A Phase III, Randomized, Multicenter,Open-Label, Comparative Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for the First-Line Treatment in Patients With Extensive Disease Small-Cell Lung Cancer (SCLC) (CASPIAN)
Phase: PHASE3
Conditions: Small Cell Lung Carcinoma Extensive Disease
Sponsor: AstraZeneca

Clinical Study Protocol
Drug Substance
Durvalumab (MEDI4736) 
and tremelimumab
Study Code
D419QC00001
Edition Number
6.0
Date
16 January 2020
EudraCT
2016-001203-23
A Phase III, Randomized, Multicenter, Open-Label, Comparative Study to 
Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab 
in Combination With Platinum-Based Chemotherapy for the First-Line 
Treatment in Patients with Extensive Disease Small-Cell Lung Cancer 
(SCLC) (CASPIAN)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden  
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
001
002
003
004
005
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
2(186)
VERSION HISTORY
Version  6.0, 
Updates per Durvalumab IB edition 15 and Tremelimumab IB edition 10. Sections 
updated: 1.3.2.1, 1.3.2.2, 1.3.2.3
New CSP language on malignancies. Section updated: 6.2
Updated AESI list for Durvalumab. Section updated: 6.5
Updated language when applying Toxicity Management Guidelines as a standalone clinical 
document. Sections updated: 1.3.2.1, 3.9, 5.2.7, 6.5, 6.9, 6.9.1, 7.7
Addition of language regarding long-term follow up and clarification of data collection post 
primary database lock. Sections updated: 4.3, 5.1.2, 9.3, 9.4, added Table 12 
Appendix E [Dose Modification and Toxicity Management Guidelines]: This section 
was removed to have Toxicity Management Guidelines as a standalone Annex. 
Version 5.0, 
Update of Multiple Testing Procedure (MTP). Sections updated: Synopsis, 8.2, 8.5, 8.5.10 
and Figure 6
Version 4.0, 
Update of primary and secondary objectives and the rationale, removal of BICR. Sections 
updated: Synopsis, List of abbreviations and definitions of terms, Sections 1.1.5.1, 
1.2.4, 1.3.1.3, 1.3.2.4, 2.1, 2.2, 4, 5.1, 5.1.1, 8.4.1.1, 8.4.1.3, 8.5.2.1, 8.5.2.2, Table 11, 
Figure 3, and Appendix F
Update of Multiple Testing Procedure (MTP) and interim analysis plan including maturity. 
Sections updated: Synopsis, 8.1,  8.2, 8.3, 8.4.1.1,8.4.1.2, 8.4.1.3, 8.5, 8.5, 8.5.1.1, 8.5.2.1, 
8.5.2.2, 8.5.2.3, 8.5.2.4, 8.5.10, 8.6, Figure 3 and Table 11
Clarification regarding follow up scan . Sections updated: Figure 4, Figure 4 footnote b, 
Table 3 and Appendix F
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
3(186)
Clarification on PK non-compartmental analysis and patient reported outcomes. Sections 
updated : 8.4.4.2 and 8.5.3.3
Minor administrative changes for clarification and to correct typographical errors
Version 3.0, 
Update of primary and secondary objectives. Sections updated: Synopsis, Sections 1.2.4, 
2.1 and 2.2 
Update of information regarding primary and secondary variables, MTP and alpha 
allocation, interim analysis, power, critical values of hazard ratio for PFS and OS analyses, 
projected number and percentage of PFS and OS events at interim/final analyses, projected 
alpha allocation at interim/final analyses and projected study duration. Sections updated:
Synopsis, Sections 8.1,  8.2,  8.5, 8.5.1.1, 8.5.1.2, 8.5.10, Figure 6 and Table 11
Clarification regarding time period for collection of adverse events. Section updated:
Table 3 footnote C. 
Removal of the information that samples taken for paraneoplastic auto-antibody research 
will be used for retrospective TMB analysis. Section updated: Section 5.5.1.
Addition of information regarding safety data to be collected following the final DCO of the 
study. Section updated: Section 6.3.12.
Addition of language to allow long term survival follow up post analysis of OS. Sections 
updated: Synopsis, Sections 5.1.2, 6.3.12, 9.3 and Table 3 footnote f.
Addition of information regarding the request for at least one subsequent scan after each 
initial progression event for all patients if possible. Sections updated: Section 4,  Table 2, 
Table 2  footnote f and Table 3
Removal of mainland China to allow patients dosed in CFDA approved sites in Taiwan to 
be included and correction to the definition of China Cohort. Sections updated: Synopsis, 
list of abbreviations and definitions of terms Sections 1.4, 2.4, 8.2 and 8.6
Addition of information regarding the preparation of durvalumab and tremelimumab doses 
for administration with an IV bag. Sections updated: Sections 7.1.2 and 7.1.3
Removal of the information regarding confirming responses. Sections updated: Section 
5.1
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
4(186)
Change to language regarding treatment through progression. Sections affected : Synopsis 
and Section 7.2
Removal the references to irRECIST. Sections updated:  list of abbreviations and 
definitions of terms, Sections 1.2.4, 5.1.1, 8.4.1.1, 8.4.1.2,  8.5.1.2 and Table 11
Clarification regarding the collection of second progression and subsequent anticancer 
therapy. Sections updated: Section 8.4.1.4 and Table 3
Additional information regarding analysis of Patient-reported outcomes. Sections updated: 
Sections 8.4.3 and  8.5.3.
Minor administrative changes for clarification and to correct typographical errors
Version 2.0, 
Changes to the protocol are summarized below:
Update to the Toxicity Management Guidelines, to be consistent with updates across the 
clinical programme and to the Investigator’s Brochure. The main changes are to the General 
Guidance section, addition of specific guidance for myocarditis and myositis/polymyositis, 
and update to specific guidance for Endocrinopathy. Sections updated: Sections 4, 6.9 and 
Appendix E.
A 2-day window has been added to Cycle 1, Day 1 to allow the administration of study 
treatment to start up to 2 days after randomization, in order to allow sites sufficient time to 
prepare and label the study treatments. Sections updated: Figure 4, Table 2, Sections 3.3 
and 7.2.2).
Updates to the descriptions of risks for durvalumab, tremelimumab, and the combination of 
durvalumab + tremelimumab, in line with updates across the clinical programme. Sections 
updated: Sections 1.3.2, 1.3.2.1, 1.3.2.2, and 1.3.2.3.
Clarification that the APF6, APF12 and OS18 endpoints are equivalent to PFS at 6 months, 
PFS at 12 months and OS at 18 months, respectively.  Sections updated: Synopsis, List of 
abbreviations, and Sections 1.2.4 and 2.2.
Updates to the Adverse Events of Special Interest. Section updated: Section 6.5.
The 7-day window has been removed from the checks on survival status for those patients 
who have withdrawn consent or are lost to follow-up. Section updated: Section 3.10.2.1.
Addition of options to continue recruitment in mainland China, following achievement of 
the global recruitment target of 795 randomized patients and a further objective to evaluate 
consistency in efficacy and safety among SCLC patients in mainland China, as required by 
the China Food and Drug Administration. Sections updated: Synopsis, Sections 1.4, 8.2, 
and 8.6. 
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
5(186)
To include an exploratory objective to investigate the relationship between a patient’s tumor 
mutational burden (TMB) and efficacy outcomes. Sections updated: Table 2, Sections 2.4 
and 5.5.1. 
Updates and clarification of the description of guidelines for evaluation of objective tumor 
response using RECIST 1.1. Sections updated: Section 5.1 and Appendix F.
Removal of the paraneoplastic auto-antibody research at selected sites; samples collected so 
far on study will be used for TMB analysis.  These analyses have been removed due to sub-
optimal sample collection at selected sites and limited sample stability. Any samples 
collected for this purpose (as per Version 1.1 of the CSP) will be used for retrospective 
TMB analysis, subject to receipt of re-consent.  This will ensure utilization of all samples 
collected on study and will enrich the sample set for the TMB analysis, as it will provide 
baseline samples for some of the patients already randomized in CASPIAN. Sections 
updated: Table 2, Table 3, Section 3.1 and Section 5.5.1.
Addition of text to describe how patients can continue to receive their assigned treatment 
after the final data cut-off (DCO). Section updated: Synopsis, Section 7.2.2.
Minor administrative changes for clarification and to correct typographical errors.
Version 1.1, 
Initial creation
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
6(186)
PROTOCOL SYNOPSIS
A Phase III, Randomized, Multicenter, Open-Label, Comparative Study to 
Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab 
in Combination With Platinum-Based Chemotherapy for the First-Line 
Treatment in Patients with Extensive Disease Small-Cell Lung Cancer 
(SCLC) (CASPIAN)
International Coordinating Investigator.
Study site(s) and number of patients planned
This study will randomize approximately 795 eligible patients to receive 
durvalumab + tremelimumab + etoposide and cisplatin or carboplatin (etoposide and 
platinum-based chemotherapy [EP]; Arm 1), durvalumab + EP (Arm 2), or EP alone (Arm 3) 
at sites worldwide. Once global enrollment achieves 795 randomized patients, recruitment will 
continue in China only. Up to 189 patients from China will be randomized into the study (see 
Section 8.6 for detail).  The choice of platinum agent is at the Investigator’s discretion, but 
must be in accordance with eligibility criteria. 
Study design
This is a phase III, randomized, open-label, multicenter, global study to determine the efficacy 
and safety of combining durvalumab ± tremelimumab with EP followed by durvalumab ± 
tremelimumab maintenance therapy versus EP alone as first-line treatment in patients with 
extensive-disease small-cell lung cancer (SCLC).
This study is planned to randomize approximately 795 eligible patients at sites worldwide. 
Patients who fulfill all the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1:1 ratio in a stratified manner according to the planned platinum-based 
therapy for Cycle 1 (cisplatin or carboplatin) to receive treatment with 
durvalumab + tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or EP (Arm 3).  
Durvalumab with or without tremelimumab will be concurrently administered with first-line 
chemotherapy (EP) in the experimental arms (Arm 1 and Arm 2) and will continue to be 
administered post-chemotherapy until confirmed progressive disease (PD).  The control arm 
(Arm 3) can receive up to 6 cycles of EP and prophylactic cranial irradiation if clinically 
indicated, at the Investigators’ discretion.  
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
7(186)
Tumor assessments will be performed at Screening as baseline with follow-up at 
Week 6 ±1 week from the date of randomization, at Week 12 ±1 week from the date of 
randomization, and then every 8 weeks ±1 week until confirmed objective disease 
progression.  
Global recruitment will be completed once approximately 795 patients have been randomized. 
Once global enrollment is completed, recruitment will continue in China only.  A total of up 
to 189 patients from China will be randomized (see Section 8.6 for detail). 
Objectives
Primary objective:
Outcome measures:
To assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
EP and the efficacy of durvalumab + EP 
treatment compared with EP in terms of OS 
OS
EP  Etoposide and platinum-based chemotherapy; OS  Overall survival.
Secondary objectives:
Outcome measures:
To further assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
EP and the efficacy of durvalumab + EP 
compared with EP in terms of PFS, ORR, 
APF6 (PFS rate at 6 months), APF12 (PFS rate 
at 12 months), and OS18 (OS rate at 18 
months)
PFS, ORR, APF6 and APF12 using site Investigator 
assessments according to RECIST 1.1
OS18
To assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
durvalumab + EP in terms of PFS and OS
PFS using site Investigator assessments according to 
RECIST 1.1 
OS
To assess the PK of both durvalumab and 
tremelimumab
Concentration of durvalumab and tremelimumab in 
blood and non-compartmental PK parameters, such as 
peak concentration and trough (as data allow; sparse 
sampling)
To investigate the immunogenicity of 
durvalumab and durvalumab + tremelimumab
ADA (confirmatory results: positive or negative; 
titers [ADA neutralizing antibodies will also be 
assessed])

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
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Secondary objectives:
Outcome measures:
To assess the effect of treatment on SCLC 
symptoms and health-related QoL using 
EORTC QLQ-C30 v3 and QLQ-LC13
EORTC QLQ-C30: symptoms (fatigue, pain, 
nausea/vomiting, dyspnea, loss of appetite, insomnia, 
constipation, and diarrhea).  Health-related 
QoL/functioning (physical function, role function, 
emotional function, cognitive function, social 
function, and global health status/QoL).
EORTC QLQ-LC13: disease-related symptoms 
(dyspnea, cough, hemoptysis, chest pain, 
arm/shoulder pain, and other pain).
Changes in WHO/ECOG performance status will also 
be assessed.
ADA  Anti-drug antibody; AE  Adverse event; APF12  Proportion of patients alive and progression free at 
12 months from randomization (ie, PFS rate at 12 months); APF6  Proportion of patients alive and progression 
free at 6 months from randomization (ie, PFS rate at 6 months); ECOG  Eastern Cooperative Oncology Group; 
EORTC  European Organisation for Research and Treatment of Cancer; EP  Etoposide and platinum-based 
chemotherapy; OS  Overall survival; OS18  Overall survival at 18 months after randomization; PFS  Progression-
free survival; PK  Pharmacokinetic(s); QLQ C30 v3  30-item Core Quality of Life Questionnaire, version 3; 
QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; QoL  Quality of life; RECIST 1.1  Response 
Evaluation Criteria in Solid Tumors, version 1.1; WHO  World Health Organization.
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
durvalumab and durvalumab + tremelimumab 
in combination with EP treatment compared 
with EP
AEs; physical examinations; vital signs including 
blood pressure and pulse rate; and laboratory findings 
including clinical chemistry, hematology, and 
urinalysis
AE  Adverse event; EP  Etoposide and platinum-based chemotherapy.
A further objective, to fulfil China Food and Drug Administration (CFDA) requirements, is to 
evaluate the consistency in efficacy and safety among patients from China for benefit-risk 
assessment of durvalumab + tremelimumab in combination with EP treatment compared to EP 
and durvalumab + EP compared to EP.
Target patient population
Adult patients (aged ≥18 years) with histologically or cytologically documented extensive 
disease (American Joint Committee on Cancer Stage (7th edition) IV SCLC [T any, N any, 
M1 a/b]), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal 
volume that is too large to be encompassed in a tolerable radiation plan.  Patients must have 
World Health Organization/Eastern Cooperative Oncology Group performance status of 0 
or 1.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
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Duration of treatment
Unless specific treatment discontinuation criteria are met, patients in Arms 1 and 2 will 
continue therapy until disease progression, as per investigator assessment. Unless specific 
treatment discontinuation criteria are met, treatment can continue for up to 6 cycles for 
patients in Arm 3.
Patients who continue to receive benefit from their assigned treatment at the final data cut-off 
(DCO) and database lock 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 lock, it is recommended that the 
patients continue the scheduled site visits according to the limited schedule in section 9.3. and 
investigators monitor the patients’ safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage adverse events (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 lock, patients currently receiving treatment with durvalumab 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 assessments per its protocol.  Any 
patient who would be proposed to move to such study would be given a new informed consent 
form.
Progression during treatment
Patients in all arms with PD by RECIST 1.1 (unconfirmed and confirmed) who, in the 
Investigator’s opinion, continue to receive benefit from their assigned treatment and who meet 
the criteria for treatment in the setting of PD may continue to receive their assigned treatment 
for as long as they are gaining clinical benefit. This also applies to EP; however, EP is
restricted to a maximum of 4 cycles for patients in Arms 1 and 2 and a maximum of 6 cycles 
for patients in Arm 3. 
Follow-up of patients post-discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy will be followed 
up until confirmed disease progression and for survival. 
Survival
All patients randomized in the study should be followed up for survival. Survival assessments 
may continue per protocol (every 2 months) post the primary analysis of OS unless instructed 
otherwise by AstraZeneca.
Investigational product, dosage, and mode of administration
!
Durvalumab 1500 mg ± tremelimumab 75 mg will be administered via IV infusion, 
concurrently with chemotherapy starting on week 0 and continued post 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
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chemotherapy. In Arm 1 up to 5 combination doses of durvalumab + tremelimumab 
will be administered; the detailed dose and schedule is illustrated in Figure 1
!
N.B. If a patient’s weight falls to 30 kg or below the patient should receive weight-
based dosing equivalent to 20 mg/kg of durvalumab and 1 mg/kg tremelimumab 
until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg plus tremelimumab 75 mg. 
!
EP: the dose of etoposide + carboplatin or cisplatin investigated will not exceed the 
product label dose for the given indication dose (etoposide [80 to 100 mg/m2] via 
IV infusion with either carboplatin [area under the curve (AUC) 5-6] via IV 
infusion or cisplatin [75 to 80 mg/m2] via IV infusion) starting on Week 0, for up to 
a maximum of 4 doses/cycles in Arms 1 and 2 and a maximum of 6 cycles in 
Arm 3.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
11(186)
Figure 1
Dosing Scheme
Treatment arms
During Chemotherapy
Q3W
Post Chemotherapy
Q4W
Cycle 1
Week 0
Cycle 2
Week 3
Cycle 3
Week 6
Cycle 4
Week 9
Week 12
Week 16
Week
20 to PD
Arm 1
EP +
Durva + Treme
EP +
Durva + Treme
EP +
Durva + Treme
EP +
Durva + Treme
Durva
Durva + 
Treme*
Durva
Arm 2
EP +
Durva
EP +
Durva
EP +
Durva
EP +
Durva
Durva
Durva
Durva
Arm 3
EP
EP
EP
EP**
*
In the case of dose delay(s) more than one durvalumab + tremelimumab combination dose can be given post chemotherapy to ensure that up to 
5 combination doses are administered in Arm 1.
**
In Arm 3, EP can be given for an additional 2 cycles Q3W on Weeks 12 and 15 (ie, total 6 cycles post-randomization) if clinically indicated, at the 
investigator’s discretion before patients enter Follow-up.  Prophylactic cranial irradiation (PCI) can also be given at investigators’ discretion.  This does 
not alter the planned scan schedule Q8W starting at Week 12 for patients in Arm 3. 
Durvalumab dose will be 1500 mg during chemotherapy and post-chemotherapy; tremelimumab dose will be 75mg during and post chemotherapy. 
Note: Patients whose weight falls to 30 kg or below must receive weight-based dosing equivalent to 20 mg/kg of durvalumab and 1mg/kg tremelimumab until 
the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg and 75 mg of tremelimumab. 
EP  Etoposide and platinum-based chemotherapy; Durva  Durvalumab; PD  Progressive disease; Treme  Tremelimumab; Q3W  Every 3 weeks; Q4W  Every 
4 weeks.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
12(186)
Safety Confirmation
An independent data monitoring committee (IDMC) comprised of independent experts will be 
convened to confirm the safety and tolerability of the proposed dose and schedule of 
durvalumab ± tremelimumab in combination with platinum based chemotherapy at two early 
stages of enrolment. A step wise approach will be adopted. The initial safety review will take 
place when the first 30 patients (10 in each arm) have completed the 1st cycle of treatment and 
had 21 days of follow up. A second review will take place when an additional 30 patients (10 
in each arm) have completed the 1st cycle of treatment and have had 21 days of follow up, 
making a total of 60 patients. At the time of 2nd review, it is expected that the initial 30 
patients would have had at least 6 weeks of follow up, with some patients receiving much 
longer. These two reviews will be carried out by the IDMC in an unblinded manner. After 
review of the unblinded data, the IDMC will make a recommendation on whether the study 
should continue recruitment as planned, or hold recruitment. The IDMC  recommendation will 
be communicated to all sites when available.
In addition, the IDMC will meet approximately every 6 months thereafter to continue safety 
monitoring.
Statistical methods 
The primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + 
EP treatment compared with EP (Arm 1 vs. 3) and the efficacy of durvalumab + EP treatment 
compared with EP (Arm 2 vs 3) in terms of OS. OS is defined as the time from the date of 
randomization until death due to any cause. 
The 2 primary endpoints of this study are OS (Arm 1 vs. 3) and OS (Arm 2 vs. 3). To control
for type 1 error, a significance level of 1% will be used for the analysis of OS (Arm 1 vs. 3), 
and a significance level of 4% will be used for the analysis of OS (Arm 2 vs. 3). The study 
will be considered positive (a success) if either of the OS analysis results are statistically 
significant. 
Secondary efficacy variables include PFS for durvalumab + tremelimumab + EP versus EP 
(Arm 1 vs. 3), PFS for durvalumab + EP versus EP (Arm 2 vs. 3), OS and PFS for 
durvalumab + tremelimumab + EP versus durvalumab + EP (Arm 1 vs. 2), objective response 
rate, the proportion of patients alive and progression free at 6 and 12 months from 
randomization and the proportion of patients alive at 18 months. PFS (per RECIST 1.1 as 
assessed by the site Investigator) is defined as the time from the date of randomization until 
the date of objective PD or death (by any cause in the absence of progression) regardless of 
whether the patient withdraws from randomized therapy or receives another anticancer 
therapy prior to progression. All endpoints related to tumor assessment are assessed by site 
Investigator. 
Efficacy data will be summarized and analyzed on an intent-to-treat (ITT) basis, and the 
treatment arms will be compared on the basis of randomized treatment, regardless of the
treatment actually received.  Patients who were randomized but did not subsequently go on to 
receive study treatment are included in the ITT population.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
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There will be 2 data cut-off timepoints in the study. The  interim analysis of OS will occur 
when approximately 318 OS events have occurred (60% maturity) in the durvalumab + 
tremelimumab + EP and EP treatment arms and approximately 318 OS events have occurred 
(60% maturity) in the durvalumab + EP and EP treatment arms (approximately 28 months 
after the first patient is randomized). 
The data cut-off for the final analysis of OS (the second data cut-off) will occur when 
approximately 425 OS events have occurred across the durvalumab + tremelimumab + EP and 
EP treatment arms (80% maturity) and approximately 425 OS events have occurred across the 
durvalumab + EP and EP treatment arms (80% maturity). If the average true OS HR is 0.69, 
the study will have 89% power to demonstrate a statistically significant difference at the  final 
analysis with a 2-sided 0.93% significance level (for an overall alpha of 1%) for the 
comparison of durvalumab + tremelimumab + EP versus EP (Arm 1 vs 3), and 96% power to 
demonstrate a statistically significant difference at a 2-sided 3.57% significance level (for an 
overall alpha of 4%) for the comparison of durvalumab + EP versus EP (Arm 2 vs 3); this 
translates to a 4.8-month benefit in median OS over EP (15.7 months vs 10.9 months).The 
smallest treatment difference that would be statistically significant is an average HR of 0.78 
for durvalumab + tremelimumab + EP versus EP and 0.82 for durvalumab + EP versus EP. 
With a 15-month recruitment period and a minimum follow-up period of 27 months assumed, 
it is anticipated that this analysis will be performed 42 months after the first patient has been 
randomized. 
At the time of each data cut-off, secondary efficacy endpoints will also be assessed. The 
complete testing strategy is described in Section 8.
OS will be analyzed using a stratified log-rank test (stratified for platinum-based therapy 
planned at Cycle 1 [cisplatin or carboplatin]).  The effect of treatment will be estimated by the 
HR together with its corresponding confidence interval and p-value for the ITT population.  
PFS, programmatically derived from site Investigator assessments, will be analyzed in the 
same way as OS above.
Safety data will be summarized descriptively and will not be formally analyzed.
China data
Global recruitment will be complete once approximately 795 patients have been randomized. 
Once global enrollment is completed, recruitment will continue in China only.  A total of up 
to 189 patients from China will be randomized (see Section 8.6 for details).  To evaluate 
consistency as required by the CFDA, the efficacy and safety in the China cohort will be 
analyzed separately using the same statistical methods as for the global cohort analysis unless 
otherwise specified (see Section 8.6).  Owing to late recruitment of patients in the expansion 
cohort, data cut-offs for the China cohort analyses may be different from global data cut-off to 
ensure appropriate evaluation.  The analysis  will be performed when the OS data from the 
China patients are of similar maturity, where significant clinical efficacy is established  in the 
global cohort.  Safety and tolerability will be summarized for the China Safety Analysis Set. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
14(186)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................6
TABLE OF CONTENTS...................................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 21
1.
INTRODUCTION ............................................................................................. 25
1.1
Background and rationale for conducting this study ........................................... 25
1.1.1
Immunotherapies ............................................................................................... 26
1.1.2
Durvalumab ....................................................................................................... 27
1.1.3
Tremelimumab................................................................................................... 27
1.1.4
Durvalumab + tremelimumab combination therapy............................................ 28
1.1.5
Rationale for conducting this study .................................................................... 28
Rationale for the combination of durvalumab ± tremelimumab with 
chemotherapy.....................................................................................................28
1.1.6
Study aim...........................................................................................................30
1.2
Rationale for study design, doses, and control groups......................................... 30
1.2.1
Durvalumab and tremelimumab dose and treatment regimen justification .......... 30
Durvalumab+ tremelimumab combination therapy dose rationale....................... 30
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy......................................................................................................32
Durvalumab monotherapy dose rationale ........................................................... 32
Rationale for fixed dosing .................................................................................. 34
1.2.2
Rationale for proposed phase III dose and schedule............................................ 34
Safety confirmation of proposed doses............................................................... 37
1.2.3
Rationale for control arm: standard care therapy ................................................ 38
1.2.4
Rationale for endpoints ...................................................................................... 39
1.3
Benefit-risk and ethical assessment ....................................................................40
1.3.1
Potential benefits................................................................................................ 40
Durvalumab .......................................................................................................40
Durvalumab + tremelimumab.............................................................................40
Durvalumab ± tremelimumab with chemotherapy ............................................. 41
1.3.2
Overall Risks ..................................................................................................... 42
Durvalumab .......................................................................................................42
Tremelimumab................................................................................................... 43
Durvalumab + tremelimumab.............................................................................43
Durvalumab ± tremelimumab with chemotherapy .............................................. 44
1.3.3
Overall benefit-risk assessment ..........................................................................46

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1.4
Study design ...................................................................................................... 47
2.
STUDY OBJECTIVES...................................................................................... 51
2.1
Primary objectives ............................................................................................. 51
2.2
Secondary objectives.......................................................................................... 51
2.3
Safety objectives................................................................................................ 52
2.4
Exploratory objectives ....................................................................................... 53
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................... 54
3.1
Inclusion criteria ................................................................................................ 55
3.2
Exclusion criteria ............................................................................................... 57
3.3
Patient enrollment and randomization ................................................................ 59
3.4
Procedures for handling incorrectly enrolled or randomized patients .................. 60
3.5
Methods for assigning treatment groups............................................................. 61
3.6
Methods for ensuring blinding ...........................................................................61
3.7
Methods for unblinding......................................................................................61
3.8
Restrictions........................................................................................................61
3.9
Discontinuation of investigational product ......................................................... 63
3.9.1
Procedures for discontinuation of patient from IP............................................... 64
3.10
Criteria for withdrawal.......................................................................................65
3.10.1
Screen failures ...................................................................................................65
3.10.2
Withdrawal of the informed consent...................................................................65
Survival status for patients who withdrew consent and were lost to follow-
up.......................................................................................................................65
3.11
Discontinuation of the study............................................................................... 66
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 67
4.1
Screening/Enrollment period..............................................................................77
4.2
Treatment period................................................................................................ 77
4.2.1
Safety Confirmation Period................................................................................77
4.3
Follow-up period................................................................................................ 78
5.
STUDY ASSESSMENTS.................................................................................. 78
5.1
Efficacy assessments.......................................................................................... 78
5.1.1
Reading of scans ................................................................................................ 79
5.1.2
Survival assessments.......................................................................................... 80
5.2
Safety assessments............................................................................................. 80
5.2.1
Laboratory safety assessments............................................................................ 80

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5.2.2
Physical examination ......................................................................................... 82
5.2.3
Electrocardiogram.............................................................................................. 82
5.2.4
Vital signs..........................................................................................................83
5.2.5
Early Patient review for safety ........................................................................... 84
5.2.6
WHO/ECOG performance status........................................................................ 84
5.2.7
Other Safety Assessments .................................................................................. 84
5.3
Other assessments.............................................................................................. 85
5.3.1
Patient-reported outcomes..................................................................................85
EORTC QLQ-C30 ............................................................................................. 86
EORTC QLQ-LC13........................................................................................... 86
PRO-CTCAE .....................................................................................................86
Patients’ Global Impression of Change............................................................... 86
EQ-5D-5L.......................................................................................................... 87
5.3.2
Administration of the patient-reported outcome questionnaires .......................... 87
5.3.3
Health care resource use..................................................................................... 88
5.4
Pharmacokinetics ............................................................................................... 88
5.4.1
Collection of samples for pharmacokinetics analysis .......................................... 88
5.4.2
Collection of samples to measure for the presence of ADAs............................... 89
Storage and destruction of pharmacokinetic/ADA samples................................. 89
5.5
Biomarkers ........................................................................................................ 89
5.5.1
Exploratory biomarkers......................................................................................90
5.5.2
Labeling and shipment of biological samples ..................................................... 92
5.5.3
Chain of custody of biological samples .............................................................. 92
5.5.4
Withdrawal of informed consent for donated biological samples ........................ 92
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 93
6.1
Definition of adverse events............................................................................... 93
6.2
Definitions of serious adverse event ................................................................... 93
6.3
Recording of adverse events............................................................................... 94
6.3.1
Time period for collection of adverse events ...................................................... 94
6.3.2
Follow-up of unresolved adverse events............................................................. 94
6.3.3
Variables............................................................................................................95
6.3.4
Causality collection............................................................................................ 96
6.3.5
Relationship to protocol procedures ................................................................... 96
6.3.6
Adverse events based on signs and symptoms .................................................... 96
6.3.7
Adverse events based on examinations and tests ................................................ 97
6.3.8
Hy’s law ............................................................................................................97
6.3.9
Disease progression............................................................................................ 97
6.3.10
New cancers....................................................................................................... 97
6.3.11
Deaths................................................................................................................98
6.3.12
Safety Data To Be Collected following the final DCO of the study .................... 98
6.4
Reporting of serious adverse events ................................................................... 98
6.5
Adverse events of special interest.......................................................................99

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6.6
Overdose.......................................................................................................... 101
6.6.1
Durvalumab or tremelimumab.......................................................................... 101
6.6.2
Standard of Care .............................................................................................. 101
6.7
Pregnancy ........................................................................................................ 101
6.7.1
Maternal exposure............................................................................................ 101
6.7.2
Paternal exposure............................................................................................. 102
6.8
Medication Error.............................................................................................. 102
6.9
Management of IP-related toxicities................................................................. 104
6.9.1
Durvalumab and durvalumab + tremelimumab................................................. 104
6.9.2
Standard-of-care agents.................................................................................... 105
6.10
Study governance and oversight....................................................................... 106
6.10.1
Safety Confirmation......................................................................................... 106
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 107
7.1
Identity of investigational products .................................................................. 107
7.1.1
Order of Administration................................................................................... 107
7.1.2
Durvalumab (MEDI4736)................................................................................ 108
7.1.3
Tremelimumab................................................................................................. 109
7.1.4
Standard of Care: EP........................................................................................ 110
7.2
Dose and treatment regimens ........................................................................... 110
7.2.1
Treatment regimens.......................................................................................... 110
7.2.2
Duration of treatment and criteria for treatment through progression................ 114
7.3
Labeling........................................................................................................... 115
7.4
Storage............................................................................................................. 115
7.5
Compliance...................................................................................................... 115
7.6
Accountability.................................................................................................. 115
7.7
Concomitant medications and other treatments................................................. 116
7.7.1
Other concomitant treatment ............................................................................ 118
7.7.2
Durvalumab drug-drug interactions.................................................................. 118
7.8
Post-study access to study treatment................................................................. 118
8.
STATISTICAL ANALYSES........................................................................... 119
8.1
Statistical considerations.................................................................................. 119
8.2
Sample size estimate ........................................................................................ 119
8.3
Definitions of analysis sets............................................................................... 120
8.3.1
Full analysis set................................................................................................ 121
8.3.2
Safety analysis set............................................................................................ 121
8.3.3
PK analysis set................................................................................................. 121
8.4
Outcome measures for analyses........................................................................ 121
8.4.1
Calculation or derivation of efficacy variables.................................................. 121

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.
RECIST 1.1-based endpoints ........................................................................... 121
Primary endpoints............................................................................................ 122
Secondary endpoints ........................................................................................ 122
Exploratory endpoints ...................................................................................... 123
8.4.2
Calculation or derivation of safety variables..................................................... 124
Adverse events................................................................................................. 124
Safety assessments........................................................................................... 124
8.4.3
Calculation or derivation of patient-reported outcome variables ....................... 125
EORTC QLQ-C30 ........................................................................................... 125
Lung cancer module (EORTC QLQ-LC13)...................................................... 125
Calculation or derivation of health state utility (EQ-5D-5L) ............................. 126
8.4.4
Calculation or derivation of pharmacokinetic variables .................................... 126
Population pharmacokinetics and exposure-response/safety analysis................ 126
Pharmacokinetic non-compartmental analysis .................................................. 126
Immunogenicity analysis.................................................................................. 126
8.5
Methods for statistical analyses........................................................................ 126
8.5.1
Analysis of the primary variable(s)................................................................... 130
Overall survival................................................................................................ 130
8.5.2
Analysis of the secondary variable(s) ............................................................... 132
Progression-free survival.................................................................................. 132
Objective response rate .................................................................................... 132
Proportion of patients alive and progression free at 6 and 12 months................ 132
Proportion of patients alive at 18 months (OS18) ............................................. 133
8.5.3
Patient-reported outcomes................................................................................ 133
Mixed-model repeated measures analysis......................................................... 133
Time to deterioration........................................................................................ 133
EORTC QLQ-C30 ........................................................................................... 133
EORTC QLQ-LC13......................................................................................... 134
PRO-CTCAE ................................................................................................... 134
Patients’ Global Impression of Change............................................................. 134
EQ-5D-5L........................................................................................................ 134
8.5.4
Health care resource use................................................................................... 134
8.5.5
Safety data ....................................................................................................... 134
8.5.6
Pharmacokinetic data ....................................................................................... 135
8.5.7
Immunogenicity analysis.................................................................................. 135
8.5.8
Pharmacokinetic/pharmacodynamic relationships ............................................ 135
8.5.9
Biomarker data................................................................................................. 135
8.5.10
OS interim analysis .......................................................................................... 135
8.6
China cohort .................................................................................................... 136
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 137
9.1
Training of study site personnel ....................................................................... 137
9.2
Monitoring of the study.................................................................................... 137
9.2.1
Source data ...................................................................................................... 138

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9.2.2
Study agreements............................................................................................. 138
9.2.3
Archiving of study documents.......................................................................... 138
9.3
Study timetable and end of study...................................................................... 138
9.4
Data management by AstraZeneca or delegate ................................................. 140
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 141
10.1
Ethical conduct of the study ............................................................................. 141
10.2
Patient data protection...................................................................................... 141
10.3
Ethics and regulatory review ............................................................................ 141
10.4
Informed consent ............................................................................................. 142
10.5
Changes to the protocol and informed consent form......................................... 142
10.6
Audits and inspections ..................................................................................... 142
11.
LIST OF REFERENCES ................................................................................. 144
LIST OF TABLES
Table 1
Highly effective methods of contraception (<1% failure rate)............................63
Table 2
Schedule of assessments for Arms 1, 2, and 3 Treatment period........................69
Table 3 
Schedule of assessments for patients who have completed/discontinued 
treatment with durvalumab + tremelimumab + EP, durvalumab + EP, or EP.....75
Table 4
Clinical chemistry.............................................................................................81
Table 5
Hematology ......................................................................................................81
Table 6
Urinalysis..........................................................................................................82
Table 7
List of investigational products for this study..................................................107
Table 8
Prohibited concomitant medications................................................................116
Table 9
Supportive medications...................................................................................118
Table 10 Summary of outcome variables and analysis populations ................................120
Table 11 Pre-planned statistical and sensitivity analyses to be conducted.......................127
Table 12 Schedule of study assessment and relevant eCRF pages to be completed 
during Long-term follow-up. ..........................................................................139
Table 13 Summary of methods of assessment ................................................................165
Table 14 Evaluation of target lesions ............................................................................170
Table 15 Evaluation of non-target lesions ......................................................................171
Table 16 Overall visit response......................................................................................172

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LIST OF FIGURES
Figure 1 Dosing Scheme .................................................................................................11
Figure 2 Study Schematic for CCTG Study.....................................................................36
Figure 3 Overall study design..........................................................................................49
Figure 4 Study flow chart................................................................................................50
Figure 5 Dosing Scheme ...............................................................................................113
Figure 6 Multiple testing procedures for controlling the type 1 error rate.......................129
LIST OF APPENDICES
Appendix A  Additional Safety Information....................................................................152
Appendix B  International Airline Transportation Association (IATA) 6.2 Guidance 
Document.......................................................................................................154
Appendix C  Genetic Research........................................................................................156
Appendix D  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law..................................................................................159
Appendix E Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors)...........................164
Appendix F Patient Reported Outcomes: EORTC QLQ-C30, EORTC QLC-LC13, 
PRO-CTCAE, EQ-5D-5L, and PGIC..............................................................177

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from randomization 
(ie, PFS rate at 12 months)
APF6
Proportion of patients alive and progression free at 6 months from randomization 
(ie, PFS rate at 6 months)
AST
Aspartate aminotransferase
AUC
Area under the drug concentration-time curve
AUCss
Area under the drug concentration-time curve at steady state
BP
Blood pressure
C
Cycle
C/D
Cycle/Day
CCTG
Canadian Cancer Trials Group
CD
Cluster of differentiation
CFDA
China Food and Drug Administration
CI
Confidence interval
CR
Complete response
CRF
Case report form (electronic/paper)
CRO
Clinical Research Organization
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CXCL
Chemokine (C-X-C motif) ligand
DCO
Data cut-off
DCR
Disease control rate
DL1
Dose level 1
DLL3
Delta-like canonical Notch ligand 3
DLT
Dose-limiting toxicity

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Abbreviation or special 
term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
ED
Extensive-stage disease
EORTC
European Organisation for Research and Treatment of Cancer
EP
Etoposide and platinum-based chemotherapy
ePRO
Electronic patient-reported outcome (device)
EQ-5D-5L
EuroQol 5-Dimension, 5-level health state utility index
ESMO
European Society for Medical Oncology
EU
European Union
FAS
Full analysis set
GCP
Good Clinical Practice
Gx
Genetic Research
GMP
Good Manufacturing Practice
HbsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HPV
Human papilloma virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN-γ
Interferon gamma
IgG
Immunoglobulin G
IL
Interleukin
ILD
Interstitial lung disease
imAE
Immune-mediated adverse event
IP
Investigational product 
IRB
Institutional Review Board, synonymous to Ethics Committee (EC) and 
Independent Ethics Committee (IEC)

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Abbreviation or special 
term
Explanation
ITT
Intent to treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LD
Limited-stage disease
LPLV
Last patient last visit
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labor, and Welfare
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small-cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
OS18
Overall survival at 18 months after randomization
PCI
Prophylactic cranial irradiation
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PFS2
Progression-free survival after subsequent anticancer therapy
PGIC
Patient’s Global Impression of Change
PK
Pharmacokinetic(s)
PNS
Paraneoplastic syndrome
PR
Partial response
PRO
Patient-reported outcome
PRO-CTCAE
Patient-reported outcomes version of the CTCAE
Q2W
Every 2 weeks
Q3W
Every 3 weeks

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Abbreviation or special 
term
Explanation
Q4W
Every 4 weeks
Q8W
Every 8 weeks
Q12W
Every 12 weeks
QLQ-C30 v3
30-item Core Quality of Life Questionnaire, version 3
QLQ-LC13
13-item Lung Cancer Quality of Life Questionnaire
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event 
SAP
Statistical analysis plan
SCLC
Small-cell lung cancer
SD
Stable disease
SoC
Standard of care
sPD-L1
Soluble programmed cell death ligand 1
STS
Soft-tissue sarcoma
TB
Total bilirubin
TIL
Tumor-infiltrating lymphocyte
TL
Target lesion
TMB
Tumor mutational burden
ULN
Upper limit of normal
US
United States
VT
Verbatim Term
WBDC
Web-Based Data Capture
WHO
World Health Organization
WT
Weight

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.59 million deaths (19.4% of the total 
cancer deaths; GLOBOCAN 2012).
Small-cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung 
cancers (Puglisi et al 2010).  SCLC is perhaps the most aggressive form of the disease, 
distinguishable from non-small-cell lung cancer (NSCLC) by its rapid doubling time, high 
growth fraction, and early dissemination.  It is strongly associated with tobacco smoking and 
is also associated with an extremely high mutation rate.  Inactivation of TP53 and RB1 occurs 
frequently, and in a recent study in which sequencing of SCLC tumors was carried out, 
recurrent mutations were identified in the CREBBP, EP300, and MLL genes that encode 
histone modifiers (Peifer et al 2012).  Furthermore, mutations in PTEN, SLIT2, and EPHA7 
(as well as focal amplifications of the FGFR1 tyrosine kinase gene) were observed.
A 2-stage system dividing patients into limited and extensive disease was developed in 1973 
by the United States (US) Veteran’s Administration Lung Cancer Study Group.  Limited 
disease was defined as tumor tissue that could be encompassed in a single radiation port, and 
extensive-stage disease (ED) was defined as any tumor that extended beyond the boundaries 
of a single radiation port.  At present, limited disease is identified in ~30% of patients, and ED 
is identified in ~70% of patients. 
Four to six cycles of platinum based chemotherapy, etoposide in combination with either 
cisplatin or carboplatin, without maintenance therapy has been the standard care (SoC) for 
patients with ED SCLC for the past 25 years (Pignon et al 1992, Roth et al 1992), and are 
recommended by major worldwide oncology treatment guidelines, ie, ASCO, NCCN, ESMO. 
Despite high initial response rates of up to 70% (Rossi et al 2012), it is estimated that 80% of 
patients with limited stage and almost all patients with ED SCLC will relapse or experience 
disease progression (Clark and Ihde 1998).  Therefore, the prognosis for patients with SCLC 
in general and particular ED SCLC is poor; the reported 2-year survival is only 5% and 5 
years survival rate is less than 2% (Rossi et al 2012).  
There are no large Phase III studies comparing cisplatin/etoposide and carboplatin/etoposide.
A large meta-analysis of 4 studies (including >600 LD and ED patients), performed by Rossi 
et al 2012, showed similar efficacy between carboplatin- and cisplatin-containing regimens; 
median OS was 9.6 months for cisplatin and 9.4 months for carboplatin (hazard ratio [HR], 
1.08; 95% confidence interval [CI], 0.92 to 1.27; p=0.37). Objective response rate (ORR) was 
67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to 1.16; p=0.83).
Several large phase III studies using EP as the comparator in this setting have consistently 
reported the median PFS between 4-6 months and median OS between 7-11 months (Slotman 

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et al 2015). Most recent published data on EP as control arm of a randomized phase III study 
reported median PFS in 1st line treatment of ED-SCLC as 4.4 months and median OS as 
10.9 months (Reck et al 2016).
1.1.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn 
et al 2004).  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. PD-L1 acts at multiple sites in the body to help regulate immune responses 
by delivering inhibitory signals to T cells through the PD-1 and CD80 receptors.  PD-L1 is a 
member of the B7 family of ligands that inhibit T-cell activity through binding to the PD-1 
receptor (Keir et al 2008) and to CD80 (Butte et al 2007).  PD-L1 expression is an adaptive 
response that helps tumors evade detection and elimination by the immune system. Expression 
of PD-L1 protein is induced by inflammatory signals that are typically associated with an 
adaptive immune response (eg, IFNγ) and can be found on both tumor cells (TC) and tumor 
infiltrating immune cells (IC).  The binding of PD-L1 to PD-1 on activated T cells delivers an 
inhibitory signal to the T cells, preventing them from killing target TC, and protecting the 
tumor from immune elimination (Zou and Chen 2008).  PD-L1 may also inhibit T cells 
through binding to CD80, although the exact mechanism is still not elucidated (Butte et al 
2007; Paterson et al 2011).
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination.  The binding of an anti-PD-L1 agent to the PD-
L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells.  This activity overcomes PD-L1-mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is 
different from direct agonism of a stimulatory receptor such as CD28.  In vivo studies have 
shown that durvalumab inhibits tumor growth in xenograft models via a T cell-dependent 
mechanism (Stewart et al 2015). 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types of cancers.  Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance antitumor immune responses in patients with cancer.  Results of 
non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-L1/PD-1 
pathway have shown evidence of clinical activity and a manageable safety profile, supporting 
the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance antitumor 
immune response in cancer patients (Brahmer et al 2012; Hirano et al 2005; Iwai et al 2002; 
Okudaira et al 2009; Topalian et al 2012; Zhang et al 2008) with responses that tend to be 
more pronounced in patients with tumors that express PD-L1 (Powles et al 2014; Rizvi et al 
2015; Segal et al 2015).  In addition, a high mutational burden eg, in bladder carcinoma 
(Alexandrov et al 2013) may contribute to the responses seen with immune therapy. 

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In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a 
negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife and Bluestone 2008). Blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor 
activity in animal models, including killing of established murine solid tumors and induction 
of protective antitumor immunity. Therefore, it is expected that treatment with an anti CTLA-
4 antibody will lead to increased activation of the human immune system, increasing 
antitumor activity in patients with solid tumors.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade 
of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) 
and programmed death ligand 1 (PD-L1) has promising clinical activity.  Ipilimumab was 
granted United States (US) Food and Drug Administration (FDA) approval for the treatment 
of metastatic melanoma and is currently under investigation for several other malignancies 
whilst nivolumab and pembrolizumab, two anti-PD-1 agents and atezolizumab, an anti-PD-L1 
agent have been granted approvals by agencies such as the United States of America Food and 
Drug Administration and the European Medicines Agency approval for the treatment of a 
number of malignancies including metastatic melanoma, squamous and non-squamous cell 
non-small-cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial 
carcinoma. In addition, there is data from agents in the anti-PD-1/PD-L1 class showing 
clinical activity in a wide range of tumor types.
1.1.2
Durvalumab
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC).  It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer.  (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.)  Durvalumab has been engineered to reduce antibody-dependent 
cellular cytotoxicity and complement-dependent cytotoxicity. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in 
their restored proliferation and release of interferon gamma (IFNγ) (Stewart et al 2015).
To date durvalumab has been given to more than 1800 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents.  Details on the safety 
profile of durvalumab monotherapy are summarized in Section 1.2.1.3 and Section 6.5.  Refer 
to the current durvalumab Investigator’s Brochure (IB) for a complete summary of non-
clinical and clinical information including safety, efficacy and pharmacokinetics. 
1.1.3
Tremelimumab
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4 
cluster of differentiation [CD]152), a cell surface receptor that is expressed primarily on 
activated T cells and acts to inhibit their activation. Tremelimumab completely blocks the 
interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of 

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cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood 
mononuclear cells and whole blood (Tarhini and Kirkwood 2008). Tremelimumab is being 
developed by AstraZeneca for use in the treatment of cancer.  
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. Details on the safety 
profile of tremelimumab monotherapy are summarized in Section 1.3.2.2. Refer to the current 
tremelimumab IB for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics.
1.1.4
Durvalumab + tremelimumab combination therapy
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant targeting both 
PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); 
therefore, in addition to evaluating both agents in the monotherapy setting in a number of 
cancer indications AstraZeneca is also investigating the use of durvalumab + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish the safety, 
PK/pharmacodynamics, and preliminary anti-tumor activity of durvalumab + tremelimumab 
combination therapy in patients with advanced NSCLC.  The dosing schedule utilized is 
durvalumab every 2 or 4 weeks (Q2W, Q4W) up to 12 months, combined with tremelimumab 
Q4W up to Week 24 for 7 doses then every 12 weeks (Q12W) for 2 additional doses for up to 
12 months.  The study is ongoing and continues to accrue.  In addition, other clinical studies 
have since started looking at the combination in both NSCLC and other oncology indications.
To date more than 800 patients have received the combination using a number of doses and 
dosing schedules.  Details on the safety profile of durvalumab + tremelimumab combination 
therapy are summarized in Sections 1.2.1.1 and 1.3.2.3.  Refer to the current editions of the 
durvalumab and tremelimumab IBs for a complete summary of non-clinical and clinical 
information including safety, PK and efficacy.
1.1.5
Rationale for conducting this study
ED SCLC is an aggressive malignancy, the prognosis remains poor despite favorable initial 
response to chemotherapy.  Platinum-based chemotherapy has been the standard treatment for 
over 2 decades.  Although patients have good responses to chemotherapy initially, almost all 
patients with ED-SCLC will relapse quickly.  These facts indicate a significant unmet medical 
need. Novel therapies are urgently needed to improve clinical outcomes. 
1.1.5.1
Rationale for the combination of durvalumab ±  tremelimumab with 
chemotherapy
Nonclinical and clinical studies have indicated that blockade of immune checkpoints 
(PD-1/PD-L1 and CTLA-4) can have a positive effect on antitumor immunity.  One potential 
strategy is to combine these nonredundant and potential synergistic single-agent immune 
checkpoint inhibitors, thereby producing an additive improvement in tumor response (Larkin 

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et al 2015, Postow et al 2015).  Patients with SCLC may be particularly susceptible to these 
immunotherapies given the high mutational burden of this disease (Salgia and Skarin 1998).
The use of combination chemotherapy is a mainstay of oncology therapy.  The goal of 
combination chemotherapy is to utilize agents that affect cancer cells by different 
mechanisms, thus reducing the risk of developing resistance.  Current investigations are now 
adding immunotherapeutics to chemotherapeutics to broaden antitumor responses.
Checkpoint inhibitors have been tested in NSCLC, either used alone or in combination with 
chemotherapy.  Preliminary efficacy data from Study D4190C00006 have demonstrated that 
durvalumab+tremelimumab is active and well tolerated.  As of 15 April 2015, in 63 patients 
with at least 16 weeks of follow up, the objective response rate is 27%. 
Recently the IMpower133 study was presented at the World Congress on Lung Cancer (Horn 
et al., September 2018). IMpower133 was a randomized placebo-controlled phase III study, 
comparing atezolizumab + etoposide/platinum (EP) with placebo + EP in frist line treatment 
of  ED-SCLC. The study demonstrated a statistically significant improvement in OS with the 
combination of atezolizumab + etoposide/platinum (EP) compared to placebo + EP; the 
median OS was 12.3 months in the atezolizumab +EP  group and 10.3 months in EP+ placebo 
group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P = 0.007). 
The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard 
ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). The safety profile 
of atezolizumab plus carboplatin and etoposide was consistent with the previously reported 
safety profile of the individual agents, with no new findings observed.
Nivolumab as monotherapy or in combination with ipilimumab (anti-CTLA-4 mAb) has also 
been investigated in relapsed SCLC in CheckMate 032 (Antonia et al 2016). In this study, 
nivolumab at 3mg/kg was tested as monotherapy, and nivolumab 1mg/kg + ipilimumab 
3mg/kg, and nivolumab 3mg/kg+ipi 1mg/kg were assessed. The objective response rates 
reported were similar: 10%, 14% and 10%, respectively. Median survival data have also been 
recently reported of 4.4 months, 7.7 months and 6.0 months, respectively. Although the 
observed spectrum of toxicities was that expected for these agents, the fact that lower rates of 
Grade 3 or 4 toxicities were observed in the ipilimumab arm at 3mg/kg (compared to other 
tumor types) suggests that patients with SCLC tolerate CTLA4 blockade better. 
The safety and efficacy of checkpoint inhibitors combined with chemotherapy have also been 
demonstrated across multiple tumor types.  Data for durvalumab ± tremelimumab with 
standard platinum based chemotherapy in advanced cancers are being generated from 
2 ongoing Phase I studies; an internal study D419SC00001  (n=6) and a phase Ib study 
(NCT02537418) run by the Canadian Cancer Trials Group (CCTG; n=111 as of an October 
2016 cut-off).  The combinations tested are tolerable and manageable; details on the safety 
profile found in these studies are summarized in Sections 1.2.2 and 1.3.2.4.  Preliminary 
results from the CCTG study will be presented for the NSCLC cohorts in IASLC 2016; the 
overall objective response rate in NSCLC cohorts (n=24) was 52.9%.

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In addition, KEYNOTE-021 Cohorts A-C is a multi-arm phase I study of pembrolizumab in 
combination with various chemotherapy regimens as 1st line treatment for NSCLC. The study 
has reported an objective response rate of 55% (Langer et al 2016).
In summary, the preliminary efficacy, safety, and tolerability data of durvalumab ± 
tremelimumab generated to date, together with early positive signals with other PD-1 and 
CTLA-4 checkpoint inhibitors in combination with chemotherapy support the development of 
these treatments in combination with EP chemotherapy in ED SCLC.
1.1.6
Study aim
This is a Phase III, randomized, open-label, comparative, multicenter, global study to 
determine the efficacy and safety of combining durvalumab ± tremelimumab with EP 
followed by durvalumab ± tremelimumab maintenance therapy versus EP alone as first-line 
treatment in patients with ED SCLC.  
1.2
Rationale for study design, doses, and control groups
This is a Phase III, randomized, comparative study to assess the benefit-risk profile of adding 
immunotherapy to first-line chemotherapy versus current SoC of chemotherapy.  Given the 
different treatment administration schedules and treatment durations, this study will use an 
open-label design. 
1.2.1
Durvalumab and tremelimumab dose and treatment regimen justification
1.2.1.1
Durvalumab+ tremelimumab combination therapy dose rationale
The durvalumab + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of durvalumab and 
tremelimumab that would yield sustained target suppression (PD-L1 and CTLA-4 
respectively), demonstrate promising efficacy, and have an acceptable safety profile. 
Pharmacokinetics/Pharmacodynamics data
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of 
durvalumab in combination with a Q4W schedule of tremelimumab. The Q4W schedule was 
included to align with the Q4W dosing of tremelimumab.  PK simulations from durvalumab 
monotherapy data indicated that a similar area under the drug concentration-time curve at 
steady state (AUCss; 4 weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg 
Q4W dosing with durvalumab.  The observed durvalumab PK data from the D4190C00006 
study were in line with the predicted monotherapy PK data developed pre-clinically and in 
line with that seen in the first-time-in-human (FTIH), single agent study (CD-ON-MEDI4736-
1108) in patients with advanced solid tumors.  This demonstrates similar exposure of 
durvalumab 20 mg/kg Q4W and 10 mg/kg Q2W, with no alterations in PK when durvalumab 
and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together.  While the median 
maximum plasma concentration at steady state (Cmax,ss) is expected to be higher with 
20 mg/kg Q4W (approximately 1.5 fold) and median trough concentration at steady state 
(Ctrough,ss) is expected to be higher with 10 mg/kg Q2W (approximately 1.25 fold), this is not 

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expected to impact the overall safety and efficacy profile, based on existing preclinical and 
clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with durvalumab 
monotherapy. There was evidence of augmented pharmacodynamic activity relative to 
durvalumab monotherapy with combination doses containing 1 mg/kg tremelimumab, 
including both the 15 and 20 mg/kg durvalumab plus 1 mg/kg tremelimumab combinations.
Clinical data
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of durvalumab ranging from 3 to 
20 mg/kg.  Tremelimumab was given on a Q4W schedule whilst durvalumab was explored in 
both a Q4W and Q2W schedule, with the goal of identifying the dose combination that best 
optimizes the risk:benefit profile in an acceptable range of PK and pharmacodynamic values.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  
Between the 10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 
3 mg/kg tremelimumab cohorts treated at the Q2W schedule, the number of patients reporting 
any AE, ≥ Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
durvalumab + 3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg 
tremelimumab cohort.  A similar pattern was noted in the Q4W regimens, suggesting that, as 
the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events 
may be anticipated.  Further, the SAEs frequently attributed to immunotherapy, pneumonitis, 
colitis and other immune mediated events, were more commonly seen in cohorts using either 3 
mg/kg or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts.  Together, these 
data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared to minimize 
the rate of toxicity when combined with durvalumab.  As a result, all combination doses 
utilizing either the 3 or 10-mg/kg doses of tremelimumab were eliminated in the final dose 
selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of durvalumab may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of durvalumab.
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showed 
strong evidence of clinical activity.  No dose-limiting toxicities (DLTs) were reported in this 
cohort.  
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg durvalumab Q4W 

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cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.  
All together, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose 
combination (equivalent to fixed doses of 1500 mg and 75 mg respectively) should be selected 
for further development. 
Refer to the current durvalumab IB for a complete summary of non-clinical and clinical 
information on the durvalumab + tremelimumab combination, including safety, efficacy and 
pharmacokinetics.  
1.2.1.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks [Q3W] for 4 doses and then discontinued), shows 
that patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%.  Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up (Schadendorf et al 2013).  
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 
!
Nivolumab (anti-PD-1) was dosed Q2W for up to 96 weeks in a large Phase I 
dose-escalation and expansion study, and showed responses were maintained for a 
median of 22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months 
for NSCLC (doses 1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma 
patients (doses 1 and 10 mg/kg) at the time of data analysis (Brahmer et al 2014, 
Drake et al 2013, Hodi et al 2014).  
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics such as tremelimumab, durvalumab, or the combination of the two agents.  
The durvalumab + tremelimumab combination regimen will be administered for 4 doses Q3W 
in combination with chemotherapy followed by durvalumab monotherapy Q4W until disease 
progression. One additional combination dose will be administered post chemotherapy – see 
Section 1.2.2.
1.2.1.3
Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors and from a Phase I trial performed in Japanese patients with 
advanced solid tumor (D4190C00002).

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PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a 
particular regimen given the linearity seen at doses higher than 3 mg/kg.   The expected 
half-life with doses ≥3 mg/kg Q2W is approximately 21 days.  A dose-dependent suppression 
in peripheral sPD-L1 was observed over the dose range studied, consistent with engagement 
of durvalumab with PD-L1.  A low level of immunogenicity has been observed.  No patients 
have experienced immune-complex disease following exposure to durvalumab (For further 
information on immunogenicity, please see the current IB).  
Data from Study D4190C00006 (phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W.  
(For further information on PK observations in Study D4190C00006 , please see the current 
IB).  
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg Q2W or 15 mg/kg Q3W (Fairman et al 2014). Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W 
regimens, as represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 
20 mg/kg Q4W (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg 
Q2W (~1.25 fold).  Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to 
be consistent with 10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected 
to (a) achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; 
(c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.
Given the similar area under the drug concentration-time curve (AUC) and modest differences 
in median peak and trough levels at steady state, the observation that both regimens maintain 
complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg Q4W 
and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W.  
Clinical data
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy and pharmacokinetics at the 20 mg/kg Q4W regimen.

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1.2.1.4
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from a 
phase I study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid 
tumors). Population PK analysis indicated only minor impact of body weight (WT) on the PK 
of durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and 
fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady 
state PK concentrations (5th, median and 95th percentiles) using the population PK model. A 
fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median body WT of 
~75 kg). A total of 1000 patients were simulated using body WT distribution of 40–120 kg. 
Simulation results demonstrate that body WT-based and fixed dosing regimens yield similar 
median steady state PK concentrations with slightly less overall between-patient variability 
with fixed dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses = 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) 
(Wang et al 2014).  The population PK model indicated minor impact of body WT on PK of
tremelimumab (coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg 
Q4W; based on median body WT of ~75 kg) regimens were compared using predicted PK 
concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body weight distribution of 40 to 120 kg.  Similar to 
durvalumab, simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
patient variability with fixed dosing regimen.
Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, 
Zhang et al 2012, Narwal et al 2013).  Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed 
dosing being better for 7 of 12 antibodies (Wang et al 2009). In addition, they investigated 
18 therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 
18 in terms of reducing the between-patient variability in pharmacokinetic/pharmacodynamics 
parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens.  Based on average body WT of 
75 kg, a fixed dose of 1500 mg durvalumab (equivalent to 20 mg/kg) and a fixed dose of 
75 mg tremelimumab (equivalent to 1 mg/kg) is included in the current study.
1.2.2
Rationale for proposed phase III dose and schedule 
The dosing schedule proposed is aligned with the standard fixed dosing of 1500 mg 
durvalumab plus 75 mg tremelimumab for 4 cycles followed by durvalumab monotherapy 
(1500 mg), which is supported by efficacy and safety as well as tolerability data across 
multiple studies in multiple tumor types (see Section 1.2.1).  To conform to the chemotherapy 
schedule in the study, we propose to use standard durvalumab+tremelimumab dose and ratio 
at a Q3W dosing interval, rather than the standard Q4W schedule. 

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The safety of a Q3W dosing schedule in combination with chemotherapy has been explored in 
an ongoing study D419SC00001 (described below), 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 (see below for more 
detail).  The 1120 mg dose of durvalumab is the Q3W equivalent of the standard 1500 mg 
Q4W dose.  The tremelimumab dose was not lowered proportionally to 56 mg as 75 mg is the 
lowest tested biologically effective dose. 
In this study, we propose to use the phase III fixed dose of durvalumab, so this study will 
combine 75 mg tremelimumab with 1500 mg durvalumab Q3W in combination with 
chemotherapy. The relative increase in dose density of durvalumab (ie, 1500 mg Q3W 
instead of Q4W) is supported by the fact that toxicities attributable to durvalumab do not 
appear dose dependent, and pharmacokinetic modeling reveals no meaningful differences in 
drug levels between Q3W and Q4W dosing.
Supportive Clinical Data
The safety and tolerability data that support the proposed combination and schedule is based 
on two ongoing phase I/IB studies investigating the safety and tolerability of durvalumab + 
tremelimumab in combination with various chemotherapy regimens in solid tumors: an 
AstraZeneca internal study ( D419SC00001) and CCTG study (NCT02537418). 
AstraZeneca Phase I Study ( D419SC00001).
This phase I study is evaluating the safety and tolerability of durvalumab + tremelimumab in 
combination with first-line chemotherapy regimens in patients with locally advanced or 
metastatic solid tumors.  The tumor types originally included: ovarian/peritoneal/fallopian 
tube cancer, squamous cell carcinoma of the head and neck (SCCHN), triple-negative breast 
cancer (TNBC), small cell lung carcinoma (SCLC), and gastric/gastro-esophageal junction 
(GEJ) cancer. 
In the SCLC cohort, durvalumab 1120 mg + tremelimumab 75 mg Q3W is given concurrently 
with carboplatin AUC 5 mg/mL/min and etoposide 100 mg/m2 Q3W, followed by durvalumab 
1120 mg monotherapy Q3W.  
As of Dec 6, 2016, 6 patients with SCLC had completed 4 cycles of treatment.  No DLT was 
reported during the first cycle of treatment (a 21-days period).  One patient developed grade 4 
hepatitis with elevation of ALT, AST and GGT at C5D1.  Although the onset of this event 
was one day after the protocol defined DLT period of 4 cycles, it was considered as a DLT 
following discussion with investigator.  The liver enzymes were normalized within 16 days 
after steroid use and was confirmed not to be a Hy’s law case.  As there was only one DLT 
reported in 6 patients, the safety profile of this combination with chemotherapy at Q3W 
schedule is declared tolerable and manageable. 
CCTG study (NCT02537418)

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This is an ongoing multi-center, phase I study of single or double immunotherapy 
(durvalumab ± tremelimumab) in combination with multiple standard platinum based 
chemotherapy regimens in patients with incurable advanced or metastatic cancer and is 
sponsored and conducted by the Canadian Clinical Trial Group (CCTG).  Chemotherapy 
regimens assessed in the study include cisplatin+pemetrexed, cisplatin+gemcitabine, 
cisplatin+etoposide, carboplatin+pemetrexed, carboplatin+gemcitabine, nab-
paclitaxel+carboplatin, and etopside+carboplatin at standard doses for each regimen.
The dose escalation and dose regimen are outlined below (Figure 2).  Another dose level 
(DL3- durvalumab 1125mg + tremelimumab 56mg (maximum 6 doses of tremelimumab) 
Q3W with chemotherapy) was added after the protocol was initiated.  A total of four dose 
levels of durvalumab ± tremelimumab are being assessed.
Figure 2
Study Schematic for CCTG Study
As of an October 2016 data cut off, a total of 111 patients have been dosed with 
7 chemotherapy regimens across multiple tumor types; the majority of patients enrolled have 
been metastatic/advanced NSCLC patients (44%), followed by SCLC (16%) then bladder 
cancer (7%), and most have had no prior chemotherapy (71%).  SCLC patients enrolled into 
the etoposide-carboplatin cohorts started IO treatment in cycle 3 of chemotherapy; all other 
chemotherapy regimens assessed the IO combination starting at cycle 1. 
Overall, toxicities related to the chemotherapy core regimen appeared as expected in severity 
and frequency (See section 1.3.2.4 for more detail on the safety profile from this study). 
Overall, across all dose levels, there was no clear dose dependency in any of the reported AEs 
and there was no DLT reported per protocol defined criteria (DLT period of 21 days). 
Toxicities related to durvalumab and tremelimumab were also those expected for these agents, 
although a number of potential IO related toxicities such as diarrhea, skin rash, hepatic 
function changes or pneumonitis were difficult to differentiate from those reported for 
cytotoxic agents.  As expected, there were more IO related toxicities reported for dose levels 
containing tremelimumab.  In general, all regimens were tolerable and manageable at all dose 
levels.  There was no discernible difference in the tolerability profile when IO treatment was 

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administered in cycle 1 (including SCLC patients) versus cycle 3 of chemotherapy for SCLC 
patients only.
In general, the overall safety profile from these two studies appears to be consistent with 
available safety and tolerability data for durvalumab in combination with tremelimumab. 
PK Modelling
PK modelling has been carried out to predict the effect of switching from a Q4W regimen to a 
Q3W regimen for both durvalumab (1500 mg; 4 doses) and tremelimumab (75 mg; 4 doses) 
exposures.  Results suggest that a Q3W regimen would yield similar exposures to Q4W; both 
durvalumab and tremelimumab are expected to yield a slightly higher Cmax and Cmin on a 
3 week schedule, but a lower AUC.  For durvalumab, Cmax values were 660 vs. 596 (μg/mL), 
Cmin, were 144 vs. 94 (μg/mL), and AUC was 5879 vs.6061 (μg/mL) for Q3W and Q4W 
schedule, respectively.  For tremelimumab, Cmax is 26.1 vs. 25.1 (μg/mL), Cmin is 7.2 vs. 
5.7 (μg/mL), and AUC is 267 vs. 289 (μg/mL), respectively for the Q3W vs. Q4W regimen.  
Therefore, PK modeling suggests that a Q3W schedule does not impose a significant 
increased safety risk based on expected durvalumab and tremelimumab exposures.
Taken together, the totality of data provides sufficient safety data to support the combination 
of 1500mg durvalumab plus 75mg tremelimumab with chemotherapy.  There is supportive 
safety data for the combination of 1120 mg durvalumab plus 75 mg tremelimumab Q3W x 4 
doses followed by 1120 mg durvalumab Q3W from Study  D419SC00001. The safety of the 
combination of 1125 mg durvalumab (Q3W) plus tremelimumab 75mg (multiple doses, Q6W) 
or 225mg (3 doses, Q6W) or 56mg (multiple doses, Q3W) with chemotherapy has been 
assessed in more than 100 patients in the CCTG Phase I trial. Clinical data from NSCLC 
patients in Study D4190C00006 suggest that increasing the dose of durvalumab has no 
significant impact on the safety and tolerability of the durvalumab and tremelimumab 
combination. In addition, PK modelling data suggest there will be a minimal impact on IP 
exposure if the standard doses (1500/75) are given on a Q3W regimen. 
Additional dose of Tremelimumab
Patients in Arm 1 will receive additional one dose of durvalumab + tremelimumab post 
chemotherapy at week 16 if patient complete all 4 doses of durvalumab + tremelimumab 
during chemotherapy. The rationale to have an additional dose of tremelimumab after 
chemotherapy is based on the possibility that chemotherapy may limit the responsiveness of T 
cells to tremelimumab, and that tremelimumab given after chemotherapy will help control 
rapid progression that is inherent to the clinical course of SCLC, thereby sustaining the 
responses that may have been achieved during induction.
1.2.2.1
Safety confirmation of proposed doses 
To better support the use of the 1500 mg durvalumab ±75mg tremelimumab Q3W in this 
study and to ensure safety and tolerability in this larger phase III study, a safety confirmation 
of the proposed dose and schedule will be conducted within the protocol by an independent 

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data monitoring committee (IDMC). A step wise approach will be adopted. An initial safety 
review will take place when the first 30 patients (10 in each arm) have enrolled and completed 
the 1st cycle of treatment and had 21 days of follow up. These 30 patients will be continued to 
be followed for long term safety.  A second review will take place when an additional 
30 patients (10 each arm) complete the 1st cycle of treatment and have had 21 days follow up, 
giving a total of 60 patients. At the time of this second review, it is expected that the initial 
30 patients will have longer term follow up that may extend into the maintenance period. This 
safety review will be carried out by the IDMC in an unblinded fashion. The IDMC will make 
a recommendation on whether recruitment should continue, be modified or be held. The 
IDMC will continue to monitor the study conduct approximately every 6 months thereafter
(see Section 6.10).
1.2.3
Rationale for control arm: standard care therapy 
International guidelines (European Society for Medical Oncology [ESMO] and the National 
Comprehensive Cancer Network [NCCN]) currently recommend treatment with 4 to 6 cycles 
of platinum-based chemotherapy (EP), either cisplatin or carboplatin in combination with 
etoposide, without maintenance therapy for ED SCLC; this has been widely adopted in 
clinical practice across the world.  
Although 6 cycles of EP have not been shown to be superior to 4 cycles in the overall 
population, 1 group did report a trend favoring 6 cycles of EP for an ED SCLC subgroup 
(Veslemes et al 1998).  The use of 4 cycles of EP in the experimental arms (Arms 1 and 2) in 
this study is consistent with that observed in other trials combining platinum-based 
chemotherapy with investigational agents, particularly immunotherapies, to minimize the 
toxicity burden to patients.  Patients in the control arm (Arm 3) can receive up to 6 cycles of 
EP; patients who demonstrate continued tumor volume reduction after 4 cycles of EP can 
continue with an additional 2 cycles of EP at investigators’ discretion.
Cisplatin and carboplatin have indistinguishable clinical efficacy but are different in terms of 
cost and toxicity profiles.  The selection of cisplatin or carboplatin in combination with 
etoposide is at the investigator’s discretion, but must be in accordance with eligibility criteria, 
specifically inclusion 11, in Section 3.1.  These agents are commonly used in ED SCLC and 
will be given as per the product label for the indication and the NCCN and ESMO guidelines 
(Früh et al 2013, Kalemkerian et al 2013).
!
Etoposide: 80 to 100 mg/m2 daily on Days 1 to 3 (total dose 300 mg/m2) given  
Q3W
!
Carboplatin: AUC 5-6 on Day 1 given  Q3W
!
Cisplatin: 75 to 80 mg/m2 intravenous (IV) on Day 1 given  Q3W
Prophylactic cranial irradiation (PCI) will be permitted for patients in Arm 3 only; this will be 
at the investigators’ discretion as per SoC guidance for ED SCLC.  PCI is not permitted for 
patients in Arms 1 and 2 due to the unknown risks of combining PCI with immunotherapies.

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1.2.4
Rationale for endpoints
The primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + 
EP treatment compared with EP and the efficacy of durvalumab + EP treatment compared 
with EP in terms of OS. OS is the golden standard endpoint in oncology drug evaluation. The 
recent data from the IMpower133 study reinforces the importance of OS in this clinical 
setting.
PFS may serve as a surrogate endpoint for OS when differences between treatment arms are of 
sufficient magnitude and clinical importance (FDA Guidance 2011, Pazdur 2008). In certain 
settings, the utility of survival as an endpoint may potentially be confounded by subsequent 
therapies. Specifically, there are currently a number of molecules, that target the PD-1/PD-L1 
pathway, which are in late-stage development to which patients with SCLC in the EP arm of 
this study may have access to upon progression. Nivolimab has recently received FDA 
approval for 3rd line treatment of ED SCLC. Access to these agents creates challenges in being 
able to fully characterize the effects of study treatment on OS if patients subsequently receive 
these immunotherapeutic agents.  The comparison of the durvalumab + tremelimumab + EP 
and the durvalumab + EP arms will provide information as to the relative contribution of 
adding tremelimumab to the established benefit-risk profile of durvalumab + EP.  This 
comparison is not currently included in the multiplicity-controlled statistical testing procedure 
because the proposed study is not powered for the comparison.  However, the treatment 
difference will be summarized descriptively to evaluate the relative benefit-risk difference 
between the 2 experimental arms.
Antitumor activity, including the secondary endpoint of PFS, will be assessed per site 
investigators according to RECIST 1.1 guidelines. 
Objective response rate is commonly used in oncology to directly measure treatment effect on 
the tumor. Other secondary efficacy endpoints of proportion of patients alive and progression 
free at 6 months from randomization (APF6 [PFS rate at 6 months]), proportion of patients 
alive and progression free at 12 months from randomization (APF12 [PFS rate at 12 months]) 
and overall survival at 18 months after randomization (OS18) will be examined to further 
evaluate the antitumor effect and survival benefit of durvalumab ± tremelimumab + EP 
compared with EP. APF6, APF12, and PFS will be assessed using site Investigator 
assessments according to RECIST 1.1. 
The secondary endpoints of patient-reported symptoms and health-related quality-of-life 
(HRQoL) assessed using the EORTC QLQ-C30 v3 and QLQ-LC13 will show the overall 
benefits and toxicity of the treatment from the patient’s perspective and will aid in assessing 
the benefit-risk evaluation.  These PRO questionnaires are well-established instruments that 
have been used extensively in lung cancer clinical studies.  
The PK and immunogenicity of durvalumab and tremelimumab are being examined to assess 
any potential impact on PK, pharmacodynamics, safety, and efficacy parameters.  Biological 
samples will be used to explore potential biomarkers in tumor and serum that may influence 
pathogenesis, response, and clinical characteristics.

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1.3
Benefit-risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
durvalumab and tremelimumab prior to the overall benefit-risk assessment.
1.3.1
Potential benefits
1.3.1.1
Durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single-agent study (Study 1108) in patients with advanced solid tumors.  
Overall, as of 7 May 2015, 456 of 694 patients treated with durvalumab 10 mg/kg Q2W were 
evaluable for response (defined as having ≥24 weeks follow-up, measurable disease at 
Baseline, and ≥1 follow-up scan or discontinued because of disease progression or death 
without any follow-up scan).  Data from patients with SCLC in this study, although limited 
(n=19), showed a favorable disease control rate (DCR) of 26.3% when durvalumab was given 
10 mg/kg Q2W.
In PD-L1 unselected patients, the ORR, based on investigator’s assessment per RECIST 1.1, 
ranged from 0% in uveal melanoma to 20.0% in bladder cancer, and DCR at 24 weeks ranged 
from 4.2% in triple-negative breast cancer to 39.1% in advanced cutaneous melanoma.  
PD-L1 status was known for 383 of the 456 response evaluable patients.  Across the 
PD-L1-positive tumors, ORR was highest (>10%) for bladder cancer, advanced cutaneous 
melanoma, and hepatocellular carcinoma (33.3% each); NSCLC (26.7%); and squamous cell 
carcinoma of the head and neck (18.2%).  Moreover, in the PD-L1-positive subset, DCR at 
24 weeks was highest (>10%) in advanced cutaneous melanoma (66.7%), NSCLC (36.0%), 
hepatocellular carcinoma and bladder cancer (33.3% each), and squamous cell carcinoma of 
the head and neck (18.2%).
1.3.1.2
Durvalumab + tremelimumab
Preliminary efficacy data from Study 6 have demonstrated that this combination is clinically 
active and well tolerated in NSCLC.  As of 15 April 2015, 63 patients with at least 16 weeks 
of follow-up were evaluable for response across various durvalumab + tremelimumab dose 
regimens.  Of these, 17 patients (27%) had a best overall response of PR, 14 patients (22%) 
had a best response of SD, 22 patients (35%) had PD, and 10 patients (16%) were NE.  The 
ORR (confirmed and unconfirmed CR or PR) was 27%, and the DCR (CR, PR, or SD) was 
49% as assessed by RECIST 1.1 (Eisenhauer et al 2009).  In the 20-mg/kg durvalumab and 
1-mg/kg tremelimumab Q4W cohort, a total of 5 of 11 patients were evaluable for efficacy 
with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with PR, 1 patient 
(20%) with SD, and 1 patient (20%) with PD.  
As of 4 October 2015, preliminary efficacy data were available for 6 patients with SCLC 
treated in Study 10 (D4190C00010: a Phase I study of durvalumab in combination with 
tremelimumab in patients with advanced solid tumors) with the combination of durvalumab 
(20 mg/kg) and tremelimumab (1 mg/kg) administered Q4W for 4 doses, followed by 
durvalumab alone at a dose of 10 mg/kg Q2W for up to a total of 12 months.  Among the 

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6 patients with SCLC, 1 unconfirmed PR and 1 SD were observed per investigator’s 
assessment by RECIST 1.1.
Nivolumab as monotherapy, or in combination with ipilimumab (anti-CTLA-4 mAb), has also 
been investigated in relapsed SCLC in CheckMate 032 study (Antonia et al 2016).  
Nivolumab 3mg/kg as monotherapy and nivolumab 1mg/kg+ipilumab 3mg/kg, and nivolumab 
3mg/kg+ipilimumab 1mg/kg were assessed. The objective response rates reported were 
similar, 10% 14% 10%, respectively.  Median survival were 4.4 months, 7.7 months and 
6.0 months, respectively (Antonia et al 2016). 
1.3.1.3
Durvalumab ±  tremelimumab with chemotherapy
Studies evaluating agents targeting PD-L1 or CTLA-4 in combination with chemotherapy 
have yielded encouraging results (see Section 1.1.5.1). 
Durvalumab ± tremelimumab with standard platinum based chemotherapy in advanced 
cancers are being generated from an ongoing phase Ib study (NCT02537418) run by the 
Canadian Cancer Trials Group (CCTG). Preliminary results will be presented in IASLC 2016. 
Up to October 2016 cut off, a total of 111 patients have been dosed with various 
chemotherapy regimens and different tumor type. The overall objective response rate in the 
NSCLC cohort (n=24) was 52.9% (NSCLC data based on a data cut off of July 2016).
CheckMate 012 (NCT01454102) is a multi-arm Phase I study of nivolumab in combination 
with various anticancer agents or as monotherapy in chemotherapy-naïve patients with 
NSCLC.  The result just published in the Journal Of Clinical Oncology showed the objective 
response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus 
paclitaxel-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg 
plus paclitaxel-carboplatin were 33%, 47%, 47% and 43% respectively; 24-week PFS rates 
were 51%, 71%, 38% and 51% respectively.  On the basis of these results, the antitumor 
activity of first-line nivolumab in combination with platinum doublets is highly promising 
(Rizvi et al 2016). 
In addition, the phase II KEYNOTE-021 study showed that the addition of pembrolizumab to 
standard-of-care carboplatin and pemetrexed followed by pembrolizumab for 2 years and 
indefinite pemetrexed maintenance therapy significantly improved the proportion of patients 
who achieved an objective response compared with carboplatin and pemetrexed alone 
followed by indefinite pemetrexed maintenance therapy in patients with chemotherapy-naive, 
advanced non-squamous NSCLC (Langer et al 2016).  In the study, 123 patients with 
stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC were randomized to receive four 
cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 
months treatment with pembrolizumab (200 mg every three weeks). 33 of 60 patients (55%; 
95% CI 42, 68) in the pembrolizumab plus chemotherapy group achieved an objective 
response compared with 18 of 63 patients (29%; 18, 41) in the chemotherapy alone group 
(estimated treatment difference 26% [95% CI 9-42%]; p=0.0016). 

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The recently reported IMpower133 study compared atezolizumab in combination with EP 
chemotherapy in 1L ED-SCLC to placebo + EP. Result demonstrated a statistically significant 
improvement in OS with the combination of atezolizumab + EP compared to placebo + EP 
with median OS of 12.3 months in the atezolizumab + EP group compared to 10.3 months in 
placebo + EP group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P 
= 0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively 
(hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). 
On the basis of these clinical data, the antitumor activity of PD-L1/CTLA-4 monoclonal 
antibodies in combination with first-line platinum-/taxane-based doublets is highly promising. 
Given the synergistic potential of durvalumab and tremelimumab, the combination of both 
these drugs with chemotherapy has the potential to further improve the response rates and 
response durability along with overall survival.
1.3.2
Overall Risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune-mediated effects can occur in 
nearly any organ system, and are most commonly seen as gastrointestinal AEs such as colitis 
and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and 
liver enzyme elevations, skin events such as rash and dermatitis, and endocrinopathies 
including hypo- and hyper-thyroidism.
1.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis and  pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency,hyper-and 
hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/dermatitis, myocarditis, 
myositis/polymyositis, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (e.g. Guillain Barre syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy, clinical studies AEs at an incidence of > 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 

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monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 6.9)  
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
1.3.2.2
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhea, enterocolitis and intestinal perforation), endocrine disorders (hypo- and 
hyper-thyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus); 
elevations in lipase and amylase and clinical manifestations of pancreatitis; hepatic events 
(including immune mediated hepatitis, and liver enzyme elevations); pneumonitis and ILD; 
neurotoxicity (including encephalitis, peripheral motor and sensory neuropathies and Guillain-
Barre syndrome) thrombocytopenia, anemia and neutropenia; infusion-related reactions and 
hypersensitivity/anaphylactic reactions; renal events (including nephritis/autoimmune 
nephritis and acute kidney injury autoimmune arthritis, Sjogren's syndrome and giant cell 
temporal arteritis and ulcerative colitis); hyperglycemia and diabetes mellitus.
For information on all identified and potential risks with tremelimumab please always refer to 
the current version of the tremelimumab IB.
In monotherapy clinical studies, AEs reported at an incidence of > 20% include events such as 
diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting and dyspnea. 
Approximately 16% of patients experienced an AE that resulted in permanent discontinuation 
of tremelimumab, and approximately 45% of patients experienced an SAE. Please see the 
current version of the IB for a detailed summary of monotherapy data, including AEs, SAEs, 
and CTC Grade 3 to 5 events reported across the tremelimumab program.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB. 
1.3.2.3
Durvalumab + tremelimumab
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study  D4190C00006, in patients with NSCLC, 
and is being studied in a number of other ongoing clinical trials and in a number of different 
indications and has so far shown a manageable safety and tolerability profile.  
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20 mg/kg and a tremelimumab dose of 1 mg/kg) are similar to 

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those for durvalumab and tremelimumab monotherapy. Emerging data from Study 
D4190C00006, other studies evaluating the combination and from combinations of other 
agents in the same class indicate an increased frequency and/or severity of some of these 
immune-mediated toxicities.
For information on all identified and potential risks with the durvalumab+tremelimumab 
combination please always refer to the current version of the durvalumab IB.
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs reported at an incidence of >20% included events such as fatigue, 
diarrhoea, nausea, decreased appetite, pruritus, dyspnea, constipation and anemia. Please see 
the current version of the durvalumab IB for a detailed summary of combination therapy data, 
including AEs, SAEs, and CTC Grade 3 to 5 events reported across the durvalumab program, 
including durvalumab in combination with tremelimumab.
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation 
of study drug and approximately 16% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study investigator.
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB.
1.3.2.4
Durvalumab ± tremelimumab with chemotherapy
There are two ongoing studies evaluating the safety and tolerability of combining durvalumab 
and tremelimumab with different chemotherapy regimens in patients with solid tumors, one is 
an AZ internal study (D419SC00001), the other is CCTG study NCT02537418– see 
Section 1.2.2).
In the AstraZeneca internal study (D419SC00001) 6 patients with SCLC were evaluable for 
safety at the time of this report.  Common adverse events reported were neutropenia (6 pts), 
nausea (4 pts), decreased appetite (4 pts), rash (3 pts), diarrhea (2 pts) and pyrexia (2 pts). 
Diarrhea, skin rash were generally low grade, with the exception of one grade 3 erythroderma 
that responded to topical steroids. One patient with intermittent grade 1 diarrhea required 
steroid treatment and resolved.  Cycle 4 was modified in this patient where IO was held and 
chemotherapy was dose reduced to 75% due to grade 4 neutropenia. Grade 3 and above events 
were febrile neutropenia (2 pts), platelet decrease (1 pt), and lung infection (1 pt) which were 
considered to be chemotherapy related, hepatitis (1 pt), and erythroderma (1 pt) which were 
considered to be immune related.  Febrile neutropenia, lung infection, hepatitis were reported 
as SAE. 2 patients had Grade 3/4 lipase/amylase elevation at baseline and were considered not 
drug related; these were due to pancreatic metastasis at baseline confirmed by imaging.  One 
patient died due to disease progression as primary cause and a secondary cause of lung 
infection. Two patients discontinued treatment due to immune related hepatitis and persistent 
skin rash.  Two patients continue on active study treatment and are being followed up for long 
term safety. 

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In the CCTG study (NCT02537418) a total of 488 cycles have been administered up to the 
data cut off of October 2016 with 103 patients evaluable for non-hematologic adverse events. 
Overall all patients experienced at least one AE (100%), 96% were considered by investigator 
as causally related to chemotherapy, 75% was considered as causally related to durvalumab  
and 55% was considered as causally related to tremelimumab.  A total of 69 events (26% of 
all events) were CTC grade ≥3, regardless of causality. Of these, 20 events were considered 
by investigators as causally related to durvalumab treatment and 15 events were considered as 
causally related to tremelimumab treatment. SAE events were reported in 38% of patients 
(39/103) regardless of causality; 19% related to chemotherapy, 15% was considered by 
Investigator as related to durvalumab, while 11% was related to tremelimumab treatment. 
Note that some events considered related to durvalumab and tremelimumab treatment may be 
reported in the same patient(s).
Overall the common adverse events reported were grade 1-2 with the most commonly 
reported being fatigue (93%), nausea (72%), dyspnea (63%), constipation (59%), and cough 
(52%) regardless of causality.  Most common chemotherapy related adverse events were 
fatigue (62%), nausea (58%), vomiting (32%), anorexia (28%), alopecia (27%) and peripheral 
sensory neuropathy (24%). Most common durvalumab-related adverse events were fatigue 
(42%), rash maculo-papular (17%), nausea (16%) and diarrhea (12%). Most common 
tremelimumab-related adverse events were fatigue (26%), rash maculo-papular (13%) and 
diarrhea (11%).  Most common CTC grade >3 events were fatigue (11 events), thrombotic 
events (9), dyspnea (7), lung infection (7), diarrhea (7).  Transient elevations in amylase and 
lipase were seen but no patient had clinical or radiological evidence of pancreatitis.  TSH 
elevations of ≥5 x ULN were documented in 10 patients (10%) and 6 patients required 
initiation of thyroid replacement therapy on study. Three of these patients with elevated TSH 
had a previous history of hypothyroidism. 
On all dose levels, dose delays of durvalumab were mostly for administrative reasons/patient 
request and neutropenia related to chemotherapy, while durvalumab ± tremelimumab were 
interrupted in 4 patients because of pneumonitis, colitis or rash. 
Seven patients (6.7%) discontinued durvalumab ± tremelimumab due to adverse events: 
pneumonitis (3pts), hepatitis (1), myocarditis (1), hyperthyroidism (1) and limbic encephalitis 
(1). 
There were seven deaths within 30 days of the last dose of protocol therapy.  Two of these 
were considered to be at least possibly related to durvalumab or tremelimumab; one patient 
 had diarrhea, hyperthyroidism and myocarditis, which was steroid 
responsive but later declined active therapy. The cause of death has not yet been determined. 
The post mortem examination has not been reported. One patient 
 had 
confusion and possible encephalitis. 
The 2 possibly related fatal cases are briefly described as follows: 
PPD
PPD

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Case Report No. 
 – An event of myocarditis (Grade 5) occurred in a 
74 year old female with metastatic SCLC who on Cycle 1 Day 12 presented with s/s of fever, 
nausea, vomiting and decreased neutrophil count of 0.68 for which patient was eventually 
admitted. She developed diarrhea. CT abdomen showed liver metastasis, with inflammatory 
changes of duodenum suggestive of uncomplicated duodenitis or ulcer. Patient also developed 
acute renal failure and pulmonary edema. On Cycle 1 Day 16 the patient presented with s/s of 
Grade 4 heart failure and myocarditis as well as Grade 3 thyroiditis that initially responded to 
steroid administration.  She was sent home only to be readmitted with weakness, fever, 
dizziness and dehydration.  The patient’s condition deteriorated despite steroids, supportive 
treatment (inotropic support, use of ace inhibitors) and eventually died.  Preliminary autopsy 
report showed multiple metastases in the involved lungs (effusions), liver, and lymph nodes. 
Except for atherosclerosis, there were no evidence of myocardial infarction nor pulmonary 
emboli.
Case Report No. 
. An event of limbic encephalitis (Grade 5) occurred 
in a 65 year old female with metastatic SCLC who on Cycle 2 Day 27 presented with s/s of 
limbic encephalitis (eg, cognitive decline, restlessness, agitation, EEG findings suggestive of 
encephalopathy, CSF findings of increased WBC and protein, MRI finding of no intracranial 
mass, and despite treatment with antibiotics, steroids, the patient eventually died.  
Confounding factors that may likely also provide alternative cause/explanation for this event 
include the following: 1) a possible paraneoplastic effect of underlying SCLC, 2) concomitant 
medications that included treatment with phenobarbitone and midazolam, 3) underlying 
diabetes mellitus for which patient had insulin/oral hypoglycemic treatment and 4) possible 
CNS infection. 
Overall, toxicities related to the chemotherapy core regimen and to durvalumab and 
tremelimumab were as expected for these agents.  In general, the combination of durvalumab 
plus tremelimumab with chemotherapy appears tolerable and manageable. 
External clinical data also supports these findings. In a randomized Phase III study in patients 
with ED SCLC treated with etoposide-platinum ± ipilimumab, the overall incidence of 
treatment-related Grade 3/4 AEs was 48% for chemotherapy plus ipilimumab and 44% for 
chemotherapy plus placebo. The most common immune-related AEs in patients treated with 
chemotherapy + ipilimumab involved skin (rash and pruritus) and gastrointestinal tract 
(diarrhea) (Reck et al 2016). Furthermore, in the setting of single-IO + EP, the recently 
published IMpower133 study demonstrated that  the safety profile of atezolizumab plus EP 
was consistent with the previously reported safety profile of the individual agents, with no 
new findings observed (Horn L et al., September 2018).
1.3.3
Overall benefit-risk assessment
There remains a significant unmet medical need for additional treatment options for patients 
with ED SCLC.  Four or six cycles of platinum-based chemotherapy has been considered the 
standard treatment regimens for 2 decades; however, OS remains poor with a 2-year survival 
rate of 5% despite favorable initial responses.  The vast majority of ED SCLC patients will 
relapse with a median time to progression of 4 to 6 months and a median OS of 7 to 
PPD
PPD

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11 months.  The poor prognosis reflects the limited treatment options available, highlighting 
the need for the development of newer therapeutic options.
Treatment with durvalumab and/or tremelimumab has shown activity in several tumor types in 
a subset of patients deriving meaningful and durable benefit.  Efficacy data for patients treated 
with durvalumab monotherapy have shown clinical activity across several tumor types.  
Preliminary data generated from patients with NSCLC treated with durvalumab + 
tremelimumab combination therapy have also shown early signs of clinical activity, and data 
from the literature indicate that the combination may act synergistically (Wolchok et al 2013).  
Thus, these agents may potentially offer benefit to this patient population.  Also, as presented 
in Section 1.1.5.1, the studies evaluating agents targeting PD-L1 or CTLA-4 in combination 
with chemotherapy has yielded encouraging efficacy data, with a seemingly tolerable toxicity 
profile.
Therefore, the rationale for this study is supported by the available nonclinical and clinical 
safety data, the limited survival benefit provided by the currently available treatment options 
to patients, the limited life expectancy due to malignant disease, the activity seen with 
durvalumab alone and in combination with tremelimumab in a number of tumor types, the 
preliminary data on the efficacy and tolerability of the combination of PD-L1 or CTLA-4 with 
chemotherapy, and the strength of the scientific hypotheses evaluating the safety and 
tolerability of adding durvalumab ± tremelimumab to first-line standard platinum-based 
chemotherapy for the treatment of first-line ED SCLC. 
Based on these considerations, the proposed treatments may have the potential to provide 
meaningful clinical benefit by generating durable clinical responses, thereby potentially 
extending survival.  Therefore, the overall benefit-risk assessment supports the proposed study 
to evaluate the safety and tolerability of the combination of durvalumab and tremelimumab 
with standard platinum-based chemotherapy regimens.
1.4
Study design 
This is a Phase III, randomized, open-label, comparative, multicenter, global study to 
determine the efficacy and safety of durvalumab + tremelimumab + EP or durvalumab + EP 
versus EP chemotherapy as first-line treatment in patients with ED SCLC.  A schematic 
diagram of the overall study design is shown in Figure 3, and a detailed study flow chart is 
shown in Figure 4.  
This study will randomize approximately 795 eligible patients at sites worldwide.  Once 
global enrollment of 795 patients is completed, recruitment will continue in China only.  A 
total of up to 189 patients from China will be randomized (see Section 8.6 for detail).
Patients will be randomized in a 1:1:1 ratio in a stratified manner according to the planned 
platinum-based therapy for Cycle 1 (cisplatin or carboplatin) to receive treatment with 
durvalumab + tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or EP (Arm 3).  Cross 
over will not be permitted as part of this study.  Doses and treatment regimens are described in 
Section 7.2.  Assessments will be conducted as indicated in Table 2 and Table 3.

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Tumor assessments will be performed at Screening as baseline with follow-ups at Week 6 
±1 week from the date of randomization, at Week 12 ±1 week and then every 8 weeks 
±1 week until confirmed objective disease progression (please refer to Appendix E)

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Figure 3
Overall study design
Durva  Durvalumab; ED  Extensive-stage disease; EP  Etoposide and platinum-based chemotherapy; OS  Overall survival; PCI prophylactic cranial 
irradiation; SCLC  small-cell lung cancer; Treme  Tremelimumab.
Note that only one dose of tremelimumab will be administered post chemotherapy in Arm 1 if a patient receives 4 combination doses during chemotherapy, 
ie, up to 5 durvalumab+tremelimumab combination doses in total – see Section 7.2.

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Figure 4
Study flow chart
a
Informed consent and completion of study procedures and baseline CT/MRI tumor assessment.  
b
A follow up scan is requested after every radiological PD on study where possible; this is irrespective of whether the 
PD needs to be confirmed or not as set out in Appendix E. As long as the patient is clinically stable, in the event of 
radiologic PD according to RECIST 1.1, an additional scan should be performed preferably at the next scheduled 
imaging visit and no less than 4 weeks after the prior assessment of radiologic PD (please refer to Appendix E)
c
A window of up to 2 days is permitted between randomization and first dose of IP.
CR  Complete response; Durva  Durvalumab; EP  Etoposide and platinum-based chemotherapy; OS  Overall survival; 
PD  Progressive disease; PR  Partial response; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; 
SCLC  Small-cell lung cancer; SD  Stable disease; Treme  Tremelimumab.
Screening Visit: Screening to complete eligibility assessments (Days -21 to -1)a
Day 1 (Cycle 1): First day of treatment for randomized patientsc
Durvalumab + tremelimumab + EP (Arm 1) durvalumab+ EP (Arm 2)
or EP (Arm 3)
assessments per Table 2
Tumor assessment using RECIST 1.1 performed at screening as baseline,
then Week 6 (between Cycles 2 and 3), then Week 12 ± 1 week from the date of
randomization then every 8 weeks ± 1 week until 
RECIST 1.1-defined progression. All patients require one follow up scan post initial 
progression if possibleb
Discontinuation of treatment either due to confirmed 
objective disease progressionb
or another reason
Standard chemotherapy may 
be offered by physician
Follow-up assessment per Table 3

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2.
STUDY OBJECTIVES 
All objectives will be evaluated for all patients, unless otherwise indicated.
2.1
Primary objectives
Primary objective:
Outcome measures:
To assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
EP and durvalumab + EP treatment compared 
with EP in terms of OS 
OS
EP  Etoposide and platinum-based chemotherapy; OS  Overall survival.
2.2
Secondary objectives
Secondary objectives:
Outcome measures:
To further assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
EP and durvalumab + EP treatment compared 
with EP in terms of PFS, ORR, APF6 (PFS 
rate at 6 months), APF12 (PFS rate at 12 
months), and OS18 (OS rate at 18 months)
PFS, ORR, APF6 and APF12 using site Investigator 
assessments according to RECIST 1.1
OS18
To assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
durvalumab + EP in terms of PFS and OS
PFS using site Investigator assessments according to 
RECIST 1.1 
OS
To assess the PK of durvalumab and 
durvalumab + tremelimumab 
Concentration of durvalumab and tremelimumab in 
blood and non-compartmental PK parameters, such as 
peak concentration and trough (as data allow; sparse 
sampling)
To investigate the immunogenicity of 
durvalumab and durvalumab + tremelimumab
ADA (confirmatory results: positive or negative; 
titers [ADA neutralizing antibodies will also be 
assessed])
To assess the effect of the treatment on 
changes in symptoms and health-related QoL 
using EORTC QLQ-C30 v3 and QLQ-LC13
EORTC QLQ-C30: symptoms (fatigue, pain, 
nausea/vomiting, dyspnea, loss of appetite, insomnia, 
constipation, and diarrhea).  Health-related 
QoL/functioning (physical function, role function, 
emotional function, cognitive function, social 
function, and global health status/QoL).
EORTC QLQ-LC13: disease-related symptoms 
(dyspnea, cough, hemoptysis, chest pain, 
arm/shoulder pain, and other pain).
Changes in WHO/ECOG performance status will also 
be assessed.

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ADA  Anti-drug antibody; AE  Adverse event; APF12  Proportion of patients alive and progression free at 
12 months from randomization (ie, PFS rate at 12 months); APF6  Proportion of patients alive and progression 
free at 6 months from randomization (ie, PFS rate at 6 months); ECOG  Eastern Cooperative Oncology Group; 
EORTC  European Organisation for Research and Treatment of Cancer; EP  Etoposide and platinum-based 
chemotherapy; OS  Overall survival; OS18  Overall survival at 18 months after randomization; PFS  Progression-
free survival; PK  Pharmacokinetic(s); QLQ-C30 v3  30-item Core Quality of Life Questionnaire, version 3; 
QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; QoL  Quality of life; RECIST 1.1  Response 
Evaluation Criteria in Solid Tumors, version 1.1; WHO  World Health Organization.
2.3
Safety objectives
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
durvalumab and durvalumab + tremelimumab 
in combination with EP treatment compared 
with EP
AEs; physical examinations; vital signs including 
blood pressure and pulse rate; electrocardiograms; 
and laboratory findings including clinical chemistry, 
hematology, and urinalysis
AE  Adverse event; EP  Etoposide and platinum-based chemotherapy.

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2.4
Exploratory objectives
Exploratory objectives:
Outcome measures:
To further assess the efficacy of durvalumab + 
tremelimumab + EP treatment compared with 
EP and to assess the efficacy of durvalumab + 
EP compared with EP in terms of PFS2
PFS2 using local standard clinical practicea
To investigate the relationship between 
durvalumab PK exposure and clinical 
outcomes, efficacy, AEs, and/or safety 
parameters, and biomarkers, if deemed 
appropriate 
A graphical and/or a data modelling approach will be 
used to analyze durvalumab PK exposure and the 
relationship with clinical outcomes, efficacy, AEs, 
and/or safety parameters, as deemed appropriate.
To characterize EP PK when in combination 
with durvalumab and tremelimumab
Concentration of etoposide, cisplatin or carboplatin in 
blood
To explore the impact of treatment and disease 
on health care resource use
Health care resource use will be captured, including 
inpatient admissions, intensive care unit admissions, 
and length of stay in hospital
To explore the impact of treatment and disease 
state on health state utility using the EQ-5D-5L
The EQ-5D-5L health state utility index will be used 
to derive health state utility based on patient-reported 
data
To assess AEs by patient self-reporting of 
specific CTCAE symptoms
Collection of approximately 11 symptoms via the 
patient-reported outcomes version of the CTCAE 
(PRO-CTCAE)
To assess patients’ overall impression of the 
change in their health status since the start of 
study treatment
PGIC item will be collected directly from patients. 
To investigate the relationship between a 
patient’s expression of select genes, for 
example IFN-γ, within the tumor 
microenvironment and efficacy outcomes with 
durvalumab ± tremelimumab and EP
Levels of gene expression, for example, IFN-γ, within 
the tumor microenvironment relative to efficacy 
outcomes (for example, APF6, APF12, PFS, and OS) 
To investigate the relationship between a 
patient’s PD-L1 expression and spatial 
distribution within the tumor 
microenvironment and efficacy outcomes with 
durvalumab ± tremelimumab and EP
Tumoral and/or infiltrating immune cell expression of 
PD-L1 and spatial distribution within the tumor 
microenvironment relative to efficacy outcomes (for 
example,APF6, APF12, PFS, and OS) 
To investigate the relationship between a 
patient’s level of DLL3 expression on tumor 
cells and efficacy outcomes with durvalumab ± 
tremelimumab and EP
Tumoral expression of DLL3 relative to efficacy 
outcomes (for example,APF6, APF12, PFS, and OS) 

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Exploratory objectives:
Outcome measures:
To investigate the relationship between a 
patient’s TMB and/or somatic 
mutations/genomic alterations and efficacy 
outcomes with durvalumab ± tremelimumab 
and EP
Levels of TMB and somatic aberrations in tumor 
and/or plasma relative to efficacy outcomes (for 
example, APF6, APF12, PFS, and OS)
To explore potential biomarkers in residual 
biological samples (eg, tumor and blood), 
which may influence the progression of cancer 
(and associated clinical characteristics) and/or 
prospectively identify patients likely to 
respond to durvalumab or durvalumab + 
tremelimumab treatment
Correlation of biomarkers with response to 
durvalumab or durvalumab + tremelimumab 
treatment and/or the progression of cancer
To collect and store DNA according to each 
country’s local and ethical procedures for 
future exploratory research into genes/genetic 
variation that may influence response 
(ie, distribution, safety, tolerability, and 
efficacy) to study treatments and/or 
susceptibility to disease (optional)
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety, or response parameters 
observed in patients treated with durvalumab or 
durvalumab + tremelimumab and/or susceptibility to 
disease
AE  Adverse event; APF12  Proportion of patients alive and progression free at 12 months from randomization 
(ie, PFS rate at 12 months); APF6  Proportion of patients alive and progression free at 6 months from 
randomization (ie, PFS rate at 6 months); CTCAE  Common Terminology Criteria for Adverse Events; DLL3 
Delta-like canonical Notch ligand 3; DNA  Deoxyribonucleic acid; EQ-5D-5L  EuroQol 5-Dimension, 5-level 
health state utility index; OS  Overall survival; PD-L1  Programmed cell death ligand 1; PFS  Progression-free 
survival; PFS2  Progression-free survival after subsequent anticancer therapy; PGIC  Patient’s Global Impression 
of Change; PK  Pharmacokinetic(s); TMB  Tumor mutational burden
a
PFS2 will be defined as the time from the date of randomization to the earliest progression event 
subsequent to that used for the PFS endpoint or death.
A further objective, to fulfil China Food and Drug Administration (CFDA) requirements, is to 
evaluate the consistency in efficacy and safety among patients from China for benefit-risk 
assessment of durvalumab + tremelimumab in combination with EP treatment compared to EP 
and durvalumab + EP compared to EP.
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria (Section 3.1) and none of the exclusion 
criteria (Section 3.2) for this study at the screening and randomization visits.  Under no 
circumstances will there be exceptions to this rule.

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3.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Male or female ≥18 years at the time of Screening. In Japan, patients must be aged 
≥ 20 years at the time of Screening.
2.
Written informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act in the US, European Union [EU] Data 
Privacy Directive in the EU) obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations.
3.
Histologically or cytologically documented extensive disease (American Joint 
Committee on Cancer Stage (7th edition) IV SCLC [T any, N any, M1 a/b]), or T3-
4 due to multiple lung nodules that are too extensive or have tumor/nodal volume 
that is too large to be encompassed in a tolerable radiation plan.
∀
Brain metastases; must be asymptomatic or treated and stable off steroids and 
anti-convulsants for at least 1 month prior to study treatment.  Patients with 
suspected brain metastases at screening should have a CT/MRI of the brain 
prior to study entry.
4.
Provision of an archived tumor tissue block (or at least 15 newly cut unstained 
slides) where such samples exist (refer to Section 5.5 and Laboratory Manual for 
details).
5.
Patients must be considered suitable to receive a platinum based chemotherapy 
regimen as 1st line treatment for the ED-SCLC. Chemotherapy must contain either 
cisplatin or carboplatin in combination with etoposide. 
6.
Life expectancy ≥12 weeks at Day 1.
7.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0 or 1 at enrollment.
8.
Body weight >30 kg.
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.
10.
No prior exposure to immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 
(anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.

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11.
Adequate organ and marrow function as defined below:
∀
Hemoglobin ≥9.0 g/dL.
∀
Absolute neutrophil count ≥1.5 × 109/L (use of granulocyte colony-stimulating 
factor is not permitted at screening).
∀
Platelet count ≥100 × 109/L.
∀
Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in 
consultation with their physicians.
∀
In patients without hepatic metastasis: ALT and AST ≤2.5 × ULN.
∀
In patients with hepatic metastases, ALT and AST ≤5 × ULN.
∀
Measured or calculated creatinine clearance: >60mL/min for patients on 
cisplatin and >45mL/min for patients on carboplatin, as determined by 
Cockcroft-Gault (using actual body weight):
Males:
Creatinine CL = 
Weight (kg) × (140 – Age)
(mL/min)
72 × Serum creatinine (mg/dL)
Females:
Creatinine CL = 
Weight (kg) × (140 – Age) 
× 0.85
(mL/min)
72 × Serum creatinine (mg/dL)
12.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if 
they have been amenorrheic for 12 months without an alternative medical cause.  
The following age-specific requirements apply:
∀
Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
∀
Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses 
>1 year ago, had chemotherapy-induced menopause with last menses >1 year 

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ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
2.
Previous IP assignment in the present study.
3.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an 
interventional study.
4.
Participation in another clinical study with an IP during the last 4 weeks.  
5.
Medical contraindication to etoposide-platinum (carboplatin or cisplatin)-based 
chemotherapy.
6.
Any history of radiotherapy to the chest prior to systemic therapy or planned 
consolidation chest radiation therapy.  Radiation therapy outside of the chest for 
palliative care (ie, bone metastasis) is allowed but must be completed before first 
dose of the study medication.
7.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment.  Concurrent use of hormonal therapy for non-cancer related conditions 
(eg, hormone replacement therapy) is acceptable.
8.
Major surgical procedure (as defined by the investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
9.
History of allogeneic organ transplantation.
10.
Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic 
treatment (systemic steroids or immunosuppressive agents) or has a clinical 
symptomatology suggesting worsening of PNS. 
11.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis with the 
exception of diverticulosis, systemic lupus erythematosus, sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, and uveitis, etc]).  The following are exceptions to this 
criterion:

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∀
Patients with vitiligo or alopecia
∀
Patients with hypothyroidism (eg, following Hashimoto syndrome) and stable 
on hormone replacement 
∀
Any chronic skin condition that does not require systemic therapy
∀
Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician
∀
Patients with celiac disease controlled by diet alone
12.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, interstitial lung disease, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, serious 
chronic gastrointestinal conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs or compromise the ability of the patient 
to give written informed consent.
13.
History of another primary malignancy except for 
∀
Malignancy treated with curative intent and with no known active disease ≥5 
years before the first dose of IP and of low potential risk for recurrence
∀
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease
∀
Adequately treated carcinoma in situ without evidence of disease 
14.
History of leptomeningeal carcinomatosis.
15.
History of active primary immunodeficiency.
16.
Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in 
line with local practice), hepatitis B (known positive HBV surface antigen [HbsAg] 
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 
antibodies).  Patients with a past or resolved HBV infection (defined as the presence 
of hepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible.  
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.
17.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab or tremelimumab.  The following are exceptions to this 
criterion:

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∀
Intranasal, inhaled, topical steroids or local steroid injections (eg, intra articular 
injection).
∀
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent.
∀
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).  Premedication with steroids for chemotherapy is acceptable.
18.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.  Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 
30 days after the last dose of IP.
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 monotherapy or 180 days 
after the last dose of durvalumab + tremelimumab combination therapy.
20.
Known allergy or hypersensitivity to durvalumab, tremelimumab, etoposide, 
carboplatin, cisplatin, or any of their excipients
21.
Prior randomization or treatment in a previous durvalumab and/or tremelimumab 
clinical study regardless of treatment arm assignment.
For patients who have consented to Genetics Sample the following exclusion criteria apply:
!
Previous allogeneic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection
For procedures for withdrawal of incorrectly enrolled patients, see Section 3.4.
3.3
Patient enrollment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening.
At Screening (Days -21 to -1), the investigator(s) or suitably trained delegate(s) will perform 
the following:
1.
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed.
2.
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) in the 
following format (ECCNNXXX: CC being the country code, NN being the center 

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number, and XXX being the patient enrollment code at the center).  This number is 
the patient’s unique identifier and is used to identify the patient on the electronic 
case report forms (eCRFs).
3.
Determine patient eligibility.  See Section 3.1 and Section 3.2.
4.
Obtain signed informed consent for genetic research study (optional).
5.
Choose platinum agent that the patient would receive in cycle 1 (based on the most 
appropriate option for the patient).  The information will be recorded in the 
IVRS/IWRS system at randomization.
The above does not list the exact sequence of study related procedures, but provides the steps 
that should be taken during the screening period prior to randomization of the patient.
At randomization, once the patient is confirmed to be eligible, the investigator or suitably 
trained delegate will obtain a unique randomization number via the IVRS/IWRS. Numbers 
will start at 001 and will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for entry into the study. The system will randomize the eligible patient to 1 of the 
3 treatment arms. 
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system. 
Patients will begin treatment on Day 1, although a window of up to 2 days is permitted 
between randomization and first dose of IP.  Patients must not be treated unless all eligibility 
criteria have been met.  
If a patient withdraws from participation in the study, then his or her 
enrollment/randomization code cannot be reused.  Withdrawn patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication.  There can be no exceptions to this rule.  Patients 
who are enrolled but found to not meet all the eligibility criteria must not be randomized and 
must not be initiated on treatment and must be withdrawn from the study as a screen failure.
When 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 the Study Physician and the investigator should discuss whether 
to continue or discontinue the patient from treatment.  The Study Physician must ensure that 
all decisions are appropriately documented.

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3.5
Methods for assigning treatment groups
The actual treatment given to patients will be determined by the randomization scheme in the 
IVRS/IWRS.  The randomization scheme will be produced by a computer software program 
that incorporates a standard procedure for generating randomization numbers.  One 
randomization list will be produced for each of the randomization strata.  A blocked 
randomization will be generated, and all centers will use the same list in order to minimize 
any imbalance in the number of patients assigned to each treatment arm. 
Patients will be identified to the IVRS/IWRS per country regulations.  Randomization codes 
will be assigned strictly sequentially, within each stratum, as patients become eligible for 
randomization.  The IVRS/IWRS will provide the kit identification number to be allocated to 
the patient at the randomization visit and following treatment visits.  
3.6
Methods for ensuring blinding
Not applicable; this study is not blinded.
3.7
Methods for unblinding 
Not applicable; this study is not blinded.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Female patient of childbearing potential
∀
Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception 
(Table 1) from the time of Screening and must agree to continue using such 
precautions for 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy.  
Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period.  Cessation of birth control after this point 
should be discussed with a responsible physician.  Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period 
is an acceptable practice; however, periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of birth control.  
Female patients should also refrain from breastfeeding throughout this period.
2.
Male patients with a female partner of childbearing potential
∀
Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from Screening 
through 180 days after receipt of the final dose of durvalumab + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab 

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monotherapy.  Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception.  Male patients should 
refrain from sperm donation throughout this period.
∀
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 1).  
Note: Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply: 
!
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
!
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy).
Highly effective methods of contraception, defined as those that result in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 1.  
Note that some contraception methods are not considered highly effective (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).
!
Patients in the SoC (Arm 3) group: Follow the local prescribing information 
relating to contraception, the time limits for such precautions, and any additional 
restrictions for agents in the SoC (Arm 3) group.

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Table 1
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods
Copper T intrauterine device
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
Etonogestrel implants: eg, Implanon or Norplan
Intravaginal device: eg, ethinylestradiol and 
etonogestrel
Medroxyprogesterone injection: eg, Depo-
Provera 
Normal and low-dose combined oral 
contraceptive pill
Norelgestromin/ethinylestradiol transdermal 
system
Cerazette (desogestrel)
a
This is also considered a hormonal method.
3.
PCI will not be permitted in Arms 1 and 2 due to the unknown effects of combining 
PCI with immunotherapies.  It will be permitted in Arm 3 if clinically indicated at 
investigators’ discretion.
4.
All patients: Patients should not donate blood or blood components while 
participating in this study and through 180 days after receipt of the final dose of 
durvalumab + tremelimumab combination therapy or 90 days after receipt of the 
final dose of durvalumab or until alternate anticancer therapy is started.  
5.
Restrictions relating to concomitant medications are described in Section 7.7.
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP (durvalumab + tremelimumab + EP, 
durvalumab + EP, or EP) if any of the following occur in the patient in question:
!
Withdrawal of consent from further treatment with IP.  The patient is, at any time, 
free to discontinue treatment, without prejudice to further treatment.  A patient who 
discontinues treatment is normally expected to continue to participate in the study 
unless they specifically withdraw their consent to further participation in any study 
procedures and assessments (see Section 3.10.2).
!
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates 
further dosing.
!
An AE that meets criteria for discontinuation as defined in the Toxicity 
Management Guidelines or as defined in the local prescribing information for the 
SoC agent. 

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!
Evidence of a new paraneoplastic syndrome(s) or worsening of an existing 
paraneoplastic syndrome(s).
!
Pregnancy or intent to become pregnant.
!
Noncompliance with the study protocol that, in the opinion of the investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits).
!
Initiation of alternative anticancer therapy including another investigational agent.
!
Confirmed PD, as per investigator assessment. 
3.9.1
Procedures for discontinuation of patient from IP
At any time, patients are free to discontinue IP without prejudice to further treatment.  A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs.  If possible, they will be seen and assessed by an 
investigator(s).  AEs will be followed up (see Section 6).  The Study Physician should be 
notified of any ongoing AE that may delay treatment or necessitate permanent discontinuation 
of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment.  Patients who are 
permanently discontinued will enter the Follow-up period (see Table 3).  
Patients who permanently discontinue drug for reasons other than confirmed objective 
RECIST disease progression should continue to have RECIST scans performed Q6W ± 
1 week for the first 12 weeks, then Q8W ± 1 week until confirmed objective disease 
progression/death (whichever comes first) as defined in Table 3.
If a patient is discontinued for unconfirmed progression then the patient should also continue 
to have RECIST scans performed Q6W ± 1 week for the first 12 weeks, then Q8W ± 1 week 
until confirmed objective disease progression or until death (whichever comes first) as defined 
in Table 3.
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in Table 3 as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
If a patient is withdrawn from study, see Section 3.11.

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3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not be randomized.  These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/meets 
exclusion criteria).  This reason for study withdrawal is only valid for screen failures (ie, not 
randomized patients).  Patients can be re-screened a single time, but they cannot be 
re-randomized. 
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn their 
consent to survival follow-up.  Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE.  The investigator will follow-up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to:
-
all further participation in the study including any further follow up (eg, survival 
contact telephone calls)
-
withdrawal to the use of any samples (see Section 5.5.4).
3.10.2.1
Survival status for patients who withdrew consent and were lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.
At the time 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.”  

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!
Lost to follow-up: site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status.  (The SURVIVE module will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under 
applicable local laws to obtain a current survival status.  (The applicable CRF 
modules will be updated.)   
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that meet any of the following criteria:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug
!
are not considered to be consistent with continuation of the study
In addition, the study may be stopped based on the findings of the interim safety analysis 
conducted by the Independent Data Monitoring Committee (IDMC) (see Section 6.10).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.  If this study is discontinued, all other studies involving 
durvalumab or tremelimumab will remain open to enrollment and screening, if deemed 
appropriate by AstraZeneca.

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4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and treatment periods in this study are presented in Table 2
and the procedures for the follow-up period are presented in Table 3. Patients treated in Arms 
1 and 2 who continue beyond week 20 will continue with all week 20 assessments defined in 
Table 2 until confirmed progression or termination of treatment (Table 2). Patients who 
discontinue or complete treatment (ie, patients in arm 3 who complete 4 cycles of 
chemotherapy) will follow assessments as defined in Table 3. All patients must follow the 
scan schedule which is at baseline, week 6±1 week, week 12±1 week and Q8W ±1 week from 
randomization thereafter until confirmed PD. Follow up visits should be planned to align to 
this scan schedule where possible.
For all treatment arms
-
PRO and tumor efficacy (RECIST) assessment dates are not affected by dose delays 
and remain as originally scheduled, as they are based on the date of randomization 
(not the date of therapy).
-
AstraZeneca requests that at least one subsequent scan is acquired and sent to 
AstraZeneca-appointed imaging Contract Research Organization  after each initial 
progression event for all patients, across all arms of the study if possible.
-
All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures, etc required for dosing should be 
performed within 3 days prior to dosing.
For durvalumab monotherapy or durvalumab + tremelimumab combination arms
!
Patients may delay dosing under certain circumstances:   
-
Dosing may be delayed per the Toxicity Management Guidelines, due to either 
an immune or a non-immune-related AE. Note: EP is the SoC and is expected 
to cause hematologic non-immune-related AEs for which the non-immune-
related Toxicity Management Guidelines should not be applied.  Sites should 
utilize dose delays, dose modifications, G-CSF or component transfusions (eg, 
platelet transfusions) as necessary per local standards to maintain the dose and 
schedule of EP treatment to optimize tolerability for individual patients.  
Communication with the Sponsor for questions is welcomed.
∀
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible.
∀
Dosing intervals of subsequent cycles (during chemotherapy interval is 
21 days, post chemotherapy interval is 28 days) may be shortened as clinically 

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feasible in order to gradually align treatment cycles with the schedule of tumor 
efficacy (RECIST) and PRO assessments.  Subsequent time between 2 
consecutive doses cannot be less than 21 days during chemotherapy and less 
than 22 days after chemotherapy, based on the half-lives of durvalumab and 
tremelimumab (see current IBs for durvalumab and tremelimumab).  
Standard of Care Arm:
-
Patients may delay and subsequently resume dosing per local standard clinical 
practice (see above).
-
If dosing must be delayed for reasons other than treatment-related toxicity, dosing
will occur as soon as feasible.

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Table 2
Schedule of assessments for Arms 1, 2, and 3 Treatment period
Screening
During Chemotherapy
1 cycle = 3 weeks
Post-Chemotherapy
1 cycle = 28 days
For details 
see Section
C1
C1/D8
C2
C2/D8
C3
C3/D8
C4
C4/D8
C5
C6
C7 to PD
(4 weeks)
Week
0
1
3
4
6
7
9
10
12
16
20
Day
-21 to -1
1
8
22
29
43
50
64
71
Window (days) unless a dose 
delay is needed for toxicity 
management
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent for study 
procedures including biomarker 
sample collection
X
4.1, 10.4
Consent for genetic sample and 
analysis (optional)
X
Appendix C  
Genetic 
Research
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical examination 
(based on symptoms)
X
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signs (temperature, 
respiratory rate, blood pressure, 
and pulse rate)a
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
12-lead ECGb
X
As clinically indicated
5.2.3
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including 
baseline characteristics and 
tobacco use
X
4.1
Eligibility criteria
X
X
3.1, 3.2

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Screening
During Chemotherapy
1 cycle = 3 weeks
Post-Chemotherapy
1 cycle = 28 days
For details 
see Section
C1
C1/D8
C2
C2/D8
C3
C3/D8
C4
C4/D8
C5
C6
C7 to PD
(4 weeks)
Week
0
1
3
4
6
7
9
10
12
16
20
Day
-21 to -1
1
8
22
29
43
50
64
71
Window (days) unless a dose 
delay is needed for toxicity 
management
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory assessments
Clinical chemistry
Xc
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Hematology
Xc
X
X
X
X
X
X
X
X
X
X
X
5.2.1
TSH, free T3, and free T4d
X
X
X
X
X
X
X
X
5.2.1
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Hepatitis B and C and HIV
X
5.2.1
Pregnancy teste
X
X
X
X
X
X
X
X
5.2.1
Efficacy assessments
Tumor evaluation (CT or MRI) 
(RECIST 1.1) f
Xg
RECIST 1.1 tumor assessments should be performed at Week 6 ±1 week, at Week 12±1 week then every 8 
weeks ±1 week relative to the date of randomization until RECIST 1.1-defined progression. All patients 
require one follow up scan post initial progression where possible.
5.1
PK
Durvalumab PK sample (serum; 
Arms 1 and 2 only)
Xi
Xj
Xj
5.4.1
Tremelimumab PK sample 
(serum; Arm 1 only)
Xi
Xj
Xj
5.4.1
Etoposide PK sample (serum or 
plasma; selected sites only)k
X
5.4.1

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Screening
During Chemotherapy
1 cycle = 3 weeks
Post-Chemotherapy
1 cycle = 28 days
For details 
see Section
C1
C1/D8
C2
C2/D8
C3
C3/D8
C4
C4/D8
C5
C6
C7 to PD
(4 weeks)
Week
0
1
3
4
6
7
9
10
12
16
20
Day
-21 to -1
1
8
22
29
43
50
64
71
Window (days) unless a dose 
delay is needed for toxicity 
management
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Carboplatin or cisplatin PK 
sample (serum or plasma; 
selected sites only)k
X
5.4.1
Monitoring
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
5.2.6
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Drug accountability
X
X
X
X
X
X
X
7.6
IP administration (Interval between 2 consecutive doses cannot be less than 21 days during chemotherapy and less than 22 days after chemotherapy)
Arm 1: durvalumab + tremelimumab + EP
Durvalumabl,m
Xz
X
X
X
X
X
Xn
7.2.1
Tremelimumabl,m,n
Xz
X
X
X
X
7.2.1
Etoposideo,p
Xz
X
X
X
7.2.1
Carboplatin or cisplatino,q
Xz
X
X
X
7.2.1
Arm 2: durvalumab + EP
Durvalumab l,m
Xz
X
X
X
X
X
Xn
7.2.1
Etoposide o,p
Xz
X
X
X
7.2.1
Carboplatin or cisplatin o,q
Xz
X
X
X
7.2.1

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Screening
During Chemotherapy
1 cycle = 3 weeks
Post-Chemotherapy
1 cycle = 28 days
For details 
see Section
C1
C1/D8
C2
C2/D8
C3
C3/D8
C4
C4/D8
C5
C6
C7 to PD
(4 weeks)
Week
0
1
3
4
6
7
9
10
12
16
20
Day
-21 to -1
1
8
22
29
43
50
64
71
Window (days) unless a dose 
delay is needed for toxicity 
management
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Arm 3: EP (4-6 cycles)
Etoposide p
Xz
X
X
Xr
7.2.1
Carboplatin or cisplatin q
Xz
X
X
Xr
7.2.1
PRO assessments timing
EORTC QLQ-C30 v3, EORTC 
QLQ-LC13, EQ-5D-5L, and 
PRO CTCAE s,t
X
X
X
X
X
X
X
X 
5.3.1.1, 
5.3.1.2, 
5.3.1.3,
5.3.1.5
Patient’s Global Impression of 
Change (PGIC)s,u
X
X
X
X
X
X 
5.3.1.4
Other laboratory assessments and assays
Immunogenicity assessment for 
durvalumab and tremelimumab 
(ADA sampling to identify 
ADA responses in patient 
circulation) v
X
Xw
5.4.2
Mandated archival/diagnostic 
tumor sample <3 years old, 
where available. Samples 
should only be sent for patients 
who are enrolled and 
randomized 
X
5.5.1

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Screening
During Chemotherapy
1 cycle = 3 weeks
Post-Chemotherapy
1 cycle = 28 days
For details 
see Section
C1
C1/D8
C2
C2/D8
C3
C3/D8
C4
C4/D8
C5
C6
C7 to PD
(4 weeks)
Week
0
1
3
4
6
7
9
10
12
16
20
Day
-21 to -1
1
8
22
29
43
50
64
71
Window (days) unless a dose 
delay is needed for toxicity 
management
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Plasma sample for tumor 
mutational burden (TMB)
X 
(pre-
dose)
Gx sample (optional DNA 
element for long-term 
storage/future use)x
X
Appendix C 
Genetic 
Research
Health economics measurements
Hospital resource use module 
(HOSPAD) y
X
X
X
X
X
X
X
X
5.3.3
a
Body weight is recorded along with vital signs.
b
Any clinically significant cardiovascular findings require a confirmatory ECG.
c
Screening laboratory assessments must be obtained within 7 days prior to Day 1. If screening clinical chemistry and hematology assessments are performed within 3 days 
prior to Day 1 (first infusion day), they do not need to be repeated at Day 1. Results for urea and electrolytes, full blood count, and liver function tests must be available 
before commencing an infusion (samples must have been obtained within 3 days prior to the infusion). 
d
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
e
Pregnancy test will be performed in women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
f
RECIST 1.1 assessments will be performed on images from CT scans (preferred) or MRI scans, each preferably with IV contrast, of the chest and abdomen (including 
liver and adrenal glands).  Additional anatomy should be scanned based on signs and symptoms of individual patients at Baseline and Follow-up. A follow up scan is 
requested after every radiological PD on study where possible; this is irrespective of whether the PD needs to be confirmed or not as set out in Appendix F. As long as the 
patient is clinically stable, in the event of radiologic PD according to RECIST 1.1, an additional scan should be performed preferably at the next scheduled imaging visit 
and no less than 4 weeks after the prior assessment of radiologic PD (please refer to Appendix F). If an unscheduled assessment was performed and the patient has not 
reached PD, every attempt should be made to perform the subsequent assessments at their next scheduled visit.
g
Patient’s diagnostic scan may be used as a baseline scan if taken within 28 days of randomization and in accordance with the requirements outlined in Appendix F.
h
Patients will have scans done Q6W for the first 12 weeks, and then Q8W thereafter (relative to the date of randomization) until confirmed objective disease progression. 
Patients with confirmed PD who continue to receive durvalumab ± tremelimumab combination therapy at the discretion of the Investigator (following consultation with 
AstraZeneca) can receive their assigned treatment until no longer having clinical benefit.

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i
PK sampling should be performed within 10 minutes of the end of infusion.
j
Both PK samples are to be taken before the tremelimumab infusion at Cycle 2, and this will be before the durvalumab infusion in Cycle 5.
k
Selected sites only: Etoposide PK sample – collect at the end of infusion, 6 hours post infusion, and 24 hours post infusion.  Cisplatin PK sample – collect at the end of 
infusion, 1 hour post infusion, and 3 hours post infusion.  Carboplatin PK sample – collect at the end of infusion, 6 hours post infusion, and 24 hours post infusion.
l
In cycles including tremelimumab, tremelimumab will be administered first followed by durvalumab.  Durvalumab infusion will start approximately 60 minutes 
(maximum 2 hours) after the end of tremelimumab infusion.  The 60-minute observation period is recommended after the first infusion of both tremelimumab and 
durvalumab.  If no clinically significant infusion reactions are observed during or after the first cycle involving tremelimumab and durvalumab, subsequent infusion 
observation periods can be undertaken at the investigator’s discretion (30 minutes after each infusion is suggested).
m
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing an infusion (samples must have been obtained within 
3 days prior to the infusion).
n
Durvalumab treatment is continued until PD. Patients with confirmed PD who continue to receive durvalumab ± tremelimumab combination therapy at the discretion of 
the Investigator (following consultation with AstraZeneca) can receive their assigned treatment until no longer having clinical benefit
o
The immunotherapy agents are infused first followed by the etoposide + cisplatin/carboplatin regimen
p
Infuse over 0.5 to 1 hour.
q
If cisplatin, infuse over 1 to 2 hours.  If carboplatin, infuse over 0.5 to 1 hour.
r
EP Q3W up to 4 doses; extension into Weeks 12 and 15 is at the investigators’ discretion.  Note: tumor evaluation at Week 12 ± 1 week and Q8W thereafter and PRO 
collection Q4W until PD are required irrespective of the number of cycles of EP given
s
For the PRO collection, the research nurse or study coordinator should ensure that the patient completes the questionnaire prior to any other study procedures and before 
discussion of PD to avoid introducing bias to the patient’s responses to the questions. The EORTC QLQ-C30 should always be completed prior to the EORTC QLQ-
LC13 module.
t
PRO-CTCAE will only be administered in countries where a linguistically validated version exists.
u
PGIC will only be administered after the patient has received started to receive treatment.
v
ADA for tremelimumab will be assessed for Arm 1 patients only; ADA for durvalumab will be performed for Arm 1 and 2 patients only.
w
A sample to look for antibodies to tremelimumab will be taken 90 days ± 7 days after last dose of tremelimumab
x
The sample for genetic research will be obtained at Day 1 pre-dose (at or after randomization). If for any reason the sample is not drawn at Day 1, it may be taken at any 
visit until the last study visit.  Only one sample should be collected per patient for genetics during the study, after obtaining signed optional informed consent.  
y
The site should complete the HOSPAD form at every scheduled and unscheduled clinic visit up to and including the study treatment discontinuation follow-up visit.  If 
the patient discontinues study treatment for reasons other than RECIST 1.1 assessed PD, the HOSPAD form should continue to be completed until PD has been 
confirmed.
z
A window of up to 2 days is permitted between randomization and first dose of IP. Randomization on Friday and dosing on Monday will be accepted.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
ADA  Anti-drug antibody; AE  Adverse event; C  Cycle; CR  Complete response; CT  Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; D  
Day; ECG  Electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EORTC  European Organisation for Research and Treatment of Cancer; EP  Etoposide and 
platinum-based chemotherapy; EQ5D-5L  EuroQol 5-dimension, 5-level health state utility index; HIV  Human immunodeficiency virus; HOSPAD  Hospital resource use 
module; IP  Investigational product; IV  Intravenous; MRI  Magnetic resonance imaging; NA  Not available; PD  Progressive disease; PGIC  Patient’s Global Impression of 
Change; PGx  Pharmacogenetic research; PK  Pharmacokinetic(s); PR  Partial response; PRO  Patient-reported outcomes; PRO-CTCAE  Patient-reported outcomes version of 
the CTCAE; Q3W  Every 3 weeks; Q4W Every 4 weeks; QLQ C30 v3  30 item Core Quality of Life Questionnaire, version 3; QLQ-LC13  13-item Lung Cancer Quality of 
Life Questionnaire; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-
stimulating hormone; WHO  World Health Organization.

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Table 3
Schedule of assessments for patients who have completed/discontinued treatment with 
durvalumab + tremelimumab + EP, durvalumab + EP, or EP
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
Every 2 months 
(±2 weeks)
28
2
3
4
6
8
10
12
Physical examination (full)a
X
Vital signs (temperature, respiratory rate, 
blood pressure, and pulse rate)
X
Weight
X
X
X
X
Pregnancy testb
X
As clinically indicated
AE/SAE assessmentc
X
X
X
Concomitant medications
X
X
X
WHO/ECOG performance statusd
At timepoints consistent with tumor assessments, at 30, 60, and 90 days and at initiation of subsequent anticancer therapy
Subsequent anticancer therapye
To be checked and recorded on every visit
Survival statusf
X
X
X
X
X
X
X
X
Hematologyo
X
X
X
Clinical chemistry
X
X
X
TSH, free T3, and free T4 g
X
X
X
Immunogenicity assessment (Durvalumab 
and Tremelimumab ADA sampling to 
identify ADA responses in patient 
circulation)h
Xi
EORTC QLQ-C30 v3j, EQ-5D-5Lj, EORTC 
QLQ-LC13j, PRO-CTCAE j,k, and PGICj
Q4W until PD, then on Day 28 post PD, then 2 months post PD and then Q8W (±2 weeks) until second progression/death 
(whichever comes first)
Hospital resource use module (HOSPAD)l
X
Tumor assessment (CT or MRI)m
RECIST 1.1 tumor assessments should be performed at Week 6 ±1 week, at Week 12±1 week then every 8 weeks ±1 week 
relative to the date of randomization until RECIST 1.1-defined progression. All patients require one follow up scan post initial 
progression if possible.

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Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
Every 2 months 
(±2 weeks)
28
2
3
4
6
8
10
12
Second progression assessment n
Patients who discontinue study drug following progression will be assessed every 12 weeks for a second progression (using the 
patient’s status at first/confirmed progression as the reference for assessment of second progression). A patient’s progression 
status is defined according to local standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death (using the patient’s status at first progression as the reference for assessment of 
second progression). 
a
Physical examinations are described in Section 5.2.2.
b
Pregnancy test will be performed in women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
c
AEs and SAEs will be collected until 90 days following discontinuation of study treatment (ie, the last dose of durvalumab, durvalumab + tremelimumab or EP) 
d
WHO/ECOG performance status should also be collected at other site visits that the patient attends; if appropriate, site staff are available to collect such information.  In 
addition, WHO performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
e
Details of any treatment for SCLC (including surgery) after the last dose of study treatment must be recorded in the eCRF
f
Patients may be contacted in the week following data cut-off to confirm survival status. Details of any treatment for SCLC (including surgery) after the last dose of study 
treatment must be recorded in the eCRF. Every effort should be made to contact patients by telephone to follow and record survival status. Survival assessments may 
continue per protocol (every 2 months) post the primary analysis of OS unless instructed otherwise by AstraZeneca
g
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h
ADA for tremelimumab will be assessed for Arm 1 patients only; ADA for durvalumab will be performed for Arm 1 and 2 patients only.
i
A sample to look for antibodies to tremelimumab will be taken 90 days ± 7 days after last dose of tremelimumab.
j
For the PRO data collection, the research nurse or study coordinator should ensure that the patient completes the questionnaire prior to any other study procedures and 
before discussion of PD to avoid introducing bias to the patient’s responses. The EORTC QLQ-C30 should always be completed prior to the EORTC QLQ-LC13 
module.
k
PRO-CTCAE will only be administered in countries where a linguistically validated version exists.
l
The site should complete the Hospital Admission (HOSPAD) form at every scheduled clinic visit up to and including the study treatment discontinuation follow-up visit.  
If the patient discontinues study treatment for reasons other than RECIST 1.1 assessed PD, the HOSPAD form should continue to be completed until PD has been 
confirmed.
m
Only for patients yet to progress, RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast, of the chest and 
abdomen (including liver and adrenal glands). Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  Additional anatomy 
should be imaged based on signs and symptoms of individual patients.   A follow up scan is requested after every radiological PD on study where possible; this is 
irrespective of whether the PD needs to be confirmed or not as set out in Appendix F. As long as the patient is clinically stable, in the event of radiologic PD according to 
RECIST 1.1, an additional scan should be performed preferably at the next scheduled imaging visit and no less than 4 weeks after the prior assessment of radiologic PD 
(please refer to Appendix F).If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits (relative to the date of randomization).
n
For patients who discontinue their assigned IP following confirmed PD, available readings of CT/MRI from local practice will be collected from the patients’ medical 
charts while information on subsequent anticancer treatment and/or PFS2 is collected.  
o
For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed as clinically indicated.

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4.1
Screening/Enrollment period
All screening and enrollment procedures will be performed according to the assessment 
schedules in Table 2.  Demographic data and other characteristics will be recorded including 
date of birth or age, gender, smoking history, and race/ethnicity, according to local 
regulations.  A standard medical and surgical history will be obtained.  
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening 
evaluations.  If laboratory or imaging procedures were performed for alternate reasons prior to 
signing consent, these can be used for screening purposes with consent of the patient. 
However, all screening laboratory and imaging results must have been obtained within 
21 days of randomization (except if using a patient’s diagnostic scan which may be used as a
baseline scan if taken within 28 days of randomization and in accordance with the 
requirements outlined in Appendix E). All patients will be asked to provide consent to supply 
a sample of their tumor (archived or newly acquired biopsy) where available.  This consent is 
included in the main patient informed consent form (ICF).  
Screening/baseline evaluations may be performed over more than 1 visit.
The timing of vital sign assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the timepoints indicated in Table 2.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2).
Whenever vital signs, electrocardiograms (ECGs), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: ECG, vital signs and 
then blood draws.  The timing of the vital signs assessments should be such that it allows the 
blood draw (eg, PK blood sample) to occur at the timepoints indicated in Table 2.
!
Patients in Arm 3 only:
Patients who receive additional cycles of EP and/or PCI at investigators’ discretion will be 
expected to follow the assessment schedule in Table 3 after 4 cycles of EP; additional visits or 
scans due to the optional extension of EP or PCI will be recorded as unscheduled 
visits/assessments.
4.2.1
Safety Confirmation Period
This applies to the first 60 patients randomised to the study and will be split into two parts; an 
unblinded safety review carried out by the IDMC will be conducted after the initial 30 patients 
have had a minimum of 21 days follow up and again after an additional 30 patients have been 
randomised and had 21 days of follow up (see Section 6.10.1 for details). All procedures will 
follow the same assessment schedule as for the treatment period (Table 2). 

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4.3
Follow-up period
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see 
Table 3).  
Patients who permanently discontinue drug for reasons other than objective RECIST disease 
progression should continue to have RECIST scans performed Q6W ± 1 week for the first 
12 weeks (relative to the date of randomization), and then Q8W ± 1 week thereafter until 
confirmed objective disease progression/death (whichever comes first) as defined in Table 3.
If a patient is discontinued for unconfirmed progression then the patient should also continue 
to have RECIST scans performed Q6W ± 1 week for the first 12 weeks (relative to the date of 
randomization), and then Q8W ± 1 week thereafter until confirmed objective disease 
progression or until death (whichever comes first) as defined in Table 3.
All procedures to be conducted during the Follow-up period will be performed according to 
the assessment schedule (see Table 3).
Whenever vital signs, electrocardiograms (ECGs), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: ECG, vital signs, and 
then blood draws.  The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the timepoints indicated in Table 3.
All patients will be followed for survival until the end of the study.  The schedule of study 
procedures for patients in long-term follow up is presented in Table 12 in Section 9.3 Study 
timetable and end of study.
5.
STUDY ASSESSMENTS  
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the eCRFs as specified in this 
study protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the clinical study agreement (CSA).  The 
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments 
This study will evaluate the primary endpoint of OS. Secondary objective efficacy 
assessments of PFS, proportion of patients alive and progression free at 6 and 12 months from 
randomization (APF6, APF12) and ORR will be derived (by AstraZeneca) from site 
Investigator assessment according to RECIST 1.1.   OS18 will also be evaluated.

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Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV 
contrast, of the chest, abdomen, and pelvis, collected during screening/baseline and at regular 
(follow-up) intervals during study treatment.  Any other areas of disease involvement should 
be additionally imaged based on the signs and symptoms of individual patients. 
The RECIST 1.1 guidelines (Appendix E) provide a method of assessment of change in tumor 
burden in response to treatment.  Screening/Baseline imaging should be performed no more 
than 28 days before randomization, and ideally should be performed as close as possible to 
and prior to the start of study treatment.  The RECIST 1.1 assessments of baseline images 
identify target (defined measurable) and non-target lesions, and each lesion (and any new 
lesion) is evaluated in subsequent, on-treatment follow-up images.  This allows determination 
of follow-up target lesion response, non-target lesion response, and overall time-point tumor 
responses (CR, PR, SD, PD or NE).
Efficacy for all patients (all arms) will be assessed on images collected Q6W ±1 week for the 
first 12 weeks relative to the date of randomisation, and Q8W ± 1 week thereafter until 
confirmed objective disease progression or off-study. It is important to follow the assessment 
schedule as closely as possible [refer to the study plans in Table 2 (treatment period), and 
Table 3 (follow up)].  If an unscheduled imaging assessment is performed and the patient has 
not progressed, every attempt should be made to perform the subsequent assessments at his or 
her next regularly scheduled imaging visit.
AstraZeneca requests that at least one subsequent scan is acquired (and sent to the 
AstraZeneca-appointed imaging Contract Research Organization) after each initial 
progression event for all patients, across all arms of the study,  no earlier than 4 weeks after 
and no later than the next regularly scheduled imaging visit after the initial progression event.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) after the 
initial assessment of progression, then the patient should continue to be followed with 
scheduled imaging until objective disease progression.
Following objective disease progression, patients should continue to be followed up for 
survival every 2 months (8 weeks) as outlined in the follow-up schedules of assessments 
(Table 3). In addition, all patients will be contacted in the week following data cut-off to 
confirm survival status.
5.1.1
Reading of scans
Although scan assessments will be performed by Investigators, all images, including 
unscheduled visit scans, will be collected on an ongoing basis and sent to an AstraZeneca-
appointed imaging Contract Research Organization for QC and storage in the event that 
central review is required. Management of patients will be based solely upon the results of the 
RECIST 1.1 assessment conducted by the Investigator. 

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5.1.2
Survival assessments
Assessments for survival must be made every 2 months following treatment discontinuation.  
Survival information may be obtained via telephone contact with the patient or the patient’s 
family, or by contact with the patient’s current physician.  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cut-off for the primary analysis of PFS  and all subsequent survival analyses to provide 
complete survival data. These contacts should generally occur within 7 days of the data cutoff. 
Survival assessments may continue as per protocol (every 2 months) post the primary analysis 
of OS. 
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
Table 2 and Table 3). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Clinically significant abnormal laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.  The date, time of collection, and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 4 (clinical chemistry), Table 5
(hematology), and Table 6 (urinalysis).
Other safety tests to be performed at Screening include assessment for hepatitis B surface 
antigen (HbsAg), hepatitis C antibodies, HIV antibodies.

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Table 4
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSH
Chloridec
T3 freed (reflex)
Creatinine clearancec
T4 freed(reflex)
Creatinine 
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyl transferasec
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed.  For sites where only one of these 
parameters is routinely measured, then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyl transferase, and magnesium, 
testing are to be performed at Screening, on Day 1 (unless screening laboratory assessments are performed 
within 3 days prior to Day 1), and if clinically indicated.
d
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; T3  Triiodothyronine; T4  Thyroxine; 
TSH  Thyroid-stimulating hormone.
Table 5
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Absolute eosinophil counta
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed 
at Baseline on Day 0 (unless all Screening laboratory hematology assessments are performed within 3 days prior to 
Day 0), and as clinically indicated.
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by data management if entered 
as percentage. Total white cell count therefore has to be provided.

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Table 6
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for 
red blood cells.
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix D for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law.  These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a Hy’s law case or if any of the individual liver test parameters fulfill any of the 
SAE criteria.  
All patients should have further chemistry profiles performed at 28 days (±3 days), 2 months 
(±1 week) and 3 months (±1 week) after permanent discontinuation of IP (see Table 3).
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  Situations in which laboratory safety results should be 
reported as AEs are described in Section 6.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must have further tests performed until the laboratory values have 
returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (Table 2 and 
Table 3).  Full physical examinations will include assessments of the head, eyes, ears, nose, 
and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems.  Height will be 
measured at Screening only.  Targeted physical examinations are to be utilized by the 
investigator on the basis of clinical observations and symptomatology.  Situations in which 
physical examination results should be reported as AEs are described in Section 6.3.6.
5.2.3
Electrocardiogram
Resting 12-lead ECGs will be recorded at Screening and as clinically indicated throughout the 
study (see Table 2).  ECGs should be obtained after the patient has been in a supine position 
for 5 minutes and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  

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Situations in which ECG results should be reported as AEs are described in Section 6.3.7.
5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse rate, temperature, and respiration rate) will be 
evaluated according to the assessment schedules (Table 2 and Table 3).  Body weight is also 
recorded at each visit along with vital signs.
First infusion
On the first infusion day, BP and pulse rate will be collected/recorded in the eCRF prior to, 
during, and after infusion of each IO agent. BP and pulse rate will be collected prior to each 
infusion of EP therapy and as clinically indicated.
BP and pulse rate will be collected from patients in Arms 1 and 2 before, during, and after 
each infusion at the following times (based on a 60-minute infusion):
!
Prior to the beginning of each infusion (measured once from approximately 
30 minutes before up to 0 minutes [ie, the beginning of the infusion]) 
!
Approximately 30 minutes during the infusion (halfway through infusion) 
!
At the end of the infusion (approximately 60 minutes ±5 minutes)
!
A 1-hour observation period is recommended after the first infusion of durvalumab 
+ tremelimumab + EP and durvalumab + EP.  If no clinically significant infusion 
reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the investigator’s discretion (suggested 30 minutes 
after each durvalumab + tremelimumab + EP and durvalumab + EP infusion).
If the infusion takes longer than 60 minutes, then BP and pulse rate measurements should 
follow the principles as described above or be taken more frequently if clinically indicated.  
Additional monitoring with assessment of vital signs is at the discretion of the investigator per 
standard clinical practice or as clinically indicated.  
Subsequent infusions
BP, pulse rate, and other vital signs should be measured and collected/recorded in the eCRF 
prior to the start of the infusion.  Patients should be carefully monitored, and BP and other 
vital signs should be measured during and after infusion as per institution standard and as 
clinically indicated.  Any clinically significant changes in vital signs should be entered onto an 
unscheduled vital signs case report form (CRF) page.
Situations in which vital signs results should be reported as AEs are described in 
Section 6.3.7.  For any AEs of infusion reactions, please enter the vital signs values into the 
CRF.

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5.2.5
Early Patient review for safety
Patients will be evaluated 7 days after the first dose of each cycle of chemotherapy across all 
arms to ensure early identification and management of toxicities.
We strongly recommend for any patient experiencing Grade 3-4 neutropenia that G-CSF is 
administered according to local practice.
5.2.6
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2 and Table 3) based on the following:
!
0 = Fully active; able to carry out all usual activities without restrictions.
!
1 = Restricted in strenuous activity but ambulatory and able to carry out light work 
or work of a sedentary nature (eg, light housework or office work).
!
2 = Ambulatory and capable of self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours.
!
3 = Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours.
!
4 = Completely disabled; unable to carry out any self-care and totally confined to 
bed or chair.
!
5 = Dead
Any significant changes from baseline or screening must be reported as an AE.
5.2.7
Other Safety Assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Toxicity Management Guidelines will be applied.  The results of the 
full diagnostic workup (including high-resolution computed tomography (HRCT), blood and 
sputum culture, hematological parameters etc) will be captured in the eCRF.  It is strongly 
recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary 
hemorrhage.  In the presence of confirmatory HRCT scans where other causes of respiratory 
symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered and 
the Toxicity Management Guidelines should be followed.  

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Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected.
!
Physical examination
∀
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed.
!
SpO2
∀
Saturation of peripheral oxygen (SpO2)
!
Other items
∀
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers which are related to 
disease progression.  
(iii)
Additional Clinical chemistry: CRP, LDH
5.3
Other assessments
5.3.1
Patient-reported outcomes
“PRO” is an umbrella term referring to all outcomes and symptoms that are directly reported 
by the patient.  PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical studies.  The following PROs will be administered in this study: EORTC 
QLQ-C30 v3 (core questionnaire), EORTC QLQ-LC13 (lung cancer module), 
patient-reported outcomes version of the CTCAE (PRO-CTCAE), Patient’s Global Impression 
of Change (PGIC), and the EuroQol 5-Dimension, 5-level health state utility index 
(EQ-5D-5L) (see Appendix F).
The PRO instruments will be completed by the patients using a handheld ePRO device.  All 
assessments should be completed without assistance from anyone according to the assessment 
schedules (see Table 2 and Table 3).  It takes approximately 30 minutes for patients to 
complete the questionnaires; therefore, the burden to the patient is moderate. 

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5.3.1.1
EORTC QLQ-C30
The EORTC QLQ-C30 v3 questionnaire is included for the purpose of assessing HRQoL and 
is a well-established measure of HRQoL/health status and commonly used as an endpoint in 
cancer clinical studies.  It assesses HRQoL/health status through 9 multi-item scales: 
5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, pain, and nausea and vomiting), and a global health and quality-of-life (QoL) scale.  
Six single-item symptom measures are also included dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties (see Appendix F).  For each of the 
15 domains, final scores are transformed such that they range from 0 to 100, where higher 
scores indicate greater functioning, greater HRQoL, or greater level of symptoms (Aaronson 
et al 1993).
5.3.1.2
EORTC QLQ-LC13
For patients with SCLC, a disease-specific 13-item self-administered questionnaire for lung 
cancer was developed (EORTC QLQ-LC13; Appendix F) to be used in conjunction with the 
EORTC QLQ-C30 (Bergman et al 1994).  It comprises both multi-item and single-item 
measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) 
and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, 
sore mouth, and dysphagia).  Similar to the EORTC QLQ-C30, all questions except one have 
a 4-point scale: “not at all”, “a little”, “quite a bit” and “very much”.  One question 
(no. 43, “Did you take any medicine for pain?”) has a response option of “yes” or “no”.  The 
scoring approach for the EORTC QLQ-LC13 is similar to the EORTC QLQ-C30.
5.3.1.3
PRO-CTCAE
The PRO-CTCAE is included to address tolerability from the patients’ perspective.  It was 
developed by the National Cancer Institute (NCI).  The PRO-CTCAE will only be 
administered in those countries where a linguistically validated version exists.  It was 
developed in recognition that collecting symptom data directly from patients using PRO tools 
can improve the accuracy and efficiency of symptomatic AE data collection.  This was based 
on findings from multiple studies demonstrating that physicians and nurses underestimate 
symptom onset, frequency, and severity in comparison with patient ratings (Antonia et al 
2014, Litwin et al 1998, Sprangers and Aaronson 1992).  These symptoms have been 
converted to patient terms (eg, the CTCAE term “myalgia” has been converted to “aching 
muscles”).  For several symptoms, like fatigue and pain, additional questions are asked about 
symptom frequency, severity, and interference with usual activities.  The items included in the 
PRO-CTCAE have undergone extensive qualitative review among experts and patients.  
These items have been extensively evaluated by cancer patients to be clear, comprehensible, 
and measure the symptom of interest.  In this study, only items that are considered relevant for 
the study, site of cancer, and cancer treatment are selected (see Appendix F).
5.3.1.4
Patients’ Global Impression of Change
The PGIC item is included to assess how a patient perceives his/her overall change in health 
status since the start of study treatment. Patients will choose from response options from 
“very much improved” to “very much worse.”

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5.3.1.5
EQ-5D-5L
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol Group 1990).  Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of health care as well as in population health surveys.  
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Each dimension has 5 response options (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) that reflect increasing 
levels of difficulty (EuroQol Group 2013).
Since 2009, the EuroQol Group has been developing a more sensitive version of the EQ-5D 
(the EQ-5D-5L) that expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5L version 
improves upon the properties of the 3L measure in terms of reduced ceiling effect, increased 
reliability, and an improved ability to differentiate between different levels of health (Janssen
et al 2008a, Janssen et al 2008b, Pickard et al 2007).
The patient will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual 
analogue scale, where the patient will be asked to rate current health status on a scale of 0 to 
100, with 0 being the worst imaginable health state (see Appendix F).
5.3.2
Administration of the patient-reported outcome questionnaires
Patients will complete the PRO assessments by using an electronic tablet (ePRO) during clinic 
visits. 
Each center must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.  The PRO questionnaires must be 
administered and completed at the clinic as per the schedule of assessments.  The PRO 
questionnaires will be administered on the days specified in the schedules of assessments (see 
Table 2 and Table 3).  The EORTC QLQ-C30 should always be completed prior to the 
EORTC QLQ-LC13 module.
It is important that the site staff carefully explain the significance and relevance of the data to 
participating patients so that they are motivated to comply with data collection.  The following 
best practice guidelines should be followed when collecting PRO data via an electronic 
device:
!
It is preferred that PRO questionnaires are completed prior to any other study 
procedures (following informed consent) and before discussion of disease 
progression to avoid biasing the patient’s responses to the questions.
!
PRO questionnaires must be completed in private by the patient.

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Patients should be given sufficient time to complete the PRO questionnaires at their 
own speed.
!
The research nurse or appointed site staff should stress that the information is 
confidential.  Therefore, if the patient has any medical problems, he/she should 
discuss them with the doctor or research nurse separately from the ePRO 
assessment.
!
The research nurse or appointed site staff must train the patient on how to use the 
ePRO device using the materials and training provided in the ePRO device. The 
research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not clarifying items.  The patient 
should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. 
A key aspect of study success is to have high PRO compliance. Therefore, it is essential to 
follow the schedule of assessments and that sites make sure the device is charged and fully 
functional at all times in order to minimize missing data.
5.3.3
Health care resource use
The assessment of health care resource use will increase the understanding regarding the 
relationship between treatment and tumor-related cancer symptoms on resource use, such as 
the need for palliative procedures to address obstruction and bleeding.  This will be captured 
and analyzed to inform submissions to payers.
To investigate the impact of treatment and disease on health care resource use, the following 
variables will be captured by hospital resource use module HOSPAD form:
!
Planned and unplanned hospital attendances beyond study protocol mandated visits 
(including physician visits, emergency room visits, day cases, and admissions) 
!
Primary sign or symptom the patient presents with
!
Length of hospital stay
!
Length of any time spent in an intensive care unit
5.4
Pharmacokinetics
5.4.1
Collection of samples for pharmacokinetics analysis
Blood samples for determination of etoposide, carboplatin, cisplatin, durvalumab, and 
tremelimumab concentration in serum or plasma will be obtained according to the assessment 
schedules (see Table 2 and Table 3).  Samples for etoposide, carboplatin, and cisplatin will be 
collected from selected sites only and will include approximately 6 patients per arm dosed 
with etoposide and carboplatin and approximately 6 patients per arm dosed with etoposide and 
cisplatin.  AstraZeneca will inform the selected sites once this requirement has been fulfilled.

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Samples for determination of durvalumab, tremelimumab, etoposide, cisplatin, and 
carboplatin concentration in serum or plasma will be analyzed by a designated third party on 
behalf of AstraZeneca. Samples will be collected, labeled, stored, and shipped as detailed in 
the Laboratory Manual. Full details of the analytical method used will be described in a 
separate Bioanalytical Validation Report.  
5.4.2
Collection of samples to measure for the presence of ADAs
The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 2 and Table 3). 
Samples will be measured for the presence of ADAs and ADA neutralizing antibodies for 
both IPs (durvalumab and tremelimumab) using validated assays.  Tiered analysis will be 
performed to include screening, confirmatory, and titer assay components, and 
positive-negative cut points previously statistically determined from drug-naïve validation 
samples will be employed. 
5.4.2.1
Storage and destruction of pharmacokinetic/ADA samples
Durvalumab and tremelimumab PK and ADA samples will be disposed of a maximum of 
10 years after the IPs are approved for marketing.
EP PK samples will be disposed of after the Bioanalytical Report finalization or six months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for 
future analyses. PK and ADA samples may be disposed of or destroyed or anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, pooled PK samples to 
further evaluate and validate the analytical method.  Results from such analyses may be 
reported separately from the clinical study report (CSR). Anonymised EP PK samples will be 
retained for no more than 5 years after the CSR is finalised.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca-assigned Biobank or 
designee; see details in the Laboratory Manual).
5.5
Biomarkers
  
By participating in this study the patient consents to the collection and use of donated 
biological samples as described here.  Tissue samples will be obtained from all screened 
patients where available. Based on availability of tissue, additional exploratory biomarkers 
may be evaluated as described in Section 5.5.1  Samples will be obtained according to the 
assessment schedules provided in Table 2 and Table 3.

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Details for collection, volumes, storage, and shipment of biologic samples are presented 
separately in the Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to immunotherapy. 
The results may be pooled with biomarker data from other durvalumab and tremelimumab 
studies to evaluate biological responses across indications and to compare results in 
monotherapy versus combination settings.
5.5.1
Exploratory biomarkers
Blood and tumor samples for exploratory biomarker analyses will be obtained according to the 
schedules presented in Table 2.  Details for collection, volumes, storage, and shipment of 
biologic samples are presented separately in the Laboratory Manual. 
Baseline measures (and on-treatment changes) will be correlated with outcomes.  Note that 
samples will be obtained from patients randomized to each treatment arm.  Comparisons will 
be made between baseline measures to determine if biomarkers (or combination of markers) 
are prognostic or predictive of outcomes associated with Arms 1, 2, and 3.
The exploratory biomarker plan is described by sample type below.
Tumor mutational burden (TMB) and somatic mutations/alterations – tumor and 
plasma
SCLC is characterized by its high mutational load, as described in Section 1.1. Recent data 
from a Phase I/II study CheckMate 032 (A Phase I/II, Open-label Study of Nivolumab 
Monotherapy or Nivolumab Combined With Ipilimumab in Subjects With Advanced or 
Metastatic Solid Tumors) have shown that patients with a high tumor burden (TMB high) 
derive greater clinical benefit from PD-1 blockade alone or in combination with CTLA-4 
blockade. To better understand the significance of this finding and any impact this may have 
on patients in the present study (CASPIAN), we plan to assess tumor burden in both tumor 
and blood samples.
The overall mutation burden and/or somatic mutations/genomic alterations in tumor tissue 
and/or plasma may be assessed using methodologies including, but not limited to, whole 
exome sequencing to targeted sequencing. Such measurements may be correlated with 
response.
Tumor markers
This study will mandate the collection of archival/diagnostic tumor tissue, where available, 
which will be analyzed for various markers by immunohistochemistry.  

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A primary goal is to measure PD-L1, TMB, somatic mutations/genomic alterations and 
Delta-like canonical Notch ligand 3 (DLL3) expression to support exploratory objectives of 
investigating the following:
1.
The relationship between a patient’s PD-L1 expression and spatial distribution 
within the tumor microenvironment and efficacy outcomes with durvalumab, 
tremelimumab and EP. 
2.
The relationship between a patient’s tumor mutational burden and/or presence of 
somatic mutations/genomic alterations and efficacy outcomes with durvalumab, 
tremelimumab and EP.
3.
The impact, if any, of the level of DLL3 expression on efficacy outcomes with 
durvalumab, tremelimumab and EP (once a validated assay becomes available).
Other markers that may be assessed, subject to availability of tissue, include CD8 and 
CD4/FoxP3 protein expression in an effort to enumerate cytotoxic versus regulatory T cells.  
Based on availability of tissue, a panel of additional, immune-relevant markers expressed on 
TILs or on tumor cells may be assessed.  Markers of special interest include, but are not 
limited to Ox40, GITR, PD-L2, Tim-3, CD137 and Lag 3.
Other tissue-based approaches may be pursued including RT-QPCR and in situ hybridization 
(eg, for detection of IFN-γ signaling genes such as CXCL9, CXCL10, IFN-γ itself, and DLL3), 
and/or somatic mutation detection methodologies.
Management of biomarker data
The biomarker data will have unknown clinical significance.  AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study investigator, general physician, or any other third party, unless 
required to do so by law.  The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
Summaries and analyses for exploratory biomarkers may be documented in a separate analysis 
plan and be reported outside the CSR in a separate report. The results of this biomarker 
research may be pooled with biomarker data from other studies involving durvalumab or 
tremelimumab to generate hypotheses to be tested in future research.
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. 

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5.5.2
Labeling and shipment of biological samples
The Principal Investigator ensures that samples are labeled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix B (IATA 6.2 Guidance Document). 
Any samples identified as Infectious Category A materials are not shipped, and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labeling, shipment, and containment provisions are approved.
5.5.3
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of shipments.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of 
external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered with the AstraZeneca Biobank Team during the entire life cycle.
5.5.4
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed or destroyed and the action is documented.  If samples have already been analyzed,
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will perform the following:
!
ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples
!
ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed, or destroyed and the action is documented

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!
ensure that the organisation(s) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed or destroyed, the action 
is documented, and the signed document is returned to the study site
!
ensure that the patient and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product.  An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver), or the abnormal results of an investigation (eg, 
laboratory findings, ECG).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both SAEs and non-serious AEs.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
!
results in death
!
is immediately life-threatening
!
requires in-patient hospitalization or prolongation of existing hospitalization 
!
results in persistent or significant disability/incapacity 
!
is a congenital abnormality or birth defect
!
is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above

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Adverse Events (AEs) for malignant tumours reported during a study should 
generally be assessed as Serious AEs. If no other seriousness criteria apply, the
‘Important Medical Event’ criterion should be used. In certain situations, however, 
medical judgement on an individual event basis should be applied to clarify that the 
malignant tumour event should be assessed and reported as a Non-Serious AE. For 
example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfill the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumor as an AE is 
valid and should occur. Also, some types of malignant tumours, which do not 
spread remotely after a routine treatment that does not require hospitalization, may 
be assessed as Non-Serious; examples include Stage 1 basal cell carcinoma and 
Stage 1A1 cervical cancer removed via cone biopsy. Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (e.g., Richter's 
transformation of B cell chronic lymphocytic leukemia into diffuse large B cell
lymphoma) should not be considered a new malignant tumour 
For further guidance on the definition of an SAE, see Appendix A.
All SAEs (ie, those occurring after the AE and SAE collection period) considered to be 
reasonably related to the study treatments or to the research must be notified to the sponsor 
with no time limit.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs and SAEs will be collected from the time of the patient signing the informed consent 
form  until the follow-up period is completed (90 days after the last dose of durvalumab ± 
tremelimumab or EP).  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.
6.3.2
Follow-up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued study drug, or the 
study has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.

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6.3.3
Variables 
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Maximum CTCAE grade reported 
!
Changes in CTCAE grade
!
Whether the AE is serious or not
!
Investigator causality rating against the IPs (yes or no)
!
Action taken with regard to IPs
!
Administration of treatment for the AE
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
Seriousness of criteria fulfilled
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Whether an autopsy was performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication, as explained in Section 6.3.4
!
Description of SAE
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 

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the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.  A copy of the CTCAE version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between SAEs and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but it is not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The investigator will assess the causal relationship between the IPs and each AE and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medications and study 
procedures.  Note that, for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes.”
A guide to the interpretation of the causality question is found in Appendix A.
6.3.5
Relationship to protocol procedures
The investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment-emergent 
(ie, SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (eg, blood collection).  The following guidelines should be used by investigators to 
assess the relationship of SAEs to the protocol:
!
Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record.
!
Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study patient’s medical record.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you 
were last asked?” or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to record a list 
of signs and symptoms.  However, if a diagnosis is known and there are other signs or 

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symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR.  Deterioration as compared with baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.  Whenever possible, the reporting 
investigator should use the clinical term rather than the laboratory term (eg, anemia versus low 
hemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs.  Please refer to Appendix D for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE.  Events that are unequivocally due to disease 
progression should not be reported as an AE during the study.
6.3.10
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.

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6.3.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:
!
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF in the Statement of Death page.  It should not be reported as an SAE.
!
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study Monitor/Physician as 
an SAE within 24 hours.  It should also be documented in the Statement of Death 
page in the eCRF.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death.
!
Deaths with an unknown cause should always be reported as an SAE.  It should also 
be documented in the Statement of Death page in the eCRF. A post-mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
post-mortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes.
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page.  If the death 
occurred as a result of an event that started after the defined safety follow-up period and the 
event is considered to be due to a late onset toxicity to study drug, then it should also be 
reported as an SAE.
6.3.12
Safety Data To Be Collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database lock, it 
is recommended that the patients continue the scheduled site visits according to Table 12 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 Toxicity 
Management Guidelines. All data post the final DCO and database lock will be recorded in 
the patient notes only and not reported for the purposes of this study, with the exception of 
data collected in CRFs as per Table 12. 
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 lock must 
be reported as detailed in Section 6.4.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.

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If any SAE occurs during the course of the study, then the investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs in which important or relevant information is missing, active 
follow-up is undertaken immediately.  The investigator or other site personnel will inform
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately, but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigator or other site personnel indicates that an AE is serious in the WBDC 
system, an automated e-mail alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site personnel will 
report the SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator or study site personnel how to 
proceed.
The reference documents for the definition of expectedness or listedness are the IBs for 
durvalumab and tremelimumab.
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such.
6.5
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and rapid communication by the 
Investigator to the Sponsor.  An AESI may be serious or non-serious.  The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this IP.
AESIs for durvalumab ± tremelimumab include, but are not limited to, events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy.  These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy.  An immune-mediated adverse event 
(imAE) is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology.  
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 

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support an imAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE. 
If the investigator has any questions in regards to an AE being an imAE, the investigator 
should promptly contact the Study Physician.
AESIs/imAEs observed with durvalumab ± tremelimumab include the following:
!
Diarrhea/Colitis and intestinal perforation
!
Pneumonitis
!
Hepatitis
!
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus)
!
Rash/Dermatitis
!
Nephritis/Blood creatinine increases
!
Pancreatitis 
!
Myocarditis
!
Myositis/Polymyositis
!
Rare/less frequent imAEs including neuromuscular toxicities (eg, Guillain-Barré, 
and myasthenia gravis)
!
Other inflammatory responses that are rare/less frequent with a potential immune-
mediated etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, hematological ,rheumatological events, 
vasculitis, non-infections meningitis and non-infectious encephalitis. It is possible 
that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs.
!
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions 
with a different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab IBs. More specific guidelines for their 
evaluation and treatment are described in detail in the Toxicity Management Guidelines (see 
Section 6.9). 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 

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apply to AEs considered causally related to the study drug/study regimen by the reporting 
Investigator.
6.6
Overdose
6.6.1
Durvalumab or tremelimumab
Use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is 
considered to be an overdose.  There is currently no specific treatment in the event of 
overdose of durvalumab or tremelimumab, and possible symptoms of overdose are not 
established. 
!
An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the eCRF and in the Overdose eCRF 
module.
!
An overdose without associated symptoms will only be reported in the Overdose 
eCRF module.
If an overdose of an AstraZeneca IP occurs during the course of the study, then the 
investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply (see 
Section 6.4).  For other overdoses, reporting must occur within 30 days.
6.6.2
Standard of Care
For patients randomized to the SoC (Arm3) group please refer to the local prescribing 
information for treatment of cases of overdose. If any overdose is associated with an AE or 
SAE please record the AE/SAE diagnosis or symptoms in the relevant AE modules only of the 
eCRF.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
! Pregnancy discovered before the study patient has received any study drugs.
6.7.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, 
ie, immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.7.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab + EP combination therapy, 
90 days after the last dose of durvalumab + EP, or 90 days after receipt of the final dose of 
durvalumab maintenance therapy, whichever is the longer time period.
Please follow the local prescribing information relating to contraception and the time limit for 
such precautions for EP agents.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 180 days after the 
last dose of durvalumab + tremelimumab combination therapy, 90 days after the last dose of 
durvalumab + EP or 90 days after the last dose of durvalumab monotherapy, whichever is the 
longer time period, should, if possible, be followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the patient’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.
6.8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient. 

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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error: 
!
occurred
!
was identified and intercepted before the patient received the drug
!
did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually 
given to the patient
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as 
a solid tablet 
!
Drug not stored as instructed eg, kept in the fridge when it should be at room 
temperature 
!
Wrong patient received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one 
of the above listed events that would otherwise have been a medication error 
!
Patient accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Patient failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  

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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, ie, 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 (see Section 6.4) and within 30 days for all other medication errors.
6.9
Management of IP-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.
!
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, 
disease progression, concomitant medications, and infections). This includes EP 
induced toxicity. In the event that toxicities are clearly attributed to chemotherapy, 
both EP and durvalumab ± tremelimumab should be delayed. 
!
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related and the Toxicity Management Guidelines  should be 
followed. 
!
In the event that durvalumab ± tremelimumab is discontinued or delayed as part of 
the toxicity management guidance EP should still be administered as scheduled; 
every effort should be made to ensure patients receive at least 4 cycles of EP across 
all arms in the study, if conditions allow.
If unsure how to manage a patient please contact the study physician at AstraZeneca to discuss 
individual cases. All toxicities will be graded according to NCI CTCAE, Version 4.03.  
6.9.1
Durvalumab and durvalumab + tremelimumab
Comprehensive Toxicity Management Guidelines  have been developed to assist investigators 
with the recognition and management of toxicities associated with the use of the immune-
checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) and tremelimumab (CTLA-4 
inhibitor).  Given the similar underlying mechanisms of toxicities observed with these two 
compounds, these guidelines are applicable to the management of patients receiving either 

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drug as monotherapy or in combination.  Additionally, these guidelines are applicable when 
either drug is used alone or in combination and is administered concurrently or sequentially 
with other anti-cancer drugs (i.e. antineoplastic chemotherapy, targeted agents), as part of a 
protocol specific treatment regimen.  The Toxicity Management Guidelines provide 
information for the management of immune-mediated reactions, infusion-related reactions, 
and non-immune mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or combination checkpoint inhibitor regimens, with specific instructions for dose 
modifications (including discontinuations) and treatment interventions.  Investigators are 
advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other cancer treatment. The most current version of 
the Toxicity Management Guidelines is provided to investigative site as an Annex document 
and is maintained within the Site Master File.  In addition, a version of the current TMGs is 
available through the following link: https://tmg.azirae.com. Please contact the clinical study 
associate for information on how to gain access to this website. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related. 
In addition, there are certain circumstances in which durvalumab and tremelimumab should be 
permanently discontinued (see Section 3.9 of this protocol and Toxicity Management 
Guidelines).  
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab 
can be modified based on toxicities observed as described in the 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 durvalumab monotherapy and the durvalumab + 
tremelimumab regimen by the reporting investigator.
Dose reductions are not permitted.  In case of doubt, the investigator should consult with 
the Study Physician.
The current Toxicity Management Guidelines is maintained within the Site Master File. 
Please contact your clinical trial associate for information on how to gain access to this 
website.
6.9.2
Standard-of-care agents
Chemotherapies are associated with a number of unwanted effects. EP-related toxicity 
management, dose adjustment, including dose delays and reductions should be performed as 
indicated in the local prescribing information for the relevant agent. In the event of 
unfavorable tolerability, patients can switch between cisplatin and carboplatin therapy at any 
point on study (assuming eligibility for the switched therapy is met).

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EP is the SoC and is expected to cause hematologic non-immune-related AEs for which the 
non-immune-related Toxicity Management Guidelines should not be applied.  Sites should 
utilize dose delays, dose modifications, G-CSF or component transfusions (eg, platelet 
transfusions) as necessary per local standards to maintain the dose and schedule of EP 
treatment to optimize tolerability for individual patients.  Communication with the Sponsor for 
questions is welcomed.
In the event that an AE can reasonably be attributed to EP, dose adjustment of EP should be 
attempted before modifying the administration of durvalumab ± tremelimumab.
In the event that EP is delayed, durvalumab ± tremelimumab should also be delayed and to be 
resumed as soon as feasible. Every effort should be made to ensure patients receive at least 
4 cycles of EP across all arms in the study, if conditions allow.
6.10
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
investigators.
6.10.1
Safety Confirmation
An IDMC comprised of independent experts will be convened to confirm the safety and 
tolerability of the proposed dose and schedule of durvalumab ± tremelimumab in combination 
with platinum based chemotherapy at two early stages of enrolment. A step wise approach 
will be adopted. The initial safety review will take place when the first 30 patients (10 in each 
arm) have completed the 1st cycle of treatment and had 21 days of follow up. A second 
review will take place when an additional 30 patients (10 in each arm) who have completed 
the 1st cycle of treatment and have had 21 days of follow up. At the time of the 2nd review, it 
is expected that the initial 30 patients would have had at least 6 weeks of follow up, with some 
patients receiving much longer. These two reviews will be carried out by the IDMC in an 
unblinded manner. After review, the IDMC will make a recommendation on whether the study 
should continue recruitment as planned, or hold recruitment. The IDMC recommendation will 
be communicated to all sites when available.
In addition, the IDMC will meet approximately every 6 months thereafter to continue safety 
monitoring.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.

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7.
INVESTIGATIONAL PRODUCT AND OTHER 
TREATMENTS
7.1
Identity of investigational products
AstraZeneca will supply durvalumab (MEDI4736) and tremelimumab, whereas the EP 
treatments will be supplied locally (Table 7).
Table 7
List of investigational products for this study
Investigational product
Dosage form and strength
Durvalumab (MEDI4736)
50 mg/mL, solution for infusion 
after dilution, IV
Tremelimumab
20 mg/mL, solution for infusion 
after dilution, IV
Etoposide and platinum-based chemotherapy
Etoposidea
IV (as sourced locally)
Carboplatina
IV (as sourced locally)
Cisplatina
IV (as sourced locally)
a
Under certain circumstances when local sourcing is not feasible, an etoposide and platinum-based 
chemotherapy treatment may be supplied centrally through AstraZeneca.
IV  Intravenous.
7.1.1
Order of Administration
Arm 1: 
Patients will receive 1 dose of tremelimumab (75mg) via IV infusion over 60 minutes, which 
will be followed by durvalumab (1500 mg) via IV infusion over 60 minutes. 
We recommend a 60-minute observation period after each immunotherapy agent is 
administered at least for cycle 1.  
If no issues are seen after tremelimumab is given during the first cycle, then at the 
investigator’s discretion durvalumab can be given immediately after tremelimumab in 
subsequent cycles. 
If no issues are seen after durvalumab is given during the first cycle, we recommend reducing 
the observation period after durvalumab administration to 30 minutes.
This will then be followed by carboplatin or cisplatin as an IV infusion over 60 minutes, 
followed by etoposide sequentially administered by a 60-minute IV infusion on Days 1, 2, and 
3 of each cycle.

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Arm 2: 
Patients will receive durvalumab (1500 mg) via IV infusion over 60 minutes.
We recommend a 60-minute observation period after durvalumab is administered at least for 
cycle 1.  
If no issues are seen after durvalumab is given during the first cycle, we recommend reducing 
the observation period after durvalumab administration to 30 minutes.
This will then be followed by carboplatin or cisplatin as an IV infusion over 60 minutes, 
followed by etoposide sequentially administered by a 60-minute IV infusion on Days 1, 2, and 
3 of each cycle.
Arm 3:
Patients will receive carboplatin or cisplatin as an IV infusion over 60 minutes, followed by 
etoposide sequentially administered by a 60-minute IV infusion on Days 1, 2, and 3 of each 
cycle.
7.1.2
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0.  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 (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) 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 (MEDI4736) vial to the start of administration should not exceed:
!
24 hours at 2°C to 8°C (36°F to 46°F)
!
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm  filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of 
durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.

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If weight falls to ≤ 30 kg weight-based dosing at 20 mg/kg will be a administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm  filter
Standard infusion time 1 hour.  In the event that 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 (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded. 
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.3
Tremelimumab 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial concentrate 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 container until use to prevent excessive 
light exposure.
Preparation of tremelimumab doses 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 the start of administration should not exceed: 
!
24 hours at 2°C to 8°C (36°F to 46°F)
!
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 75 mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration 
ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm filter. Add 3.8 mL (ie, 75 mg of tremelimumab, with the dose volume rounded to the 

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nearest tenth mL) 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. 
If weight falls to ≤ 30 kg, weight-based dosing at 1 mg/kg will be a administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab 
concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter.
Standard infusion time is 60 minutes (± 5 minutes). In the event that 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.  
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.4
Standard of Care: EP
EP will either be locally sourced or centrally supplied by AstraZeneca and will be 
administered according to prescribing information or treatment guidance in general use by the 
Investigating site, including the sequence of drug administration. Under certain circumstances 
when local sourcing is not feasible, AstraZeneca will centrally supply the drug, and will be 
labeled with local language translated text in accordance with regulatory guidelines.
7.2
Dose and treatment regimens
Patients will be randomized in a 1:1:1 ratio to receive treatment with 
durvalumab + tremelimumab + EP combination therapy, durvalumab (MEDI4736) + EP, or 
EP.
7.2.1
Treatment regimens
Durvalumab (MEDI4736) + tremelimumab combination therapy + standard-of-care 
therapy (Arm 1)
During Chemotherapy:

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Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 mins
4 doses Q3W 
Weeks 0, 3, 6 and 9
Tremelimumab
75 mg 
IV
60 mins
4 doses Q3W 
Weeks 0, 3, 6 and 9
EP
Etoposide [80-
100 mg/m2] with either 
carboplatin [area under 
the curve 5-6] or 
cisplatin [75-80 mg/m2]
IV
120 mins
4 doses Q3W 
Weeks 0, 3, 6 and 9
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing – equivalent to 20 mg/kg 
of durvalumab and 1mg/kg of tremelimumab Q3W until the weight improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab at 1500mg and tremelimumab at 75mg. 
EP  Etoposide and platinum-based chemotherapy; IV  Intravenous; Q3W  Every 3 weeks.
Post-Chemotherapy:
Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 mins
Q4W 
Week 12 to PD*
Tremelimumab
75 mg 
IV
60 mins
1 dose at Week 16**
*
Patients are treated until PD unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met
**
In the case of dose delay(s) more than one durvalumab + tremelimumab combination dose can be given 
post chemotherapy to ensure that up to 5 combination doses are administered in Arm 1
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing – equivalent to 20 mg/kg 
of durvalumab and 1mg/kg of tremelimumab q4w until the weight improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab at 1500mg and tremelimumab at 75mg. 
IV  Intravenous; Q4W  Every 4 weeks.
Durvalumab (MEDI4736) + EP therapy (Arm 2)
During Chemotherapy
Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 mins
4 doses Q3W 
Weeks 0, 3, 6 and 9
EP
Etoposide [80-100 mg/m2] 
with either carboplatin [area 
under the curve 5-6] or 
cisplatin [75-80 mg/m2]
IV
120 mins
4 doses Q3W 
Weeks 0, 3, 6 and 9

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Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing equivalent to 20 mg/kg 
of durvalumab Q3W until the weight improves to >30 kg, at which point the patient should start receiving 
the fixed dosing of durvalumab 1500mg. 
EP  Etoposide and platinum-based chemotherapy; IV  Intravenous; Q3W Every 3 weeks.
Post-Chemotherapy:
Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 mins
Q4W 
Week 12 to PD*
*
Patients are treated until PD unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing equivalent to 20 mg/kg 
of durvalumab Q4W until the weight improves to >30 kg, at which point the patient should start receiving 
the fixed dosing of durvalumab 1500mg. 
IV  Intravenous; PD  Progressive disease; Q4W  Every 4 weeks.
EP therapy (Arm 3)
Agent
Dose
Route
Duration
Schedule
EP
Etoposide [80-100 mg/m2] 
with either carboplatin [area 
under the curve 5-6] or 
cisplatin [75-80 mg/m2]
IV
120 mins
4 dosesa Q3W 
Weeks 0, 3, 6 and 9 
a
An additional 2 doses of EP (Weeks 12 and 15) can be given at the investigators’ discretion if clinically 
indicated.
Prophylactic cranial irradiation (PCI) is permitted for patients in Arm 3 at the investigators’ discretion if 
clinically indicated.
Patients who receive extra cycles of EP and PCI will still be expected to follow the planned scan schedule visits 
as detailed in Table 2 and Table 3. 
EP  Etoposide and platinum-based chemotherapy; IV  Intravenous; Q3W  Every 3 weeks.
The full dosing schema is provided below in Figure 5.

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Figure 5
Dosing Scheme
Treatment arms
During Chemotherapy
Q3W
Post Chemotherapy
Q4W
Cycle 1
Week 0
Cycle 2
Week 3
Cycle 3
Week 6
Cycle 4
Week 9
Week 12
Week 16
Week
20 to PD
Arm 1
EP +
Durva + Treme
EP +
Durva + Treme
EP +
Durva + Treme
EP +
Durva + Treme
Durva
Durva + 
Treme*
Durva
Arm 2
EP +
Durva
EP +
Durva
EP +
Durva
EP +
Durva
Durva
Durva
Durva
Arm 3
EP
EP
EP
EP**
*
In the case of dose delay(s) more than one durvalumab + tremelimumab combination dose can be given post chemotherapy to ensure that up to 5 
combination doses are administered in Arm 1
**
In Arm 3, EP can be given for an additional 2 cycles Q3W on Weeks 12 and 15 (ie, total 6 cycles post-randomization) if clinically indicated, at the 
investigators’ discretion before patients enter Follow-up.  PCI can also be given at investigators discretion.  This does not alter the planned scan schedule 
Q8W starting at Week 12 for patients in Arm 3.
Durvalumab dose will be 1500 mg during chemotherapy and 1500 mg post-chemotherapy; tremelimumab dose will be 75 mg. 
Note: Patients whose weight falls to 30 kg or below must receive weight-based dosing – equivalent to 20 mg/kg of durvalumab and 1mg/kg of tremelimumab 
until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab at 1500mg and tremelimumab at 
75mg. 
EP  Etoposide and platinum-based chemotherapy; Durva  Durvalumab; Treme  Tremelimumab. 

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7.2.2
Duration of treatment and criteria for treatment through progression
Treatment with chemotherapy (EP) in Arms 1 and 2 will be limited to 4 cycles on a Q3W 
schedule subsequent to randomization.  Patients in Arm 3 may receive an additional 2 cycles 
of EP (so 6 in total post-randomization), as clinically indicated, at the investigators’ 
discretion.
Immunotherapy treatment, durvalumab ± tremelimumab, will be administered beginning on 
Day 1 (note: a window of up to 2 days is permitted between randomization and first dose of 
IP) until confirmed PD unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.
Patients in all arms with PD by RECIST 1.1 (unconfirmed and confirmed) who, in the 
Investigator’s opinion, continue to receive benefit from their assigned treatment and who meet 
the criteria for treatment in the setting of PD may continue to receive their assigned treatment 
for as long as they are gaining clinical benefit. This also applies to EP; however, EP is 
restricted to a maximum of 4 cycles for patients in Arms 1 and 2 and a maximum of 6 cycles 
for patients in Arm 3.
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) will not be eligible for continuing durvalumab ± 
tremelimumab. 
For all patients who are treated through progression, the investigator should ensure patients do 
not have any significant, unacceptable or irreversible toxicities that indicate continuing 
treatment would not further benefit the patient. 
Patients who AstraZeneca and the investigator determine may not continue treatment after PD 
will be followed up for survival.  Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until confirmed disease progression and for survival.
Following confirmed disease progression, standard chemotherapy can be offered by the 
investigator.
For patients randomized to Arm 3, crossover to durvalumab + tremelimumab or durvalumab 
monotherapy following confirmed disease progression will not be permitted.
Post final data cut-off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database lock 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 lock, it is recommended that the patients 
continue the scheduled site visits according to Table 12 and investigators monitor the patient’s 
safety laboratory results prior to and periodically during treatment with durvalumab in order to 

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manage AEs in accordance with the durvalumab toxicity management guidelines (please see 
Section 6.9.1).
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database lock, patients currently receiving treatment with durvalumab 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 form.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labeling.  Label 
text will be translated into local language.  Label text prepared for durvalumab (MEDI4736) 
will show the product name as ‘MEDI4736’ or ‘durvalumab (MEDI4736)’ or ‘durvalumab’ 
depending upon the agreed product name used in the approved study master label document.  
All naming conventions are correct during this transitional period.
Labels will be provided as either a single panel label or as multi-language booklet labels.
7.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements.  A temperature log will be used to record the temperature 
of the storage area.  Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection.  A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage 
facility.  Storage conditions stated in the IB may be superseded by the label storage.
The IP label on the pack/bottle/carton for etoposide/carboplatin/cisplatin specifies the 
appropriate storage for these agents.  
7.5
Compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.  The 
study personnel will account for all study drugs.
Drug accountability should be performed until the patient stops study treatment completely.  
Study site personnel will account for all study drugs received at the site, for all unused study 

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drugs, and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and 
return should be signed.
7.7
Concomitant medications and other treatments 
The investigator must be informed as soon as possible about any medication taken from the 
time of Screening until the end of the clinical treatment phase of the study (final study visit), 
including the Follow-up period following the last dose of study drug.  Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF.
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Restricted, prohibited, and permitted concomitant medications are described in Toxicity 
Management Guidelines.
For chemotherapy agents, please refer to the local prescribing information with regards to 
warnings, precautions, and contraindications.
Table 8
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
For all treatment arms
Any investigational anticancer therapy other than 
those under investigation in this study
Should not be given concomitantly whilst the 
patient is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Should not be given concomitantly whilst the 
patient is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy 
for cancer treatment other than those under 
investigation in this study
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent use of 
hormones for non-cancer-related conditions 
[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])
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP

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Prohibited medication/class of drug:
Usage:
For the durvalumab ± tremelimumab treatment arms only
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:
!
Use of immunosuppressive medications 
for the management of IP-related AEs. 
!
Short-term premedication for patients 
receiving combination agents EP where 
the prescribing information for the agent 
requires the use of steroids for 
documented hypersensitivity reactions.
!
Use in patients with contrast allergies.
!
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy 
related events experienced by the patient (eg, 
chronic obstructive pulmonary disease, radiation, 
nausea, etc).
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 90 days 
after the last dose of tremelimumab during the 
study
Sunitinib
Should not be given concomitantly or through 90 
days after the last dose of tremelimumab (acute 
renal failure has been reported with combination 
therapy of tremelimumab and sunitinib)
EGFR TKIs 
Should not be given concomitantly. 
Should be used with caution in the 90 days post 
last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence 
of transaminase increases (with 1st generation 
EGFR TKIs) has been reported when durvalumab 
has been given concomitantly.
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concurrently unless agreed by 
the sponsor
AE  Adverse event; CTLA-4  Cytotoxic T-lymphocyte-associated antigen 4; EGFR  Epidermal growth factor 
receptor; EP  Etoposide and platinum-based chemotherapy; IP Investigational product; PD-1  Programmed 
cell death 1; PD-L1  Programmed cell death ligand 1; SoC  Standard of care; TKI  Tyrosine kinase 
inhibitor.

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Table 9
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the 
investigator
Best supportive care (including antibiotics, G-
CSF and other hematopoietic factors, nutritional 
support, correction of metabolic disorders, 
optimal symptom control, and pain management 
[including palliative radiotherapy to non-target 
lesions, etc])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
Herbal and natural remedies
Should be avoided during the study (with the 
exception of homeopathic remedies, which may 
be used following discussion with AstraZeneca)
7.7.1
Other concomitant treatment
Medications other than those described in Section 7.7 that are considered necessary for the 
patient’s safety and well-being may be given at the discretion of the investigator and should be 
recorded in the appropriate sections of the eCRF.
7.7.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-
clinically or in patients.  As durvalumab is a monoclonal antibody and therefore a protein, it 
will be degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance.  It is therefore not expected that durvalumab will induce or 
inhibit the major drug metabolising cytochrome P450 pathways.  As a result, there are no 
expected pharmacokinetic drug-drug interactions.  The mechanism of action of durvalumab 
involves binding to PD-L1, and therefore significant pharmacodynamic drug interactions with 
the commonly administered concomitant medications are not expected.  Despite this, 
appropriate clinical monitoring in all of the planned clinical studies will be conducted to 
evaluate any potential drug-drug interactions.
7.8
Post-study access to study treatment
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab (MEDI4736) monotherapy up to confirmed progression (see 
Section 7.2.2).

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8.
STATISTICAL ANALYSES
8.1
Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 
3 months of the first randomized patient, and any subsequent amendments will be 
documented, with final amendments completed prior to reporting of the data.  The primary 
aim of the study is to compare the efficacy and safety of durvalumab + tremelimumab + EP 
with EP alone and the efficacy and safety of durvalumab + EP with EP alone.  
Sections 8.2 to 8.5 describe the statistical analyses that apply to the global cohort data.  For 
the China cohort, the same definitions of outcome measures (Section 8.4) and methods of 
statistical analyses (Section 8.5) will be applied unless specified otherwise in Section 8.6 or 
the supplementary China SAP.  The same OS treatment effect under the alternative hypothesis 
is assumed in the plan for the China cohort analyses.
8.2
Sample size estimate
The study will randomize approximately 795 eligible patients 1:1:1 to durvalumab + 
tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or EP (Arm 3).  The randomization 
will be stratified based on planned platinum-based therapy in cycle 1 (carboplatin or 
cisplatin).  Once global enrollment achieves 795 randomized patients, recruitment will 
continue in China only.  A total of up to 189 patients from China will be randomized into the 
study (see Section 8.6 for details).
The primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + 
EP treatment compared with EP (Arm 1 vs. 3) and the efficacy of durvalumab + EP treatment 
compared with EP (Arm 2 vs. 3) in terms of OS. To control for type 1 error, a significance 
level of 1% will be used for the analysis of Arm 1 vs. 3, and a significance level of 4% will be 
used for the analysis of Arm 2 vs. 3. The study will be considered positive (a success) if either 
of the OS analysis results are statistically significant. The sizing assumes a 3-month delay in 
separation of the OS and PFS curves between arm 1 vs. arm 3 and between arm 2 vs. arm 3, 
hence the use of average HRs.
There will be 2 data cut-off timepoints in the study. The interim analysis of OS will occur 
when approximately 318 OS events have occurred (60% maturity) in the durvalumab + 
tremelimumab + EP and EP treatment arms and approximately 318 OS events have occurred 
(60% maturity) in the durvalumab + EP and EP treatment arms. With a 15 month recruitment 
period in the global cohort and a minimum follow-up period of approximately 13 months, it is 
anticipated that this analysis will be performed approximately 28 months after the first patient 
is randomized). 
The data cut-off for the primary analysis of OS will occur when approximately 425 OS events 
have occurred across the durvalumab + tremelimumab + EP and EP treatment arms 
(80%maturity) and approximately 425 OS events have occurred across the durvalumab + EP 

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and EP treatment arms (80% maturity). If the average true OS HR is 0.69, the study will have 
89% power to demonstrate a statistically significant difference at the final analysis with a 2-
sided 0.93% significance level (for an overall alpha of 1%) for the comparison of durvalumab 
+ tremelimumab + EP versus EP (Arm 1 vs 3), and 96% power to demonstrate a statistically 
significant difference at a 2-sided 3.57% significance level (for an overall alpha of 4%) for the 
comparison of durvalumab + EP versus EP (Arm 2 vs 3); this translates to a 4.8-month benefit 
in median OS over EP (15.7 months vs 10.9 months).The smallest treatment difference that 
would be statistically significant is an average HR of 0.78 for durvalumab + tremelimumab + 
EP versus EP and 0.82 for durvalumab + EP versus EP. With a 15-month recruitment period 
and a minimum follow-up period of 27 months assumed, it is anticipated that this analysis will 
be performed 42 months after the first patient has been randomized.
A key secondary objective is to assess the efficacy of durvalumab + tremelimumab + EP 
treatment compared with EP (Arm 1 vs. 3) and the efficacy of durvalumab + EP treatment 
compared with EP (Arm 2 vs. 3) in terms of PFS. These analyses of PFS will be included in 
the MTP, as described in Section 8.5. If the average true PFS HR is 0.71, the study will have 
90% power to demonstrate a statistically significant difference at the 5% level (using a 2-sided 
test) for the PFS comparisons when approximately 360 PFS events have been observed in the 
two treatment arms to be compared.
The secondary objective comparisons of durvalumab + tremelimumab + EP vs. durvalumab + 
EP for OS and PFS are not included in the MTP.  
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 10.
Table 10
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
OS, PFS
Full analysis set (ITT population)
APF6, APF12, ORR, OS18, PROs, and 
symptom endpoints
Full analysis set (ITT population)
Demography
Full analysis set (ITT population)
PK data
PK analysis Set
Safety data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
ECGs
Safety analysis set

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AE  Adverse event; APF12  Proportion of patients alive and progression free at 12 months from randomization 
(ie, PFS at 12 months); APF6  Proportion of patients alive and progression free at 6 months from randomization 
(ie, PFS at 6 months); ECG  Electrocardiogram; ITT  Intent-to-treat population; ORR Objective response rate; 
OS  Overall survival; OS18  Overall survival at 18 months after randomization; PFS  Progression-free survival; 
PK  Pharmacokinetic(s); PRO  Patient-reported outcome.
8.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients.  The FAS will be used for all 
efficacy analyses (including PROs).  Treatment arms will be compared on the basis of 
randomized study treatment, regardless of the treatment actually received.  Patients who were 
randomized but did not subsequently go on to receive study treatment will be included in the 
analysis in the treatment arm to which they were randomized.
8.3.2
Safety analysis set
The safety analysis set will consist of all patients who received at least 1 dose of study 
treatment.  Safety data will not be formally analyzed but summarized using the safety analysis 
set, according to treatment received, that is, erroneously treated patients (eg, those randomized 
to treatment A but actually given treatment B) will be summarized according to the treatment 
they actually received.
8.3.3
PK analysis set
All patients who received at least 1 dose of IP per the protocol for whom any postdose data 
are available will be included in the PK analysis set.  The population will be defined by the 
Study Physician, Pharmacokineticist, and Statistician prior to any analyses being performed.  
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
8.4.1.1
RECIST 1.1-based endpoints
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 overall visit response 
of CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline 
and previous assessments.  Baseline will be assessed within the 21 days prior to randomization 
(unless the diagnostic scan is used as baseline, in which case this can be within 28 days prior 
to randomization – see Appendix E). If a patient has had a tumor assessment that cannot be 
evaluated, then the patient will be assigned a visit response of NE (unless there is evidence of 
progression, in which case the response will be assigned as PD).
Please refer to Appendix E for the definitions of CR, PR, SD, PD, and NE.

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8.4.1.2
Primary endpoints
The primary endpoints of this study are OS (Arm 1 vs. 3) and OS (Arm 2 vs. 3).
Overall survival
OS is defined as the time from the date of randomization until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note: Survival calls will be made in the week following the date of data cut-off for the 
analysis; if patients are confirmed to be alive or if the death date is after the data cut-off date, 
these patients will be censored at the date of data cut-off.  Death dates may be found by 
checking publicly available death registries.
8.4.1.3
Secondary endpoints
Progression-free survival
PFS (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of randomization until the date of objective disease progression or death (by any cause in 
the absence of progression), regardless of whether the patient withdraws from randomized 
therapy or receives another anticancer therapy prior to progression.  Patients who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable RECIST 1.1 assessment.  However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of the 
latest evaluable RECIST 1.1 assessment.  If the patient has no evaluable visits or does not 
have baseline data, he or she will be censored at Day 1 unless the patient dies within 2 visits 
of Baseline.  
The PFS time will always be derived based on scan/assessment dates, not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:
-
The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression.
-
For investigational assessments, the date of progression will be determined based on 
the earliest RECIST 1.1 assessment/scan dates of the component that indicates 
progression.
-
When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
Note: For target lesions, only the latest scan date is recorded in the RECIST 1.1 eCRF out of 
all scans performed at that assessment for the target lesions, and similarly for non-target 

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lesions, only the latest scan date is recorded out of all scans performed at that assessment for 
the non-target lesions.
In the absence of significant clinical deterioration, the investigational site is advised to 
continue the patient on their randomized durvalumab + tremelimumab + EP or durvalumab 
+ EP treatment until progression has been confirmed.  If progression is not confirmed, the 
patient should continue their randomized durvalumab + tremelimumab + EP or durvalumab 
+ EP treatment and on-treatment assessments.  Treatment through PD in the EP arm is at the 
investigator’s discretion; however, a follow up scan is required for all patients in the EP arm, 
even if a subsequent treatment is started.
Objective response rate
ORR (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR. The denominator is a subset of the ITT 
population who has measurable disease at Baseline. Data obtained up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR. Patients who go off treatment without progression, receive a subsequent therapy, and 
then respond will not be included as responders in the ORR.
Proportion of patients alive and progression free at 6 and 12 months
The APF6 and APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 
as assessed using site Investigator assessments) at 6 and 12 months, respectively.
Proportion of patients alive at 18 months
The OS18 will be defined as the Kaplan-Meier estimate of OS at 18 months.
8.4.1.4
Exploratory endpoints
Time from randomization to second progression (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death.  The date of second 
progression will be recorded by the Investigator in the eCRF and defined according to local 
standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death.  The site will be asked whether the patient has 
had a second progression event on a regular basis (see Table 3) following the first progression 
event used for the primary variable PFS (the first progression) and the status recorded.  
Patients alive and for whom a second disease progression has not been observed will be 
censored at the last time known to be alive and without a second disease progression, that is, 
censored at the latest of the PFS or PFS2 assessment date if the patient has not had a second 
progression or death.

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Version 6.0
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8.4.2
Calculation or derivation of safety variables
8.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure.  These will be collected for all patients.  Data from all 
cycles of treatment will be combined in the presentation of safety data.  
“On treatment” will be defined as assessments between date of start dose and 90 days 
following discontinuation of IP (90 days after the last dose of durvalumab + tremelimumab 
combination therapy or durvalumab monotherapy or EP). For AEs, on treatment (or treatment-
emergent AEs) will be defined as any AEs that started after dosing or prior to dosing and 
which worsens following exposure to the treatment.
AEs observed up until 90 days following discontinuation of study treatment (ie, 90 days after 
the last dose of durvalumab, tremelimumab, or EP) or until the initiation of the first 
subsequent therapy following discontinuation of treatment (whichever occurs first) will be 
used for the reporting of AE summary tables.  This will more accurately depict AEs 
attributable to study treatment only because a number of AEs up to 90 days following 
discontinuation of study treatment are likely to be attributable to subsequent therapy.  
However, to assess the longer term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of study treatment (ie, 
without taking subsequent therapy into account).
Further details will be provided in the SAP.  Any events in this period that occur after a 
patient has received further therapy for cancer (following discontinuation of IP) will be 
flagged in the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of study 
treatment will be produced.  These events will not be included in AE summaries. 
8.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment.  
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT):
QTcF = QT/RR^ (1/3), where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] ×0.02)

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
125(186)
The denominator used in laboratory summaries will only include evaluable patients (ie, those 
who had sufficient data to have the possibility of an abnormality).  
For example:
-
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded.
-
If a CTCAE criterion does not consider changes from baseline, to be evaluable, the 
patient need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.3
Calculation or derivation of patient-reported outcome variables
PRO questionnaires will be assessed using the EORTC QLQ-C30 with the QLQ-LC13 
module (HRQoL and lung cancer-specific symptoms), PRO-CTCAE, PGIC, and EQ-5D-5L. 
All items/questionnaires will be scored according to published scoring guidelines or the 
developer’s guidelines if published guidelines are not available. All PRO analyses will be 
based on the FAS (intent-to-treat [ITT] population), unless stated. The PRO data will be 
assessed using mean/responder analyses based on published thresholds. Qualitative research 
with patients, clinicians and a review of the literature determine that the key symptoms and 
issues for patients are insomnia, appetite loss, dyspnea, hemoptysis, cough, chest pain, fatigue 
as well as physical functioning and global health status decline. These 7 symptoms have been 
identified as primary measures of interest. The physical functioning and overall health status 
domains of the EORTC QLQ-C30 are furthermore pre-specified endpoints of interest.
8.4.3.1
EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties), and a global measure of health status.  The EORTC QLQ-C30 will 
be scored according to the EORTC QLQ-C30 scoring manual (Fayers et al 2001).  An 
outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom 
scales/symptom items, each of the functional scales, and the global health status scale in the 
EORTC QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual.  Higher scores on the 
global health status and functioning scales indicate better health status/function, but higher 
scores on symptom scales/items represent greater symptom severity.
8.4.3.2
Lung cancer module (EORTC QLQ-LC13)
The QLQ-LC13 is a lung cancer-specific module from the EORTC for lung cancer comprising 
13 questions to assess lung cancer symptoms, treatment-related side effects, and pain 
medication.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
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8.4.3.3
Calculation or derivation of health state utility (EQ-5D-5L)
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  For each dimension, respondents will select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems, and extreme 
problems).  A unique EQ-5D health state is referred to by a 5-digit code allowing for a total of 
3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses).  
Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied 
(Oemar et al 2013, Janssen et al 2008a, Janssen et al 2008b).  In addition to the descriptive 
system, respondents also assess their health on the day of assessment on a visual analogue 
scale, ranging from 0 (worst imaginable health) to 100 (best imaginable health).  This score is 
reported separately.  
8.4.4
Calculation or derivation of pharmacokinetic variables
8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modeling 
approach.  The impact of physiologically relevant patient characteristics (covariates) and 
disease on PK will be evaluated.  The relationship between PK exposure and effect on safety 
and efficacy endpoints will be evaluated.  The results of such an analysis will be reported in a 
separate report.  The PK, pharmacodynamic, demographic, safety, and efficacy data collected 
in this study may also be combined with similar data from other studies and explored using 
population PK and/or PK-pharmacodynamic methods.
8.4.4.2
Pharmacokinetic non-compartmental analysis
PK concentration data and summary statistics will be tabulated by time point. Peak and trough 
concentrations will be determined as data allow. Samples below the lower limit of 
quantification will be treated as missing in the analyses.
8.4.4.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab and tremelimumab.  
The immunogenicity titer and the presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs.  The effect of immunogenicity on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
8.5
Methods for statistical analyses
The formal statistical analysis will be performed to test the main hypotheses for OS: 
!
H0: No difference between durvalumab + tremelimumab + EP and EP

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
127(186)
!
H1: Difference between durvalumab + tremelimumab + EP and EP
!
H0: No difference between durvalumab + EP and EP
!
H1: Difference between durvalumab + EP and EP
The 2 primary endpoints are OS (Arm 1 vs. 3) and OS (Arm 2 vs. 3).The study has been sized 
to characterize the OS benefit of durvalumab + tremelimumab + EP versus EP and the OS 
benefit of durvalumab + EP versus EP.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm. 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to randomization.
All data collected will be listed.  Efficacy and PRO data will be summarized and analyzed 
based on the FAS.  PK data will be summarized and analyzed based on the PK analysis set.  
Safety data will be summarized using the safety analysis set.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
The following table (Table 11) details which endpoints are to be subjected to formal statistical 
analysis, together with pre-planned sensitivity analyses, making it clear which analysis is 
regarded as primary for that endpoint.  Note: all endpoints compare durvalumab + 
tremelimumab + EP versus EP and durvalumab + EP versus EP  in all randomized patients 
(ITT population), unless otherwise indicated.
Table 11
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Overall survival
Primary analysis using a stratified log-rank test for 
-
durvalumab + tremelimumab + EP versus EP 
-
durvalumab + EP versus EP 
Secondary analysis using a stratified log-rank test for: 
-
durvalumab + tremelimumab + EP versus durvalumab + EP 
(ITT population)
Sensitivity analysis using a Kaplan-Meier plot of time to censoring 
where the censoring indicator of the primary analysis is reversed –
attrition bias

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Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank tests for:
Secondary analysis using site Investigator tumour data 
(RECIST 1.1) for: 
-
durvalumab + tremelimumab + EP versus EP (ITT 
population) 
-
durvalumab + EP versus EP (ITT population)
-
durvalumab + tremelimumab + EP versus durvalumab + EP 
(ITT population)
Sensitivity analyses using alternative censoring rules – attrition bias 
Objective response rate
Logistic regression using Investigator data (RECIST 1.1)
Proportion of patients alive and 
progression free at 6 and 
12 months
Kaplan-Meier estimates with 95% CI for progression-free survival at 
6 and 12 months
Proportion of patients alive at 
18 months 
Kaplan-Meier estimates with 95% CI for overall survival at 18 
months 
Change from baseline in QLQ-
C30 and QLQ-LC13 key 
symptom scores 
Average change from baseline using a Mixed Model Repeated
Measurements (MMRM) analysis
Time to symptom deterioration 
(EORTC QLQ-C30 v3 and 
LC13 endpoints)
Stratified log-rank test
EORTC  European Organisation for Research and Treatment of Cancer; EP  Etoposide and platinum-based 
chemotherapy; ITT  Intent-to-treat; QLQ-C30 v3  30-item Core Quality of Life Questionnaire, version 3; QLQ-
LC13  13-item Lung Cancer Quality of Life Questionnaire; RECIST 1.1  Response Evaluation Criteria in Solid 
Tumors, version 1.1.
All outputs will be summarized by treatment arm for all randomized patients (ITT).  
Multiple testing strategy
The multiple testing procedure (Figure 6) will define which significance levels should be 
applied to the interpretation of the raw p-values.
In order to strongly control the type I error at 5% 2-sided, a multiple testing procedure (MTP) 
with gatekeeping strategy will be used across the 2 primary endpoints of OS (Arm 1 vs. 3), OS 
(Arm 2 vs. 3) and the key secondary endpoint of PFS (Arm 1 vs. 3) and PFS (Arm 2 vs. 3). If 
the higher-level hypothesis in the MTP is rejected for superiority, the following hypothesis 
will then be tested as shown in Figure 6.

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Version 6.0
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Hypotheses will be tested using a multiple testing procedure with an alpha-exhaustive 
recycling strategy (Burman et al 2009). With this approach, hypotheses will be tested in a pre-
defined order as outlined in Figure 6. According to alpha (test mass) splitting and alpha 
recycling, the test mass that becomes available after each rejected hypothesis is recycled to 
secondary hypotheses not yet rejected
Note given OS is tested at multiple timepoints (i.e., interim and final analyses), the OS tests 
for the same comparison (i.e., shown in 1 box in the MTP) will be considered as 1 test family. 
As long as one test in the family can be rejected, the family is rejected thus the assigned total 
alpha to the family can be recycled to next MTP level. This testing procedure stops when the 
entire test mass is allocated to non-rejected hypotheses. Implementation of this pre-defined 
ordered testing procedure, including recycling, will strongly control type I error at 5% (2-
sided), among all key hypotheses. 
Figure 6 shows the multiple testing framework.
Figure 6
Multiple testing procedures for controlling the type 1 error rate
OS  Overall survival; PFS  Progression-free survival; EP Etoposide and platinum-based chemotherapy.
The testing procedure is hierarchical in that it starts with testing the 2 primary endpoints as 
outlined in Figure 6. The overall 5% type 1 error will be initially split between the 2 primary 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
130(186)
endpoints: an alpha level of 4% will be allocated to the analysis of OS (Arm 2 vs. 3), and an 
alpha level of 1% will be allocated to the analysis of OS (Arm 1 vs. 3).
If the OS (Arm 2 vs. 3) analysis is significant, then 4% alpha will be recycled to the OS (Arm 
1 vs. 3) endpoint;  
If the OS (Arm 1 vs. 3) analysis is significant, then 1% alpha will be recycled to the OS (Arm 
2 vs. 3) endpoint;  
If both OS primary analyses are significant, then 5% alpha will be recycled to the PFS (Arm 2 
vs. 3) endpoint. If PFS (Arm 2 vs. 3) is significant, then the 5% alpha will be recycled to PFS 
(Arm 1 vs. 3).
Spending alpha between the analyses in MTP in this way will strongly control type 1 error 
(Glimm et al 2009)
For the OS endpoint, there is 1 IA planned, and the alpha level will be controlled at the 
interim and primary analysis timepoints by using the Lan-DeMets (Lan and De Mets, 1983) 
spending function that approximates an O’Brien Fleming approach. The O’Brien Fleming 
boundaries for the OS interim and final analyses will be adjusted depending on the alpha used 
for the OS endpoint. 
In addition, durvalumab + tremelimumab + EP will be compared with durvalumab + EP for 
OS and PFS.  This comparison is not included in the MTP.
8.5.1
Analysis of the primary variable(s)
8.5.1.1
Overall survival
The primary analyses of the primary OS endpoints will occur when approximately 425 deaths 
have occurred across the durvalumab + tremelimumab + EP and EP treatment arms (80% 
maturity) and approximately 425 deaths have occurred across the durvalumab + EP and EP 
treatment arms (80% maturity). OS will be analyzed using a stratified log-rank test adjusting 
for planned platinum therapy in cycle 1 (carboplatin or cisplatin).
The effect of durvalumab + tremelimumab + EP versus EP treatment as well as durvalumab + 
EP versus EP treatment will be estimated by the HR together with its corresponding ([1-
adjusted alpha] × 100%) CI and p-value for the ITT population.  
The HR and CI can be estimated from the Cox proportional hazards model.
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up, 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment. 

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A secondary analysis of OS will be performed to compare durvalumab + tremelimumab + EP 
versus durvalumab + EP.  These analyses will be performed using the same methodology as 
for the primary endpoints described above.  The analysis to compare durvalumab + 
tremelimumab + EP versus durvalumab + EP will not be included in the multiple testing 
strategy.
The assumption of proportionality will be assessed.  Proportional hazards will be tested firstly 
by examining plots of complementary log-log (event times) versus log (time) and, if these 
raise concerns, by fitting a time-dependent covariate to assess the extent to which this 
represents random variation.  If a lack of proportionality is evident, the variation in treatment 
effect will be described by presenting piecewise HR calculated over distinct time periods.  In 
such circumstances, the HR can still be meaningfully interpreted as an average HR over time 
unless there is extensive crossing of the survival curves.  If lack of proportionality is found, 
this may be a result of treatment-by-covariate interactions, which will be investigated.
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
which is achieved by a Kaplan-Meier plot of time to censoring, where the censoring indicator 
of OS is reversed.
A subgroup analysis will be conducted comparing OS between durvalumab + tremelimumab + 
EP and durvalumab + EP versus EP in the following subgroups of the FAS: planned platinum 
therapy (carboplatin or cisplatin), age, gender, performance status, smoking status, AJCC 
stage (III/IV), CNS metastasis at baseline (Y/N), ethnicity, and geographical region.
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors. Forest 
plot(s) will be generated.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made, since all these analyses will be considered supportive of the analysis of OS.
For each subgroup level of a factor, the HR and 95% CI will be calculated from a Cox 
proportional hazards model that only contains a term for treatment. These HRs and associated 
two-sided 95% CIs will be summarised and presented on a forest plot, along with the results 
of the overall primary analysis. 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analyzed.  In 
this case, only descriptive summaries will be provided.

Clinical Study Protocol
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Study Code D419QC00001
Version 6.0
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8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Progression-free survival
The analysis of the secondary PFS endpoint will be conducted using PFS programmatically 
derived from site Investigaror tumor assessments according to RECIST 1.1. The analysis will 
be performed in the ITT population using a stratified log-rank test adjusting for planned 
platinum therapy (carboplatin or cisplatin). The effects of durvalumab + EP versus EP 
treatment, and of durvalumab + tremelimumab + EP versus EP treatment, will be estimated by 
the HR together with corresponding 95% CIs and p-values.
A secondary analysis of PFS will be performed to compare durvalumab + tremelimumab + EP 
versus durvalumab + EP.  This analysis will be performed using the same methodology as 
described above, but will not be included in the multiple testing strategy.
The assumption of proportionality will be assessed in the same way as for OS.  The analysis 
will be based on the programmatically derived PFS using site Investigator assessments.  
In addition, as a sensitivity analysis, patients who take subsequent therapy prior to progression 
or death will be censored at their last evaluable assessment prior to taking the subsequent 
therapy.  
Subgroup analyses and a forest plot will be provided for PFS comparing durvalumab ±
tremelimumab + EP and EP alone in the same way as previously specified for OS. 
No adjustment to the significance level for testing will be made since all these subgroup and 
sensitivity analyses will be considered supportive of the primary analysis of PFS.
8.5.2.2
Objective response rate
The ORR will be based on the programmatically derived RECIST using site Investigator data.  
The ORR will be compared between durvalumab + tremelimumab + EP versus EP as well as 
durvalumab + EP versus EP using logistic regression models.  The results of the analysis will 
be presented in terms of an odds ratio together with its associated profile likelihood CI and p-
value (based on twice the change in log-likelihood resulting from the addition of a treatment 
factor to the model).  This analysis will be performed in the ITT population. 
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  Overall visit response data will be listed for all patients (ie, the FAS).  For 
each treatment arm, best overall response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE).  No formal statistical analyses are planned for BoR.
8.5.2.3
   Proportion of patients alive and progression free at 6 and 12 months
The APF6 and APF12 will be summarized (using the Kaplan-Meier curve) and presented by 
treatment arm along with confidence intervals using the log-log transformation.  
This analysis will be performed in the ITT population.

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8.5.2.4
   Proportion of patients alive at 18 months (OS18)
The proportion of patients alive at 18 months (ie, OS18) will be summarized (using the 
Kaplan-Meier curve) and presented by treatment arm along with confidence intervals using 
the log-log transformation.  
8.5.3
Patient-reported outcomes
For PRO symptoms and health related quality of life endpoints, the main concepts of interest 
have been identified using a literature review, and detailed qualitative interviews with SCLC 
patients and clinicians. The key symptoms were: cough, hemoptysis, dyspnea, chest pain, 
insomnia, fatigue and appetite loss. Therefore, these key SCLC symptoms will be identified as 
primary measures of interest. In addition, physical functioning and overall health status 
domains of the EORTC QLQ-C30 are furthermore pre-specified endpoints of interest. 
8.5.3.1
Mixed-model repeated measures analysis
Change from baseline in cough, hemoptysis, dyspnea and chest pain as assessed by the 
EORTC QLQ - LC13 and insomnia, fatigue and appetite loss as assessed by the EORTC QLQ 
-C30 will be the primary analysis and assessment of PRO outcome measures. The analysis 
will be performed using a linear mixed model for repeated measures analysis of change from 
baseline in the scores for each assessment time point. 
8.5.3.2
Time to deterioration
Time to symptom and function/HRQoL deterioration will be analyzed for each of the 
symptom scales/items, function scales, and global health status/QoL in EORTC QLQ-C30 and 
QLQ-LC13. This will be achieved by comparing between treatment groups using a stratified 
log-rank test as described for the primary analysis of OS. The HR and 95% CI for each 
scale/item will be presented graphically on a forest plot.
For each of the symptom scales/items, functional scales, and global health status/QoL, time to 
deterioration will be presented using a Kaplan-Meier plot. Summaries of the number and 
percentage of patients experiencing a clinically relevant deterioration or death and the median 
time to deterioration will also be provided for each treatment group.
Further details on how this data will be analysed and the threshold for a clinically relevant 
change will be detailed and pre-specified in the SAP.
8.5.3.3
EORTC QLQ-C30
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score, and each functional domain will be reported by visit for each treatment 
arm.  Graphical presentations may also be produced as appropriate.   Details be will provided 
in the SAP. 

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8.5.3.4
EORTC QLQ-LC13
Summaries of original and change from baseline values of each symptom (dyspnea, cough, 
hemoptysis, chest pain, arm/shoulder pain, and other pain) and each treatment-related side 
effect (sore mouth, dysphagia, peripheral neuropathy, and alopecia) will be reported by visit 
for each treatment arm.  Graphical presentations may also be produced as appropriate. Details 
will be provided in the SAP.  
8.5.3.5
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS.  Further details will be provided in the SAP. 
8.5.3.6
Patients’ Global Impression of Change
PGIC data will be presented using summaries and descriptive statistics based on the 
FAS. Further details will be provided in the SAP.
8.5.3.7
EQ-5D-5L
Descriptive statistics, graphs, and listings will be reported for health state utility values and 
the visual analogue scale by visit as well as the change in these scores from baseline.  To 
support future economic evaluations, additional appropriate analyses may be undertaken 
(eg, mean health state utility pre- and post-treatment and pre- and post-progression) and will 
be outlined in the payer analysis plan.
8.5.4
Health care resource use
The potential impact the disease and treatment have on health care resource use will be 
analyzed for the purposes of submissions to payers.  Descriptive statistics (as appropriate, 
including means, median, ranges or frequencies, and percentages) will be provided for each 
arm on the different types of hospital admissions, the length of stay of people admitted into 
hospital for at least 1 overnight stay, and length of stay of people admitted to intensive 
care/high dependency units, as well as the primary sign or symptom the patient presents with.  
To support submissions to payers, additional analyses may be undertaken, and these will be 
outlined in a separate payer analysis plan.
8.5.5
Safety data
Safety and tolerability data will be presented by treatment arm using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient.  The number of patients experiencing each AE will be summarized by treatment arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to durvalumab + tremelimumab combination 

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therapy, durvalumab monotherapy, and EP alone will be summarized.  Time on study;
durvalumab + tremelimumab, durvalumab, and EP dose delays/interruptions; and EP dose 
reductions will also be summarized.  At the end of the study, appropriate summaries of all 
safety data will be produced, as defined in the SAP. 
8.5.6
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary will 
be provided for all evaluable patients in the PK analysis population.
8.5.7
Immunogenicity analysis
Immunogenicity results will be listed by patient, and a summary of the number and percentage 
of patients who develop detectable anti-durvalumab and anti-tremelimumab antibodies will be 
provided.  The immunogenicity titer and neutralizing ADA data will be listed for samples 
confirmed positive for the presence of anti-durvalumab and anti-tremelimumab antibodies.  
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated if data allow.
8.5.8
Pharmacokinetic/pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or by using an appropriate data modeling approach.
8.5.9
Biomarker data
The relationship of DLL3, TMB, somatic alterations and PD-L1 expression and, if 
appropriate, other exploratory biomarkers to clinical outcomes (including but not restricted to 
PFS) may be presented based on sample availability. Summaries and analyses for exploratory 
biomarkers may be documented in a separate analysis plan and reported outside the CSR in a 
separate report.
8.5.10
     OS interim analysis
One OS interim analysis is planned for durvalumab + tremelimumab + EP versus EP as well 
as for durvalumab + EP versus EP. This analysis will be performed by an IDMC. The interim 
analysis of OS will be conducted when approximately 318 OS events have occurred (60% 
maturity) in the durvalumab + tremelimumab + EP and EP treatment arms and approximately 
318 OS events have occurred (60% maturity) in the durvalumab + EP and EP treatment arms. 
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for the multiplicity introduced by including an interim analysis for superiority 
(Lan and DeMets 1983).  
The criterion for superiority is a statistically significant improvement in OS at the interim 
analysis.  If 75% of the OS events required at the time of the final OS analysis are available at 
the time of the interim analysis (ie, 318/425 OS events have occurred), the 2-sided 
significance level to be applied for the OS (Arm 2 vs 3) at the interim and final analysis would 

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be 1.43% and 3.57%, respectively and the 2-sided significance level to be applied for the OS 
(Arm 1 vs 3) at the interim and final analysis would be 0.23% and 0.93%, respectively.
If the OS interim analysis result does not meet the criterion of stopping for superiority, then all 
patients will continue to be followed for survival. 
The recommendations from the IDMC will not reveal the results of the analyses but will take 
the form of “Continue/Modify/Recommend early submission/Stop.” Details of the IDMC plan 
and communication process is provided in the IDMC Charter.
8.6
China cohort
The China cohort is defined as all patients from sites in China accredited by CFDA and 
enrolled into the study prior to the last patient last visit (LPLV) of the global cohort.  The 
China cohort will include approximately 189 randomized patients.  The global cohort consists 
of all patients randomized by the documented date of last patient randomized of the global 
cohort.  Once global enrollment is complete, recruitment across all sites except for those from 
China will be closed, and the recruitment of patients in China will continue.  Hence, a patient 
randomized in the China cohort prior to the last patient randomized in the global cohort will 
be included in both the global FAS and China FAS.  A patient randomized in the China cohort 
after the last patient was randomized in the global cohort will be included only in the China 
FAS.
Per CFDA guidance, in addition to the evaluation of the global cohort data for primary, 
secondary, and safety objectives, evaluation of consistency in efficacy and safety in the 
Chinese and Asian populations is required to facilitate the benefit-risk assessment for Chinese 
patients.  Thus, the efficacy and safety data in the China cohort will be summarized and 
analyzed separately where the same endpoint definitions (as described in Section 8.4) and the 
same methods for statistical analyses (as detailed in Section 8.5) are applied.  
The China FAS will include all patients randomized in the China cohort and will be used for 
all China only efficacy analyses.  
The China safety analysis set will consist of all patients randomized in the China cohort who 
receive at least one dose of study treatment.
Efficacy analyses for the China cohort will be performed when the OS data from the patients 
in this cohort are of similar maturity to those of the global cohort where significant clinical 
efficacy is established in the global cohort, eg, if OS efficacy is established at the primary 
analysis, a similar maturity to this will be used for the consistency evaluation.
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or patients are available (eg, ≥20 OS events) unless specified otherwise,
descriptive statistics only will be presented.  No adjustment for multiplicity will be made and 

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the procedure for hierarchical testing detailed in Section 8.5 will not be followed.  OS efficacy 
evaluation for the China cohort will be performed once, respectively.
Details of the China cohort and Asian population analyses, including the vendor to perform 
the analyses, will be specified in the China supplementary SAP, which is to be finalized 
before the global cohort database locks for analyses.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is enrolled in the study, an AstraZeneca representative will review and 
discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and train them in any study-specific procedures and IVRS/IWRS, WBDC, 
and any ePRO systems to be 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).
9.2
Monitoring of the study
During the study, an AstraZeneca 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 study drug accountability checks are 
being performed
!
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice and other records relevant to the 
study), including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts).
!
Ensure that withdrawal of informed consent for the use of the patient’s biological 
samples is reported, biological samples are identified and disposed of or destroyed 
accordingly, and the action is documented and reported to the patient

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The AstraZeneca representative will be available between visits if the investigators or other 
staff at the centers need information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement (CSA) for location of source data.
9.2.2
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of the Clinical Study Protocol shall prevail with 
respect to the conduct of the study and the treatment of patients.  In all other respects not 
relating to study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before any patients are enrolled.
9.2.3
Archiving of study documents
The investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The investigator will be notified by AstraZeneca when recruitment is complete.
The end of the study is defined as “the last visit of the last patient undergoing the study.” The 
last patient in the global cohort was enrolled in  Quarter 2, 2018. The estimated date of the last 
patient in the China cohort will be later than the estimated date of the last patient completed in 
the global cohort. The study is expected to end by Quarter 1, 2021. 
Data collection during long-term follow up until study end:
After the primary analysis of OS is conducted, we will continue to follow ongoing patients in 
study for limited information (see Table 12).
Subjects continuing Durvalumab should be followed for below assessments Q4W (+/-1w). 
Subjects off-treament should be followed for below assessments Q8W (+/-1w). All SAEs 
experienced by patients whilst receiving treatment or within 90 days of treatment 
discontinuing must continue to be reported to the Sponsor within the usual timelines (ie, 
immediately, or no later than 24 hours of when the site become aware of the SAE).

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Table 12. Schedule of study assessment and relevant eCRF pages to be completed during 
Long-term follow-up.
Assessment
Relevant eCRF page
Durvalumab Exposure (applicable 
only for patients continuing 
treatment post final analysis)
EX
Discontinuation (only for patients 
continuing Durvalumab treatment 
post final analysis)
DOSDISC
Survival assessment
SURVIVE
Statement of death
DEATH
Subsequent anti-cancer therapy
CAPRX1, CAPRXR2
Hospitalization and hospital 
resource utilisation
HOSPAD
All SAEs experienced by patients 
whilst receiving treatment or 
within 90 days of treatment 
discontinuing.
If SAE is reported then all data 
relevant to the SAE (e.g. 
concomitant medications, 
laboratory data, dosing 
data, new medical or surgical 
history) should be submitted as 
part of the SAE report.
SAE
Performance Status
PSTAT
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP or if recruitment is slow. AstraZeneca may also terminate the 

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entire study prematurely if concerns for safety arise within this study or in any other study 
involving durvalumab and/or tremelimumab.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by AstraZeneca Data Management Centre staff 
according to the Data Management Plan.  
The data collected through third party sources will be obtained and reconciled against study 
data. 
AEs and medical/surgical history will be classified according to the terminology of the agreed 
version of MedDRA.  Medications will be classified according to the WHO Drug Dictionary.  
Classification coding will be performed by the Medical Coding Team at the AstraZeneca Data 
Management Centre.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, a clean file will be declared.  
Any treatment-revealing data may be added thereafter, and the final database will be locked 
for the primary endpoint.  Data collection per section 9.3 will continue post this lock for 
collection of limited data in long term survivors.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or
external to AstraZeneca.

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the AstraZeneca policy on Bioethics and Human Biological Samples.  
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An EC/IRB should approve the final Clinical Study Protocol, including the final version of the 
ICF and any other written information and/or materials to be provided to the patients.  The 
investigator will ensure the distribution of these documents to the applicable EC/IRB and to 
the study site staff.
The opinion of the EC/IRB should be given in writing.  The investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final Clinical 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.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, ECs/IRBs, and Principal Investigators 
safety updates or reports according to local requirements.
In line with local regulations, Principal Investigator may be responsible for providing the 
EC/IRB with reports of any serious and unexpected adverse drug reactions from any other 
study conducted with the IP.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.

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10.4
Informed consent
The Principal Investigator(s) at each center will:
!
Ensure that each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk, and benefit of the study
!
Ensure that each patient is notified that he or she is free to discontinue from the 
study at any time
!
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided
!
Ensure that each patient provides a signed and dated informed consent before 
conducting any procedure specifically for the study
!
Ensure that the original, signed ICF(s) is/are stored in the investigator’s Study File
!
Ensure that a copy of the signed ICF is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant EC/IRB and, 
if applicable, also by the national regulatory authority, before implementation.  Local 
requirements are to be followed for new version of the Clinical Study Protocols.
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator.  For distribution to EC/IRB, see Section 10.3.
If a change to Clinical Study Protocol requires a change to a center’s ICF, AstraZeneca and 
the center’s EC/IRB are to approve the revised ICF before the revised form is used. 
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to determine if data 

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were recorded, analyzed, and accurately reported according to the Clinical Study Protocol, 
Good Clinical Practice (GCP), guidelines of the International Conference on Harmonisation
(ICH), and any applicable regulatory requirements.  The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the center.

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Appendix A  Additional Safety Information
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
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A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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

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Appendix C  Genetic Research
RATIONALE AND OBJECTIVES
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies
GENETIC RESEARCH PLAN AND PROCEDURES
Selection of genetic research population
Study selection record
All enrolled patients will be asked to participate in this genetic research. Participation is 
voluntary, and if a patient declines to participate, there will be no penalty or loss of benefit.  
The patient will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and:
Provide informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
Previous allogeneic bone marrow transplant
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Discontinuation of patients from this genetic research
Specific reasons for discontinuing a patient from this genetic research are:
Withdrawal of consent for genetic research: Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 

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study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 5.5.4 of the main Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients on Day 1 pre-dose 
(at or after randomization). Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding patients who may withdraw due to an adverse event 
(AE), such patients would be important to include in any genetic analysis.  If for any reason 
the sample is not drawn on Day 1, it may be taken at any visit until the last study visit.  Only 
one sample should be collected per patient for genetics during the study.  Samples will be 
collected, labelled, stored and shipped as detailed in the Laboratory Manual.
For blood volume, see Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 15 
years from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional, second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable by the second, unique number only.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the patient enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study, the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 

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principal investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, 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 patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organization or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate.

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Appendix D  Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. Specific guidance on the managing liver abnormalities can be 
found in Sections 5.2.1 and 6.3.8 of the protocol.
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 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (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 Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TB) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP). 
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TB ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, 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 TB, but there is no specified timeframe within which the elevations 
in transaminases and TB must occur.

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Identification of Potential Hy’s Law Cases
In order 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 ≥ 3xULN
!
AST ≥ 3xULN
!
TB ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see two definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
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:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section 6.3.8)
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
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 

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!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
!
Complete the three Liver CRF 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 in order 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 subject 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 TB elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a 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 AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TB 
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.
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:

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!
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 When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
!
Determine if there has been a significant change in the patients’ condition compared 
with the last visit where PHL criteria were met 
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law criteria 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 total bilirubin) 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.
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment 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 question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
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Section  Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment? 
If No: follow the process described in Potential Hy’s Law Criteria met 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 Potential 
Hy’s Law Criteria Met 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 TB) 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’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf

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Appendix E Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors)
1.
INTRODUCTION
This Appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for this study with regards to Investigator 
assessment of tumor burden including protocol-specific requirements for this study. 
Additional special guidance is provided for determination of confirmation of radiological 
progression.
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS
Measurable:
A lesion, that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes, which must have short axis1 diameter of ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements.
Non-measurable:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2). 
!
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination (manual palpation) that is not 
measurable by CT or MRI.
!
Previously irradiated lesions3
!
Brain metastasis
!
Skin lesions assessed by clinical examination
                                               
1 The short axis is defined as the longest axis perpendicular to the long axis of the tumor.
2 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).
3 Localised post-radiation changes which affect lesion sizes may occur. Therefore, lesions that have been 
previously irradiated will not be considered measurable and must be selected as NTL at baseline and followed up 
as part of the NTL assessment.

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Special cases:
!
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.
!
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected over cystic lesions as Target Lesions 
(TLs).
Target Lesions (TLs):
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. Lymph nodes, in any location (local/regional and distant), are collectively 
considered as a single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or multilobed organ (eg, lung) is each 
considered as a single organ.
Non-Target Lesions (NTLs):
Additional measurable lesions not recorded as TLs and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline.
3.
IMAGING MODALITIES
The same method of assessment on the same imaging technique should be used to 
characterize each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods of assessment (imaging modalities) to be used for RECIST 1.1 
assessment of TLs, NTLs and new lesions, is provided in Table 13, (please see below).
Table 13
Summary of methods of assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Clinical examination 
CT (preferred)
MRI
Plain X-ray, Chest X-ray
Bone scan
FDG-PET/CT
Clinical examination 
Ultrasound
CT  Computed tomography; FDG-PET/CT  18FFluorodeoxyglucose positron emission tomography/CT; MRI 
Magnetic resonance imaging.

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3.1
CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible images for measurement of TL, assessment of NTL, and 
identification of any new lesions. 
It is recommended that IV contrast-enhanced CT examinations of the chest and abdomen 
(including the entire liver and both adrenal glands) will be used to assess tumor burden at 
baseline and follow-up visits. Any other areas of disease involvement (eg, pelvis, brain) 
should be additionally imaged based on the signs and symptoms of individual patients. In 
patients who are sensitive to IV CT contrast, a non-contrast CT examination of the chest and 
an MRI with IV MRI contrast of the abdomen is appropriate. In patients with severely 
compromised renal function a non-contrast CT examination of the chest and abdomen is 
appropriate. For brain lesion assessment, MRI with IV contrast is the preferred method over 
IV contrast-enhanced CT. It is strongly recommended to maintain use of the same imaging 
modality (CT or MRI), acquisition protocol, facility, and scanner across all imaging time 
points per patient.
3.2
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for assessment of TL.  Clinically detected lesions can be selected as TLs if they 
are assessed by CT or MRI scans.  Clinical examination can be used to assess NTLs in 
patients that also have other lesions assessable by CT, MRI or plain X-ray and to identify the 
presence of new lesions.
3.3
X-ray
3.3.1
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
3.3.2
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
3.4
Ultrasound 
In this study, ultrasound examination will not be used for assessment of TL and NTL as it is 
not a reproducible acquisition method (operator dependent), is subjective in interpretation and 
may not provide an accurate assessment of true tumor size.  Ultrasound examination can, 
however, be used to identify the presence of new lesions.  Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
3.5
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.

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3.6
Tumor markers 
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1. 
3.7
Histology and cytology
Histology on tumor biopsy samples will not be used as part of the tumor response assessment 
as per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment in this study.  An effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be 
considered to be disease progression due to New Lesions or progression of NTLs, 
respectively. 
3.8
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  New lesions may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan, however, a newly 
observed equivocal hot-spot on a bone scan which cannot be verified with correlative imaging 
(CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that time point.
3.9
FDG-PET/CT
18F- Fluoro-deoxyglucose positron emission tomography/computed tomography 
(FDG-PET/CT) scans may be used as a method for identifying new lesions, according to the 
following algorithm:  New lesions will be recorded where there is positive 18F- Fluoro-
deoxyglucose uptake4 not present on baseline or prior FDG-PET scan or in a location 
corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline 
or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI scans, then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to verify new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
                                               
4 A positive FDG-PET scan lesion should be reported only when uptake is greater than approximately twice that 
of the surrounding tissue or liver.

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performed, as part of a PET/CT examination, is of identical diagnostic quality (with 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST 1.1 tumor assessments. Caution that this is not recommended because 
the PET portion of the CT introduces additional (PET) data that may bias an Investigator if it 
is not routinely or serially performed.
4.
TUMOR RESPONSE EVALUATION 
4.1
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including the entire liver and both adrenal glands) must be used at each subsequent 
follow-up assessment.  Additional imaging may be performed based on the signs and 
symptoms of the patient (eg, new lesions at follow up).
The baseline scan for this study must be done within 21 days prior to Day 1 of Cycle 1 and 
ideally should be performed as close as possible to the start of investigational product. The 
patient’s diagnostic scan can be used as the baseline scan if it complies with recommended 
Image Acquisition Guidelines for assessing tumor burden in the chest and abdomen (including 
liver and adrenal glands) within 28 days prior to randomization.
Efficacy for all patients will be assessed by objective tumor assessments every 6 weeks ± 1 
week for the first 12 weeks (relative to the date of randomization; see Table 2 and Table 3 of 
the Clinical Study Protocol), then every 8 weeks ± 1 week thereafter until objective disease 
progression as defined by RECIST 1.1 (irrespective of the reason for stopping treatment/or 
subsequent therapy).
For patients who discontinue study drug due to toxicity in the absence of objective 
progression, objective tumor assessments should be continued every 6 weeks ± 1 week for 12 
weeks (relative to the date of randomization) then every 8 weeks ± 1 week until confirmed 
objective disease progression. 
Radiographic progression (PD by RECIST 1.1) requires collection of a the subsequent scan no 
earlier than 4 weeks after the prior assessment of PD and no later than the next regularly 
scheduled imaging visit. In patients receiving study treatment beyond the first RECIST 1.1-
defined PD, if progression is not confirmed with the subsequent scan then the patient may 
continue on study treatment and continue with imaging assessments on their regular schedule.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
Additional assessments will be performed post objective disease progression for patients 
remaining on treatment, or until subsequent cancer therapy according to the clinical study 
protocol.

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4.2
Target lesions
4.2.1
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved, 
should be identified as TLs at baseline.  Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.  
Special cases:
!
For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis diameter. 
!
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.
!
If a TL has completely disappeared, the diameter should be recorded as 0 mm for the 
current and all subsequent scans.  If a lesion appears in the same location on a 
subsequent scan, it will be recorded as a New Lesion.
!
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 
!
If two or more TLs merge, then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  
!
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should 
be recorded, even if it is below 5 mm.
!
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion, and the overall visit assessment will be designated as PD. 
!
When a TL has had any intervention eg, definitive radiotherapy, embolization, 
surgery, etc., during the study, the size of the TL should still be provided where 

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possible and the intervention recorded in the RECIST case report form for that 
time-point and in all subsequent TL assessments (see ‘Not evaluable’ below). If a 
TL has been completely removed (surgery) or disappears following an intervention, 
the diameter should be recorded as 0 mm.
4.2.2
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (Table 14).
Table 14
Evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient decrease in sum of diameter to qualify for PR nor 
sufficient increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) - this 
includes the baseline sum if that is the smallest on study.  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm from nadir.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (eg, missing anatomy) or had a lesion intervention at 
this visit.  
Note: if the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.
4.3
Non-target lesions
4.3.1
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.  
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits.  At each visit an overall assessment of the NTL response should be recorded 
by the Investigator.  This section provides the definitions of the criteria used to determine and 
record overall response for NTL at the investigational site at each visit (Table 15).

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Table 15
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non-CR/non-PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion.
To achieve ’unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
4.4
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously new lesion has been assessed as 
unequivocal and then the progression date should be declared using the date of the initial scan 
when the new lesion first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
4.5
Symptomatic deterioration
Symptomatic (clinical) deterioration is not a descriptor of an objective response: it is a reason 
for stopping study therapy.

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Patients with ’symptomatic deterioration’ requiring discontinuation of treatment without 
objective radiologic evidence of disease progression at that time should continue to undergo 
tumor assessments where clinically feasible.
4.6
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 16.
Table 16
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE
No
PR
SD 
Non-PD or NE
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/non-PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
NA
NA
No 
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR: Complete response, PR: Partial response, SD: Stable disease, PD: Progressive disease, NE: Not evaluable, 
NA: Not applicable (relevant when no TLs or NTLs are present at baseline), NED: No Evidence of Disease 
(relevant when neither TLs nor NTLs are present at baseline).
5.
CONFIRMATION OF RADIOLOGICAL PROGRESSION
A follow-up scan is collected after the initial RECIST 1.1-defined PD, preferably at the next 
(and no later than the next) scheduled imaging visit, and no less than 4 weeks after the prior 
assessment of PD, and the Confirmation of Radiological Progression criteria described below 
are applied for tumor assessments of this follow-up scan.  Patients with radiological PD who 
continue to receive study treatment at the discretion of the Investigator and patient (following 
consultation with AstraZeneca) can receive treatment until no longer having clinical benefit.
Confirmation of radiological progression guidelines are set for the following reasons: 
!
For patient management and treatment decisions

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!
In the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 
disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression. 
Confirmation of Radiological Progression Criteria:
Confirmation of radiological progression guidelines are used to evaluate scans subsequent to a 
prior radiological PD.  An immediate prior RECIST 1.1-defined radiologic PD would be 
considered confirmed if any of the following criteria are met in a subsequent follow-up scan 
(acquired preferably at the next regularly scheduled imaging visit but no sooner than 4 weeks 
after RECIST 1.1-defined PD scan):
!
≥20% increase in the sum diameters of TLs compared with the nadir at 
2 consecutive visits, each with an absolute increase of at least 5 mm in sum of 
diameters compared to nadir (as per RECIST 1.1 definition)
!
and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint (as per RECIST 1.1 definition) 
!
and/or significant progression (worsening) of pre-existing new lesions at the 
follow-up scan time point compared with the immediate prior time point (Note: Pre-
existing new lesions are evaluated as NTLs at the confirmatory scan time-point)
!
and/or additional (brand) new unequivocal lesions at the follow-up scan time point 
(as per RECIST 1.1 definition).
NOTE: In order to have confirmed radiological progression, there should be two consecutive 
assessments meeting the PD definition, the first PD by RECIST 1.1 and the second PD using 
the confirmation of radiological progression criteria (above). If the first assessment fulfilling 
the PD definition by RECIST 1.1 is not confirmed, the patient may continue with assessments 
until the next PD by RECIST 1.1, which will also require a follow-up scan evaluated using the 
Confirmation of Radiological Progression criteria. If the first PD (by RECIST 1.1) is not 
confirmed by the immediate next scan, then the Investigator should not change the PD 
assessment of the first scan.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until objective 
disease progression.
6.
CENTRAL REVIEW
All images will be collected, quality checked, and stored centrally by an Imaging CRO 
appointed by AstraZeneca.  Guidelines for image acquisition, storage at the investigative site 
as source data, and transfer to the imaging CRO will be provided in a separate document.

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7.
SPECIFICATIONS FOR RADIOLOGICAL IMAGING
These notes are recommendations for use in clinical studies.  The use of standardized 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken. 
If specified, all images will be collected, quality checked and stored centrally by the imaging 
CRO appointed by AstraZeneca.  Guidelines for image acquisition, anonymization, storage at 
the investigative site as source data and transfer to the imaging CRO will be provided in a 
separate document. The management of patients will be based solely upon the local 
assessments conducted by the Investigator.
7.1
CT Scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous 
throughout all the anatomical region of interest.  
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
7.1.1
Anatomic coverage
Optimal anatomic coverage for most solid tumors is the chest and abdomen (and pelvis if 
indicated).  Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients.  Because a lesion later identified in a body part 
not scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points.  This will enable better consistency not only of tumor 
measurements but also identification of new disease.
7.1.2
Contrast administration
Optimal visualisation and measurement of metastases in solid tumors requires consistent 
administration (dose and rate) of IV contrast as well as timing of scanning.  Typically, most 
abdominal imaging is performed during the portal venous phase and (optimally) about the 
same time frame after injection on each examination.  An adequate volume of a suitable 
contrast agent should be given so that the metastases are demonstrated to best effect and a 
consistent method is used on subsequent examinations for any given patient.  It is very 
important that the same technique be used at baseline and on follow-up examinations for a 
given patient.  For patients who develop contraindications to contrast after baseline contrast 
CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) 
should be performed should also be based on the tumor type, anatomic location of the disease 
and should be optimised to allow for comparison to the prior studies if possible.  Each case 
should be discussed with the radiologist to determine if substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point forward.  

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Care must be taken in measurement of TLs on a different modality and interpretation of non-
target disease or new lesions, since the same lesion may appear to have a different size using a 
new modality.  Oral contrast is recommended to help visualise and differentiate structures in 
the abdomen.
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic (chest) examination 
without contrast and abdominal (and pelvis) MRI with contrast.  If MRI cannot be performed 
then CT without IV contrast is an option for the thorax and abdomen (and pelvis 
examination). For brain imaging, MRI with IV contrast is the preferred method.
7.1.3
Slice thickness and reconstruction interval
It is recommended that CT scans be performed at 5mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition.  Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm.  If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TL should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
7.2
MRI SCAN
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis (and other anatomies eg, neck) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed.  The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimised for the specific body part being imaged as well as the scanner utilised.  CT of the 
chest is typically recommended over MRI due to significant motion artifacts (heart, major 
blood vessels, breathing) associated with MRI.  It is beyond the scope of this appendix to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts and diseases.  
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques if possible. 
For these reasons, CT is the imaging modality of choice.

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8.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer 
2009;45:228-47.  

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Appendix F Patient Reported Outcomes: EORTC QLQ-C30, EORTC 
QLC-LC13, PRO-CTCAE, EQ-5D-5L, and PGIC

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Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
184(186)

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
185(186)

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419QC00001
Version 6.0
Date 16 January 2020
186(186)

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d419qc00001-csp-v6
Document Title:
D419QC00001 Clinical Study Protocol version 6
Document ID:
Version Label:
7.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
22-Jan-2020 00:05 UTC
Content Approval
20-Jan-2020 11:29 UTC
Qualified Person Approval
28-Jan-2020 22:26 UTC
Content Approval
17-Jan-2020 13:02 UTC
Content Approval
CCI
CCI
PPD
PPD
PPD
PPD