taken within 8 days of each other. In the 
event of hepatic function abnormality where the etiology is unknown, timely follow-up 
investigations and inquiries should be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event. 
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the diagnosis 
should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE.
Hepatic function abnormality of unknown etiology, or which is considered attributable to 
investigational product, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to the appropriate sponsor representative(s) as an SAE 
using the eCRF (see Section 5.5 for additional information). The investigator will review the 
data with the medical monitor. The investigator should then use clinical judgment to establish 
the cause based on local standard of care and follow the subject by conducting testing as 
clinically indicated.
•
If, after appropriate workup, in the opinion of the investigator, the underlying diagnosis 
for the abnormality remains unexplained, or is considered attributable to investigational
product, permanent discontinuation of dosing for the study subject should be considered.

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Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. If the etiology of the event remains unconfirmed and/or is 
considered related to investigational product (see Appendix 3 Additional Safety Guidance), a 
prompt cumulative review of safety data and the circumstances of the event in question will 
be conducted and assessed by the MedImmune safety review committee (or equivalent) to 
determine whether continued dosing of current study subjects and/or study entry should be 
interrupted, whether the protocol will be modified, or whether the study will be discontinued 
permanently. Review and approval by the MedImmune safety review committee (or 
equivalent) is required for resumption of subject dosing or study entry in the event that the 
study is interrupted. Where applicable, regulatory authorities IRBs/IECs will be notified of 
any actions taken with the study.
5.6.3
Pregnancy
If pregnancy occurs in a female subject who has received investigational product, the 
investigator or other site personnel informs the appropriate sponsor study representative(s) 
within 24 hours of when he or she becomes aware of it.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed 
up and documented even if the subject was discontinued from the study.
If the pregnancy results in an SAE, the designated sponsor representative works with the 
investigator to ensure that all relevant information is provided to the sponsor’s Patient Safety 
data entry site within the timeframes outlined above in Section 5.5. For pregnancies that do 
NOT result in an SAE, all relevant information should be provided to the sponsor’s Patient 
Safety data entry site within 30 days. The same timelines apply when outcome information is 
available.
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. 
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.

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Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to the appropriate sponsor representative(s) using the pregnancy 
form. The sponsor will endeavor to collect follow-up information on such pregnancies 
provided the partner of the study subject provides consent.
5.6.4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the subject 
or has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error. 
•
occurred
•
was identified and intercepted before the subject received the drug
•
did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
•
Drug name confusion
•
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the subject
•
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
•
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 
•
Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 
•
Wrong subject received the medication (excluding IVRS/IWRS errors)
•
Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
•
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
•
Subject accidentally missed drug dose(s) e.g. forgot to take medication
•
Accidental overdose (will be captured as an overdose)
•
Subject failed to return unused medication or empty packaging

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•
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If an medication error occurs  in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but 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 and within 30 days for all other medication errors.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a sponsor representative will review and 
discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s).
•
Confirm that facilities remain acceptable.
•
Confirm that the investigational team is adhering to the protocol, data are being 
accurately and timely recorded in the eCRFs, biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed.

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•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts).
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data. 
Original images are stored on hard media (eg, optical disk, film, avi file, or hardcopy) as 
source documents. If images are acquired at a remote imaging facility, copies on hard media 
should be stored at the investigative site as source documents. 
6.2.2
Study Agreements
The principal investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of clinical study protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between MedImmune and the principal investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the end of the study (defined below), regardless of the number of doses of 
investigational product that was received. 

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The end of the study (“study completion”) is defined when the last patient discontinues study 
treatment. 
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure 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 
durvalumab treatment following the final DCO and database closure, it is recommended that 
the patients continue the scheduled site visits and investigators monitor the patient’s safety 
laboratory results prior to and periodically during treatment with durvalumab in order to 
manage AEs in accordance with the durvalumab toxicity management guidelines.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab (in Parts 1-3) 
may be transitioned to such a study, and the current study would reach its end. The roll-over 
or safety extension study would ensure treatment continuation with visits assessment per its 
protocol. Any patient that would be proposed to move to such study would be given a new 
Informed Consent.
6.4
Data Management
Data management will be performed according to the Data Management Plan.
A Web Based Data Capture 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 ensures 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.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 

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requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the principal investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
7.2
Subject Data Protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
MedImmune will not provide individual genotype results to subjects, any insurance 
company, any employer, their family members, general physician or any other third party, 
unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject. For example, in the 
case of a medical emergency, a MedImmune medical monitor or an investigator might know 
a subject’s identity and also have access to his or her genetic data. Also regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
7.3
Ethics and Regulatory Review
An IRB/IEC 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 subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC and to 
the study site staff in all countries except Japan. In Japan, the head of the study site will 
distribute the documents to the applicable IRB/IEC and to the principal investigator who will 
then distribute the documents to the site staff and any sub-investigators as appropriate.

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The opinion of the IRB/IEC should be given in writing. For all countries except Japan, the 
investigator should submit the written approval to MedImmune before enrollment of any 
subject into the study. For Japan, the head of the study site should submit a notification of 
direction/determination as well as a copy of the IRB/IEC written approval to the 
MedImmune representative and the principal investigator before enrollment of any subject 
into the study.
The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune 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 IRB/IEC annually.
For Japan only: the head of the study site should seek the opinion of the IRB/IEC with 
respect to the appropriateness of continuing the study at the study site at least once a year 
when the duration of the study exceeds one year. The principal investigator should submit 
progress reports to the IRB/IEC via the head of the study site at the time of the protocol re-
approval.
Before enrollment of any subject 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.
MedImmune representatives will handle the distribution of any of these documents to the 
national regulatory authorities.
MedImmune will provide regulatory authorities, IRB/IEC, and principal investigators or head 
of study site (Japan only) with safety updates/reports according to local requirements, 
including suspected unexpected serious adverse reactions, where relevant.
Each principal investigator or head of study site (Japan only) is responsible for providing the 
IRB/IEC with reports of any serious and unexpected adverse drug reactions from any other 
study conducted with the investigational product. MedImmune representatives will provide 
this information to the principal investigator so that he/she can meet these reporting 
requirements.

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7.4
Informed Consent
The principal investigator(s) at each center will:
•
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
•
Ensure each subject is notified that they are free to discontinue from the study at any time
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject 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 subject
•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the principal 
investigator or head of study site (Japan only) and MedImmune.
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.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune representatives will distribute any subsequent amendments and new versions of 
the protocol to each principal investigator(s). For distribution to IRB/IEC, see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune representatives and 
the site’s IRB/IEC 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/IEC.

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7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC 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 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 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site.

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8
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9.
9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 1
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Major changes to the protocol are summarized below. 
1. Synopsis: The synopsis was updated to align with the body of the protocol.
2. Section 1.4.4 (Clinical Experience with Other Inhibitors of the PD-1/PD-L1 Pathway in 
Subjects with HCC): Added this section to present nivolumab in HCC data.
3. Section 1.5.1 (Benefit-risk Evaluation): Updated section as follows:
a.
Referenced the nivolumab data presented in Section 1.4.4.
b. Clarified that Dose Level -1 may be evaluated if RP2D is not tolerated as assessed by 
prospectively designed parameters.
c.
Specified that pre-dose noncancerous liver tissue biopsy will be requested if the 
biopsy can be done safely during the same procedure used to obtain tumor biopsies.
4. Section 3.1.1 (Overview): Updated section as follows:
a.
Reduced total number of subjects to be enrolled from “129” to “120”.
b. Part 1, Stage 1: Reduced sample size from “9” to “6”.
c.
Part 1, Stage 2: Revised this section to indicate that if DLTs exceed the limit at the 
RP2D, then subjects will be treated at Dose Level -1. 
d. Part 2: Reduced minimum number of subjects with HCV+ HCC that may enroll in 
Part 2 after Part 1, Stage 1 has been observed for at least 6 weeks from “6” to “3”. In 
addition, indicated that HBV+ HCC subjects may not enroll in Part 2 until a RP2D 
has been identified based on subjects enrolled in Part 1, Stage 2 (instead of Part 1, 
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e.
Specified that pre-dose (screening) noncancerous liver tissue biopsy will be requested 
if the biopsy can be done safely during the same procedure used to obtain tumor 
biopsies. In addition, noted that post-dose fresh tumor biopsy is optional.
5. Section 3.1.2.1 (durvalumab in Combination with Tremelimumab [Part 1 and Arm A of 
Part 2): Updated section as follows:
a.
Specified that durvalumab 15 mg/kg (Dose Level -1) will be administered if needed. 
b. Revised the duration of treatment so that durvalumab monotherapy at 20 mg/kg Q4W
will continue until any of the study discontinuation criteria are met. 
c.
Added that subjects who progress on durvalumab monotherapy may be retreated with 
the durvalumab and tremelimumab combination. 
d. Updated the treatment schema (Figure 3.1.2.1-1) to reflect the change in treatment 
duration.
6. Section 3.1.2.2 (durvalumab Monotherapy [Arm B of Part 2): Revised the duration of 
treatment so that durvalumab monotherapy at 20 mg/kg Q4W will continue until any of 
the study discontinuation criteria are met. Updated the treatment schema 
(Figure 3.1.2.2-1) to reflect the change in treatment duration.
7. Section 3.1.3.2 (Tremelimumab Monotherapy [Arm B of Part 2): Revised the duration of 
treatment so that tremelimumab monotherapy Q12W will continue until any of the study 
discontinuation criteria are met. Updated the treatment schema (Figure 3.1.2.3-1) to 
reflect the change in treatment duration.
8. Section 3.1.2.4 (Criteria for Treatment Beyond Progression and Retreatment): Removed 
retreatment during the follow-up period.
9. Section 3.2.1 (Dose Rationale): Revised text to reflect the change in treatment duration 
outlined in Section 3.1.2.
10. Section 3.2.2 (Rationale for Study Population): Added nivolumab data in HCC.
11.
 
12. Section 4.1.1 (Number of Subjects): Reduced number of subjects in Part 1 from “15 to 
20” to “12”.
13. Section 4.1.2 (Inclusion Criteria): Revised the following criteria:
a.
For inclusion criterion #8, specified that noncancerous liver tissue biopsy will be 
requested if the biopsy can be done safely during the same procedure used to obtain 
pretreatment tumor biopsies. In addition, clarified that on-treatment tumor biopsies 
are encouraged but not required.
b. For inclusion criterion #11, specified that subjects should continue contraception and 
abstain from sperm/egg cell donation for 90 days after the last dose of durvalumab or 
tremelimumab and for 180 days after the last dose(s) of durvalumab in combination 
with tremelimumab. 
14. Section 4.2.1 (Enrollment/Screening Period): Updated Table 4.2.1-1 as follows:
a.
Specified that “qualitative” HBeAg will be assessed. 
b.
 
 
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c.
Revised footnote “a” to include collection of fresh tumor biopsy samples.
d. Revised footnote “d” to indicate that noncancerous liver tissue biopsy will be 
requested if the biopsy can be done safely during the same procedure used to obtain 
pretreatment tumor biopsies.
15. Section 4.2.2 (Treatment Period): Updated section as follows:
a.
 
b.
 
 
c.
 
 
 
16. Section 4.2.3 (Follow-up Period): Updated section as follows:
a.
Removed text that referenced 12-month treatment duration.
b. In Table 4.2.3, specified vital signs parameters and indicated that “qualitative” 
HBeAg will be assessed. Removed footnotes that referenced 12-month treatment 
duration as well as footnotes for specific 
 In addition, revised 
table title from “Schedule of Follow-up Procedures” to “Schedule of End of 
Treatment and Follow-up Procedures”.
17. Section 4.3.1 (Efficacy): Specified that MRI scans of the chest and abdomen are 
acceptable and that scans of the head, neck, and pelvis are optional.
18. Section 4.3.2.1 (Fresh Tissue Biopsies): Specified that noncancerous liver tissue biopsy 
will be requested if the biopsy can be done safely during the same procedure used to 
obtain pretreatment tumor biopsies. In addition, indicated that fresh tumor biopsies are 
now optional rather than mandatory and number of core biopsies was reduced from “3” to 
“1”.
19. Section 4.3.3.4 (Vital Signs): Indicated that pulse oximetry will be assessed at all 
timepoints where vital signs are assessed and not just at screening. 
20. Section 4.3.8 (Estimate of Volume of Blood to be Collected): Reduced blood volumes.
21. Section 4.5.1 (Identity of Investigational Product[s]), Section 4.5.1.2 (Investigational 
Product Dose Preparation), and Section 4.5.1.4 (Treatment Administration): Added D5W 
as another diluent option for durvalumab.
22. Section 4.5.1.5 (Monitoring of Dose Administration): Changed durvalumab 
/tremelimumab combination therapy and tremelimumab monotherapy treatment window 
from “7” to “3” days.
23. Section 4.8.2 (Sample Size and Power Calculation): Reduced the number of subjects in 
Part 1 from “9” to “6”
24. Section 5 (Assessment of Safety): Updated entire section to be consistent with revised 
safety template language.
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25. Appendix 2 (Management of Study Medication Related Toxicities): Updated all tables in 
this section based on the current version of the guidelines (02Jul2015).
9.2
Protocol Amendment 2
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Major changes to the protocol are summarized below. 
1. Protocol Synopsis: The synopsis was updated to align with the body of the protocol.
2.
 Section 4.2.1 (Enrollment/Screening Period; 
Table 4.2.1-1 [Schedule of Screening/Baseline Procedures]); Section 4.2.2 (Treatment 
Period; Table 4.2.2-1 [Schedule of Treatment Period Study Procedures Weeks 1 to 25] 
and Table 4.2.2-2 [Schedule of Treatment Period Study Procedures Week 29 and 
Beyond]); Section 4.2.3 (Follow-up Period; Table 4.2.3-1 [Schedule of End of Treatment 
and Follow-up Procedures]); Section 4.3.1 (Efficacy); Section 4.3.4 (Clinical Laboratory 
Tests); and Section 4.8.3.2 (Analysis of Efficacy): Added the tumor marker, 
 which 
is standard of care for these subjects to allow for potential consideration of tumor marker 
levels in conjunction with RECIST response in evaluating the overall clinical response of 
the HCC subjects enrolled in this study.
3. Section 3.1.1 (Overview); Section 3.1.2 (Treatment Regimen); Section 4.1.1 (Number of 
Subjects); Section 4.1.2 (Inclusion Criteria); Section 4.1.3 (Exclusion Criteria); 
Section 4.1.7 (Replacement of Subjects); Section 4.3.1 (Efficacy); Section 4.8.2 (Sample 
Size and Power Calculations); and Section 4.8.7 (Interim Analysis): Changed the original 
Part 1 to Part 1A and added Part 1B (Combination Efficacy Gating Cohort). The rationale 
for adding Part 1B is to determine if there is sufficient evidence of clinical activity for the 
combination of durvalumab and tremelimumab in subjects with HCC to warrant opening 
a randomized Phase 2 evaluation of the combination and each monotherapy component 
(Part 2). Sample size was increased to account for the enrollment of approximately 
24 subjects in the newly added Part 1B.
4. Section 3.1.2.4 (Criteria for Treatment Beyond Progression, Retreatment, and Treatment 
After an Immune-related Adverse Event): Added criteria (from Study D4190C00010) to 
allow continuing treatment with durvalumab monotherapy after a toxicity on durvalumab 
and tremelimumab combination therapy.
5. Section 3.2.4 (Rationale for Interim Analysis Criteria): Added this section to describe the 
rationale for the interim analysis criteria.
6. Section 4.1.2 (Inclusion Criteria): Revised the following criteria:
◦
Criterion 1: Added a higher minimum age limit (≥ 20 years) for Japan subjects.
◦
Criterion 4: Excluded subjects who received systemic therapies other than sorafenib 
to allow enrollment of a more homogenous population. This change was made to 
decrease the confounding factor that could occur in interpreting efficacy data from a 
single arm study where patients exposed to a variable number of prior therapies can 
enroll.
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◦
Criterion 5: Excluded patients with Child-Pugh Score class ≥ B7 which will restrict 
enrollment to those patients with the most robust liver function thereby optimizing the 
risk-benefit profile.
◦
Criterion 11d: Changed bilirubin criterion to exclusively include total bilirubin ≤ 2.0
× ULN which will be easier for sites to implement and restrict enrollment to those 
patients with the most robust liver function thereby optimizing the risk-benefit 
profile.
◦
Criteria 12 and 13, and Table 4.1.2-1 (Highly Effective Methods of Contraception):
Revised contraception language to align with current standard MedImmune safety 
language. In addition, made changes to meet Japan requirements.
7. Section 4.1.3 (Exclusion Criteria): Revised Criterion 3 to reflect a more conservative 
definition of exclusionary ascites to optimize the risk-benefit ratio.
8. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples): 
Revised the language for Samples Obtained for Genetic Research or Future Research to 
clarify that the samples collected will only be used for future research already specified in 
the protocol.
9. Section 4.2.1 (Enrollment/Screening Period; Table 4.2.1-1 [Schedule of 
Screening/Baseline Procedures]): In footnote ‘a’ of Table 4.2.1-1, changed the duration 
of the screening period from “Days -14 to -1” to “Days -28 to -1” only for informed 
consent, disease assessment and fresh biopsy collection to allow flexibility with 
scheduling and ease potential burden on the subjects. In addition, markers of menopause 
for females who require laboratory testing (according to inclusion criterion #12) were 
added to the schedule of screening/baseline procedures.
10. Section 4.2.1 (Enrollment/Screening Period; Table 4.2.1-1 [Schedule of 
Screening/Baseline Procedures]) and Section 4.2.2 (Treatment Period; Table 4.2.2-1 
[Schedule of Treatment Period Study Procedures Weeks 1 to 25] and Table 4.2.2-2 
[Schedule of Treatment Period Study Procedures Week 29 and Beyond]): To be 
consistent with Section 4.1.2 (Inclusion Criteria), specified that pregnancy testing will 
only apply to females of childbearing potential.
11. Section 4.2.1 (Enrollment/Screening Period; Table 4.2.1-1 [Schedule of 
Screening/Baseline Procedures]); Section 4.2.2 (Treatment Period; Table 4.2.2-1 
[Schedule of Treatment Period Study Procedures Weeks 1 to 25] and Table 4.2.2-2 
[Schedule of Treatment Period Study Procedures Week 29 and Beyond]); Section 4.2.3 
(Follow-up Period; Table 4.2.3-1 [Schedule of End of Treatment and Follow-up 
Procedures]); and Section 4.3.3.4 (Child-Pugh Score): Added assessment of Child-Pugh 
Score (which is standard of care for this class of patients) to schedule of procedures as 
this was inadvertently omitted in the previous version of the protocol. Added 
Section 4.3.3.4 (Child-Pugh Score) to describe the Child-Pugh classification of cirrhosis 
severity.
12.
 
 
 
 
 
 
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13. Section 4.3.4 (Clinical Laboratory Tests): Specified that bicarbonate testing is not 
required in countries where this is not standard. 
14. Section 4.3.8 (Estimate of Volume of Blood to be Collected): Updated to align with 
changes to assessments in Section 4.2.
15. Section 4.5.1.4 (Treatment Administration): Clarified window for infusion duration to 
decrease confusion with site interpretation of text.
16. Section 4.5.1.6 (Reporting Product Complaints); Section 4.5.3 (Labeling); Section 4.5.6 
(Accountability); Section 7.3 (Ethics and Regulatory Review); and Section 7.5 (Changes 
to the Protocol and Informed Consent Form): Revised to meet Japan requirements.
17. Section 4.8.1 (General Considerations) and Section 4.8.3.2 (Analysis of Efficacy): 
Replaced “Full Analysis Set” with “Response Evaluable Population” to align with current 
nomenclature within MedImmune biostatistics group.
18. Section 5.3 (Definition of Adverse Events of Special Interest): Added new AESI 
language in order to align with standard MedImmune language.
19. Appendix 2 (Management of Study Medication Related Toxicities): Updated the toxicity 
management guidelines to align with the current 02Oct2015 version.
9.3
Protocol Amendment 3
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. Major changes to the protocol are summarized below. 
1. Title Page: Updated the medical monitor and associated contact information.
2. Protocol Synopsis: The synopsis was updated to align with the body of the protocol.
3. Section 1.4 (Summary of Clinical Experience): Updated the clinical experience of 
durvalumab in combination with tremelimumab to support the additional treatment arms 
and to remind the site personnel to refer to the IBs for current study drug information. 
4. Section 1.5.1 (Benefit-risk Evaluation): Updated risks associated with study drugs to be 
consistent with the current IBs. Added mitigation of risk for the higher tremelimumab 
dose by including a safety run-in cohort (Part 2B). 
5. Section 2.1.2 (Secondary Objectives) and Section 2.2.2 (Secondary Endpoints): Revised 
the secondary efficacy objective and its corresponding endpoint to add clarification on 
the parameters for evaluating clinical activity, including ORR, DC, DoR, TTP, PFS, and 
OS, based on investigator assessments and BICR according to RECIST v1.1. 
6.
 
 
7.
 
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8. Section 3.1.1 (Overview); Section 3.1.2 (Treatment Regimen); and Section 4.1.1 
(Number of Subjects): Part 2B has been added to evaluate the safety of an additional 
treatment regimen of durvalumab in combination with a higher single dose of 
tremelimumab. Part 3 is a 4 arm randomized comparison of the treatment arms assessed 
in Part 2A (using a corresponding fixed-based dose) and Part 2B. Part 3 has been 
included to more thoroughly assess the efficacy of the treatment arms along with 
 evaluation. The following revisions were made based on the 
additional treatment arms:
◦
Arm D Part 2B: durvalumab 1500 mg in combination with tremelimumab 300 mg for 
1 dose as combination therapy followed by durvalumab 1500 mg Q4W as 
monotherapy (approximately 6 to 12 subjects)
Arm A Part 3: durvalumab 1500 mg in combination with tremelimumab 75 mg Q4W 
for 4 doses as combination therapy followed by durvalumab 1500 mg Q4W as 
monotherapy (approximately 64 subjects) 
Arm B Part 3: durvalumab 1500 mg Q4W as monotherapy (approximately 
64 subjects)
Arm C Part 3: Tremelimumab 750 mg Q4W for 7 doses then Q12W as monotherapy 
(approximately 32 subjects)
Arm D Part 3: durvalumab 1500 mg in combination with tremelimumab 300 mg for 
1 dose as combination therapy followed by durvalumab 1500 mg Q4W as 
monotherapy (approximately 64 subjects)
◦
Dosing information for Part 1A, Part 1B, and Part 2A was added to the description of 
each part in Section 3.1.1 for clarity. 
◦
The reference to RP2D was removed because this study will be investigating 
additional treatment regimens. 
◦
The presentation of the treatment regimens was updated to table format for 
clarification and the associated figures were updated to show the additional dosing 
regimens. 
◦
The number of subjects and the Study Flow Diagram (Figure 3.1.1-1) were updated to 
reflect the additional treatment arms.
9. Section 3.1.1 (Overview); Section 4.1.1 (Number of Subjects); Section 4.8.2 (Sample 
Size and Power Calculations); and Section 4.8.8 (Analysis of Chinese Subjects in 
Part 2A): Allowance for additional Chinese subjects to enroll into Part 2A was added. 
The corresponding statistics for Part 2A were updated and Section 4.8.8 was added to 
further detail the statistical analysis for the additional Chinese cohort. 
10. Section 3.1.1 (Overview); Section 3.2.3 (Rationale for Endpoints); Section 4.2.1 
(Enrollment/Screening Period; Table 4.2.1-1 [Schedule of Screening/Baseline 
Procedures]); and Section 4.3.2.1 (Fresh Tissue Biopsies): Added a statement to clarify 
that subjects enrolled in Part 2B or Part 3 must provide a newly acquired (fresh or 
acquired within 3 months, preferred) or archival (< 3 years) tumor sample at screening.
11. Section 3.1.2.1 (Criteria for Treatment Beyond Progression, Retreatment, and Treatment 
After a Treatment-related AE): The retreatment section was updated to allow all subjects 
who receive combination therapy in any arm to be retreated with the same combination 
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regimen as previously assigned if they experience PD while on durvalumab monotherapy 
or if retreated after a treatment-related AE. 
12. Section 3.2.1 (Dose Rationale) and Section 8 (References): Rationale to support the 
additional fixed dosing regimens was added along with the appropriate references.
13. Section 3.2.4 (Rationale for interim analysis) and Section 4.8.7 (Interim analysis): Added 
language to allow for another interim analysis after approximately 10 subjects per 
treatment arm in Part 3 have been enrolled. This analysis will be used to test for futility 
for the monotherapy arms (Arms B and C) and for safety in the higher single-dose 
combination therapy arm (Arm D). 
14. Section 4.1.2 (Inclusion Criteria): Revised the following criteria:
◦
Criterion 7: Revised text to clarify that all subjects in all arms of the study with 
confirmed HBV infection (defined as HBsAg positive or HBV DNA detectable) must 
be treated with antiviral therapy prior to enrollment, must remain on antiviral therapy 
for the duration of treatment, and continue antiviral therapy for 6 months after the last 
dose of study treatment.  
◦
Criterion 8a: Revised text to clarify that a previously irradiated lesion can be 
considered a target lesion only if no other non-irradiated measureable lesions exist.
◦
Criterion 9: Added text to clarify that subjects in Part 2B and Part 3 must provide a 
tumor sample, which may be an archival tumor tissue sample (< 3 years) if the subject 
cannot provide a newly acquired (fresh or acquired within 3 months, preferred) tumor 
tissue sample. 
◦
Criterion 3: specified for part c that management of the disease is per local 
institutional practice
15. Section 4.1.3 (Exclusion Criteria): Revised the following criteria:
◦
Criteria 12 and 13: Revised text to clarify that all subjects in all arms of the study will 
not be eligible if they are co-infected with hepatitis viruses.
16. Section 4.1.7 (Replacement of Subjects): Updated text to indicate that subjects in Part 1B, 
Part 2A, and Part 2B of the study may be replaced if they discontinue prior to receiving 
the first dose of study medication. Subjects randomized in Part 3 will not be replaced.
17. Section 4.2.1 (Enrollment/Screening Period; Table 4.2.1-1 [Schedule of 
Screening/Baseline Procedures]): Revised the following assessment:
 
 
◦
Added BCLC classification at screening
18. Section 4.2.2 (Treatment Period; Table 4.2.2-1 [Schedule of Treatment Period Study 
Procedures Weeks 1 to 25]): Revised the following assessments and footnotes:
 
 
 
 
 
 
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◦
 
 
◦
 
 
◦
 
◦
◦
 
◦
Footnote ‘a’ was revised to include imaging instructions.
◦
Footnote ‘e’ vital signs collection instructions were revised to include the new 
treatment arms.
◦
 
 
◦
 
◦
Added footnote ‘l’ to tremelimumab administration to indicate that tremelimumab 
will be administered in combination with durvalumab for 1 dose only to subjects 
enrolled in Arm D of Part 2B and Arm D of Part 3. 
19. Section 4.2.2 (Treatment Period; Table 4.2.2-2 [Schedule of Treatment Period Study 
Procedures Week 29 to End of Study]): Revised the title to indicate an end to the study. 
Revised the following footnotes:
◦
 
◦
Footnote ‘b’ vital signs collection instructions were revised to include the new 
treatment arms.
20. Section 4.2.3 (Follow-up Period; Table 4.2.3-1 [Schedule of End of Treatment and 
Follow-up Procedures]): Revised the following footnotes:
◦
 
◦
Removed the 6 month sample collection timepoint and associated footnote for 
 and qualitative HBeAg and anti-HBe.
◦
Revised footnote ‘a’ to include imaging instructions and to clarify that disease 
assessments will only be discontinued if the EOT visit is for PD.
◦
Revised footnote ‘g’ to include new combination dosing arms (Arm A of Part 3) for 
tremelimumab end of treatment procedures and to indicate the end of treatment date 
as 90 days after the last dose for subjects in Arm D of Part 2B and Arm D of Part 3 
who receive only 1 dose of tremelimumab.
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21.
 
22. Section 4.5.1.1 (Dose Calculation) and Section 4.5.1.2 (Investigational Product Dose 
Preparation): The calculation for the additional fixed doses was added for both study 
drugs.
23. Section 4.6.1 (Methods for Assigning Treatment Groups): Revised text to state that 
subjects enrolled in Part 2B will be assigned to Arm D and subjects in Part 3 will be 
randomized in a ratio of 2:2:1:2 to 1 of up to 4 treatment arms (Arms A, B, C, and D). 
24. Section 4.8.1 (General Considerations): Updated the timing of the main efficacy analysis 
to occur 12 months after the last patient is randomized.
25. Section 4.8.2 (Sample Size and Power Calculations): Revised text to include statistics for 
the addition of treatment arms in Part 2B and Part 3. 
26. Section 4.8.3.2 (Analysis of Efficacy): Revised text to indicate that the efficacy data will 
be analyzed for each part separately and for Part 2 and Part 3 combined and presented by 
treatment arm. The efficacy analysis for the additional fixed dosing arms as well as the 
landmark efficacy endpoint analysis of 6-month TTP rate was added. 
 was removed 
from the efficacy analysis section because it was included in the clinical laboratory tests 
(Section 4.3.4).
27. Section 4.8.4 (Safety): Revised text to indicate that safety summaries will be performed 
for each part separately and for Part 2 and Part 3 combined and presented by treatment 
arm.
28.
 
 
29. Section 5.3 (Definition of Adverse Events of Special Interest): Revised the AESIs 
observed with durvalumab in combination with tremelimumab treatment to be consistent 
with the current IBs. 
30. Section 6.3 (Study Timetable and End of Study), Section 3.1.1 (Overview), Section 4.2.2 
(Treatment Period; Table 4.2.2-2 [Schedule of Treatment Period Study Procedures Week 
29 to End of Study]), Section 4.3.1 (Efficacy): The end of study definition was revised to 
when the last patient discontinues treatment. 
31.
 
 
 
 
 
32. Addition of Appendix 6 Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluations of Hy’s Law to complement section 5.6.2 
9.4
Protocol Amendment 4
1. Title Page and Appendix 10.1: changed global clinical lead
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2. Synopsis and 6.3 Study Timetable and End of Study: Post final Data Cut Off (DCO) -
Recommended update based on AZ protocol template 2.1 
3. Synopsis, 4.8.3.1 Efficacy Endpoint Definitions: added in new efficacy endpoint of 
TTR (Time to Response), which is a standard endpoint and to compare efficacy 
among the different arms.
4. Table 1.4.1-1: Overview of Ongoing Clinical Studies of durvalumab in Which 
Subjects Have Been Treated – amended error (changed footnote b to a)
5. Section 3.1.2.1: revised the retreatment section because progressive disease should be 
confirmed by imaging and removed Treatment After a Treatment related AE 
paragraphs as sites should refer to TMG 
6. Table 3.1.2.1: Revised Part 3 Arm C to correct the tremelimumab dose from “750 
mg/kg” to “750 mg”. 
7. Section 4.1.2 Inclusion Criteria: changed inclusion criteria 3 (moved 3b to #7 and 3c 
to #8); inclusion criteria 7 (to provide clarification on HBV DNA detectable vs 
undetectable, and which patients must be treated with antiviral therapy); inclusion 
criteria 8 (moved 3c to 8); inclusion criteria 9 (to align with AZ protocol template 2.1 
and removed requirement of "Tumor lesions used for biopsy should not be lesions 
used as RECIST target lesions"); inclusion criteria 11 (minor changes); and inclusion 
criteria 14 and 15 (to align with AZ protocol template 2.1)
8. Section 4.1.3 Exclusion Criteria: changed exclusion criteria 1, 2, 4, 10, 11 (which is 
now 10), 12 (which is now 11), 15 (which is now 13) and 21 (which is now 19) to 
provide further clarification on eligibility of patients
9. Section 4.1.6 Survival Status for Withdrawn Consent and Lost to Follow-Up Patients: 
recommended update based on AZ protocol 2.1
10. Table 4.2.2-1 (Schedule of Treatment Period Study Procedures Weeks 1-25): 
removed footnote “l” from Tremelimumab administration (for both 4 dosing cycles 
and 1 dosing cycle) as it was added in error; revised footnote “l” to specify the visit 
window for blood sample collection on Week 2 Day 1 (± 1 day) and Week 4 Day 1 (± 
1 day); revised and changed placement of footnotes “I” and “k” to provide more 
information for patients in Arm D of part 2B and part 3; added footnote “c” to other 
assessments that do not need to be repeated if performed within 3 days of 1st dose; 
edited footnote “a” as disease assessments and dosing will not always be within 7 
days of each other; and added footnote “q” for hepatitis B patients
11. Table 4.2.2-2 Schedule of Treatment Period Study Procedures Week 29 to End of 
Study: added footnote “f” for hepatitis B patients   
12. Table 4.2.3-1 Schedule of End of Treatment and Follow-up Procedures: added 
footnote “h” for hepatitis B patients
13. Section 4.3.2.1 Fresh Tissue Biopsies: removed language to allow the same lesion 
used for baseline biopsy to also be used as a target lesion for RECIST as long as it is 
suitable for accurate repeated measurements.
14. Section 4.5.1.2 Investigational Product Dose Preparation: edited to reflect: 1) There 
are no restrictions on treme dosing material; 2) Diluent does not need to be removed 
from IV bag before adding drug; and 3) Dextrose can be used with either drug. 

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15. Section 4.5.1.5 Monitoring of Dose Administration: as per TMG, updated to not 
allow skipping or missing of doses; dose is just held until drug can be resumed as per 
(or permanently discontinued)
16. Section 4.8.3.1 Efficacy Endpoint Definitions:  added time to response efficacy 
endpoint.
17. Section 5.3 Definition of Adverse Events of Special Interest: Changes to AESIs based 
on updated IBs (Durvalumab edition 12 and Tremelumumab edition 8) and AZ 
protocol template 2.1
18. Section 5.4.1 Time Period for Collection of Adverse Events: To further specify that 
AEs to be collected from "the time the patient signs informed consent form" (as 
opposed to "signature of informed consent"); and added more information on 
AEs/SAEs that are past the 90 days post dose but due to late onset toxicity to study 
drug 
19. Section 5.4.4 Safety Data to be Collected following the Final DCO of the Study: 
recommended update based on AZ protocol template 2.1
20. General: revised the protocol to correct the links where error messages appear.
21. Section 3.1.3 Management of Study Medication Related Toxicities and Appendix 2: 
updated to reflect latest TMG 01Nov2017 
22. Appendix 7 Hepatitis B Stratification Guidance: new appendix added to help sites 
determine infection status 
9.5
Protocol Amendment 5
1. Part 3 Arm A Recruitment Closure: Following Amendment 5, AstraZeneca will 
update Study 22 to evaluate a single durvalumab plus tremelimumab combination 
arm, based on results from the pre-planned interim analysis (see section 4.8.7 Interim 
Analysis), evaluating tolerability and clinical activity in Study 22. All other arms 
remain unchanged. All regimens evaluated were tolerable, and no new safety signal 
was identified. Following recruitment closure of this arm, if a patient has not 
completed or started all 4 doses of tremelimumab, the patient may either continue to 
complete the full schedule, or continue with durvalumab monotherapy only.
2. Part 4 addition (durvalumab + bevacizumab): VEGF has been shown to play a role in 
the development and spread of HCC (Kaseb et al 2009). Additional evidence suggests 
that the combination of PD-L1 inhibition with vascular endothelial growth factor 
(VEGF) inhibition may result in synergistic activity and improved clinical benefit 
(Barsoum et al 2014, Voron et al 2015, Yasuda et al 2013). Preliminary data from an 
ongoing Phase Ib study testing atezolizumab (a PD-L1 inhibitor) and bevacizumab 
therapy as first-line treatment in patients with advanced HCC showed promising 
clinical activity, with an ORR of 65% (Stein et al 2018). This data indicates further 
evaluation of durvalumab therapy in combination with VEGF inhibitor therapy in 
patients with advanced HCC is warranted. Bevacizumab, a mAb targeting VEGF, is 
approved by the FDA for the treatment of several types of cancer, including 
colorectal cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma, 
cervical cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer. 
Bevacizumab has immunomodulatory effects (eg, increased dendritic cell maturation, 

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9.6
Protocol Amendment 6

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&&,

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10 APPENDICES
10.1
Appendix 1 Signatures 

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Sponsor Signature(s)
A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab 
Administered as Monotherapy, or Durvalumab in Combination with Tremelimumab or 
Bevacizumab in Subjects with Advanced Hepatocellular Carcinoma
I agree to the terms of this protocol.
Signature and date: 
Electronic signature is appended
 Gaithersburg MD, 20878, USA 
Telephone number: 
33'
33'
33'

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Signature of Principal Investigator
A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab 
Administered as Monotherapy, or Durvalumab in Combination with Tremelimumab or 
Bevacizumab in Subjects with Advanced Hepatocellular Carcinoma
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Conference on Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available):
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.

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10.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.3
Appendix 3 Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03 as provided 
below. The determination of severity for all other events not listed in the NCI CTCAE v4.03 
should be made by the investigator based upon medical judgment and the severity categories 
of Grade 1 to 5 as defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc).
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.

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Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).

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Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, washout of an existing medication). 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/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).

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10.4
Appendix 4 National Institute of Allergy and Infectious Diseases 
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
The NIAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset 
and may cause death (Sampson et al, 2006). They recognize 3 categories of anaphylaxis, with 
criteria designated to capture from 80% of cases (category 1) to > 95% of all cases of 
anaphylaxis (for all 3 categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING:
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
References
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report --
second National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.

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10.5
Appendix 5 Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluations 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.

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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
!
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) (see Section 6)
!
Notify the AstraZeneca representative who will then inform the central Study Team

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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. 
#
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.

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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 as described in 
Section 6?
If no, follow the process described in the Potential Hy’s Law criteria 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 Section 4.2 of this 
Appendix 
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/Guidance
s/UCM174090.pdf.

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10.6
Appendix 6 Hepatitis B Stratification Guidance
Test
Result
Interpretation
Action
Stratified to 
Hepatitis B?
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Negative
Susceptible
None
No
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Positive
Immune due to natural 
infection or chronic 
infection without 
antigenemia
Test HBV DNA load: 
! If <10 IU/ml, (or below the limit of 
detection per local lab), no antiviral 
treatment required. Continue testing 
monthly to ensure levels do not 
exceed 10 IU/ml.
! If ≥10 IU/ml, start anti-viral 
treatment and maintain treatment 
until 6 months post last dose study 
drug.
! If subject on anti-viral therapy for 
HBV with undetectable HBV DNA 
(<10 IU/ml or under the limit of 
detection per local lab) patient will 
be stratified to HBV+ cohort.
If HBV DNA 
load ≥10 IU/ml
(or above limit of 
detection per 
local lab): Yes
If HBV DNA 
load <10 IU/ml
(or below the 
limit of detection 
per local lab): No
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Positive
Immune due to hepatitis 
B vaccination
None
No
HBsAg 
anti-HBc 
IgM anti-HBc
anti-HBs
Positive 
Positive 
Positive
Negative
Acute Infection
Start anti-viral treatment and maintain 
treatment until 6 months post last dose 
study drug
Yes
HBsAg 
anti-HBc 
IgM anti-HBc
anti-HBs
Positive 
Positive 
Negative
Negative
Chronic Infection
Start anti-viral therapy and maintain 
treatment until 6 months post last dose 
study drug
Yes
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Negative
4 potential 
interpretations:
! Resolved infection 
(most common)
! False-positive anti-
HBc: susceptible
! Low-level chronic 
infection
! Resolving acute 
infection
Test HBV DNA load: 
! If <10 IU/ml, no treatment required. 
Continue testing monthly to ensure 
levels do not exceed 10 IU/ml.
! If ≥10 IU/ml, start anti-viral 
treatment and maintain treatment 
until 6 months post last dose study 
drug
If HBV DNA 
load ≥10 IU/ml
(or above limit of 
detection per 
local lab): Yes
If HBV DNA 
load <10 IU/ml
(or below the 
limit of detection 
per local lab): No

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