A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients With Limited Stage Small Cell Lung Cancer Who Have Not Progressed Following Concurrent Chemoradiation Therapy (ADRIATIC)
Phase: PHASE3
Conditions: Small Cell Lung Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol
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Clinical Study Protocol
Drug Substance
Durvalumab and 
tremelimumab
Study Code
D933QC00001
Version
5.0
Date
10 January 2023
A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, 
International Study of Durvalumab or Durvalumab and Tremelimumab as 
Consolidation Treatment for Patients with Limited Stage Small-Cell Lung 
Cancer Who Have Not Progressed Following Concurrent Chemoradiation 
Therapy (ADRIATIC)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan
Regulatory Agency Identifying Number(s):
EudraCT: 2018-000867-10
Redacted for public disclosure
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Tremelimum
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Tremelimum
age Small
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urrent Chemo
disc
urrent Chemo
ic
Sweden
bli
Sweden
K., 3
K., 3-
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-1, Ofuka ch
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1, Ofuka ch
mber(s):
r p
mber(s):

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1. OS for the comparison of durvalumab monotherapy versus placebo has been added to 
the primary endpoint, ie, the study now has dual primary endpoints of PFS and OS for 
the comparison of durvalumab monotherapy versus placebo; the comparison of 
durvalumab plus tremelimumab versus placebo in terms of PFS and OS are now 
secondary endpoints. Sections updated: Section 1.2, Section 2.1.3, Section 3, 
Table 3, Section 4.2.1, Section 9.1, Section 9.5.1, Table 13, Section 9.5.7.
2. The amendment incorporates new and updated published clinical data that support the 
decision to revise the study design with respect to both the primary endpoint 
analysis/efficacy endpoints and the treatment effect assumptions. Sections updated: 
Section 1.2, Section 2.1.3, Section 2.3.1.1, Section 10.
3. Text relating to the planned number of patients and to the sample size calculation has 
been updated to increase the total sample size from 600 to approximately 724 patients, 
with additional patients in each of the durvalumab and placebo groups (approximately 
262 patients each). The number of patients in the durvalumab plus tremelimumab 
group is unchanged (approximately 200 patients). Sections updated: Section 1.2, 
Section 2.1.3, Section 4.1, Section 9.2.
4. As the number of patients in the durvalumab plus tremelimumab group is unchanged, 
the amendment clarifies that once 600 patients have been randomized, randomization 
will continue 1:1 in the durvalumab monotherapy and placebo groups. Sections 
updated: Section 1.1, Table 1, Section 1.2, Section 2.1.3, Section 6.1.2, Section 
6.2.1, Section 9.2.
5. Change to the study design to indicate that once 600 patients have been randomized, no 
further PK or ADA samples relevant to tremelimumab are required. Section updated: 
Section 1.1, Table 2.
6. Provision for enrolment in China to continue after global enrolment is closed to allow 
inclusion of a total of approximately 108 patients. Sections updated: Section 1.2, 
Section 4.1, Section 9.2.
7. The statistical sections have been updated to accommodate the changes described 
above. Sections affected: Section 1.2, Section 2.1.3, Section 9.1 (updated null 
hypotheses regarding the efficacy endpoints), Section 9.2 (sample size determination 
and updated timing of interim and final analyses), Section 9.3.2 (clarification of 
patients included in the analyses of the combination analysis set), Section 9.3.4
(definition of the combination safety analysis set), Section 9.4.1 (calculation or 
derivation of efficacy variables), Section 9.5.1 (updated analyses of PFS, OS, and 
duration of response [DoR]), Section 9.5.7 (updated description of methods for 
multiplicity control reflecting the updated analyses), Section 9.6 (updated details of the 
interim analyses of OS and their anticipated timing).
8. The benefit-risk assessment has been updated for durvalumab and overall. Sections 
updated: Section 1.2, Section 2.3.1.1, Section 2.3.3.
Other changes included in this amendment:
9. Clarification of the timing of the baseline tumor assessment, Section updated: 
Section 1.1, Table 1.
10. Based on current enrollment trends and given the increased sample size, the study is 
now expected to provide adequate representation of patients with Stage I/II disease. 

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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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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS .....................................................................................8
1.
PROTOCOL SUMMARY .................................................................................14
1.1
Schedule of activities (SoA)...............................................................................14
1.2
Synopsis.............................................................................................................23
1.3
Schema ..............................................................................................................32
2.
INTRODUCTION .............................................................................................34
2.1
Study rationale ...................................................................................................34
2.1.1
Durvalumab monotherapy..................................................................................34
2.1.2
Durvalumab in combination with tremelimumab................................................35
2.1.3
Study Design Change – Rationale and Impact ....................................................36
2.2
Background........................................................................................................38
2.2.1
Immunotherapies................................................................................................39
2.2.2
Durvalumab .......................................................................................................40
2.2.3
Tremelimumab...................................................................................................40
2.2.4
Durvalumab in combination with tremelimumab................................................41
2.3
Benefit/risk assessment ......................................................................................41
2.3.1
Potential benefits................................................................................................41
2.3.1.1
Durvalumab .......................................................................................................41
2.3.1.2
Durvalumab in combination with tremelimumab................................................42
2.3.2
Overall risks.......................................................................................................42
2.3.2.1
Durvalumab .......................................................................................................42
2.3.2.2
Durvalumab after completion of CRT ................................................................43
2.3.2.3
Tremelimumab...................................................................................................43
2.3.2.4
Durvalumab and tremelimumab .........................................................................44
2.3.3
Overall benefit/risk.............................................................................................45
3.
OBJECTIVES AND ENDPOINTS ....................................................................45
4.
STUDY DESIGN...............................................................................................48
4.1
Overall design....................................................................................................48
4.2
Scientific rationale for study design....................................................................50
4.2.1
Rationale for study endpoints (efficacy) .............................................................50
4.2.2
Rationale for study endpoints (other secondary and exploratory endpoints)........50
4.2.3
Rationale for treatment duration.........................................................................51
4.3
Justification for dose ..........................................................................................51
4.3.1
Durvalumab monotherapy dose rationale............................................................51
4.3.1.1
Rationale for fixed dosing ..................................................................................52
4.3.2
Durvalumab and tremelimumab dose and treatment regimen justification...........53

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4.3.2.1
Durvalumab and tremelimumab combination therapy dose rationale ..................53
4.3.2.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy ......................................................................................................55
4.4
End of study definition.......................................................................................55
5.
STUDY POPULATION.....................................................................................56
5.1
Inclusion criteria ................................................................................................56
5.2
Exclusion criteria ...............................................................................................59
5.3
Lifestyle restrictions...........................................................................................62
5.4
Screen failures....................................................................................................64
6.
STUDY TREATMENTS ...................................................................................65
6.1
Treatments administered ....................................................................................65
6.1.1
Investigational products .....................................................................................65
6.1.1.1
Durvalumab (MEDI4736) ..................................................................................66
6.1.1.2
Tremelimumab...................................................................................................67
6.1.1.3
Placebo ..............................................................................................................68
6.1.2
Dose and treatment regimens..............................................................................68
6.1.3
Duration of treatment .........................................................................................69
6.1.4
Storage...............................................................................................................70
6.2
Measures to minimize bias: randomization and blinding.....................................70
6.2.1
Patient enrollment and randomization.................................................................70
6.2.2
Procedures for handling incorrectly enrolled or randomized patients ..................72
6.2.3
Methods for assigning treatment groups .............................................................72
6.2.4
Methods for ensuring blinding............................................................................72
6.3
Treatment compliance ........................................................................................73
6.4
Concomitant therapy..........................................................................................73
6.4.1
Other concomitant treatment ..............................................................................75
6.4.2
Durvalumab drug-drug interactions....................................................................75
6.4.3
Rescue medication .............................................................................................75
6.5
Dose modification..............................................................................................76
6.6
Continued Access to Study Intervention After the End of the Study ...................76
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...76
7.1
Discontinuation of study treatment.....................................................................76
7.1.1
Procedures for discontinuation of study treatment ..............................................77
7.2
Lost to follow-up................................................................................................78
7.3
Withdrawal from the study.................................................................................78
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................79
8.1
Efficacy assessments..........................................................................................79
8.1.1
Central reading of scans .....................................................................................80

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8.1.2
Survival assessments..........................................................................................80
8.1.3
Clinical outcome assessments.............................................................................81
8.1.3.1
EORTC QLQ-C30 and QLQ-LC13....................................................................81
8.1.3.2
PRO-CTCAE .....................................................................................................81
8.1.3.3
PGIS ..................................................................................................................81
8.1.3.4
EQ-5D-5L..........................................................................................................82
8.1.3.5
Administration of electronic patient-reported outcome questionnaires ................82
8.2
Safety assessments .............................................................................................83
8.2.1
Clinical safety laboratory assessments................................................................83
8.2.2
Physical examinations ........................................................................................85
8.2.3
Vital signs..........................................................................................................85
8.2.4
Electrocardiograms ............................................................................................86
8.2.5
WHO/ECOG performance status........................................................................86
8.2.6
Other safety assessments ....................................................................................87
8.3
Collection of adverse events...............................................................................88
8.3.1
Method of detecting AEs and SAEs....................................................................88
8.3.2
Time period and frequency for collecting AE and SAE information ...................88
8.3.3
Follow-up of AEs and SAEs...............................................................................88
8.3.4
Adverse event data collection.............................................................................89
8.3.5
Causality collection............................................................................................90
8.3.6
Adverse events based on signs and symptoms ....................................................90
8.3.7
Adverse events based on examinations and tests.................................................90
8.3.8
Hy’s law.............................................................................................................91
8.3.9
Disease progression............................................................................................91
8.3.10
New cancers.......................................................................................................91
8.3.11
Deaths................................................................................................................91
8.3.12
Adverse events of special interest.......................................................................92
8.3.13
Safety data to be collected following the final DCO of the study........................93
8.4
Safety reporting and medical management .........................................................93
8.4.1
Reporting of serious adverse events....................................................................93
8.4.2
Pregnancy ..........................................................................................................94
8.4.2.1
Maternal exposure..............................................................................................94
8.4.2.2
Paternal exposure ...............................................................................................95
8.4.3
Overdose............................................................................................................95
8.4.3.1
Durvalumab or tremelimumab............................................................................95
8.4.4
Medication error, Drug abuse, Drug misuse........................................................96
8.4.4.1
Timelines ...........................................................................................................96
8.4.4.2
Medication error.................................................................................................96
8.4.4.3
Drug abuse.........................................................................................................96
8.4.4.4
Drug misuse.......................................................................................................96
8.4.5
Management of IP-related toxicities ...................................................................96
8.4.5.1
Specific toxicity management and dose modification information ......................97
8.5
Pharmacokinetics ...............................................................................................98
8.5.1
Collection of PK samples ...................................................................................98
8.5.2
Collection of ADA samples................................................................................98

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8.5.3
Storage and destruction of pharmacokinetic/ADA samples.................................98
8.6
Pharmacodynamics ............................................................................................98
8.7
Genetics (Not applicable for China) ...................................................................99
8.7.1
Optional exploratory genetic sample (Not applicable for China).........................99
8.7.2
Storage and destruction of genetic samples (Not applicable for China)...............99
8.8
Biomarkers.........................................................................................................99
8.8.1
Secondary and exploratory biomarkers.............................................................100
8.8.2
Storage, re-use, and destruction of biomarker samples......................................103
8.8.3
Labeling and shipment of biological samples ...................................................103
8.9
Health Economics ............................................................................................103
9.
STATISTICAL CONSIDERATIONS..............................................................104
9.1
Statistical hypotheses .......................................................................................104
9.2
Sample size determination................................................................................105
9.3
Populations for analyses...................................................................................106
9.3.1
Full analysis set................................................................................................107
9.3.2
Combination analysis set..................................................................................107
9.3.3
Safety analysis set ............................................................................................107
9.3.4
Combination safety analysis set........................................................................107
9.3.5
PK analysis set.................................................................................................107
9.3.6
ADA analysis set..............................................................................................107
9.4
Outcome measures for analyses........................................................................107
9.4.1
Calculation or derivation of efficacy variables..................................................107
9.4.1.1
RECIST 1.1-based endpoints............................................................................107
9.4.1.2
Progression-free survival..................................................................................108
9.4.1.3
Overall survival................................................................................................109
9.4.1.4
Objective response rate ....................................................................................109
9.4.1.5
Progression-free survival at 18 months and 24 months .....................................109
9.4.1.6
Time to death or distant metastasis...................................................................109
9.4.1.7
Proportion of patients alive at 24 months and 36 months after randomization...110
9.4.1.8
Time from randomization to second progression ..............................................110
9.4.2
Calculation or derivation of safety variables.....................................................110
9.4.2.1
Adverse events.................................................................................................110
9.4.2.2
Safety assessments ...........................................................................................111
9.4.3
Calculation or derivation of patient-reported outcome variables - EORTC 
QLQ-C30 and QLQ-LC13................................................................................111
9.4.4
Calculation or derivation of PGIS.....................................................................113
9.4.5
Calculation or derivation of PRO-CTCAE........................................................113
9.4.6
Calculation or derivation of patient-reported health state utility (EQ-5D-5L)....113
9.4.7
Calculation or derivation of pharmacokinetic variables ....................................113
9.4.7.1
Population pharmacokinetics and exposure-response/safety analysis ................113
9.4.7.2
Pharmacokinetic analysis .................................................................................113
9.4.7.3
Immunogenicity analysis..................................................................................113
9.4.8
Calculation or derivation of biomarker variables ..............................................114

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9.4.9
Calculation or derivation of pharmacogenetic variables (Not Applicable for 
China) ..............................................................................................................114
9.5
Statistical analyses ...........................................................................................114
9.5.1
Efficacy analyses..............................................................................................114
9.5.1.1
Progression-free survival..................................................................................117
9.5.1.2
Overall survival................................................................................................119
9.5.1.3
Objective response rate ....................................................................................119
9.5.1.4
Progression-free survival at 18 months and 24 months .....................................120
9.5.1.5
Time to death or distant metastasis...................................................................120
9.5.1.6
Proportion of patients alive at 24 and 36 months ..............................................120
9.5.1.7
Time from randomization to second progression ..............................................120
9.5.1.8
Duration of response ........................................................................................120
9.5.1.9
Patient-reported outcomes: EORTC QLQ-C30 and QLQ-LC13 .......................121
9.5.1.10
Health care resource use...................................................................................122
9.5.2
Safety analyses.................................................................................................122
9.5.3
Pharmacokinetic data .......................................................................................123
9.5.4
Immunogenicity data........................................................................................123
9.5.5
Pharmacokinetic/pharmacodynamic relationships.............................................123
9.5.6
Biomarker data.................................................................................................123
9.5.7
Methods for multiplicity control.......................................................................123
9.6
Interim analyses ...............................................................................................124
9.6.1
Data monitoring committee..............................................................................126
10.
REFERENCES ................................................................................................127
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .......................................................................................137
LIST OF TABLES
Table 1
Schedule of assessments for durvalumab ± tremelimumab therapy or placebo 
treatment ......................................................................................................... 15
Table 2
Schedule of assessments for patients who have completed/discontinued 
treatment with durvalumab ± tremelimumab therapy or placebo ...................... 20
Table 3
Study objectives............................................................................................... 46
Table 4
Highly effective methods of contraception (<1% failure rate)........................... 64
Table 5
Study treatments............................................................................................... 65
Table 6
Prohibited concomitant medications............................................................... 744
Table 7
Supportive medications .................................................................................... 75
Table 8
Clinical chemistry ............................................................................................ 85
Table 9
Hematology...................................................................................................... 85

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Table 10 Urinalysis......................................................................................................... 86
Table 11 Summary of outcome variables and analysis populations................................ 107
Table 12 Visit responses for symptoms and HRQoL..................................................... 113
Table 13 Pre-planned statistical and sensitivity analyses to be conducted...................... 116
Table 14 Summary of imaging modalities for tumor assessment ................................... 163
Table 15 Evaluation of target lesions ............................................................................ 167
Table 16 Evaluation of non-target lesions ..................................................................... 168
Table 17 Overall visit response..................................................................................... 169
LIST OF FIGURES
Figure 1 Study design................................................................................................... 333
Figure 2 Dosing schedule............................................................................................... 70
Figure 3 Multiple testing procedure.............................................................................1245
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................ 138
Appendix B
Adverse event definitions and additional safety information.................... 144
Appendix C
Handling of human biological samples.................................................... 150
Appendix D
Genetics (Not applicable for China)........................................................ 152
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law................................................................................... 156
Appendix F
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors)................................ 162
Appendix G
International Airline Transportation Association (IATA) 6.2 guidance 
document....................................................................................................... 172
Appendix H
Patient-reported outcomes ...................................................................... 173
Appendix I
Abbreviations........................................................................................... 182

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1.
PROTOCOL SUMMARY
1.1
Schedule of activities (SoA)
The procedures for the screening and treatment periods in this study are presented in Table 1, 
and the procedures for the follow-up period are presented in Table 2.
Whenever vital signs and blood draws are scheduled for the same nominal time, the assessments 
should occur in the following order: vital signs and then blood draws. The timing of the vital 
signs assessments should be such that it allows the blood draw (eg, pharmacokinetic [PK] blood 
sample) to occur at the time points indicated in the schedules of activities (SoAs). Whenever 
electrocardiograms (ECGs), vital signs, 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 time points indicated in the SoAs.

Patients may delay dosing under certain circumstances. 

Dosing may be delayed per the Dosing Modification and Toxicity 
Management Guidelines, due to either an immune or a non-immune-related 
adverse event (AE).

If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible.

Dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of 
tumor efficacy (Response Evaluation Criteria In Solid Tumors [RECIST]) 
and patient-reported outcome (PRO) assessments. Subsequent time between 
2 consecutive doses cannot be less than 21 days, based on the half-lives of 
durvalumab and tremelimumab (see current Investigator Brochures [IBs] for 
durvalumab and tremelimumab).

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Table 1
Schedule of assessments for durvalumab ± tremelimumab therapy or placebo treatment
Screeninga
C1
C2
C3
C4
C5 to C25
C26/
Final 
Dosi
ng 
Visit
For details, 
see Section
Week
-6 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
100
Day
-42 to -1
1b
q28days ±3 days unless dosing needs to be held for toxicity reasons
701
Informed consent
Informed consent: study proceduresc
X
6.2.1
Consent: genetic sample and analysis 
(optional, not applicable for China)d
X
8.7.1
Study procedures
Physical exam (full)
X
8.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
X
8.2.2
Vital signse
X
X
X
X
X
X
X
8.2.3
ECGf
X
As clinically indicated
8.2.4
Concomitant medications
<----------------------------------------------------------------------------------------------------------------------------->
6.4
Demography, including baseline 
characteristics and tobacco use
X
Eligibility criteria
X
5.1, 5.2
Brain MRI (preferred) or high-quality 
brain CT with IV contrastg
X
As clinically indicated
5.2
Laboratory assessments
Clinical chemistryh
X
Xi
X
X
X
X
X
Table 8
Hematologyh
X
Xi
X
X
X
X
X
Table 9
TSH (reflex free T3 or free T4j)
X
Xk
X
X
X
X
X
Table 8
Urinalysis
X
As clinically indicated
Table 10
Hepatitis B and C and HIV
X
8.2.1

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Screeninga
C1
C2
C3
C4
C5 to C25
C26/
Final 
Dosi
ng 
Visit
For details, 
see Section
Week
-6 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
100
Day
-42 to -1
1b
q28days ±3 days unless dosing needs to be held for toxicity reasons
701
Pregnancy testl
X
X
X
X
X
X
X
8.2.1
Pharmacokinetics 
Durvalumab PK sample (serum)
Xm
Xn
Cycle 5 onlyn
Xn,o
8.5
Tremelimumab PK sample (serum)p
Xm
Xn
Cycle 5 and 7 
onlyn
8.5
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
8.2.5
AE/SAE assessmentq
<------------------------------------------------------------------------------------------------------------------------------>
8.3
IP administration
Durvalumab or placebor,s
X
X
X
X
X
X
6.1.1.1, 
6.1.1.3
Tremelimumab or placebor,s
X
X
X
X
6.1.1.2, 
6.1.1.3
Drug accountability
All visits
6.3
Other assessments and assays
Durvalumab immunogenicity assessment 
(ADA sampling to identify ADA 
responses in patient circulation)
Xn
Cycle 5, 13 and 
20 onlyn
Xn,o
8.5
Tremelimumab immunogenicity 
assessment (ADA sampling to identify 
ADA responses in patient circulation)p
Xn
Cycle 5, 7 and 
10 onlyn
8.5
Whole blood for genotyping (not 
applicable for China)
Xn
8.8

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Screeninga
C1
C2
C3
C4
C5 to C25
C26/
Final 
Dosi
ng 
Visit
For details, 
see Section
Week
-6 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
100
Day
-42 to -1
1b
q28days ±3 days unless dosing needs to be held for toxicity reasons
701
Whole blood for gene expression 
(PaxGene-RNA tubes, not applicable for 
China)
Xn
Xn
Xn
8.8
Circulating soluble factors (plasma, not 
applicable for China)
Xn
Xn
Xn
Xn
Xn,t
8.8
Stool sample collection for microbiome 
analysis (optional, applicable in North 
America and Europe only)u
X
X
8.8
EORTC QLQ-LC13 (by e-device)v
X
Weekly (±1 day on weeks 1, 2, 3, 5, 6, and 7, and ±3 days on weeks 4 and 8) for the 
first 8 weeks from randomization and then every 4 weeks (±3 days) relative to 
randomization until study termination or PFS2 or death
8.1.3
EORTC QLQ-C30 (by e-device)v
X
Every 4 weeks (±3 days) relative to randomization until study termination or PFS2 or 
death
8.1.3
PRO-CTCAE (by e-device)v
X
Weekly (±1 day on weeks 1, 2, 3, 5, 6, 7, 9, 10, and 11, and ±3 days on weeks 4, 8, and 
12) for the first 12 weeks from randomization and then every 4 weeks (±3 days) relative 
to randomization until study termination or PFS2 or death
8.1.3
PGIS (by e-device)v
X
Every 8 weeks (±3 days) relative to randomization until study termination or PFS2 or 
death
8.1.3
EQ-5D-5L (by e-device)v
X
Every 8 weeks (±3 days) relative to randomization until study termination or PFS2 or 
death
8.1.3
Health resource use module (HOSPAD)
X
Every 24 weeks (±3 days) relative to randomization until treatment discontinuation
8.9
Mandatory tumor tissue samplec
X
5.1, 8.8
Optional newly acquired tumor biopsyc
X
5.1, 8.8
Genetic sample (optional DNA element 
for long-term storage/future use, not 
applicable for China)w
X
8.7

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Screeninga
C1
C2
C3
C4
C5 to C25
C26/
Final 
Dosi
ng 
Visit
For details, 
see Section
Week
-6 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
100
Day
-42 to -1
1b
q28days ±3 days unless dosing needs to be held for toxicity reasons
701
Efficacy evaluations
Tumor assessments (CT or MRI) 
(RECIST 1.1)y
Xz
On-study tumor assessments occur q8w ± 1w for the first 72 weeks (relative to the date of 
randomization), followed by q12w ±1w until up to 96 weeks relative to the date of randomization, 
and then q24w ±1w thereafter (relative to the date of randomization) until RECIST 1.1-defined 
radiological progression, plus one follow-up scan no earlier than 4 weeks later and no later than 
the next regularly scheduled imaging visit. This on-study schedule MUST be followed regardless 
of any delays in dosing. Tumor assessments up to progression may continue after the PFS 
analysis and up to the end of the study
8.1
a
The screening period starts from the last day of the final cycle of chemotherapy (eg, C4D21) or the last day of radiotherapy (whichever occurs later) and may last 
1 to 42 days prior to randomization and the first dose of IP.
b
Every effort should be made to minimize the time between randomization and starting treatment. CRT treatment, and PCI treatment if received per local standard of care, 
must be completed within 1 to 42 days prior to randomization and the first dose of IP.
c
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. All patients will be required to provide consent to supply a tumor tissue sample for entry into this study. This consent is included in the main 
patient ICF. The collection of additional biopsies upon progression is encouraged where technically and clinically feasible (not applicable for China). 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 42 days prior to randomization and the first dose of IP.
d
Consent for the optional genetic sample and analysis is included in the main patient ICF.
e
Body weight is recorded at each visit along with vital signs.
f
Triplicate ECGs required.
g
Brain MRI (preferred) or high-quality brain CT with IV contrast should be conducted after completion of CRT and within 1 to 42 days before randomization and first dose of 
IP (screening period). This scan should also be performed before commencing PCI (if PCI is indicated as per local standard of care).
h
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated.
i
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. 
j
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
k
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
l
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then every 4 weeks. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician 
or Investigator prior to commencing an infusion 
m
Within 10 minutes of the end of infusion. 
n
Pre-dose, within 60 minutes prior to start of infusion; before tremelimumab infusion in C1 to C4; before durvalumab infusion in C5 and subsequent cycles. Once 600 patients 
have been randomized, PK and ADA assessments related to tremelimumab will not be required for any newly randomized patients.
o
PK and ADA samples should be collected on the last scheduled cycle of IP (ie, the last cycle of IP that is within the maximum 24 months from the first dose of IP).
p
Samples should not be collected for newly-randomized patients once 600 patients have been randomized.

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q
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
r
During the combination portion of treatment, tremelimumab or placebo will be administered first; the durvalumab or placebo infusion will start approximately 1 hour
(maximum 2 hours) after the end of the tremelimumab or placebo infusion. If there are no clinically significant infusion reactions with the first cycle, and at the discretion of 
the Investigator, then for all other cycles, the durvalumab or placebo can be given immediately after the tremelimumab or placebo infusion has finished. Once 600 patients 
have been randomized, patients newly randomized to durvalumab monotherapy or to placebo will receive 1 infusion only. Patients randomized before 600 patients have been 
randomized will continue to receive infusions as per schedule.
s
Results for LFTs, electrolytes, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator prior to 
dosing.
t
Samples for soluble factors (plasma) should be collected on Cycles 5, 7, 9, 11, 13, 15, 17, 19, 22, and 25.
u
Optional stool samples will be requested from sites in North America and Europe only. Kits for collecting stool samples should be given to patients at a previous visit and 
samples may be collected from consenting patients, in a home setting or in the clinic, up to 3 days before the scheduled Cycle 1 or Cycle 3 visit and the sample brought (to 
the site as appropriate) at the next scheduled visit.
v
ePRO LogPads must be assigned to patients only on the day of randomization; baseline ePROs should be completed by patients prior to dosing and prior to any other 
assessments while they are still in the clinic on Cycle 1 Day 1 to ensure that the device is correctly set up and working properly. Thereafter, ePROs should be completed by 
the patients at home. PRO-CTCAE will be administered only in the languages where a linguistically validated version exists.
w
The sample for genetic research will be obtained at Day 1 pre-dose (at or after randomization, not applicable for China). 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 1 sample should be collected per patient for genetics during the study.
y
See Section 8.1 and Appendix F for additional details relevant to the imaging schedule. The follow-up scan after a RECIST 1.1-defined PD is also evaluated according to 
RECIST 1.1 criteria (Appendix F).
z
The baseline tumor assessment must be performed post-CRT as part of the screening procedures within 42 days before randomization and the first dose of IP.
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; CRT Chemoradiation therapy; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; 
ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and Treatment of Cancer; ePRO Electronic patient-
reported outcome; EQ-5D-5L  EuroQoL 5 dimension, 5 level health state utility index; HIV Human immunodeficiency virus; ICF Informed consent form; IP Investigational 
product (ie, durvalumab, tremelimumab, or placebo); LFT Liver function test; MRI Magnetic resonance imaging; PCI Prophylactic cranial irradiation; PD Progressive disease; 
PGIS Patient’s Global Impression of Severity; PK Pharmacokinetic; PRO Patient-reported outcome; QLQ C30 30 Item core quality of life questionnaire; QLQ LC13 Lung 
cancer module; qXdays Every X days; qXw Every X weeks; RECIST Response Evaluation Criteria In Solid Tumors; SAE Serious adverse event; T3 Triiodothyronine; 
T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO World Health Organization.

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Table 2
Schedule of assessments for patients who have completed/discontinued treatment with 
durvalumab ± tremelimumab therapy or placebo
Time since last dose of IP
Evaluation
Day (±3)
Week (±1 week)
48 weeks and every 
8 weeks (±2 weeks) 
until study 
termination or 
death
For details, 
see Section
30
8
12
16
24
32
40
Physical examination (full)
X
8.2.2
Vital signs (temperature, respiratory rate, blood 
pressure, and pulse)
X
8.2.3
Weight
X
X
X
8.2.3
Pregnancy testa
X
As clinically indicated
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.4
WHO/ECOG performance status
At time points consistent with tumor assessments; at Day 30 (±3), Week 8 (±1 week), and Week 12 
(±1 week); and then at initiation of subsequent anticancer therapyb
8.2.5
Second progression assessmentc
Patients who discontinue study drug following progression will be assessed every 8 weeks for a second 
progression (using the patient’s status at first 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.
8.1.2
Subsequent anticancer therapyd and survival statuse
X
X
X
X
X
X
X
8.1.2
Hematology
X
X
X
Table 9
Clinical chemistry
X
X
X
Table 8
TSH (reflex free T3 or free T4f)
X
X
X
Table 8
Durvalumab PK assessmentg
X
8.5
Tremelimumab PK assessmenth
X
8.5
Durvalumab immunogenicity assessment (ADA 
sampling) to identify ADA responsesi
X
X
8.5
Tremelimumab immunogenicity assessment (ADA 
sampling) to identify ADA responsesj
X
X
8.5

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Time since last dose of IP
Evaluation
Day (±3)
Week (±1 week)
48 weeks and every 
8 weeks (±2 weeks) 
until study 
termination or 
death
For details, 
see Section
30
8
12
16
24
32
40
Whole blood for gene expression (PaxGene-RNA 
tubes, not applicable for China)
X
X
8.8
Circulating soluble factors (including TMB; plasma, 
not applicable for China)
X
X
8.8
EORTC QLQ-LC13 (by e-device)k
Weekly (±1 day on weeks 1, 2, 3, 5, 6 and 7, and  ±3 days on weeks 4 and 8) for the first 8 weeks from 
randomization and then every 4 weeks (±3 days) relative to randomization until study termination or 
PFS2 or death
8.1.3
EORTC QLQ-C30 (by e-device)k
Every 4 weeks (±3 days) relative to randomization until study termination or PFS2 or death
8.1.3
PRO-CTCAE (by e-device)k
Weekly (±1 day on weeks 1, 2, 3, 5, 6, 7, 9, 10 and 11, and ±3 days on weeks 4, 8 and 12) for the first 
12 weeks from randomization, then every 4 weeks (±3 days) relative to randomization until study 
termination or PFS2 or death
8.1.3
PGIS (by e-device)k
Every 8 weeks (±3 days) relative to randomization until study termination or PFS2 or death
8.1.3
EQ-5D-5L (by e-device)k
Every 8 weeks (±3 days) relative to randomization until study termination or PFS2 or death
8.1.3
Health resource use module (HOSPAD)
X
Xm
8.9
Tumor assessment (CT or MRI) (RECIST 1.1)l
On-study tumor assessments occur q8w ±1w for the first 72 weeks (relative to the date of 
randomization), followed by q12w ±1w until up to 96 weeks relative to the date of randomization, and 
then q24w ±1w thereafter (relative to the date of randomization) until RECIST 1.1-defined 
radiological progression, plus one follow-up scan no earlier than 4 weeks later and no later than the 
next regularly scheduled imaging visit. This on-study schedule MUST be followed regardless of any 
delays in dosing. Additional scans to be completed per standard practice post-progression. Tumor 
assessments up to progression may continue after the PFS analysis and up to the end of the study
8.1
a
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. 
b
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/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
c
For patients who discontinue their assigned IP following progression, available readings of CT/MRI from local practice will be collected from patients’ medical charts while 
information on subsequent anticancer treatment and/or PFS2 is collected.
d
Details of any treatment for LS-SCLC (including surgery and hospitalizations) after the last dose of IP must be recorded in the eCRF. At minimum, the start date and 
description of the subsequent anticancer therapy must be collected. 
e
Patients may be contacted in the week following DCOs to confirm survival status. Details of any treatment for LS-SCLC (including surgery and hospitalizations) after the 
last dose of IP must be recorded in the eCRF.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.

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g
PK samples for durvalumab and its placebo are to be collected 12 weeks (±7 days) after treatment with  durvalumab/placebo ends. 
h
PK samples for tremelimumab and its placebo are to be collected 12 weeks (±7 days) after treatment with tremelimumab/placebo ends. If tremelimumab/placebo PK samples 
were taken at Cycle 7 as per Table 1, then the 12-week tremelimumab/placebo PK sample does not need to be collected again. Once 600 patients have been randomized, PK 
samples related to tremelimumab should not be collected for any newly randomized patients.
i
Immunogenicity samples for durvalumab and its placebo are to be collected 12 weeks (±7 days) and 24 weeks (±7 days) after treatment with the durvalumab/placebo ends.
j
Immunogenicity samples for tremelimumab and its placebo are to be collected 12 weeks (±7 days) and 24 weeks (±7 days) after treatment with tremelimumab/placebo ends. 
If tremelimumab/placebo ADA samples were taken at Cycle 7 and 10 as per Table 1, then these tremelimumab/placebo ADA samples do not need to be collected again.
Once 600 patients have been randomized, ADA samples related to tremelimumab should not be collected for any newly randomized patients.
k
ePRO LogPads assigned at randomization will be used.
l
See Section 8.1 and Appendix F for additional details relevant to the imaging schedule. The follow-up scan after a RECIST 1.1-defined PD is also evaluated according to 
RECIST 1.1 criteria (Appendix F).
m
Health resource use assessment should be performed every 24 weeks (±2 weeks) after treatment discontinuation and until PFS2 or study termination or death, whichever 
occurs first.
ADA Anti-drug antibody; AE Adverse event; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; DCO Data cut-off; ECOG Eastern 
Cooperative Oncology Group; eCRF Electronic case report form; EORTC European Organisation for Research and Treatment of Cancer; ePRO Electronic patient reported 
outcome; EQ-5D-5L  EuroQoL 5 dimension, 5 level health state utility index; IP Investigational product (ie, durvalumab, tremelimumab, or placebo); LS-SCLC Limited stage 
small-cell lung cancer; MRI Magnetic resonance imaging; PFS2 Time from randomization to second progression; PGIS Patient’s Global Impression of Severity; 
PK Pharmacokinetic; PRO Patient-reported outcome; QLQ-C30 30 Item core quality of life questionnaire; QLQ LC13 Lung cancer module; qXw Every X weeks; 
RECIST Response Evaluation Criteria In Solid Tumors; SAE Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO World 
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with recurrent SCLC, reported ORRs of 10% and 23% in patients with monotherapy and 
combination therapy, respectively, a median PFS of 1.4 months (95% CI: 1.2, 2.2 months) and 
2.6 months (95% CI: 1.4, 4.1 months) with monotherapy and combination therapy, respectively, 
and a median OS of 4.1 months (95% CI: 3.1, 9.1 months) and 7.9 months (95% CI: 3.6, 
14.2 months), respectively (Antonia 2016). These data warrant further development of 
durvalumab, an anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody (mAb), alone 
or in combination with tremelimumab, an antiCTLA-4 -mAb, in patients with LS-SCLC who 
have not progressed following platinum-based chemotherapy concurrent with radiotherapy 
(cCRT).
Study Design Change – Rationale and Impact
Since study inception in 2018, new clinical data have emerged regarding the management of 
SCLC and the role of immunotherapy:
CASPIAN
In the first-line ES-SCLC setting, the Phase III CASPIAN study (D419QC00001 
[NCT03043872]) demonstrated that addition of durvalumab to etoposide-platinum (EP) 
chemotherapy significantly improved OS (HR 0.73, 95% CI 0.59, 0.91; p = 0.0 47) (Paz-Ares et 
al 2019), confirming the role of immunotherapy (PD-L1 inhibition) in the management of 
ES-SCLC. 
In the same study, the treatment group investigating the combination of durvalumab and 
tremelimumab plus EP showed a numerical improvement in OS, but did not reach statistical 
significance (p ≤0.0418) per the prespecified statistical plan (HR 0.82, 95% CI 0.68, 1.00; 
p = 0.0451). However, safety and tolerability were consistent with known safety profiles of these 
medicines (Paz-Ares et al 2020). 
CHECKMATE-451
In the Phase III CHECKMATE-451 study (NCT02538666), which investigated the role of 
maintenance nivolumab monotherapy or nivolumab plus ipiliumumab after first-line platinum 
based chemotherapy in patients with extensive disease SCLC, the combination treatment did not 
reach statistical significance in terms of OS compared with placebo (HR 0.92, 95% CI: 0.8, 1.1; 
p = 0.37) (Owonikoko et al 2019).
CHECKMATE-032
The Phase I/II CHECKMATE-032 study (NCT01928394) published its recurrent SCLC cohort 
results in 2020, showing a higher ORR in the combination ipilimumab and nivolumab group 
compared to the nivolumab monotherapy group; however, overall efficacy results were similar in 
both groups (Ready et al 2020).
STIMULI
Data from the Phase II STIMULI study (NCT02046733) presented in 2020 indicated that 
patients with LS-SCLC who received nivolumab and ipilimumab after standard treatment 

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(chemotherapy and radiotherapy) showed no difference in PFS when compared with patients 
who received observation after standard treatment (HR 1.02, 95% CI: 0.66, 1.58; p = 0.93). This 
finding may possibly be due to the short period on active treatment observed in the study (Peters 
et al 2020). 
The accumulated evidence from the comparative trials suggests that the role of CTLA-4 
inhibition in combination with PD-1/PD-L1 inhibition remains ambiguous but not conclusive 
and that efficacy gains through the addition of CTLA4-inhibition to PD-L1 blockade may be 
limited. However, monthly blinded review of safety data from ADRIATIC has not detected a 
safety signal, hence continued evaluation of this combination therapy as a secondary objective 
remains warranted.
In view of the updated data, the sponsor has reconsidered the study hypothesis and modified the 
study design accordingly in the Version 4 Amendment:

OS for the comparison of durvalumab monotherapy versus placebo has been added to 
the primary endpoint, ie, the study now has dual primary endpoints of PFS and OS for 
the comparison of durvalumab monotherapy versus placebo; the comparison of 
durvalumab plus tremelimumab vs placebo in terms of PFS and OS are now secondary 
endpoints (Section 3).

Due to revision of the anticipated treatment effects on PFS and OS, the total sample 
size for the study has been increased from 600 to approximately 724 patients: the 
durvalumab monotherapy and placebo groups have both been increased to 
approximately 262 patients and the durvalumab plus tremelimumab combination 
treatment group has remained unchanged (approximately 200 patients).  
The following aspects of study design are also impacted:

As the number of patients in the durvalumab plus tremelimumab group is unchanged, 
once 600 patients have been randomized, randomization will continue 1:1 in the 
durvalumab monotherapy and placebo groups. 

Once 600 patients have been randomized, no further PK or ADA samples relevant to 
tremelimumab are required.

Enrolment in China may continue after global enrolment is closed to allow inclusion 
of a total of approximately 108 patients.

Several statistical sections have been updated to describe changes to the null 
hypotheses for the efficacy endpoints, the sample size determination, timing of the 
interim and final analyses, clarification of patients included in the analyses of the 
combination analysis set, the calculation or derivation of efficacy variables, the 
analyses of PFS, OS, and DoR, the description of methods for multiplicity control, and 
the updated details of the interim analyses of OS and their anticipated timing.

The benefit-risk assessment has been updated for durvalumab and overall.

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Objectives and Endpoints
Dual primary objectives:
Endpoints/variables:
To assess the efficacy of durvalumab 
monotherapy compared to placebo in terms of 
PFS 
PFS using BICR assessments according to 
RECIST 1.1
To assess the efficacy of durvalumab 
monotherapy compared to placebo in terms of 
OS
OS
Secondary objectives:
Endpoints/variables:
To assess the efficacy of durvalumab and 
tremelimumab combination therapy compared to 
placebo in terms of PFS and OS
PFS using BICR assessments according to 
RECIST 1.1
OS
To further assess the efficacy of durvalumab 
monotherapy and durvalumab and 
tremelimumab combination therapy compared to 
placebo in terms of ORR, PFS18a, PFS24a, 
TTDM, OS24, OS36, and PFS2
ORR, PFS18a, PFS24a, and TTDM using BICR 
assessments according to RECIST 1.1
OS24 and OS36
PFS2 
To assess the efficacy of durvalumab and 
tremelimumab combination therapy compared to 
durvalumab monotherapy in terms of PFS, OS, 
and ORR
PFS and ORR using BICR assessments according 
to RECIST 1.1
OS
To assess disease-related symptoms and HRQoL 
in patients treated with durvalumab 
monotherapy and durvalumab and 
tremelimumab combination therapy compared to 
placebo using the EORTC QLQ-C30 v3 and 
QLQ-LC13
EORTC QLQ-C30 and QLQ-LC13: change in 
symptoms, functioning, and global health 
status/QoL
To assess the PK of durvalumab monotherapy 
and durvalumab and tremelimumab combination 
therapy
Concentration of durvalumab and tremelimumab in 
serum (such as peak concentration and trough; 
sparse sampling)
To investigate the immunogenicity of 
durvalumab monotherapy and durvalumab and 
tremelimumab combination therapy
Presence of ADA for durvalumab and 
tremelimumab (confirmatory results: positive or 
negative)

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To investigate the relationship between PD-L1 
expression and spatial distribution within the 
tumor microenvironment and clinical outcomes 
with durvalumab monotherapy or durvalumab 
and tremelimumab combination therapy
PD-L1 expression in tumor and/or immune cells 
(cutoff ≥1%) relative to response/efficacy 
outcomes (PFS, OS, and ORR). Other PD-L1 
cutoffs may also be analyzed
Safety objective:
Endpoints/variables:
To assess the safety and tolerability profile of 
durvalumab monotherapy and durvalumab and 
tremelimumab combination therapy compared to 
placebo in patients with LS-SCLC
AEs; laboratory findings including clinical 
chemistry, hematology, and urinalysis; physical 
examinations; vital signs including blood pressure 
and pulse; and electrocardiograms
Exploratory objectives:
Endpoints/variables:
To assess treatment-related side effects in 
patients treated with durvalumab monotherapy 
and durvalumab and tremelimumab combination 
therapy compared to placebo using 
PRO-CTCAE
Change in the 9 treatment-related symptoms 
evaluated in this study
To assess the patients’ overall impression of the 
severity of their cancer symptoms using PGIS
PGIS: Proportion of patients assessing current 
symptom severity
To describe and evaluate health resource use 
associated with durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy and underlying disease
Health resource utilization measures including 
hospitalization, outpatient visits, or emergency 
department visits
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 collect blood and tissue samples, or leverage 
residual samples, for analysis of peripheral and 
tumoral biomarkers (not applicable for China)
Exploratory biomarkers, which may include but are 
not limited to, DNA, RNA, and protein-based 
assessment within the tumor microenvironment 
and/or in the periphery. Evaluation of tumor-cell 
and/or immune-cell gene expression profiles, tumor 
or ctDNA derived mutational analyses, PD-L1 
expression, SCLC molecular subtypes, 
tumor-immue spatial profiling, etc., and association 
of each biomarker with response and/or resistance
To investigate the relationship between TMB 
measured in tumor and/or blood and efficacy 
outcomes with durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy (not applicable for China) 
TMB relative to response/efficacy outcomes (ORR, 
PFS, and OS)

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To explore the relationship(s) between patient 
biomarker status and durvalumab PK exposure 
and clinical outcomes before and after treatment 
(TMB related testing or analysis will not be 
conducted on Chinese samples)
Biomarker status before and after treatment, 
durvalumab PK exposure, and relationship with 
clinical outcomes, efficacy, AEs, and/or safety 
parameters, as deemed appropriate 
To explore irRECIST as assessment 
methodologies for clinical benefit of durvalumab 
monotherapy and durvalumab and 
tremelimumab combination therapy compared to 
placebo with assessment by BICR
PFS and ORR using BICR assessment according to 
irRECIST
To collect and store DNA from tissue and/or 
blood 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 IPs and/or 
susceptibility to disease (optional, not applicable 
for China)
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety, or response parameters 
observed in patients treated with durvalumab and/or 
susceptibility to disease 
To investigate the effect of baseline colonic 
microbiome on response to treatment and the 
effect of treatment on the microbiome over time 
(applicable for EU and North America only)
Microbiome analysis of stool sample
a
Progression-free survival at 18 and 24 months following randomization (PFS18 and PFS24) is equivalent to the 
proportion of patients alive and progression-free at 18 and 24 months following randomization (APF18 and 
APF24), respectively.
ADA  Anti-drug antibody; AE  Adverse event; BICR  Blinded Independent Central Review; CTCAE Common 
Terminology Criteria for Adverse Events; ctDNA Circulating tumor DNA; EORTC European Organisation 
for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5 dimension, 5-level health state utility index; 
HRQoL Health-related quality of life; IP Investigational product; irRECIST Immune-related Response 
Evaluation Criteria In Solid Tumors; LS-SCLC Limited stage small cell lung cancer; ORR Objective 
response rate; OS Overall survival; OS24 Proportion of patients alive at 24 months from randomization; 
OS36 Proportion of patients alive at 36 months from randomization; PDL1 Programmed death ligand 1; 
PFS Progression-free survival; PFS2 Time from randomization to second progression; PFS18 Progression-
free survival at 18 months following randomization; PFS24 Progression-free survival at 24 months following 
randomization; PGIS Patient’s Global Impression of Severity; PK Pharmacokinetic(s); PRO Patient-reported 
outcome; QLQ-C30 30-item core quality of life questionnaire; QLQ-LC13  Lung cancer module; 
QoL Quality of life; RECIST  Response Evaluation Criteria In Solid Tumors; TMB Tumor mutational 
burden; TTDM  Time to death or distant metastasis. 
Overall design:
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing 
the efficacy and safety of durvalumab or durvalumab and tremelimumab combination therapy 
versus placebo as consolidation treatment in patients with LS-SCLC who have not progressed 
following definitive, platinum-based chemotherapy concurrent with radiotherapy (cCRT).

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In order to be eligible for this study, patients must have achieved complete response (CR), partial 
response (PR), or stable disease (SD) and have not progressed following definitive, 
platinum-based chemotherapy, concurrent with radiotherapy (cCRT). This cCRT treatment, and 
prophylactic cranial irradiation (PCI) treatment if received per local standard of care, must be 
completed within 1 to 42 days prior to randomization and the first dose of investigational product 
(IP; ie, durvalumab, tremelimumab, or placebo) in this study. In addition, the baseline efficacy 
assessment must be performed post-CRT as part of the screening procedures within 42 days 
before randomization and the first dose of IP.
Initially, patients will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups: durvalumab 
monotherapy, durvalumab and tremelimumab combination therapy, or placebo. Once 
600 patients have been randomized, subsequent patients will be randomized 1:1 to durvalumab 
monotherapy or placebo. Randomization will be stratified by stage (I/II versus III) based on 
tumor, node, and metastatic classification (TNM) and receipt of PCI (yes versus no).
Study Period:
Estimated date of first patient enrolled: Q3 2018
Estimated date of last patient completed: Q2 2025.
Number of patients:
Approximately 965 patients will be enrolled in order to randomize 724 patients. This includes 
approximately 524 patients randomized to the durvalumab monotherapy and placebo treatment 
groups (approximately 262 patients per treatment group), and approximately 200 patients to the 
durvalumab and tremelimumab combination treatment group.
Enrolment in China may continue after global enrolment is closed to allow inclusion of a total of 
approximately 108 patients randomized from sites in China (approximately 15% of the global 
sample size). Patients enrolled in China prior to the closure of global enrolment will be included 
in both the Global Cohort and the China Cohort. Patients enrolled in China after closure of 
global enrolment will only be analyzed in the China Cohort.
Treatments and treatment duration:
Patients will receive 1 of the following treatments, based on treatment group assignment:

Durvalumab monotherapy: Durvalumab (1500 mg intravenous [IV]) every 4 weeks 
(q4w) in combination with placebo (IV) q4w for 4 doses/cycles each, followed by 
durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will 
be 4 weeks after the final dose of durvalumab in combination with placebo . Following 
completion of enrollment in the durvalumab and tremelimumab combination therapy 
group, all patients newly randomized to durvalumab monotherapy will receive 1 
infusion only (durvalumab) from Cycle 1. Patients randomized prior to completion of 
enrolment to the durvalumab and tremelimumab treatment group will receive 
2 infusions (durvalumab and placebo) for the first 4 cycles, followed by 1 durvaluamb 
infusion from Cycle 5 onwards.

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
Placebo: Placebo (IV) q4w in combination with a second placebo (IV) q4w for 
4 doses/cycles each, followed by placebo monotherapy (IV) q4w from Cycle 5. The 
first placebo monotherapy dose q4w will be 4 weeks after the final dose of the 2 
placebo combination. Following completion of enrollment in the durvalumab and 
tremelimumab combination therapy group, all patients newly randomized to placebo 
will receive 1 infusion only (placebo) from Cycle 1. Patients randomized prior to 
completion of enrolment to the durvalumab and tremelimumab treatment group will 
receive 2 infusions (placebo + placebo) for the first 4 cycles, followed by 1 placebo 
infusion from Cycle 5 onwards.

Durvalumab in combination with tremelimumab: Durvalumab (1500 mg IV) q4w in 
combination with tremelimumab (75 mg IV) q4w for 4 doses/cycles each, followed by 
durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will 
be 4 weeks after the final dose of durvalumab in combination with tremelimumab. 
Once 600 patients have been randomized, subsequent patients will be randomized 1:1 
to the durvalumab monotherapy and placebo groups only.
Treatment in all treatment groups will continue until clinical/RECIST 1.1-defined radiological 
progression, until intolerable toxicity, or for a maximum of 24 months, whichever occurs first.
Please note, if a patient’s weight falls to 30 kg or below [≤30 kg], then the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab or placebo q4w and 1 mg/kg 
tremelimumab or placebo q4w after consultation between the Investigator and Study Physician, 
until the weight improves to above 30 kg [>30 kg], at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg or placebo plus tremelimumab 75 mg or 
placebo q4w.
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
clinical/RECIST 1.1-defined progression, until intolerable toxicity, or for a maximum of 
24 months, whichever occurs first. 
Follow-up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity, symptomatic deterioration, or clinical 
progression will be followed up with tumor assessments until RECIST 1.1-defined radiological 
progression plus one follow-up scan or until death (whichever comes first) and followed for 
survival. 
Survival
All patients randomized in the study should be followed up for survival.
Data Monitoring Committee:
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 and for the 
interim analyses. The safety review will take place after the first 20 patients have been 

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randomized into each of the 3 treatment groups (i.e. after a total of 60 patients have been 
randomized to the study). In addition, the IDMC will review planned interim analyses and 
inform the Sponsor whether the interim boundaries specified in Section 9.5.2 are met. 
Full details of the IDMC procedures, processes, and interim analyses can be found in the IDMC 
Charter.
Statistical methods
The dual primary objectives of this study are to assess the efficacy of durvalumab monotherapy 
compared to placebo in terms of PFS and OS. PFS (per RECIST 1.1 as assessed by Blinded 
Independent Central Review [BICR]) 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 anti-cancer therapy prior to progression. OS is defined as the time from the date of 
randomization until death due to any cause.
Efficacy data will be summarized and analyzed based on the full analysis set (FAS), and the 
treatment groups will be compared on the basis of randomized treatment, regardless of the 
treatment actually received. However, for efficacy analyses involving the durvalumab plus 
tremelimumab combination treatment group, only those patients randomized up to and including 
the date of the 600th patient will be included in the analyses. Patients who were randomized but 
did not subsequently go on to receive IP are included in the FAS. 
The study will be considered positive (ie, a success) if either of the null hypotheses outlined in 
Section 9.1 are rejected based on the dual primary analysis of PFS and/or OS in the FAS 
(durvalumab monotherapy versus placebo).
A multiple testing procedure will be used to strongly control the family-wise type I error rate 
(alpha) at 5% (2-sided) for the dual primary endpoints of PFS and OS. The alpha will be split 
with 0.5% allocated to PFS and 4.5% allocated to OS for the comparisons of durvalumab 
monotherapy versus placebo. If both are found to be significant, then OS and then PFS for the 
durvalumab plus tremelimumab combination versus placebo will be tested sequentially at 5%.
Three interim analyses are planned, 1 for PFS and 2 for OS. 
The interim analysis of PFS (PFS-IA) will occur when approximately 308 PFS BICR events 
have cumulated with 58.8% maturity in the durvalumab monotherapy and placebo treatment 
groups.
The first interim analysis of OS (OS-IA1) will occur at the time of the PFS interim analysis. It is 
anticipated that approximately 242 death events in the durvalumab monotherapy and placebo 
treatment groups with 46.2% maturity will have cumulated at this interim OS analysis. 
The second interim analysis of OS (OS-IA2) will occur when approximately 299 death events 
have cumulated with 57.1% maturity in the durvalumab monotherapy and placebo treatment 
groups.

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The primary PFS analysis will occur at the earliest of:
1. When approximately 370 PFS BICR events have occurred (70.6% maturity) in the 
durvalumab monotherapy and placebo treatment groups
2. At OS-IA2, if OS-IA2 is statistically significant (durvalumab monotherapy vs 
placebo)
3. 36 months after the last patient randomized
With 370 PFS BICR events, the study will have 90% power to detect a PFS HR = 0.65 (median 
PFS of 15.4 months versus 10 months) at the 2-sided 0.5% alpha level. A recruitment period of 
approximately 38 months are expected for the primary PFS analysis.
The primary OS analysis will occur when approximately 348 death events have occurred (66.4% 
maturity) in the durvalumab monotherapy and placebo treatment groups. With 348 death events, 
the study will have 80% power to detect a HR = 0.73 (median OS of 32.9 months versus 
24 months). 
The interim and primary PFS analysis will be based on the programmatically derived RECIST 
1.1 using BICR tumor assessments. PFS and OS analyses will be performed in the FAS using a 
stratified log-rank test adjusting for TNM stage (I/II versus III) and receipt of PCI (yes versus 
no). The effect of treatment will be estimated by the HR together with its corresponding CI from 
a Cox proportional hazards model. 
Safety data will be summarized descriptively and will not be formally analyzed.
Details of China subgroup analysis on efficacy and safety will be covered in the Statistical 
Analysis Plan (SAP).
1.3
Schema
The general study design is summarized in Figure 1.

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Figure 1
Study design
BID Twice daily; CR Complete response; CRT Chemoradiation therapy; D  Durvalumab; EP Etoposide and cisplatin chemotherapy; LS-SCLC Limited stage small-cell lung; PCI Prophylactic 
cranial irradiation; PD Progressive disease; PR Partial response; PS Performance status; QD Once daily; R Randomization; RT Radiotherapy; SD Stable disease; T Tremelimumab.

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2.
INTRODUCTION
Lung cancer has been among the most common cancers in the world for several decades, with an 
estimated 2.1 million new cases in 2018 (11.6% of all new cancers), and was also the most 
common cause of death from cancer in 2018, with 1.76 million deaths (18.4% of the total cancer 
deaths; GLOBOCAN 2018).
Small-cell lung cancer (SCLC) represents approximately 14% of all newly diagnosed lung 
cancers (Howlander et al 2016). In the United States (US), over 56,000 new cases of SCLC were 
diagnosed between 1983 and 2012 (Wang et al 2017). SCLC is distinguishable from non-small-
cell lung cancer (NSCLC) by its more aggressive characteristics that include rapid doubling time, 
high growth fraction, and early dissemination. It is also strongly associated with tobacco 
smoking and high tumor mutation rate (Peifer et al 2012). While the incidence of SCLC is 
declining for most age groups (Riaz et al 2012, Wang et al 2017), there has been little 
improvement in the median overall survival (OS) over the last 3 decades and this remains at 7 
months (Wang et al 2017).
A 2-stage system dividing patients into limited and extensive stage or disease was developed in 
1973 by the US Veteran’s Administration Lung Cancer Study Group (Zelen M 1973). Limited 
Stage (LS) was defined as tumor tissue that could be encompassed in a single radiation port, and 
Extensive Stage (ES) was defined as any tumor that extended beyond the boundaries of a single 
radiation port. At present, LS is diagnosed in ~30% of patients presenting with SCLC, and ES is 
diagnosed in ~70% of patients.
The standard-of-care treatment for LS-SCLC is thoracic radiotherapy (once daily with a total 
dose of 60 to 66 Gy or twice daily with a total dose of 45 Gy) combined with 4 cycles of either 
cisplatin or carboplatin and etoposide chemotherapy (Früh et al 2013, NCCN 2017). In addition, 
data suggest that prophylactic cranial irradiation (PCI; for patients that respond to initial therapy) 
may increase the OS and PFS in LS-SCLC patients (Aupérin et al 1999). Response rates for 
concurrent CRT in LS-SCLC are approximately 90%, but the majority of patients eventually 
progress, with median PFS of 10 to 15 months and median OS of 15 to 30 months (Faivre-Finn 
et al 2017, Grønberg et al 2016, Seckl et al 2017). Therefore, there is still a significant unmet 
medical need for additional treatment options for this patient population to improve PFS and OS.
2.1
Study rationale
SCLC may be particularly susceptible to immune checkpoint inhibitor therapy given the high 
mutational burden of this disease. Several recent studies analyzing data from different tumor 
types have demonstrated a correlation between mutational burden and response to checkpoint 
inhibitors targeting both PD-1 (Rizvi 2015) and CTLA-4 (Snyder et al 2014, Van Allen et al 
2015).
2.1.1
Durvalumab monotherapy
Data from 2 key AstraZeneca-sponsored studies and 1 non-AstraZeneca sponsored study suggest 
that durvalumab monotherapy may provide benefit to patients with LS-SCLC who have not 
progressed following CRT.

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
The AstraZeneca-sponsored PACIFIC study (D4191C00001 [NCT02125461]) 
evaluated sequential treatment with durvalumab versus placebo in patients with locally 
advanced, unresectable, Stage III NSCLC whose disease had not progressed following 
platinum-based concurrent CRT. The study demonstrated that the addition of 
durvalumab as sequential therapy to platinum-based CRT significantly improves PFS 
(improved median PFS from 5.6 to 16.8 months, HR of 0.52, 95% CI: 0.42, 0.65, 
p<0.0001; Antonia et al 2017) and subsequently the study also demonstrated statistical 
significant improvement in overall survival (OS) (HR of 0.68; 99.73% CI, 0.47 to 
0.997, p=0.00251); Antonia et al 2018), with well tolerated safety profile in patients 
with locally advanced NSCLC. 

In the AstraZeneca-sponsored, Phase I/IB study CD-ON-MEDI4736-1108 (hereafter 
referred to as Study 1108 [NCT01693562]), durvalumab monotherapy showed 
encouraging activity in 21 patients with pretreated ES-SCLC after a median followup 
of 36.4 months (range: 1.4 to 37.9 months), with an objective response rate (ORR) of 
9.5% and median OS of 4.8 months (95% CI: 1.3, 10.8). The 1-year OS rate was 
27.6% (95% CI: 10.2%, 48.4%). This is in contrast to a 9% 1-year OS observed with 
topotecan in refractory and resistant ES-SCLC, the only approved single agent in 
second-line treatment of ES-SCLC (Horita et al 2015). The safety profile of 
durvalumab monotherapy in Study 1108 was manageable and generally consistent 
with the known safety profile of the antiPDL1/PD1 drug class; immune-mediated AEs 
(imAEs) were manageable and generally reversible.

The CHECKMATE-032 study (NCT01928394), conducted in patients with recurrent 
SCLC, evaluated treatment with nivolumab (OPDIVO®; an antiPD-1 mAb) as 
monotherapy or in combination with ipilimumab (YERVOY®; an antiCTLA-4 mAb) 
in patients with relapsed ES-SCLC or LS-SCLC with progressive disease (PD) after at 
least 1 prior platinum-containing regimen. This has shown that nivolumab is active as 
monotherapy. Previously presented results for patients receiving nivolumab 
monotherapy included an ORR of 10%, a median PFS of 1.4 months (95% CI: 1.2, 2.2 
months), and a median OS of 4.1 months (95% CI: 3.1, 9.1 months), with manageable 
toxicity (Antonia 2016, CheckMate-032 WCLC Presentation 2016). 
Based on these data, Study D933QC00001 will evaluate the efficacy and safety of durvalumab 
monotherapy in patients with LS-SCLC who have not progressed following platinum-based 
chemotherapy concurrent with radiotherapy (cCRT).
2.1.2
Durvalumab in combination with tremelimumab
Additional data from later-line studies in patients with ES-SCLC suggest that treatment with 
durvalumab in combination with tremelimumab may provide synergistic antitumor activity in 
patients with LS-SCLC who have not progressed following CRT. 

In the AstraZeneca-sponsored, Phase I/II study (D4190C00010; hereafter referred to as 
Study 10 [NCT02261220]), durvalumab in combination with tremelimumab 
demonstrated clinical activity in heavily pretreated ES-SCLC, with an ORR of 13.3%, 
median OS of 7.9 months (95% CI: 3.2, NR), and 1-year OS rate of 41.7% (95% CI: 

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23.3%, 59.2%). The safety profile of durvalumab in combination with tremelimumab 
was manageable and generally consistent with the known safety profile of the 
antiPD-L1/PD-1 and CTLA-4 drug classes. Immune-mediated AEs were manageable 
and generally reversible.

The CHECKMATE-032 study (NCT01928394), conducted in patients with recurrent 
SCLC, evaluated treatment with nivolumab (OPDIVO®) as monotherapy or in 
combination with ipilimumab (YERVOY®) in patients with relapsed ES-SCLC or 
LS-SCLC with PD after at least 1 prior platinum-containing regimen. Previously 
presented results for patients receiving combination therapy with nivolumab and 
ipilimumab included an ORR of 23%, a median PFS of 2.6 months (95% CI: 1.4, 
4.1 months), and a median OS of 7.9 months (95% CI: 3.6, 14.2 months), with 
manageable toxicity (Antonia 2016, CheckMate-032 WCLC Presentation 2016). 
Based on these data, Study D933QC00001 will evaluate the efficacy and safety of durvalumab in 
combination with tremelimumab in patients with LS-SCLC who have not progressed following 
platinum-based chemotherapy concurrent with radiotherapy (cCRT) as secondary analyses.
In addition to safety and efficacy, the relationship between patient biomarker status (eg, PD-L1, 
tumor mutational burden, etc.) and efficacy outcomes will be evaluated as secondary or 
exploratory endpoints in this study; such data may indicate improved efficacy with either 
durvalumab monotherapy or durvalumab in combination with tremelimumab based on biomarker 
status.
2.1.3
Study Design Change – Rationale and Impact
Since study inception in 2018, clinical data have emerged regarding the management of SCLC 
and the role of immunotherapy. These data include:

In the first-line ES-SCLC setting, the Phase III CASPIAN study (D419QC00001 
[NCT03043872]) demonstrated that addition of durvalumab to etoposide-platinum 
(EP) chemotherapy significantly improved median OS from 10.3 to 13.0 months 
(HR 0.73, 95% CI: 0.59, 0.91, p = 0.047), with 34% (95% CI: 26.9, 41.0) versus 25% 
(95% CI: 18.4, 31.6) of patients alive at 18 months in the durvalumab plus EP vs EP 
treatment groups at a pre-planned interim analysis (Paz-Ares et al 2019). The OS 
benefit was sustained at final analysis with over 2 years’ follow up: median OS was 
12.9 vs 10.5 months (HR 0.75, 95% CI: 0.62, 0.91, p = 0.0032), with 22.2% versus 
14.4% of patients alive at 2 years in the durvalumab plus EP vs EP treatment groups 
(Paz-Ares et al 2020). 

In the same study, the treatment group investigating the combination of durvalumab 
and tremelimumab plus EP showed a numerical improvement in OS, but did not reach 
statistical significance compared to chemotherapy alone (EP) per the prespecified 
statistical plan (p ≤0.0418). Median OS was 10.4 vs 10.5 months (HR 0.85, 95% CI: 
0.68, 1.00, p = 0.0451), with 23.4% versus 14.4% of patients alive at 2 years in the 
durvalumab and tremelimumab plus EP vs EP treatment groups. However, safety and 
tolerability were consistent with known safety profiles of these medicines (Paz-Ares et 
al 2020). Additionally, PD-L1 correction analyses using a ≥1% cutoff in tumor and/or 

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immune cells suggest a potentially greater treatment effect with the combination of 
durvalumab and tremelimumab plus EP vs EP in patients in the PD-L1 ≥1% 
subgroups compared to those with PD-L1 < 1% (Data on file). TMB correlation 
analyses showed that TMB was not predictive of an improvement in OS for the 
durvalumab and tremelimumab plus EP combination vs EP (Goldman et al 2020).
Furthermore, there has been emerging new and updated clinical data regarding CTLA-4 
inhibitors in ES-SCLC.

As indicated above, in the Phase III CASPIAN study (NCT03043872) patients 
receiving first-line ES-SCLC treatment with the combination of durvalumab and 
tremelimumab plus EP showed numerical improvement in OS vs EP alone, but this did 
not reach statistical significance per the prespecified statistical plan (Paz-Ares et al 
2020).

The Phase III CHECKMATE-451 (NCT02538666) study investigated the role of 
maintenance nivolumab monotherapy or nivolumab plus ipiliumumab after first-line 
chemotherapy in patients with extensive disease SCLC. The combination treatment 
group did not reach statistical significance compared with placebo, with a HR of 0.92 
(95% CI: 0.8, 1.1; p = 0.37), median OS of 9.2 months (95% CI: 8.2, 10.2 months) vs 
placebo group median OS of 9.6 months (95% CI: 8.2, 11.0 months). Nivolumab 
monotherapy has shown HR of 0.84 (95% CI: 0.7, 1.0) vs placebo with median OS of 
10.4 months vs 9.6 months (Owonikoko et al 2019).

The Phase I/II CHECKMATE-032 study (NCT01928394) included a cohort of 
patients with recurrent SCLC who were randomized to receive nivolumab vs 
nivolumab plus ipilimumab. Updated results published in 2020 reported ORRs of 
11.6% and 21.9% in patients receiving nivolumab monotherapy and nivolumab in 
combination with ipilimumab, respectively. However, there were no differences in 
survival outcomes: median PFS was 1.4 months (95% CI: 1.3, 1.4 months) and 
1.5 months (95% CI: 1.4, 2.2 months) and median OS was 5.7 months (95% CI: 3.8, 
7.6 months) and 4.7 months (95% CI: 3.1, 8.3 months) for monotherapy and 
combination therapy, respectively (Ready et al 2020).

The Phase II STIMULI (NCT02046733) study investigated the efficacy and 
tolerability of standard treatment (chemotherapy and radiotherapy) alone compared 
with standard treatment followed by nivolumab and ipilimumab in patients with 
LS-SCLC. Results presented in 2020 indicated that there is no difference in PFS with 
an HR of 1.02 (95% CI: 0.66, 1.58; p = 0.93) in patients who received nivolumab and 
ipilimumab after standard treatment versus observation, with a median PFS of 
10.7 months vs 14.5 months. There was also no difference in OS, although OS data are 
immature (HR 1.06, 95% CI: 0.61, 1.86; p = 0.83). Grade ≥3 AEs were reported for 
62% of patients in the nivolumab and ipilimumab treatment arm vs 25% in the 
observation arm. Median time on active treatment was 1.7 months and the rate of 
discontinuations due to AEs was 55%. It was interpreted that the short duration of 
treatment due to the high rate of discontinuations may have impacted efficacy (Peters 
et al 2020).

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The accumulated evidence from comparative trials suggests that the role of CTLA-4 inhibition in 
combination with PD-1/PD-L1 inhibition remains ambiguous but not conclusive and that 
efficacy gains through the addition of CTLA4-inhibition to PD-L1 blockade may be limited. 
However, monthly blinded review of safety data from ADRIATIC has not detected a safety 
signal, hence continued evaluation of this combination therapy as a secondary objective remains 
warranted.
In view of the updated data, the sponsor has reconsidered the study hypothesis and modified the 
study design accordingly in the Version 4 amendment:

OS for the comparison of durvalumab monotherapy versus placebo has been added to 
the primary endpoint, ie, the study now has dual primary endpoints of PFS and OS for 
the comparison of durvalumab monotherapy versus placebo; the comparison of 
durvalumab plus tremelimumab versus placebo in terms of PFS and OS are now 
secondary endpoints (Section 3).

Due to revision of the anticipated treatment effects on PFS and OS, the total sample 
size for the study has been increased from 600 to approximately 724 patients: the 
durvalumab monotherapy and placebo groups have both been increased to 
approximately 262 patients and the durvalumab plus tremelimumab combination 
treatment group has remained unchanged (approximately 200 patients).  
The following aspects of study design are also impacted:

As the number of patients in the durvalumab plus tremelimumab group is unchanged, 
once 600 patients have been randomized, randomization will continue 1:1 in the 
durvalumab monotherapy and placebo groups. 

Once 600 patients have been randomized, no further PK or ADA samples relevant to 
tremelimumab are required.

Enrolment in China may continue after global enrolment is closed to allow inclusion 
of a total of approximately 108 patients.

Several statistical sections have been updated to describe changes to the null 
hypotheses for the efficacy endpoints, the sample size determination, timing of the 
interim and final analyses, clarification of patients included in the analyses of the 
combination analysis set, the calculation or derivation of efficacy variables, the 
analyses of PFS, OS, and DoR, the description of methods for multiplicity control, and 
the updated details of the interim analyses of OS and their anticipated timing.

The benefit-risk assessment has been updated for durvalumab and overall.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab alone 
and in combination with tremelimumab is provided in the IB.

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2.2.1
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 lymphocyte (T-cell) activation. The PD-1 receptor (CD279) is expressed on the surface of 
activated T cells (Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 
(B7-DC; CD273) (Okazaki and Honjo 2007). PD-1 and PD-L1/PD-L2 belong to a family of 
immune checkpoint proteins that act as co-inhibitory factors, which can halt or limit the 
development of T-cell response. When PD-L1 binds to PD1, an inhibitory signal is transmitted 
into the T-cell, which reduces cytokine production and suppresses T-cell proliferation. Tumor 
cells exploit this immune checkpoint pathway as a mechanism to evade detection and inhibit 
immune response.
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly overexpressed on tumor cells or on non-transformed cells in 
the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 
receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. These deactivated 
T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway represents an 
adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous 
antitumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and cluster of differentiation (CD)80 
receptors expressed on immune cells (ICs). 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 (MOA) is different from direct agonism of a stimulatory receptor such as 
CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of pre-clinical and clinical studies of mAbs targeting the PD-L1/PD-1 pathway have 
shown evidence of clinical activity and a manageable safety profile, supporting the hypothesis 
that an anti-PD-L1 antibody could be used to therapeutically enhance antitumor immune 
response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Iwai et al 2002, Okudaira et 
al 2009, Topalian et al 2012, Zhang et al 2008) with responses that tend to be more pronounced 
in patients with tumors that express PD-L1 (Powles et al 2014, Rizvi et al 2015, Segal et al 
2015). In addition, high mutational burden (eg, in bladder carcinoma; Alexandrov et al 2013) 
may contribute to the responses seen with immune therapy.
In contrast, 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 

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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 have now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as CTLA-4 and PD-L1 has promising clinical activity. 
Ipilimumab was first granted US Food and Drug Administration (FDA) approval for the 
treatment of metastatic melanoma and is currently under investigation for several other 
malignancies. Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an 
anti-PD-L1 agent, have been granted approvals by agencies for the treatment of a number of 
malignancies including metastatic melanoma, squamous and non-squamous cell NSCLC, 
squamous cell carcinoma of the head and neck, and urothelial carcinoma. In addition, there are 
data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a wide range of tumor 
types.
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand-2) with PD1 on 
T cells and CD80 (B7.1) on ICs. 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.) The 
MOA for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). 
Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune 
responses, including those that may result in tumor elimination. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the 
restored proliferation of interferon gamma (IFN-γ). In vivo studies have shown that durvalumab 
inhibits tumor growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 
2015). Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune 
response by binding to PDL1 and shifting the balance toward an antitumor response. 
Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity and 
complement-dependent cytotoxicity. 
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Sections 4.3.1 and 8.3.12. Refer to the current 
durvalumab IB for a complete summary of pre-clinical and clinical information including safety, 
efficacy, and PK. 
2.2.3
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 cytokines (interleukin 
[IL]-2 and 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. 

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Details on the safety profile of tremelimumab monotherapy are summarized in Section 2.3.2.3. 
Refer to the current tremelimumab IB for a complete summary of pre-clinical and clinical 
information including safety, efficacy, and PK.
2.2.4
Durvalumab in combination with tremelimumab
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both PD-1 
and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); therefore, 
AstraZeneca is also investigating the use of durvalumab and tremelimumab combination therapy 
for the treatment of cancer. In view of recent trial results, this will be undertaken as a secondary 
objective (see Section 2.1.3).
To date, more than 3000 patients have received the combination using a number of doses and 
dosing schedules. Details on the safety profile of durvalumab and tremelimumab combination 
therapy are summarized in Sections 4.3.1 and 2.3.2.4. Refer to the current editions of the 
durvalumab and tremelimumab IBs for a complete summary of pre-clinical and clinical 
information including safety, efficacy, and PK.
2.3
Benefit/risk assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab and tremelimumab may be found in the durvalumab IB. 
See Section 9.6.1 and Appendix A for information regarding the IDMC.
2.3.1
Potential benefits
2.3.1.1
Durvalumab
Durvalumab monotherapy was evaluated in an SCLC cohort expansion of Study 1108 
(NCT01693562). A total of 21 patients with pre-treated ES-SCLC were enrolled; the ORR was 
9.5%, median PFS was 1.5 months, OS was 4.8 months (95% CI: 1.3, 10.8), and the 1-year 
survival rate was 27.6% (95% CI: 10.2%, 48.4%) with a median follow-up of 36.4 months 
(Goldman et al 2018).
The PACIFIC study (D4191C00001 [NCT02125461]) compared sequential treatment with 
durvalumab versus placebo in patients with locally advanced, unresectable, Stage III NSCLC 
whose disease had not progressed following platinum-based chemotherapy concurrent with 
radiotherapy. The results of the PACIFIC study demonstrated that durvalumab as consolidation 
treatment after definitive CRT provides statistically significant prolongation of PFS, which 
translates to a 48% reduction of risk of relapse. The median PFS from randomization was 16.8 
months (95% CI: 13.0, 18.1 months) with durvalumab versus 5.6 months (95% CI: 4.6, 7.8 
months) with placebo (HR 0.52; 95% CI: 0.42, 0.65; p <0.0001) (Antonia et al 2017). 
Subsequently the study also demonstrated statistical significant improvement in OS with HR of 
0.68; 99.73% CI, 0.47 to 0.997, p=0.00251 (Antonia et al 2018).
The Phase III CASPIAN study (D419QC00001 [NCT03043872]) investigated durvalumab as 
part of combination therapy in the first-line ES-SCLC setting. The study demonstrated that the 
addition of durvalumab to EP chemotherapy significantly improved median OS from 10.3 to 

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13.0 months (HR 0.73, 95% CI: 0.59, 0.91; p = 0.047). In addition, in the durvalumab plus EP 
treatment group, 34% (95% CI: 26.9, 41.0) of patients were alive at 18 months compared with
25% (95% CI: 18.4, 31.6) of patients in the EP treatment group (Paz-Ares et al 2019). This 
confirmed the role of durvalumab in addition to standard of care chemotherapy, followed by 
ongoing durvalumab treatment in the first line ES-SCLC setting. Final analysis confirmed that 
the improvement in OS was sustained over 2 years’ follow-up, with HR of 0.75 (Paz-Ares et al 
2020).
2.3.1.2
Durvalumab in combination with tremelimumab
The efficacy of durvalumab and tremelimumab combination therapy was initially evaluated in an 
ongoing dose escalation and dose expansion study in patients with NSCLC 
(Study D4190C00006). 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 objective response (BoR) of PR, 14 patients (22%) had a BoR 
of SD, 22 patients (35%) had PD, and 10 patients (16%) were Not Evaluable (NE). The ORR 
(confirmed and unconfirmed CR or PR) was 27%, and the disease control rate (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.
Durvalumab in combination with tremelimumab was evaluated in 30 patients with heavily 
pre-treated ES-SCLC in Study 10 (NCT02261220): the ORR was 13.3%, the median PFS was 
1.8 months, the median OS was 7.9 months (95% CI: 3.2, NR), and the 1-year survival rate was 
41.7% (95% CI: 23.3%, 59.2%) (Cho et al 2018). 
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or 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 normal 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 that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ system 
and are most commonly seen as gastrointestinal (GI) AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypo- and hyper-thyroidism. 
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypo-thyroidism,  type I diabetes mellitus and diabetes insipidus), hepatitis/increases in 

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transaminases, nephritis/increases in creatinine, rash/dermatitis (including pemphigoid), 
myocarditis, myositis/polymyositis, immune thrombocytopenia, infusion-related reactions, 
hypersensitivity reactions, pancreatitis, encephalitis, serious infections, 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, 
and decreased appetite. 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 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 8.4.5).
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB
2.3.2.2
Durvalumab after completion of CRT
In the PACIFIC study (D4191C00001 [NCT02125461]), durvalumab treatment in patients with 
locally advanced, unresectable Stage III NSCLC who had recently completed CRT demonstrated 
a well-tolerated and manageable safety profile that was consistent with the established safety 
profile to date, with the exception of the events of pneumonitis/radiation pneumonitis (Antonia et 
al 2017, Antonia et al 2018). AEs were reported in 96.8% of patients who received durvalumab 
and 94.9% who received placebo; Grade 3 or 4 AEs were reported in 30.5% of patients who 
received durvalumab and 26.1% who received placebo. The most frequently reported Grade 3 or 
4 AE was pneumonia (4.4% and 3.8%, respectively). SAEs were reported in 28.6% and 22.6% of 
patients, respectively, and deaths due to AEs occurred in 4.4% and 6.0% of patients, 
respectively. Pneumonitis and radiation pneumonitis were notable events in multiple AE 
categories. There was a numerical increase in these events in the durvalumab group over placebo 
(32.8% vs 23.5%, respectively, patients with pneumonitis or radiation pneumonitis of any grade), 
but most of these events were low grade and manageable. Grade 3 or 4 pneumonitis was reported 
in 3.4% and 2.1% of patients in the durvalumab and placebo groups, respectively. Clinically 
important CTCAE Grade 3 and above events were infrequent and balanced between the 2 
groups. In addition to pneumonitis, the other adverse events of special interest (AESIs) and 
immune-mediated adverse events (imAEs) reported in the study were typical of the PD-1/PD-L1 
class of immunotherapies and were generally manageable and/or reversible with appropriate 
treatment guidelines, which included the use of steroids or endocrine therapy, withholding 
durvalumab until the event resolved, or permanent discontinuation of durvalumab.
2.3.2.3
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhea, enterocolitis, and intestinal perforation); endocrine disorders (hypo- and 

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hyperthyroidism, hypophysitis, and adrenal insufficiency); skin effects (rash and pruritus); 
clinical manifestations of pancreatitis (elevations in lipase and amylase); hepatic events 
(including immune mediated hepatitis and liver enzyme elevations); pneumonitis and ILD; 
neurotoxicity (including encephalitis, encephalopathy, peripheral motor and sensory 
neuropathies, and Guillain-Barré syndrome); thrombocytopenia, anemia, and neutropenia; 
infusion-related reactions and hypersensitivity/anaphylactic reactions; renal events (including 
tubulointerstitial nephritis/autoimmune nephritis and acute kidney injury, autoimmune arthritis, 
Sjogren’s syndrome, 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
2.3.2.4
Durvalumab and 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, is 
being studied in a number of other ongoing clinical studies in a number of different indications, 
and has to date 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 those for 
durvalumab monotherapy with additional risks of intestinal perforation and large intestinal 
perforation, which are unique risks for the durvalumab and tremelimumab combination. 
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 20 mg/kg and 
tremelimumab 1 mg/kg, AEs reported at an incidence of > 20% included events such as fatigue, 
diarrhea, 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.

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A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB
2.3.3
Overall benefit/risk
There remains a significant unmet medical need for additional treatment options for patients with 
LS-SCLC. Despite favorable initial responses with the current standard of care in this aggressive 
disease, the majority of LS-SCLC patients relapse with a median OS of 15 to 30 months (Faivre-
Finn et al 2017, Grønberg et al 2016, Seckl et al 2017). The poor prognosis reflects the limited 
treatment options available, highlighting the need for the development of newer therapeutic 
options.
The efficacy of treatment with checkpoint inhibitor immunotherapies in patients with SCLC has 
been observed in multiple recent studies, including studies with durvalumab alone or in 
combination with tremelimumab (eg, Study 1108 [NCT01693562] and Study 10 
[NCT02261220]). These data suggested that durvalumab is active in SCLC. The safety profile of 
durvalumab with or without tremelimumab is consistent with the pharmacology of the target and 
other agents in the immune checkpoint inhibitor class. 
Results from the PACIFIC study (D4191C00001 [NCT02125461]) further support the efficacy 
and safety of durvalumab as consolidation treatment post CRT. The results from the CASPIAN 
(D419QC00001 [NCT03043872]) study demonstrated statistical significant and sustained 
improvement in OS in patients with ES-SCLC when durvalumab was added to platinum based 
chemotherapy.
As indicated in Section 2.1.3, emerging data suggest that the efficacy of PD-L1 inhibition in 
combination with CTLA-4 inhibition in ES-SCLC is ambiguous, but not conclusive. However, 
the available data do still warrant the inclusion of a combination treatment group of durvalumab 
plus tremelimumab in the present study; the efficacy analyses for this combination will be 
considered as secondary endpoints only.
The overall benefit/risk assessment continues to support the proposed study to evaluate the 
efficacy and safety of durvalumab monotherapy and durvalumab in combination with 
tremelimumab when given as consolidation therapy in patients with LS-SCLC.
3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Dual primary objectives:
Endpoints/variables:
To assess the efficacy of durvalumab 
monotherapy compared to placebo in terms of 
PFS 
PFS using BICR assessments according to 
RECIST 1.1
To assess the efficacy of durvalumab 
monotherapy compared to placebo in terms of OS
OS

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Secondary objectives:
Endpoints/variables:
To assess the efficacy of durvalumab and 
tremelimumab combination compared to placebo 
in terms of PFS and OS
PFS using BICR assessments according to 
RECIST 1.1
OS
To further assess the efficacy of durvalumab 
monotherapy and durvalumab and tremelimumab 
combination therapy compared to placebo in 
terms of ORR, PFS18a, PFS24a, TTDM, OS24, 
OS36, and PFS2
ORR, PFS18a, PFS24a, and TTDM using BICR 
assessments according to RECIST 1.1
OS24 and OS36
PFS2
To assess the efficacy of durvalumab and 
tremelimumab combination therapy compared to 
durvalumab monotherapy in terms of PFS, OS, 
and ORR
PFS and ORR using BICR assessments according 
to RECIST 1.1
OS
To assess disease-related symptoms and HRQoL 
in patients treated with durvalumab monotherapy 
and durvalumab and tremelimumab combination 
therapy compared to placebo using the EORTC 
QLQ-C30 v3 and QLQ-LC13
EORTC QLQ-C30 and QLQ-LC13: change in 
symptoms, functioning, and global health 
status/QoL
To assess the PK of durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy
Concentration of durvalumab and tremelimumab 
in serum (such as peak concentration and trough; 
sparse sampling)
To investigate the immunogenicity of durvalumab 
monotherapy and durvalumab and tremelimumab 
combination therapy
Presence of ADA for durvalumab and 
tremelimumab (confirmatory results: positive or 
negative)
To investigate the relationship between PD-L1 
expression and spatial distribution within the 
tumor microenvironment and clinical outcomes 
with durvalumab monotherapy or durvalumab and 
tremelimumab combination therapy
PD-L1 expression in tumor and/or immune cells 
(cutoff ≥1%) relative to response/efficacy 
outcomes (PFS, OS, and ORR). Other PD-L1 
cutoffs may also be analyzed
Safety objective:
Endpoints/variables:
To assess the safety and tolerability profile of 
durvalumab monotherapy and durvalumab and 
tremelimumab combination therapy compared to 
placebo in patients with LS-SCLC
AEs; laboratory findings including clinical 
chemistry, hematology, and urinalysis; physical 
examinations; vital signs including blood pressure 
and pulse; and electrocardiograms

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Exploratory objectives:
Endpoints/variables:
To assess treatment-related side effects in patients 
treated with durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy compared to placebo using PRO-CTCAE
Change in the 9 treatment-related symptoms 
evaluated in this study
To assess the patients’ overall impression of the 
severity of their cancer symptoms using PGIS
PGIS: Proportion of patients assessing current 
symptom severity
To describe and evaluate health resource use 
associated with durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy and underlying disease
Health resource utilization measures including 
hospitalization, outpatient visits, or emergency 
department visits
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 collect blood and tissue samples, or leverage 
residual samples, for analysis of peripheral and 
tumoral biomarkers (not applicable for China)
Exploratory biomarkers, which may include but 
are not limited to, DNA, RNA, and protein-based 
assessment within the tumor microenvironment 
and/or in the periphery. Evaluation of tumor-cell 
and/or immune-cell gene expression profiles, 
tumor or ctDNA-derived mutational analyses, 
PD-L1 expression, SCLC molecular subtypes, 
tumor-immune spatial profiling, etc., and 
association of biomarkers with response and/or 
resistance
To investigate the relationship between TMB 
measured in tumor and/or blood and efficacy 
outcomes with durvalumab monotherapy and 
durvalumab and tremelimumab combination 
therapy (TMB-related testing or analysis will not 
be conducted on samples from China) 
TMB relative to response/efficacy outcomes 
(ORR, PFS, and OS)
To explore the relationship(s) between patient 
biomarker status and durvalumab PK exposure 
and clinical outcomes before and after treatment 
(TMB related testing or analysis will not be 
conducted on samples from China)
Biomarker status before and after treatment, 
durvalumab PK exposure, and relationship with 
clinical outcomes, efficacy, AEs, and/or safety 
parameters, as deemed appropriate

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To explore irRECIST as assessment 
methodologies for clinical benefit of durvalumab 
monotherapy and durvalumab and tremelimumab 
combination therapy compared to placebo with 
assessment by BICR
PFS and ORR using BICR assessment according 
to irRECIST
To collect and store DNA from tissue and/or 
blood 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 IPs and/or susceptibility to disease 
(optional, not applicable for China)
Correlation of polymorphisms with variation in 
PK, pharmacodynamics, safety, or response 
parameters observed in patients treated with 
durvalumab and/or susceptibility to disease
To investigate the effect of baseline colonic 
microbiome on response to treatment and the 
effect of treatment on the microbiome over time 
(applicable for EU and North America only)
Microbiome analysis of stool sample
a
Progression-free survival at 18 and 24 months following randomization (PFS18 and PFS24) is equivalent to the 
proportion of patients alive and progression free at 18 and 24 months following randomization (APF18 and 
APF24), respectively.
ADA  Anti-drug antibody; AE  Adverse event; BICR  Blinded Independent Central Review; CTCAE Common 
Terminology Criteria for Adverse Events; ctDNA Circulating tumor DNA; EORTC European Organisation
for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5 dimension, 5-level health state utility index; 
HRQoL Health-related quality of life; IP Investigational product; irRECIST Immune-related Response 
Evaluation Criteria In Solid Tumors; LS-SCLC Limited stage small cell lung cancer; ORR Objective response 
rate; OS Overall survival; OS24 Proportion of patients alive at 24 months from randomization; 
OS36 Proportion of patients alive at 36 months from randomization; PD-L1  Programmed death ligand 1;
PFS Progression-free survival; PFS2 Time from randomization to second progression; PFS18 Progression-
free survival at 18 months following randomization; PFS24 Progression-free survival at 24 months following 
randomization; PGIS Patient’s Global Impression of Severity; PK Pharmacokinetic(s); PRO Patient-reported 
outcome; QLQ-C30 30-item core quality of life questionnaire; QLQ-LC13  Lung cancer module; 
QoL Quality of life; RECIST  Response Evaluation Criteria In Solid Tumors; TMB Tumor mutational 
burden; TTDM  Time to death or distant metastasis.
4.
STUDY DESIGN
4.1
Overall design
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing 
the efficacy and safety of durvalumab or durvalumab and tremelimumab combination therapy 
versus placebo as consolidation treatment in patients with LS-SCLC who have not progressed 
following definitive, platinum-based chemotherapy concurrent with radiotherapy (cCRT).
In order to be eligible for this study, patients must have achieved CR, PR, or SD and have not 
progressed following definitive, platinum-based chemotherapy concurrent with radiotherapy 
(cCRT). This cCRT treatment, and PCI treatment if received per local standard of care, must be 
completed within 1 to 42 days prior to randomization and the first dose of investigational product 

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(IP; ie, durvalumab, tremelimumab, or placebo) in this study. (Additional details are provided in 
Sections 5.1 and 5.2.) In addition, the baseline efficacy assessment must be performed post-CRT 
as part of the screening procedures within 42 days before randomization and the first dose of IP.
Approximately 965 patients will be recruited and screened in order to enroll and randomize 
approximately 724 patients to 1 of 3 treatment groups: durvalumab monotherapy (approximately 
262 patients), placebo (approximately 262 patients), and durvalumab and tremelimumab 
combination therapy (approximately 200 patients). (See Section 6.1.2 for descriptions of the 
dosing regimens.) Randomization will be stratified by stage (I/II versus III) based on TNM 
classification and receipt of PCI (yes versus no). Patients will receive their assigned treatment 
until clinical/RECIST 1.1-defined radiological progression, until intolerable toxicity, or for a 
maximum of 24 months, whichever occurs first (See Section 7.1 for additional details on 
discontinuation of study treatment).
To ensure that there is no significant over recruitment beyond the planned 724 patients 
randomization target, the AstraZeneca Study Team will actively manage study enrolment. The 
AstraZeneca Study Team may close global study enrolment to all sites apart from sites in China 
at an appropriate time to ensure approximately 724 patients are randomized to the global study 
population. If necessary, recruitment of patients from sites in China will continue until 
approximately 108 patients (approximately 15%) are randomized. Enrolment of patients from 
sites in China will be actively managed by the AstraZeneca Study Team to ensure there is no 
significant over recruitment of patients from sites in China. Patients enrolled in China prior to the 
closure of global study enrolment will be included in both the Global Cohort and the China 
Cohort. Patients enrolled in China after global enrolment closure will only be analyzed in the 
China Cohort. If approximately 108 patients are enrolled in the global cohort, then the additional 
China Cohort will not be created.
For an overview of the study design, see Figure 1
Study design
, Section 1.3. For details on treatments given during the study, see Section 6.1 Treatments 
Administered. For details on what is included in the efficacy and safety endpoints, see Section 3
Objectives and Endpoints. 
4.2
Scientific rationale for study design
4.2.1
Rationale for study endpoints (efficacy)
The primary aim of this study is to assess the efficacy of durvalumab monotherapy compared to 
placebo in terms of PFS and OS. 
PFS may serve as a surrogate for OS when differences between treatment groups are of sufficient 
magnitude and are clinically important (FDA Guidance 2011, Foster et al 2015, Mauguen et al 
2013, Pazdur 2008). In particular, PFS has shown a strong surrogacy for OS in first-line ES 
SCLC studies (Foster et al 2015). In this study PFS and OS will be dual primary endpoints for 
durvalumab monotherapy versus placebo. 

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The secondary efficacy endpoints will be examined to further evaluate the antitumor effect of 
durvalumab monotherapy versus placebo. The combination of durvalumab and tremelimumab 
will be investigated versus placebo as secondary analyses. Antitumor activity will be assessed 
based on BICR assessments according to RECIST 1.1 guidelines.
Sensitivity analyses will also be performed using study site Investigator’s tumor data from all 
scans based on RECIST 1.1. 
Response to immunotherapy may differ from typical responses observed with cytotoxic 
chemotherapy, including the following differences (per Wolchok et al 2009):
1.
Response to immunotherapy may be delayed.
2.
Response to immunotherapy may occur after PD by conventional criteria.
3.
SD while on immunotherapy may be durable and represent clinical benefit.
The secondary symptoms and overall health-related quality of life (HRQoL) endpoints, assessed 
using the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core 
quality of life questionnaire, version 3 (QLQ-C30 v3) and the complementary 13-item Lung 
Cancer Quality of Life questionnaire (QLQ-LC13) will show the overall influence of the benefits 
and toxicity of the treatment from a patient’s perspective and will aid in understanding of the 
benefit/risk evaluation. These PRO questionnaires are well-established instruments that have 
been previously included in cancer clinical studies.
4.2.2
Rationale for study endpoints (other secondary and exploratory endpoints)
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or serum, 
which may influence the progression of cancer (and associated clinical characteristics) and/or 
response to durvalumab with or without tremelimumab. Blood samples will be taken to allow for 
research into PK and immunogenicity of durvalumab and tremelimumab.
SCLC is characterized by its high mutational burden. The exploratory analysis from 
CheckMate-032 [NCT01928394] have shown that, for patients treated with either nivolumab 
monotherapy or nivolumab plus ipilimumab, efficacy was enhanced among patients with a high 
tumor mutational burden (ie, high TMB). In the TMB high subgroup, the combination of 
nivolumab and ipilimumab appeared to provide greater clinical benefit compared with 
nivolumab monotherapy, with doubling 1-year survival rate (62.4% vs 35.2%, respectively; 
Hellmann et al 2018). To better understand the significance of this finding and any impact this 
may have on patients in the present study (ADRIATIC), we plan to assess tumor burden in both 
tumor and blood samples as secondary and exploratory endpoints (not applicable in China).
PD-L1 expression has also been shown to play a significant role in response to immunotherapy 
in late-stage NSCLC (Brody et al 2017, Reck et al 2016). Although such data remain sparse in 
SCLC, PD-L1 will also be evaluated as a potential predictive biomarker in this study.

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The assessment of health economic resource use data and derivation of health state utility will 
provide important information for payers and will be used within economic evaluations of 
durvalumab and tremelimumab.
4.2.3
Rationale for treatment duration
The median PFS for patients with LS-SCLC after cCRT is about 10 months, therefore 
continuation of treatment up to PD is justifiable. Treatment in this study will continue until 
clinical/RECIST 1.1-defined radiological progression, until intolerable toxicity, or for a 
maximum of 24 months, whichever occurs first (see Section 7.1). This guidance was supported 
by data from the CHECKMATE-153 study presented at the 2017 European Society for Medical 
Oncology Congress, which indicated that patients treated with nivolumab (an anti-PD-1 agent) 
until PD showed superior PFS when compared to treatment with nivolumab with a 1-year fixed 
duration (HR: 0.43; 95% CI: 0.25, 0.76), a trend toward improved OS, and no new safety signals 
after 1 year of treatment (Spigel et al 2017). In the PACIFIC study, the treatment duration was 
limited to 12 months; however, the safety data from the PACIFIC study (D4191C00001; 
NCT02125461) suggest that the risk of developing immune-modulated toxicities remains very 
low and that the cumulative probability of onset of new events was also very low beyond 
6 months of treatment. Treatment will be discontinued following clinical progression or 
RECIST 1.1-defined radiological PD to allow the patient the opportunity to utilize an alternate 
anticancer treatment. Patients that do not experience disease progression will be treated for a 
maximum of 24 months, unless there is intolerable toxicity or withdrawal of consent, or another 
discontinuation criterion is met.
4.3
Justification for dose
4.3.1
Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, pre-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 (NCT01693562) in 
patients with advanced solid tumors and from a Phase I study performed in Japanese patients 
with advanced solid tumor (D4190C00002).
PK/pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 (NCT01693562) 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 durvalumab IB). 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a similar overall 

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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 
anti-drug antibody (ADA) impact; and (d) achieve PK exposure that yielded maximal antitumor 
activity in animal models.
Given the similar area under the serum drug concentration-time curve 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 PK at the 20 mg/kg q4w regimen.
4.3.1.1
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data Study 1108 
(NCT01693562; 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 to 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 I 
through Phase III (N=654; doses= 0.01 to 15 mg/kg q4w or q90d; metastatic melanoma) (Wang 
et al 2014). Population PK modeling indicated a minor impact of body WT on the PK of 
tremelimumab (coefficient of ≤0.5). The WT-based (1 mg/kg q4w) and fixed dosing (75 mg/kg 
q4w; based on median body WT of ~75 kg) regimens were compared using predicted PK 
concentrations (5th, median, and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body WT 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 (Narwal et al 2013, Ng et al 2006, Wang 
et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 monoclonal antibodies and 

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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 PK/pharmacodynamic parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1500 mg q4w durvalumab (equivalent to 20 mg/kg q4w) and a fixed dose of 75 mg 
q4w tremelimumab (equivalent to 1 mg/kg q4w) is included in the current study.
4.3.2
Durvalumab and tremelimumab dose and treatment regimen justification
4.3.2.1
Durvalumab and tremelimumab combination therapy dose rationale
The durvalumab and 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 (sPD-L1), demonstrate promising 
efficacy, and have an acceptable safety profile. 
Pharmacokinetics/pharmacodynamics data
Study D4190C00006 included dose cohorts with both a q4w and an every 2 weeks (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 serum 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 
preclinically and in line with that seen in the first-time-in-human, single agent study 
(CD-ON-MEDI4736-1108 [NCT01693562]) 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 serum 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 expected to impact the overall safety and efficacy profile, 
based on existing pre-clinical 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 

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20 mg/kg. Tremelimumab was given on a q4w schedule, while durvalumab was explored in both 
q4w and q2w schedules, 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 AEs, including 
discontinuations due to 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 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 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. 
Altogether, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose 
combination should be selected for further development. 
Refer to the current durvalumab IB for a complete summary of pre-clinical and clinical 
information on the durvalumab and tremelimumab combination, including safety, efficacy, and 
PK.

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4.3.2.2
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). 
Data from Study D4190C00006 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, see the current durvalumab 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.
The durvalumab and tremelimumab combination regimen will be administered for 4 doses q4w 
followed by durvalumab monotherapy q4w until clinical/RECIST 1.1-defined radiological 
progression, until intolerable toxicity, or for a maximum of 24 months, whichever occurs first, or 
unless other specific discontinuation criteria are met. 
4.4
End of study definition
For the purpose of Clinical Trial Transparency the definition of the end of the study differs under 
FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for any
protocol related activity.
Food and Drug Administration requirements defines 2 completion dates:

Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes.

Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measures and AEs (for example, last participant’s last visit), whether 
the clinical study concludes according to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of the 
study including the last visit (including OS determination). 

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The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
Should the study meet the primary endpoint at any of the prescribed interim analyses, additional 
data cuts may be needed per local health authority requirements.
See Section 6.6 for details on  management following the final DCO, as well as following study 
completion.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be randomized to a study intervention. Under no circumstances can there be 
exceptions to this rule. Patients who do not meet the entry requirements are screen failures (refer 
to Section 5.4).
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
“Randomized” patients are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly enrolled or randomized patients, see Section 6.2.2.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion 
criteria apply:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
2.
Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses. 
3.
Optional provision of signed and dated written genetic informed consent prior to 
collection of sample for genetic analysis (Not applicable for China)
The ICF process is described in Appendix A 3.

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Age
4.
≥18 years at the time of screening. For patients aged <20 years and enrolled in Japan, a 
written informed consent should be obtained from the patient and his or her legally 
acceptable representative.
Type of patient and disease characteristics
5.
Histologically or cytologically documented limited-stage SCLC (Stage I-III SCLC 
[T any, N any, M0] according to the American Joint Committee on Cancer Staging 
Manual [AJCC Cancer Staging Manual, 8th Edition] or the International Association 
for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging 
Manual in Thoracic Oncology 2016]), ie, patients whose disease can be encompassed 
within a radical radiation portal. Patients who are Stage I or II must be medically 
inoperable as determined by investigator.
6.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1 at enrollment and randomization
7.
Received an appropriate first line concurrent chemoradiotherapy regimen as defined 
below, unless after consultation with the global study medical team an alternative is 
acceptable

Received 4 cycles of platinum-based chemotherapy concurrent with RT, which 
must be completed within 1 to 42 days prior to randomization and the first dose of 
IP.

The chemotherapy regimen must contain platinum and IV etoposide, administered 
as per local standard-of-care regimens.

Received a total dose of radiation of 60 to 66 Gy over 6 weeks for standard QD 
radiation schedules or 45 Gy over 3 weeks for hyperfractionated BID radiation 
schedules. Sites are encouraged to adhere to mean organ radiation dosing as 
follows:
o
Mean lung dose <20 Gy and/or V20 <35%
o
Heart V50 <25%

Radiotherapy must have commenced no later than the end of Cycle 2 of 
chemotherapy.

Receipt of 3 cycles of platinum-based chemotherapy concurrent with RT will be 
permitted if the patient has achieved disease control and in the opinion of the 
Investigator, no additional benefit will be expected with additional cycle of 
chemotherapy.

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8.
Patients must have achieved CR, PR, or SD and not have progressed following 
definitive, platinum-based chemotherapy concurrent with radiotherapy.
9.
PCI may be delivered at the discretion of investigator and local standard of care, and 
must be conducted after the end of cCRT and completed between 1 to 42 days to first 
dose of IP. 
10.
Tumor sample requirements:

Mandatory availability of tumor sample, which may include a core needle biopsy, 
newly cut unstained slides, or fine needle aspirate (FNA) cell block samples. 
(refer to Section 8.8 for details on accepted tumor samples and order of 
preference). Tissue sample should be submitted before or within 60 days of 
randomization. However, patients may be enrolled into the study before the pre-
treatment tumor tissue sample is submitted.

A newly acquired tumor biopsy (taken following completion of 
chemoradiotherapy) is optional, provided that a biopsy procedure is technically 
feasible, and the procedure is not associated with unacceptable clinical risk.
11.
Adequate organ and marrow function (independent of transfusion, infusion, or growth 
factor support for at least 14 days prior to obtaining screening labs), defined as below:

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.5 × 109 /L

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 (persistent or recurrent 
hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of 
evidence of hemolysis or hepatic pathology), who will be allowed in consultation 
with their physician.

ALT and AST ≤2.5 × ULN

Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min 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.
Must have a life expectancy of at least 12 weeks

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Weight
13.
Body weight >30 kg
Sex
14.
Male or female
5.2
Exclusion criteria
Patients are eligible to be included in the study only if none of the following exclusion criteria 
apply:
Medical conditions
1.
Mixed SCLC and NSCLC histology
2.
Extensive-stage SCLC
3.
Any history of Grade ≥2 pneumonitis
4.
History of allogeneic organ transplantation
5.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Patients 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
6.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI 
conditions associated with diarrhea, or psychiatric illness/social situations that would 
limit compliance with study requirements, substantially increase risk of incurring AEs 
or compromise the ability of the patient to give written informed consent

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7.
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
8.
History of leptomeningeal carcinomatosis  
9.
History of active primary immunodeficiency 
10.
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 (HCV), 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 and absence of HBsAg) are eligible. Patients positive for 
HCV antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA.
11.
Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Grade ≥2 from previous CRT with the exception of alopecia, vitiligo, and 
the laboratory values defined in the inclusion criteria 

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician.

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician. 
12.
Brain metastases or spinal cord compression. All patients will have an MRI (preferred) 
or CT, preferably with IV contrast of the brain, prior to study entry.
13.
Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms 
calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
14.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients 
15.
Patients who received sequential CRT for LS-SCLC (no overlap of RT with 
chemotherapy)
16.
Patients whose conditions have progressed while on concurrent CRT

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Prior/concomitant therapy
17.
Receipt of chemotherapy that exceeds 4 cycles in total. Chemotherapy regimens other 
than etoposide and platinum are not permitted.
18.
Prior exposure to immune-mediated therapy including, but not limited to, other anti-
CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic 
anticancer vaccines.
19.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone 
replacement therapy) is acceptable.
20.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if randomized, should not receive live vaccine while receiving IP and up to 
30 days after the last dose of IP. 
21.
Major surgical procedure (as defined by the Investigator) within 42 days prior to the 
first dose of IP. 
22.
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (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)
Prior/concurrent clinical study experience
23.
Participation in another clinical study with an investigational product administered in 
the last 4 weeks
24.
Previous IP assignment in the present study
25.
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
26.
Prior randomization or treatment in a previous durvalumab and/or tremelimumab 
clinical study regardless of treatment group assignment.
27.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)

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Other exclusions
28.
Female patients who are pregnant or breastfeeding and male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 3 months after the last dose of durvalumab monotherapy or 6 months after 
the last dose of durvalumab + tremelimumab combination therapy. 
29.
Judgment by the Investigator that the patient should not participate in the study 
because the patient is unlikely to comply with study procedures, restrictions, and 
requirements.
30.
Genetics research study (optional, not applicable for China ): 
Exclusion criteria for participation in the optional (DNA) genetics research component 
of the study include:

Previous allogeneic bone marrow transplant

Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1.
Female patient of child-bearing potential

Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized- male partner must use at least 1 highly
effective method of contraception (Table 4) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (90 days after 
the last dose of durvalumab monotherapy or 180 days after the last dose of 
durvalumab + tremelimumab combination therapy). Non-sterilized male partners 
of a female patient of childbearing potential must use a male condom plus 
spermicide throughout this period. Cessation of birth control after this point 
should be discussed with a responsible physician. Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Female patients should refrain from breastfeeding throughout this period. 
2.
Male patients with a female partner of childbearing potential

Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 
spermicide from the time of screening throughout the total duration of the drug 
treatment and the drug washout period (90 days after the last dose of durvalumab 
monotherapy or 180 days after the last dose of durvalumab + tremelimumab 
combination therapy). Periodic abstinence, the rhythm method, and the 

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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 4). 
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 

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.

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, or had 
chemotherapy-induced menopause with last menses >1 year ago.

Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, 
or complete hysterectomy) are eligible. 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 4. 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; 
noncopper 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).

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Table 4
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a

Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)b

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)b

Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)b

Combined Pill: Normal and low dose 
combined oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, Ortho 
Evra®)b

Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pillb
a
This is also considered a hormonal method
b
Not approved for use in Japan
3.
All patients: Patients should not donate blood or blood components while participating 
in this study and through 90 days after the last dose of durvalumab monotherapy or 
180 days after the last dose of durvalumab + tremelimumab combination therapy. 
4.
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded as 
“eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (ie, not randomized 
patients). Patients may be rescreened a single time, but they may not be re-randomized. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAE).

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6.
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to durvalumab, tremelimumab, or placebo.
6.1
Treatments administered
6.1.1
Investigational products
AstraZeneca will supply durvalumab (MEDI4736) and tremelimumab. The 0.9% (w/v) saline or 
5% (w/v) dextrose solution for the placebo will be supplied locally. See Table 5 for further 
details on the IPs.
Table 5
Study treatments
Treatment 1
Treatment 2
Placebo
Study treatment name
Durvalumab 
(MEDI4736)
Tremelimumab
0.9% (w/v) saline 
solution or 5% (w/v) 
dextrose solution
Dosage formulation
500-mg vial solution 
for infusion after 
dilution, 50 mg/mL
400-mg or 25-mg vial 
solution for infusion 
after dilution, 
20 mg/mL
Sterile solution of 
0.9% (w/v) sodium 
chloride for injection 
or 5% (w/v) dextrose
Route of administration
IV
IV
IV
Dosing instructions
1500 mg IV q4wa
75 mg IV q4w for 
4 dosesa
Dosing to match 
durvalumab or 
tremelimumab
Packaging and labeling
Study treatment will be 
provided in 500-mg 
vials. Each vial will be 
labeled in accordance 
with Good 
Manufacturing Practice 
(GMP) Annex 13 and 
per country regulatory 
requirement.b
Study treatment will be 
provided in 400-mg or 
25-mg vials. Each vial 
will be labeled in 
accordance with Good 
Manufacturing Practice 
(GMP) Annex 13 and 
per country regulatory 
requirement.
Sourced locally by 
site
Provider
AstraZeneca
AstraZeneca
Sourced locally by 
site
a
If a patient’s weight falls to ≤30 kg, the patient should receive weight-based dosing equivalent to 20 mg/kg of 
durvalumab or placebo q4w and 1 mg/kg of tremelimumab or placebo q4w, as applicable based on treatment 
assignment, until the weight improves to >30 kg, at which point the patient should start receiving the fixed 
dosing of 1500 mg durvalumab or placebo and 75 mg tremelimumab or placebo q4w, as applicable based on 
treatment assignment.
b
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or “durvalumab 
(MEDI4736)” depending upon the agreed product name used in the approved study master label document. All 
naming conventions are correct during this transitional period. 
IV Intravenous; qXw Every X weeks; w/v Weight/volume.

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6.1.1.1
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 and density of 1.054 g/mL. The label-claim volume is 10 mL. 
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from 
visible particles.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product must be kept in the original 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 must not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the final product is stored at both refrigerated and room temperatures, the total time must not 
exceed 24 hours.
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm filter. Add 30 mL (ie, 1500 mg) of durvalumab (MEDI4736) to the IV bag. 
The IV bag size should be selected such that the final concentration is within 1 to 15 mg/mL. 
Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. The IV bag 
should be covered with a translucent colored or opaque sleeve after preparation by the 
unblinded pharmacist prior to dispensing to other study personnel to maintain 
double-blind conditions.
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using an 
IV bag size selected such that the final concentration is within 1 to 15 mg/mL.
Standard infusion time is 1 hour (±10 minutes), however, if there are interruptions, the total 
allowed time must not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose is administered. 
Infusion time does not include the final flush time.

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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. 
6.1.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400-mg or 25-mg vial solution for infusion 
after dilution. The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL. The 
label-claim volume is 20 mL for the 400-mg vial and 1.25 mL for the 25-mg vial. 
Tremelimumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from or 
practically free from visible particles.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product must be kept in the original 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 must not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the final product is stored at both refrigerated and room temperatures, the total time must not 
exceed 24 hours.
A dose of 75 mg (for patients >30 kg in weight) will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final 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; dose volume rounded to the nearest tenth mL) of tremelimumab 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. The IV 
bag should be covered with a translucent colored or opaque sleeve after preparation by the 
unblinded pharmacist prior to dispensing to other study personnel to maintain 
double-blind conditions.
If patient weight falls to ≤30 kg, weight-based dosing at 1 mg/kg will be administered using an 
IV bag size selected such that the final concentration is within 0.1 to 10 mg/mL.
Standard infusion time is 1 hour (±10 minutes), however, if there are interruptions, the total 
allowed infusion time must not exceed 8 hours at room temperature. 

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Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose is administered. 
The infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. Tremelimumab does not contain preservatives, and any unused portion must be 
discarded. 
6.1.1.3
Placebo 
An IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose (approximately) matching the IV 
bag volume containing durvalumab or tremelimumab will be used for placebo. The IV bag 
should be covered with a translucent colored or opaque sleeve after preparation by the 
unblinded pharmacist prior to dispensing to other study personnel to maintain 
double-blind conditions. 
If patient weight falls to ≤30 kg, weight-based dosing will be administered at 20 mg/kg for 
durvalumab placebo, using an IV bag size selected such that the final concentration is within 1 to 
15 mg/mL, and at 1 mg/kg for tremelimumab placebo, using an IV bag size selected such that the 
final concentration is within 0.1 to 10 mg/mL.
Standard infusion time is 1 hour (±10 minutes), however, if there are interruptions, the total 
allowed infusion time must not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose is administered. 
The infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new placebo dose must be 
prepared.
6.1.2
Dose and treatment regimens
In this double-blind study, patients will receive 1 of the following treatments, based on treatment 
group assignment:

Durvalumab monotherapy: Durvalumab (1500 mg intravenous [IV]) q4w in 
combination with placebo (IV) q4w for 4 doses/cycles each, followed by durvalumab 
1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will be 4 weeks 
after the final dose of durvalumab in combination with placebo.

Placebo: Placebo (IV) q4w in combination with a second placebo (IV) q4w for 
4 doses/cycles each, followed by a single placebo q4w. The first placebo monotherapy 
dose q4w will be 4 weeks after the final dose of the 2 placebo in combination.

Durvalumab in combination with tremelimumab: Durvalumab (1500 mg IV) q4w in 
combination with tremelimumab (75 mg IV) q4w for 4 doses/cycles each, followed by 

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durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will 
be 4 weeks after the final dose of durvalumab in combination with tremelimumab.
Initially, all patients will be randomized in a 1:1:1 ratio to the 3 treatment groups. However, once 
600 patients have been randomized, subsequent patients will be randomized 1:1 to either 
durvalumab monotherapy or placebo. Patients randomized to durvalumab monotherapy or 
placebo after completion of randomization to the durvalumab and tremelimumab combination 
group, will receive only 1 infusion of durvalumab or placebo.
During combination treatment, tremelimumab or placebo will be administered first; the 
durvalumab or placebo infusion will start approximately 1 hour (maximum 2 hours) after the end 
of the tremelimumab or placebo infusion. If there are no clinically significant infusion reactions 
with the first cycle, and at the discretion of the Investigator, then for all other cycles, the 
durvalumab or placebo can be given immediately after the tremelimumab or placebo infusion has 
finished. 
Results for LFTs, electrolytes, and creatinine must be available before commencing an infusion 
(within 3 days) and reviewed by the treating physician or Investigator prior to dosing.
Treatment in all treatment groups will continue until clinical/RECIST 1.1-defined radiological 
progression, until intolerable toxicity, or for a maximum of 24 months, whichever occurs first. 
Please note, if a patient’s weight falls to 30 kg or below [≤30 kg], then the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab or placebo q4w and 1 mg/kg 
tremelimumab or placebo q4w after consultation between the Investigator and Study Physician, 
until the weight improves to above 30 kg [>30 kg], at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg or placebo plus tremelimumab 75 mg or 
placebo q4w.
Figure 2
Dosing schedule
6.1.3
Duration of treatment
All treatment will be administered beginning on Day 1 until clinical/RECIST 1.1-defined 
radiological progression, until intolerable toxicity, or for a maximum of 24 months, whichever 
occurs first.

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Post final data cut-off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure may continue to receive their assigned treatment until clinical/RECIST 1.1-
defined radiological progression, until intolerable toxicity, or for a maximum of 24 months, 
whichever occurs first. For patients continuing to receive durvalumab treatment following the 
final DCO and database closure, it is recommended that the patients continue the scheduled site 
visits and Investigators monitor the patients’ safety laboratory results prior to and periodically 
during treatment with durvalumab in order to manage AEs in accordance with the durvalumab 
Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5). 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab 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 visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new Informed Consent.
6.1.4
Storage
The unblinded pharmacist must confirm that appropriate temperature conditions have been 
maintained during transit for all study treatment received, and any discrepancies are reported and 
resolved by the supply chain before use of the study treatment.
The unblinded pharmacist will ensure that all IP is stored in a secured area, in refrigerated 
temperatures (2°C to 8°C for durvalumab and tremelimumab) 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 unblinded monitor upon detection. A calibrated 
temperature-monitoring device will be used to record the temperature conditions in the drug 
storage facility. Durvalumab storage conditions stated in the IB may be superseded by the label 
storage.
The IP provided for this study will be used only as directed in the study protocol.
IPs will not be distributed to the study site until the contract is concluded between the study site 
and AstraZeneca. The unblinded pharmacist is responsible for managing the IPs from receipt by 
the study site until the return of all unused IP to AstraZeneca. AstraZeneca will provide the study 
documents “Procedures for drug accountability” and ‘Procedures for drug storage,” which 
describe the specific requirements. 
6.2
Measures to minimize bias: randomization and blinding
6.2.1
Patient enrollment and randomization
Patients will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups: durvalumab monotherapy, 
placebo, or durvalumab and tremelimumab combination therapy. Initially, all patients will be 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups: durvalumab monotherapy, placebo, or 
durvalumab and tremelimumab combination therapy. However, once 600 patients have been 

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Patients will begin treatment on Day 1. Every effort should be made to minimize the time 
between randomization and starting treatment. Treatment can start up to 3 working days after 
randomization, as long as first dose of IP is still within 1 to 42 days after the completion of CRT. 
Patients must not be randomized and treated unless all eligibility criteria have been met. 
6.2.2
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 subsequently found not to meet all the eligibility criteria must not be randomized 
or initiated on treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca Study Physician 
immediately, and a discussion should occur between the AstraZeneca Study Physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca Study Physician must ensure all decisions are appropriately documented and that 
the potential benefit:risk profile remains positive for the patient. 
6.2.3
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 group. 
Patients will be identified to the IVRS/IWRS per country regulations. Randomization codes will 
be assigned 
, 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 subsequent treatment visits. 
6.2.4
Methods for ensuring blinding
The IVRS/IWRS will provide to the unblinded pharmacists the kit identification number to be 
allocated to the patient at the dispensing visit. Blinded and unblinded access and notifications
will be controlled using the IVRS/IWRS. Investigators will remain blinded to each patient’s 
assigned study treatment throughout the course of the study. To maintain this blind, an otherwise 
uninvolved 3rd party (ie, the unblinded pharmacist) will be unblinded and responsible for the 
reconstitution and dispensation of all study treatment and will endeavor to ensure that there are 
no differences in time taken to dispense following randomization. The IV bag should be covered 
with a translucent colored or opaque sleeve after preparation by the unblinded pharmacist prior 
to dispensing to other study personnel to maintain double-blind conditions.
The IVRS/IWRS will be programmed with blind-breaking instructions. The Sponsor must be 
notified before the blind is broken unless identification of the study treatment is required for a 
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the immediate management of the patient’s condition (eg, antidote available). In this case, the
Sponsor must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and case report form (CRF) 
(electronic or paper), as applicable. Study unblinding should not occur until database lock and all 
decisions on the evaluability of the data from each individual patient have been made and 
documented.
6.3
Treatment compliance
The administration of all IPs should be recorded in the appropriate sections of the eCRF.
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations 
should be recorded in eCRF.
Treatment compliance will be ensured by reconciliation of site drug accountability logs.
The Investigational Product Storage Manager is responsible for managing the IP from receipt by 
the study site until the destruction or return of all unused IP. The Investigator(s) is responsible 
for ensuring that the patient has returned all unused IP.
6.4
Concomitant therapy
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 including the follow-up 
period following the last dose of IP. 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose, unit, and frequency
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 the following 
tables. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5). 
In addition, PCI will not be permitted during the study. If PCI is indicated, it must be conducted 
after completion of cCRT and protocol mandated brain imaging to confirm the absence of 
cerebral metastases, and completed within 1 to 42 days prior to randomization and the first dose 
of IP.

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Table 6
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly while 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 while 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 while 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.
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP
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 infusions. The following 
are allowed exceptions:

Use of immunosuppressive medications for 
the management of IP-related AEs 

Use in patients with contrast allergies 

In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy-related 
events experienced by the patient (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 or placebo during the 
study
Sunitinib
Should not be given concomitantly or through 
90 days after the last dose of tremelimumab or 
placebo (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 or placebo (saline or dextrose 
solution). 
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.

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Prohibited medication/class of drug:
Usage
Herbal and natural remedies that may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the Sponsor
AE Adverse event; EGFR Epidermal growth factor receptor; IP Investigational product; mAb Monoclonal antibody; 
PD-1 Programmed cell death 1; PD-L1 Programmed cell death ligand 1; TKI Tyrosine kinase inhibitor. 
Table 7
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for 
those medications identified as “prohibited,” as 
listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
6.4.1
Other concomitant treatment
Medication other than that described above that is considered necessary for the patient’s safety 
and wellbeing may be given at the discretion of the Investigator and recorded in the appropriate 
sections of the CRF.
6.4.2
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-metabolizing cytochrome P450 pathways. As a result, there are no expected PK 
drug-drug interactions. The MOA 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.
6.4.3
Rescue medication
As a result of imAEs that could potentially be experienced by patients on
durvalumab ± tremelimumab, steroids and other immunosuppressant rescue medication has to be 
made available to this patient population. The 2 products that fall into the category of other 

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immunosuppressants are infliximab (eg, for colitis) and mycophenolate (eg, for hepatitis). 
AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications to the sites 
if local regulations prevent the use of infliximab and mycophenolate in this indication, as they 
are considered off-label for management of immunotherapy-related toxicities. These rescue 
medications must be receipted, controlled, and administered to all applicable patients, regardless 
of blinded treatment, by the unblinded pharmacist and stored according to the labeled storage 
conditions, with temperature excursions reported accordingly by the unblinded pharmacist. If 
required for use as a result of an imAE, then the IVRS/IWRS will provide to the unblinded 
pharmacists the kit identification number to be allocated to the patient at the time. Blinded and 
unblinded access and notifications will be controlled using the IVRS/IWRS.
6.5
Dose modification
Dose delays are permitted for immuno-oncology therapy (see Dosing Modification and Toxicity 
Management Guidelines). However, dose reduction is not permitted. 
6.6
Continued Access to Study Intervention After the End of the Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the final DCO for this study, AstraZeneca will continue to supply durvalumab to 
participants who were randomised to receive durvalumab monotherapy or durvalumab and 
tremelimumab combination therapy until PD occurs as judged by the investigator, or until 
completion of a participant’s current 24-month treatment period, or until meeting any other 
discontinuation criteria, as defined in Section 7.1. Participants should be followed according to 
the institution's standard of care assessments.  No further data collection is required, except for 
reporting of SAEs.
Participants who were randomised to receive other study interventions (ie, placebo), or who 
discontinue from the study, should continue appropriate treatment at the discretion of the 
investigator.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
An individual patient will not receive any further IP (durvalumab, tremelimumab, or placebo) 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 

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(eg, for safety and survival follow up) unless they specifically withdraw their consent 
to all further participation in any study procedures and assessments (see Section 7.3). 

An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing

Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5)

Pregnancy or intent to become pregnant

Non-compliance 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

Clinical progression or RECIST 1.1-defined radiological progression (refer to 
Appendix F)
7.1.1
Procedures for discontinuation of study treatment
Discontinuation of study treatment, for any reason, does not impact the patient’s participation in 
the study. A patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE. The patient should continue attending subsequent 
study visits, and data collection should continue according to the study protocol. If the patient 
does not agree to continue in-person study visits, a modified follow-up must be arranged to 
ensure the collection of endpoints and safety information. This follow-up could be a telephone 
contact with the patient, a contact with a relative or treating physician, or information from 
medical records. The approach taken should be recorded in the medical records. A patient that 
agrees to modified follow-up is not considered to have withdrawn consent or to have withdrawn 
from the study.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs). 
Patients who permanently discontinue IP for reasons other than RECIST 1.1-defined radiological 
progression should continue to have RECIST scans performed q8w ±1w for the first 72 weeks 
(relative to the date of randomization), followed by q12w ±1w until up to 96 weeks relative to 
the date of randomization, and then q24w ±1w thereafter (relative to the date of randomization) 
until RECIST 1.1-defined radiological PD plus one follow-up scan or death (whichever comes 
first) as defined in the SoAs.
If a patient is discontinued for RECIST 1.1-defined radiological progression, then the patient 
should have 1 follow-up scan performed no earlier than 4 weeks later and no later than the next 
scheduled imaging visit. The follow-up scan is evaluated using RECIST 1.1 criteria described in 
Appendix F.

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All patients will be followed for survival until the end of the study. 
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative. 
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
7.2
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 4.4), such that there is insufficient information to determine 
the patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than “lost 
to follow-up.” Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. If contact with a missing patient is re-established, the 
patient should not be considered lost to follow-up, and evaluations should resume according to 
the protocol.
In order to support key endpoints of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked; this includes those patients 
who withdrew consent or are classified as “lost to follow up.”

Lost to follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable CRF modules will be updated.)

In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable CRF modules 
will be updated.)   
7.3
Withdrawal from the study
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:

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
All further participation in the study including any further follow up (eg, survival 
contact telephone calls)

Withdrawal to the use of any samples (see Appendix C)
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoAs (Table 1 and Table 2). 
The Investigator will ensure that data are recorded on the eCRF. The Web Based Data Capture 
system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. If previous received chemotherapy and/or radiotherapy differs 
from those specified in the eligibility criteria, please discuss with the study team.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (eg, blood count and 
imaging assessments) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed post completion of chemoradiotherapy and up to 42 days before randomization and 
first dose of study drug.
8.1
Efficacy assessments 
This study will evaluate dual primary endpoints of PFS and OS for durvalumab monotherapy 
versus placebo. Efficacy assessments of PFS, objective response rate (ORR), PFS at 18 months 
and at 24 months from randomization (PFS18 and PFS24), and time to death or distant 
metastasis (TTDM) will be derived (by AstraZeneca) using BICR RECIST 1.1 assessments. In 
addition, OS, OS at 24 months and at 36 months from randomization (OS24 and OS36), and time 
from randomization to second progression (PFS2) will be evaluated.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV contrast, 
of the chest and abdomen (including the entire liver and both adrenal glands), collected during 
screening/baseline and at regular (follow-up) intervals during the study. Pelvic imaging is 
recommended only when primary or metastatic disease in the pelvic region is likely. Any other 

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areas of disease involvement (eg, pelvis, brain) should be additionally imaged based on the signs 
and symptoms of individual patients. It is important to follow the tumor assessment schedule as 
closely as possible (refer to the SoAs). If an unscheduled assessment is performed (eg, to 
investigate clinical signs/symptoms of progression) and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at the next scheduled visit. 
Scanning/tumor assessments continue throughout the study until RECIST 1.1-defined 
radiological progression plus one follow-up scan (if clinically feasible). Scanning/tumor 
assessments up to progression may continue after the PFS analysis and up to the end of the study.
The RECIST 1.1 guidelines (Appendix F) provide a method of assessment of change in tumor 
burden in response to treatment. Screening/Baseline imaging should be performed post-CRT 
within 42 days before randomization and start of study treatment. The RECIST 1.1 assessments 
of baseline images identify TLs (defined as measurable) and Non-Target Lesions (NTLs). On 
study images are evaluated for TLs and NTLs chosen at baseline and for New Lesions (NLs) 
when they appear. This allows determination of follow-up TL response, NTL lesion response, 
the presence of unequivocal NLs, and overall time point responses (CR, PR, SD, PD, or Not 
Evaluable [NE]).
A follow-up scan is to be collected after the initial RECIST 1.1-defined PD, no earlier than 
4 weeks later and no later than the next scheduled imaging visit.  The follow-up scan is evaluated 
using RECIST 1.1 criteria described in Appendix F.
8.1.1
Central reading of scans
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization (CRO) for QC and storage. Guidelines 
for image acquisition, de-identification, storage at the investigative site as source data, and 
transfer to the imaging CRO will be provided in a separate document. Results of these 
independent reviews will not be communicated to Investigators, and results of Investigator 
RECIST 1.1 assessments will not be shared with the central reviewers. The management of 
patients will be based, in part, upon the results of the RECIST 1.1 assessment conducted by the 
Investigator. Further details of the BICR will be documented in the Independent Review Charter 
(also referred to as “Imaging Charter”).
8.1.2
Survival assessments
Assessments for survival must be made following treatment discontinuation, as indicated in the 
SoA. 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 DCO 
for the primary analysis and all subsequent survival analyses to provide complete survival data. 
These contacts should generally occur within 7 days of the DCO.

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8.1.3
Clinical outcome assessments
A clinical outcome assessment is any assessment that may be influenced by human choices, 
judgement, or motivation and may support either direct or indirect evidence of treatment benefit. 
PRO is one type of clinical outcome assessment. 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 the effectiveness of treatments in clinical studies and will 
aid in understanding of the benefit/risk evaluation. The following PRO instruments will be 
administered in this study: EORTC QLQ-C30 v3 (core questionnaire), EORTC QLQ-LC13 (lung 
cancer module), PRO-CTCAE, Patient’s Global Impression of Severity (PGIS), and 5-level 
health state utility index (EQ-5D-5L) (see Appendix H).
8.1.3.1
EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists of 
30 items and measures symptoms, functioning, and global health status/QoL (Aaronson et al 
1993) for all cancer types. Questions are grouped into 5 multi-item functional scales (physical, 
role, emotional, cognitive, and social); 3 multi-item symptom scales (fatigue, pain, and 
nausea/vomiting); a 2-item global QoL scale; 5 single items assessing additional symptoms 
commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, and 
diarrhea), and 1 item on the financial impact of the disease. The EORTC QLQ-C30 is a valid and 
reliable PRO instrument in this patient population.
The QLQ-LC13 is a well-validated complementary module measuring lung cancer-associated 
symptoms and side effects from conventional chemotherapy and radiotherapy (Bergman et al 
1994). The QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site-specific 
pain (symptoms), sore mouth, dysphagia, peripheral neuropathy, alopecia (treatment-related 
symptoms), and pain medication.
8.1.3.2
PRO-CTCAE
The PRO-CTCAE will only be administered in countries where a linguistically validated version 
exists. 
PRO-CTCAE was developed by the National Cancer Institute (NCI) in recognition that 
collecting treatment-related symptom data directly from patients can improve accuracy and 
efficiency. This was based on findings from multiple studies demonstrating that physicians and 
nurses underestimate symptom onset, frequency, and severity in comparison with patient ratings 
(Basch et al 2009, Litwin et al 1998, Sprangers and Aaronson 1992). To date, 81 symptoms of 
the CTCAE (version 4) have been identified to be amenable to patient reporting, but not all items 
are administered in any clinical study. Response options vary in frequency, severity, and 
interference with usual activities. For this study, 9 symptoms are considered relevant for this 
cancer treatment (see Appendix H). 
8.1.3.3
PGIS
The PGIS item is included to assess how a patient perceives his/her overall current severity of 
cancer symptoms. Patients will choose from response options from “no symptoms” to “very 
severe.”

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8.1.3.4
EQ-5D-5L
The EuroQoL 5-Dimension (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 as follows: 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 analog 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 H). 
8.1.3.5
Administration of electronic patient-reported outcome questionnaires
Other than at the baseline visit where assessments are completed at site, patients will complete 
the PRO assessments outside the site by using a handheld electronic device (electronic 
patient-reported outcome [ePRO]). The following best-practice guidelines should be followed 
when collecting PRO data via an electronic device:

Site staff should explain the value and relevance of hearing directly from the patients 
how they feel. The research nurse or appointed site staff should also 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.

Remind patients that there are no right or wrong answers; avoid bias by not clarifying 
items.

Train the patients on how to use the ePRO device using the materials and training 
provided by the ePRO vendor. Also, provide guidance on whom to call if there are 
problems with the device by providing the patient information pamphlet provided by 
the ePRO vendor.

It is vital that the ePRO reporting is initiated prior to dosing and prior to any other 
assessments while the patients are still in the clinic on Cycle 1 Day 1, as specified in 
the study plan, to capture the effect of study treatment.

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
If the patient is unable to read (eg, is blind or illiterate), that patient is exempted from 
completing the ePROs and may still participate in the study. Patients exempted in this 
regard should be flagged appropriately by the site staff.

All PRO questionnaires are to be completed using the ePRO device. If the device is 
not yet at the site or there is a technical problem, the study team may grant use of a 
paper backup using electronic screenshots for baseline only. Study team approval must 
be obtained prior to the use of a paper backup using electronic screenshots at baseline. 
If not, the use of a paper backup will be considered a protocol deviation.
In order to minimize missing data, compliance must be checked frequently to identify problems 
early. If compliance drops below 90%, a check-in call from the site to ask the patient if he/she 
has any difficulties is highly recommended.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoAs (Table 1and Table 2).
8.2.1
Clinical safety laboratory 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 the 
SoAs). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Pregnancy tests 
may be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal 
clinically significant laboratory results should be repeated as soon as possible (preferably within 
24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will be 
recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 8 (clinical chemistry), Table 9
(hematology), and Table 10 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.

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The following laboratory variables will be measured:
Table 8
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatase
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSHd
Chloridec
T3 freee (reflex)
Creatinine 
T4 freee (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
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, either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
d
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
e
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.
AE Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; TSH Thyroid-stimulating 
hormone.
Table 9
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Activated partial thromboplastin timeb
International normalized ratiob
a
Can be recorded as absolute counts or as percentages.
b
For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be 
assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed within 
3 days prior to Day 1) and as clinically indicated.

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Table 10
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at screening and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red 
and white blood cells. 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a 
Hy’s law case or if any of the individual liver test parameters fulfill any of the SAE criteria. 
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months 
(±1 week), and 3 months (±1 week) after permanent discontinuation of IP (see the SoAs).
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 or 
2, unless these values are not likely to improve because of the underlying disease.
8.2.2
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 8.3.7. 
8.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs. 
First infusion day
On the first infusion day, patients will be monitored and vital signs collected/recorded in eCRF 
prior to, during, and after infusion of IP as presented in the bulleted list below. 

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BP, pulse and respiration rate will be collected from patients before, during, and after each 
infusion at the following times (based on a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [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)
If the infusion takes longer than 60 minutes, then BP, pulse and respiration rate measurements 
should follow the principles as described above or be taken more frequently if clinically 
indicated. A 1-hour observation period is recommended after the first infusion of IP. 
Subsequent infusions
BP, pulse, respiration rate and other vital signs should be measured and collected/recorded in 
eCRF prior to the start of each infusion (measured once from approximately 30 minutes before 
up to 0 minutes [ie, the beginning 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 CRF page. 
Situations in which vital signs results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, the vital signs values should be entered into the CRF.
8.2.4
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs). 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. Triplicate ECG’s should be 
obtained at the screening visit.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the 
finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.5
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see the SoAs) 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)

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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 change from baseline or screening must be reported as an AE.
8.2.6
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc.) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed. 
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected.

Physical examination

Signs and symptoms (cough, shortness of breath, and pyrexia, etc.) including 
auscultation for lung field will be assessed.

SpO2

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan

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(ii)
Tumor markers: Particular tumor markers which are related to disease 
progression. 
(iii)
Additional Clinical chemistry: C-reactive protein, lactate 
dehydrogenase (LDH) 
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, see 
Section 8.3.3. 
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.2
Time period and frequency for collecting AE and SAE information 
AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up 
period is completed (90 days after the last dose of IP). If an event that starts after the defined 
safety follow-up period noted above is considered to be due to a late-onset toxicity to study drug, 
then it should be reported as an AE or SAE as applicable.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 8.4.1. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator should notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up 

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Any AEs that are unresolved at the patient’s last AE assessment or other assessment in the study 
are followed up by the Investigator for as long as medically indicated (this may be beyond the 
90 days after the last dose of IP), but without further recording in the CRF. 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.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria 

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)

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
Causality assessment in relation to other medication, as explained in Section 8.3.5

Description of the SAE
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 4.03 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship is 
implied as “yes.”
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
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 site staff: “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 CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be
summarized in the Clinical Study Report (CSR). Deterioration as compared to baseline in 
protocol-mandated laboratory values and vital signs should therefore only be reported as AEs if 
they fulfill any of the SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting Investigator uses 
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 AE(s).
Deterioration of a laboratory value that is unequivocally due to disease progression should not be 
reported as an AE/SAE.

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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 unless unequivocally related to 
the disease under study; see Sections 8.3.9 and 8.3.10.
8.3.8
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 E for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law.
8.3.9
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 AEs during the study.
8.3.10
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 IP and have been identified after the 
patient’s inclusion in this study.
8.3.11
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 drug, must be reported as follows:

Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF 
in the Statement of Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the Statement of Death page in the 
eCRF. The report should contain a comment regarding the co-involvement of PD, if
appropriate, and should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A postmortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
postmortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual time frames.
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 

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occurred as a result of an event that started after the defined safety follow-up period and the 
event is considered to be due to a late-onset toxicity to study drug, then it should also be reported 
as an SAE.
8.3.12
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events 
in order to characterize and understand them in association with the use of this investigational 
product.
AESIs for durvalumab ± tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy.
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab and durvalumab in 
combination with tremelimumab include: 

Pneumonitis, 

Hepatitis, 

Diarrhea/colitis, 

Intestinal perforation, 

Endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), 

Nephritis, 

Rash/dermatitis, 

Myocarditis,

Myositis/polymyositis, 

Pancreatitis 

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
Rare/less frequent imAEs (including, but not limited to hematological events, 
neuromuscular toxicities [such as myasthenia gravis and Guillain-Barre syndrome], 
non-infectious encephalitis, non-infectious meningitis, pericarditis, rheumatological 
events, sarcoidosis, skin events, uveitis [and other events involving the eye], and 
vasculitis).
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 Dose Modification and Toxicity Management Guidelines 
(see Section 8.4.5). These guidelines have been prepared by the Sponsor to assist the Investigator 
in the exercise of his/her clinical judgment in treating these types of toxicities. These guidelines 
apply to AEs considered causally related to the study drug/study regimen by the reporting 
Investigator.
8.3.13
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5). All data after the final DCO and database closure 
will be recorded in the patient notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) after the final DCO and database closure must 
be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP or to the study 
procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 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 works 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.

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For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar day 
(ie, immediately but no later than 24 hours of when he or she becomes aware of it).
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture system, an automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports an SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any study drug
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day (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 provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.

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The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used to 
report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 90 
days after the last dose of durvalumab monotherapy or 180 days after the last dose of 
durvalumab + tremelimumab combination therapy. 
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 90 days after the last dose 
of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab 
combination therapy, 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.
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 the 
SoAs).
8.4.3
Overdose
8.4.3.1
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 is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately 
or not 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 provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.3.2. 
For other overdoses, reporting must occur within 30 days.

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8.4.4
Medication error, Drug abuse, Drug misuse
8.4.4.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one day, ie, immediately but no later than 24 hours of when they become aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is completed within one (initial fatal/life-threatening or follow-up fatal/life-
threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE 
associated with the event of medication error, drug abuse, or misuse (see Section 8.4.1) and 
within 30 days for all other events.
8.4.4.2
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP/study intervention or AstraZeneca NIMP that either causes 
harm to the participant or has the potential to cause harm to the participant.
The full definition and examples of Medication Error can be found in Appendix B 8.
8.4.4.3
Drug abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP/study 
intervention or AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 8.
8.4.4.4
Drug misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorised product 
information, or for unauthorised IMPs/study intervention(s) or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol and includes deliberate administration of the product by 
the wrong route.
The full definition and examples of Drug Misuse can be found in Appendix B 8.
8.4.5
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).

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
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of the assigned IP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted 

All dose modifications should be documented with clear reasoning and documentation 
of the approach taken.
All toxicities will be graded according to NCI CTCAE, Version 4.03. 
8.4.5.1
Specific toxicity management and dose modification information
Comprehensive toxicity management guidelines (TMG) 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 
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 TMGs 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 TMGs entitled “Dosing Modification and Toxicity Management 
Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune Mediated Reactions 
(MEDI4736) Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab 
Monotherapy” is provided to the investigative site as an Annex document and is maintained 
within the Site Master File. 
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 7.1of this protocol and the 
Dosing Modification 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 Dosing Modification and Toxicity Management Guidelines. These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of his/her 
clinical judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to 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.

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8.5
Pharmacokinetics
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
8.5.1
Collection of PK samples
Blood samples for determination of durvalumab and tremelimumab concentration in serum will 
be obtained according to the SoAs. 
Samples for determination of durvalumab and tremelimumab concentration in serum 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.
8.5.2
Collection of ADA samples
The presence of ADA will be assessed in serum samples taken according to the SoAs. 
Samples will be measured for the presence of ADA and neutralizing antibody (nAb) for both 
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-naive validation samples will be employed. In 
addition, the presence of nAb will be tested for all ADA-positive samples using a validated 
assay.
8.5.3
Storage and destruction of pharmacokinetic/ADA samples
PK and ADA samples will be destroyed within 5 years of CSR finalization . In China, samples 
will be destroyed after the finalization of the Bioanalytical reports.
PK and ADA samples may be disposed of, 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 
CSR.
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 the AstraZeneca-designated Biobank) – not 
applicable for China.
8.6
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study.

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8.7
Genetics (Not applicable for China)
8.7.1
Optional exploratory genetic sample (Not applicable for China)
If the patient agrees to participate in the optional genetic research study, a blood sample will be 
collected. Participation is optional. Patients who do not wish to participate in the genetic research 
may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient. Signed informed consent will be required to obtain a replacement sample unless 
it was included in the original consent.
See Appendix D for Information regarding genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in Appendix D or in the Laboratory 
Manual.
8.7.2
Storage and destruction of genetic samples (Not applicable for China)
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain patient confidentiality. Samples may be stored for a maximum of 15 years or as per 
local regulations from the date of the Last Patient’s Last Visit, after which they will be 
destroyed. DNA is a finite resource that may be used up during analyses. The results of any 
further analyses will be reported either in the CSR itself or as an addendum, or separately in a 
scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
By participating in this study, the patient consents to the mandatory collection and use of donated 
biological samples as described here. Tissue samples will be obtained from all screened patients.
At Screening, a pre-study-treatment tumor sample must be available.  The following tumor 
samples will be accepted in the following order of preference;
1. An unstained, archived tumor tissue block (formalin-fixed paraffin-embedded). Not 
applicable for patients recruited in China, where only tumor tissue slides will be 
collected (see point 2 below).
2. Newly cut, unstained slides with tissue sections 4-5 μm thick (as described in the 
Laboratory Manual). A minimum of 15 unstained slides are required for analysis of 
PD-L1 and TMB biomarkers.  Investigators are strongly encouraged to provide 15 
unstained slides, but smaller numbers of slides will be accepted if 15 slides are 
unobtainable. For patients recruited in China, newly cut, unstained slides with tissue 
sections up to 5 μm thick will be collected from an archived tumor sample. The number 
of slides should be sufficient for PD-L1 analysis (as described in the Laboratory 
Manual).
3. An optional tumor biopsy following completion of chemoradiotherapy, should be 
considered for patients without archival tumor blocks/slides, provided it is technically 

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feasible and not associated with unacceptable clinical risk (by investigator judgement). 
Patients recruited in China will only have a newly acquired tumor biopsy, if archival 
tumor slides are not available (tumor tissue slides only will be collected for patients 
recruited in China)
4. If an archival tumor blocks/slides are not available and a newly acquired tumor biopsy is 
not technically or clinically feasible, then cell blocks from FNA (Fine Needle Aspirate) 
samples will be accepted.  Samples must first be spun down to capture all the cells in a 
single pellet (as described in the Laboratory Manual).  The pellets should then be placed 
in formalin, processed and embedded in paraffin blocks in a manner identical to that of 
biopsy tissue. For patients recruited in China, tumor cell slides from FNA will be 
allowed, if no archival tumor slides available and a newly acquired tumor biopsy is not 
technically or clinically feasible.
An optional core needle tumor biopsy following completion of the most recent therapy, or upon 
evidence of PD after randomization, should be performed according to institutional practice, 
provided it is not associated with unacceptable clinical risk. If provided, the sample should be of 
a sufficient quantity to allow for analysis (see the Laboratory Manual). Tumor lesions planned 
for biopsy must not be used as index lesions for assessment of disease. This optional sample will 
not be collected from Chinese patients.
Based on availability of tissue, secondary and exploratory biomarkers may be evaluated as 
described in Section 8.8.1. Also, descriptions of secondary and exploratory, peripheral measures 
are described in this section. Samples will be obtained according to the assessment schedules 
provided in the SoAs.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to immunotherapy as described in Section 8.8.1. 
The results may be pooled with biomarker data from other durvalumab/tremelimumab studies to 
evaluate biological responses across indications and to compare results in monotherapy versus 
combination settings.
8.8.1
Secondary and exploratory biomarkers
Baseline biomarker measures will be correlated with outcomes. Note that samples will be 
obtained from patients randomized to each treatment group. Comparisons will be made between 
baseline measures to determine if biomarkers (or combination of markers) are prognostic or 
predictive of outcomes associated with durvalumab monotherapy or durvalumab and 
tremelimumab combination therapy versus placebo. 
Additional sample collections and analyses may be completed at select study sites by site 
specific- amendment. All samples collected for such exploratory analyses will be stored at the 

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study site, a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The secondary and exploratory biomarker plan is described by sample type below.
Whole blood for DNA/single-nucleotide polymorphism genotyping (Not applicable for 
China)
Genomic DNA will be extracted from whole blood obtained pre-treatment from all patients. 
Genotyping of DNA may be performed to determine association between genotype and clinical 
benefit and/or with likelihood of drug-related AEs. Genotyping data may be also be used to 
subtract naturally occurring mutations and help to unambiguously identify true somatic 
mutations in tumor tissue. Genes associated with SCLC development, progression, or likelihood 
of response to CRT may likewise be investigated. Genotyping will occur retrospectively, data 
will not be shared with patients, and results will not impact treatment decisions.
Genotypes may also be correlated with biomarker measures (eg, gene and/or protein expression) 
obtained from other sample types described in this secondary and exploratory biomarker section. 
A primary hypothesis is that different genotypes will be associated with different expression 
levels of factors within the PD-1 signaling and other immune-related pathways. Such variations 
in expression may affect the ability of an individual to mount an appropriate immune reaction to 
tumor and/or affect the likelihood of response to therapeutics targeting these pathways. 
Therefore, genotyping may provide easy-to-measure, baseline information regarding a patient’s 
immune system, and a goal of this research is to understand how such genetic information may 
be used to predict pharmacodynamic responses to therapy.
Whole blood gene expression (PaxGene-RNA) (Not applicable for China)
Whole blood samples will be obtained from all patients as described in the SoAs. Total RNA 
will be prepared for quantification of RNA, micro-RNA and/or non-coding RNA using reverse 
transcription quantitative polymerase chain reaction, microarray, sequencing, or other 
technology.
Focus is likely to be given to, but not limited to, the expression of immunomodulatory genes. 
Correlations with outcome data will be performed on predictive markers with the aim of 
identifying useful expression thresholds for identifying patients likely to receive benefit.
Soluble factors – plasma (Not applicable for China)
Plasma will be obtained from all patients as described in the SoAs. Plasma may be used to 
evaluate mutant circulating tumor DNA (ctDNA). Overall mutational burden and/or somatic 
mutations/genomic alterations in plasma may be assessed using state-of-the-art methodologies. 
The concentrations of a panel of relevant cytokines, chemokines, and other immune-related 
markers may also be measured. Such measurements may be correlated with response.

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Tumor markers
This study will mandate the availability of archival/diagnostic tumor tissue that may be analyzed 
for various biomarkers.  
SCLC is characterized by its high mutational burden, as described in Section 2.1. Recent data 
from CheckMate-032 (NCT01928394) have shown that patients with a high tumor burden 
(ie, high TMB) derive greater clinical benefit from PD-1 blockade alone or in combination with 
CTLA-4 blockade. Also, data presented from an ES-SCLC cohort in the Phase 2 
KEYNOTE-158 study (NCT02628067), showed that PD-1 blockade had greater clinical benefit 
in PD-L1-positive patients than in PD-L1 negative patients (Hyun Cheol Chung et al 2018). To 
better understand the significance of these findings and any impact this may have on patients in 
the present study (ADRIATIC), TMB may be assessed in both tumor and blood samples and 
PD-L1 status will be assessed in tumor samples. TMB related testing or analysis will not be 
conducted for China patients.
Other tissue-based biomarkers may be assessed, including but not limited to, the study of 
expression of tumor- and/or immune-related genes, SCLC molecular subtypes, and other 
pathways related to the disease or response to therapy using state-of-the-art technologies. TMB 
and somatic mutations/genomic alterations may also be assessed (not applicable for China). 
Stool sample for microbiome analysis 
Recent studies have shown that the gut microbiome may play an important role in a patient’s 
response to immunotherapy (Sivan et al 2015, Vetizou et al 2015). Stool samples collected from 
patients will be used to study microbial diversity as well as the different species of microbes 
present in the patient to be correlated with response to therapy, as well as the effect of treatment 
on the microbiome over time. These samples are optional and  will only be collected in North 
American and European countries.
Stool samples may be collected within 3 days prior to the visit at the site or by the patient in a 
home setting.
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.

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8.8.2
Storage, re-use, and destruction of biomarker samples
For all countries except China:
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. Summaries and analyses for secondary and exploratory biomarkers will be 
documented in a separate analysis plan and will 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.
For China:
Samples will be stored and disposed according to China laws and regulations.
The stained tissue slides (PD-L1 and H&E slides) will be retained at the testing laboratory as raw 
data for a minimum of 10 years after study closure and repatriated or discarded at the end of the 
retention period. Collected tissue slides for PD-L1 testing, if unstained, will be repatriated to the 
sites or discarded 5 years after study drug approved for marketing in China.
Summaries and analyses for secondary and exploratory biomarkers will be documented in a 
separate analysis plan and will 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. Samples 
collected from Chinese patients will be stored until study analysis is complete and used only for 
study purpose.
8.8.3
Labeling and shipment of biological samples
The Principal Investigator will ensure 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 C “International Airline Transportation Association 6.2 Guidance Document.”
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.
8.9
Health Economics
For the purposes of economic evaluation, it is necessary to capture health care resource use 
related to the treatment and the underlying disease. Within the study, the following will be 
captured:

Hospital episodes including the type of contact (hospitalizations, outpatient, or day 
case), reason, length of stay by ward type (including intensive care unit), and 
concomitant medications and procedures

Treatment related to AEs (including the method of delivery of the treatment)

Treatment not related to the study

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The above resource use data will mainly come from the patient’s medical record and will be 
captured in the eCRF.
The assessment of health economic resource use data will provide important information for 
payers and will be used within economic evaluations of durvalumab.
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information.
9.
STATISTICAL CONSIDERATIONS
9.1
Statistical hypotheses
The dual primary objectives are to assess the efficacy of durvalumab monotherapy compared to 
placebo in terms of PFS and OS.
The statistical hypotheses for primary PFS are:

H0: No difference between durvalumab monotherapy and placebo

H1: Difference between durvalumab monotherapy and placebo
The statistical hypotheses for primary OS are:

H0: No difference between durvalumab monotherapy and placebo

H1: Difference between durvalumab monotherapy and placebo
The study will be considered positive (ie, a success) if either of the above null hypotheses is 
rejected based on the primary analysis of PFS or OS in the FAS.
The following statistical hypotheses for the key secondary endpoints of PFS and OS comparing 
durvalumab in combination with tremelimumab versus placebo will be tested if the null 
hypothesis for both dual primary endpoints (PFS and OS, durvalumab monotherapy versus 
placebo) is rejected (see Section 9.5.7):

H0: No difference between durvalumab in combination with tremelimumab and 
placebo 

H1: Difference between durvalumab in combination with tremelimumab and placebo
Analyses will be stratified by disease stage (I/II versus III) based on the TNM classification and 
receipt of PCI (yes versus no).
Statistical analyses of the durvalumab in combination with tremelimumab group will be 
performed in the combination analysis set to prevent bias being introduced from an imbalance in 
the follow-up, recruitment period and number of patients across treatment arms.

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9.2
Sample size determination
Approximately 965 patients will be recruited globally in order to randomize approximately 
724 patients to durvalumab monotherapy (approximately 262 patients), placebo (approximately 
262 patients), or durvalumab + tremelimumab combination therapy (approximately 200 patients) 
over a period of 38 months. Initially, patients will be randomized 1:1:1 to the 3 treatment groups. 
Following implementation of CSP Version 4, once 600 patients have been randomized, a further 
124 patients will subsequently be randomized 1:1 to durvalumab monotherapy or placebo until a 
total of 724 patients have been randomized.
The primary PFS analysis will occur at the earliest of:
1. When approximately 370 PFS BICR events have occurred (70.6% maturity) in the 
durvalumab monotherapy and placebo treatment groups
2. At OS-IA2, if OS-IA2 is statistically significant (durvalumab monotherapy vs 
placebo)
3. 36 months after the last patient randomized
With 370 PFS BICR events, if the true PFS HR is 0.65 for durvalumab monotherapy versus 
placebo, the study will have approximately 90% power to demonstrate a statistically significant 
difference in PFS between durvalumab monotherapy and placebo, with an overall 2-sided 
significance level of 0.5%. The true HR of 0.65 translates to a 5.4 month benefit in median PFS 
over 10 months on placebo if PFS is exponentially distributed. The smallest treatment difference 
that would be statistically significant is an HR of 0.743 (Critical value (CV)). A recruitment 
period of approximately 38 months are expected for the primary PFS analysis. At this time, 
approximately 309 PFS BICR events are also expected to have occurred in the durvalumab in 
combination with tremelimumab and placebo treatment groups.
One interim analysis of PFS will be performed when approximately 308 PFS BICR events have 
occurred across the durvalumab monotherapy and placebo treatment groups (information fraction 
83.2%, maturity 58.8%). At this time, approximately 274 PFS BICR events are also expected to 
have occurred in the durvalumab in combination with tremelimumab and placebo treatment 
groups. With 308 PFS BICR events across the durvalumab monotherapy and placebo treatment 
groups, the study will have 75% power to detect a PFS HR of 0.65 (CV=0.700) at a 0.184% 
significance level. The alpha level (0.5%, 2 sided) will be split between the interim and primary 
analyses using the Lan and DeMets (Lan and DeMets 1983) spending function that approximates 
an O’Brien Fleming approach. The actual boundary will be calculated at the time of the interim 
analysis, based on assuming 370 PFS BICR events at the primary PFS analysis. 
The primary OS analysis will occur when approximately 348 death events have occurred (66.4% 
maturity) in the durvalumab monotherapy and placebo treatment groups. If the true OS HR is 
0.73 for durvalumab monotherapy versus placebo, the study will have 80% power to demonstrate 
a statistically significant difference in OS between durvalumab monotherapy and placebo. The 
true HR of 0.73 translates to an approximate 8.9 month benefit in median OS over 24 months on 
placebo if OS is exponentially distributed. The smallest treatment difference that would be 
statistically significant is an HR of 0.797. 

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Two interim analyses of OS will be performed. The first at the time of the PFS interim analysis 
with approximately 242 death events anticipated across the durvalumab monotherapy and 
placebo treatment groups (information fraction 69.5%, maturity 46.2%) which would provide 
48% power to detect a PFS HR of 0.73 (CV=0.725). The second with approximately 299 death 
events anticipated across the durvalumab monotherapy and placebo treatment groups 
(information fraction 85.9%, maturity 57.1%) which would provide 68% power to detect a PFS 
HR of 0.73 (CV=0.770). The alpha level (4.5%, 2-sided) will be split between the interim and 
primary analyses using the Lan and DeMets (Lan and DeMets 1983) spending function that 
approximates an O’Brien Fleming approach. The actual boundaries will be calculated at the time
of each interim, based on 348 death events being observed at the primary OS analysis. 
For a description of the analyses for PFS and OS, refer to Sections 9.5.1.1 and 9.5.1.2. For
further details of the MTP, interim analyses, alpha allocation and alpha spend, refer to Sections
9.5.7 and 9.6.
9.3
Populations for analyses
Definitions of the analysis sets for each outcome variable are provided in Table 11.
Table 11
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy data
PFS, OS, PFS18, PFS24, TTDM, OS24, OS36, PFS2, 
and PRO endpoints
Full analysis set, Combination analysis set
ORR
Full analysis set, Combination analysis set
Demography
Full analysis set, Combination analysis set
PK data
PK analysis set
Safety data
Exposure
Safety analysis set, Combination safety analysis set, 
Adverse events
Safety analysis set, Combination safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
Electrocardiograms
Safety analysis set
ADA
ADA analysis set
ADA  Anti-drug antibody; ORR  Objective response rate; OS Overall survival; OS24 Proportion of patients alive at 
24 months from randomization; OS36 Proportion of patients alive at 36 months from randomization; 
PFS Progression-free survival; PFS2 Time from randomization to second progression; PFS18 Progression-
free survival at 18 months following randomization; PFS24 Progression-free survival at 24 months following 
randomization; PK Pharmacokinetic(s); PRO Patient-reported outcome; TTDM  Time to death or distant 
metastasis.

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9.3.1
Full analysis set
The FAS will include all randomized patients. The FAS will be used for all efficacy analyses 
(including PROs). Treatment groups 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 are included in the analysis in the treatment 
group to which they were randomized.
9.3.2
Combination analysis set
For analyses involving the durvalumab and tremelimumab combination treatment group, only the 
first 600 patients randomized (across all 3 arms) will be included in the analyses, and all will be 
included in the treatment group to which they were randomized.
9.3.3
Safety analysis set
The safety analysis set (SAS) 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 SAS according to 
the 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.
9.3.4
Combination safety analysis set
The combination safety analysis set will consist of all patients from the combination analysis set 
who received at least 1 dose of study treatment. Data will be summarized according to the 
treatment they actually received.
9.3.5
PK analysis set
All patients who receive at least 1 dose of IP per the protocol for whom any post-dose data are 
available and who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses 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.
9.3.6
ADA analysis set
The ADA analysis set includes all patients in the safety analysis set who have non-missing 
baseline ADA and at least 1 non-missing post-baseline ADA result of the same IP (durvalumab 
or tremelimumab). 
9.4
Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
9.4.1.1
RECIST 1.1-based endpoints
The analysis of the primary endpoint of PFS and the analyses of the secondary endpoints of 
ORR, PFS18, PFS24, and TTDM will be based on BICR tumor assessments using RECIST 1.1. 
In addition, the primary endpoint of OS and the secondary endpoints of OS24, OS36, and PFS2 
will be evaluated.

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Blinded Independent Central Review
Images will be collected centrally, verified, and stored. For BICR, each patient’s scans will be 
reviewed by 2 independent primary radiologist reviewers using RECIST 1.1 criteria. For each 
patient, the BICR will define the overall visit response data (CR, PR, SD, PD, or NE) and the 
relevant scan dates for each time point (ie, for visits where response or progression is/is not 
identified). 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). If any of the overall visit responses (CR, PR, SD, PD, or NE) 
differ between the 2 primary radiologists, the case will be adjudicated by a third independent 
radiologist who will choose all assessments of the primary reviewer with which they agree more. 
If no differences in overall visit responses are identified, then the assessments from the primary 
radiologist who completed their review of baseline scans first will be used for the analysis. 
Endpoints (e.g., PFS) will be derived from the scan dates that contributed to the overall visit 
responses.
Further details of the BICR will be documented in the Imaging Charter.
Investigator RECIST 1.1-based assessments
All RECIST 1.1-based assessments, whether scheduled or unscheduled, will be included in the 
calculations, regardless of whether a patient discontinues study treatment or receives another 
anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, 
SD, or PD depending on the status of their disease compared with baseline and previous 
assessments. Baseline will be assessed post-CRT within the 42 days prior to randomization and 
first dose of IP. If a patient has had a tumor assessment that cannot be evaluated, then the patient 
will be assigned a visit response of not evaluable (NE; unless there is evidence of progression, in 
which case the response will be assigned as PD).
Please refer to Appendix F for the definitions of CR, PR, SD, and PD.
9.4.1.2
Progression-free survival
PFS (per RECIST 1.1, as assessed by BICR, 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 therapy or receives 
another anticancer therapy prior to progression (ie, date of event or censoring – date of 
randomization + 1). 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 prior to the 2 missed 
visits (NE is not considered a missed visit). If the patient has no evaluable visits or does not have 
baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, then they 
will be treated as an event with date of death as the event date.
The PFS time will always be derived from scan/assessment dates and not visit dates.

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RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:

For BICR assessments, the date of progression will be determined based on the earliest 
scan dates of the component that triggered the progression for the adjudicated reviewer 
selecting PD or of the reviewer who read baseline first if there is no adjudication.

For Investigator assessments, the date of progression will be determined by the earliest 
of the RECIST 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 scan 
dates contributing to a particular overall visit assessment.
A sensitivity analysis of PFS will be performed using Investigator assessments according to 
RECIST 1.1.
9.4.1.3
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 following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If patients are confirmed to be alive, or if the 
death date is post the DCO date, these patients will be censored at the date of DCO. Death dates 
may be found by checking publicly available death registries.
9.4.1.4
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 (i.e., unconfirmed response). 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. 
9.4.1.5
Progression-free survival at 18 months and 24 months 
The PFS18 and PFS24 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as 
assessed by BICR) at 18 months and 24 months, respectively.
9.4.1.6
Time to death or distant metastasis
TTDM will be defined as the time from the date of randomization until the first date of distant 
metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any NL 
that is outside of the radiation field according to RECIST 1.1 or proven by biopsy. Patients who 
have not developed distant metastasis 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 has distant metastasis or dies after 2 or more missed visits, the patient will be censored at 
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has no evaluable visits or does not have baseline data, he/she will be censored at Day 1 unless 
they die within 2 visits of baseline.
9.4.1.7
Proportion of patients alive at 24 months and 36 months after randomization 
The OS24 and OS36 will be defined as the Kaplan-Meier estimate of OS at 24 months and 
36 months after randomization, respectively. 
9.4.1.8
Time from randomization to second progression 
PFS2 will be defined as the time from the date of randomization to the earliest of the progression 
event subsequent to first subsequent therapy or death. The date of second progression will be 
recorded by the Investigator in the eCRF at each assessment and defined according to local 
standard clinical practice and may involve any of the following: objective radiological imaging, 
symptomatic progression, or death. Patients alive and for whom a second disease progression has 
not been observed should 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.
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
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 first dose of IP and 90 days following 
discontinuation of IP. For AEs, on treatment (or treatment-emergent AEs) will be defined as any 
AEs that started after first dose of IP or prior to dosing and which worsens following exposure to 
the treatment.
AEs observed up until 90 days following discontinuation of IP or until the initiation of the first 
subsequent therapy following discontinuation of treatment (whichever occurs first) will be used 
for the reporting of the AE summary tables. This will more accurately depict AEs attributable to 
study treatment only, as a number of AEs up to 90 days following discontinuation of IP 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 IP (ie, without taking subsequent therapy into account). 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 IP will be 
produced. These events will not be included in AE summaries. 
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca/MedImmune medically qualified expert 
will review the list of AEs that were not reported as SAEs and AEs leading to discontinuation. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as such 
in the CSR. A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. Examples of these are marked hematological and other laboratory 

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abnormalities and certain events that lead to intervention (other than those already classified as 
serious) or significant additional treatment.
9.4.2.2
Safety assessments
For the change-from-baseline summaries for laboratory data, physical examinations, and vital 
signs, the baseline value will be the latest result obtained prior to the start of study treatment. A 
listing of ECGs will be provided, as it will be collected as clinically indicated after screening. 
Corrected calcium product 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)
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.
9.4.3
Calculation or derivation of patient-reported outcome variables - EORTC 
QLQ-C30 and QLQ-LC13
Symptoms and overall quality of life will be assessed using EORTC QLQ-C30 and QLQ-LC13 
(secondary endpoints). Questionnaires will be scored according to published guidelines or the 
developer’s guidelines, if published guidelines are not available. All PRO analyses will be based 
on the FAS. The clinical meaningfulness threshold of the PRO analyses described below will be 
provided in the SAP.
The EORTC QLQ-C30 consists of 30 questions that are grouped into 5 multi-item functional 
scales (physical, role, cognitive, emotional, and social), 3 multi-item symptom scales (fatigue, 
pain, and nausea/vomiting), 5 single items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a 2-item global measure of health status/quality of life (GHS/QoL), and a single 
item on the financial impact of the disease. The QLQ-LC13 is a lung cancer-specific module 
from the EORTC for lung cancer comprising 13 questions to assess lung cancer symptoms 
(cough, hemoptysis, dyspnea, and site-specific pain), treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy, and alopecia), and pain medication. With the exception of a 
multi-item scale for dyspnea, all are single items. The dyspnea scale will only be used if all 
3 items have been scored; otherwise, the items are treated as single-item measures.

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All items are scored between 1 (“not at all”) to 4 (“very much”) with the exception of the 2 
GHS/QoL items which are scored 1 (“very poor”) to 7 (“excellent”). An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom 
items, the functional scales and the GHS/QoL scale according to the EORTC QLQ-C30 Scoring 
Manual (EORTC QLQ-C30 Scoring Manual, Third Edition) and the EORTC QLQ-LC13 
instructions.
Higher scores on the GHS/QoL and functioning scales indicate better health status/function, but 
higher scores on symptom scales/items represent greater symptom severity.
Changes in score compared with baseline will be evaluated. For each subscale, if <50% of the 
subscale items are missing, then the subscale score will be divided by the number of non-missing 
items and multiplied by the total number of items on the subscales (Fayers et al 2001). If at least 
50% of the items are missing, then that subscale will be treated as missing. Missing single items 
are treated as missing. The reason for any missing questionnaire will be identified and recorded. 
If there is evidence that the missing data are systematic, missing values will be handled to ensure 
that any possible bias is minimized.
Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated. A minimum clinically relevant change 
is defined as a change in the score from baseline of ≥10 for scales/items from the QLQ-C30 and 
the QLQ-LC13 (Osoba et al 1998). For example, a clinically relevant deterioration in chest pain 
(as assessed by QLQ-LC13) is defined as an increase in the score from baseline of ≥10. A 
clinically relevant improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in 
the score from baseline of ≥10. At each post-baseline assessment, change in 
symptoms/functioning from baseline will be categorized as improvment, no change, or 
deterioration as shown in Table 12.
Table 12
Visit responses for symptoms and HRQoL
Score
Change from baseline
Visit response
QLQ-C30/QLQ-LC13 symptom 
scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
QLQ-C30 functional scales and 
GHS/QoL
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
GHS  Global health status;  HRQoL Health-related quality of life; QLQ-C30  30-Item core quality of life 
questionnaire; QLQ-LC13  Lung cancer module; QoL  Quality of life.
Time to symptom deterioration and improvement rates will be evaluated for all symptoms and 
HRQoL outcomes. Further details will be provided in the SAP.

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9.4.4
Calculation or derivation of PGIS
PGIS data will be presented using summaries and descriptive statistics. Further details will be 
provided in the SAP. 
9.4.5
Calculation or derivation of PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the Full 
Analysis Set and further details will be provided in the SAP.
9.4.6
Calculation or derivation of patient-reported health state utility (EQ-5D-5L)
The health state utility will be assessed using the EQ-5D-5L (exploratory). The index comprises 
5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression; see Section 8.1.3.4). For each dimension, respondents 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 value sets are not 
available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied (Oemar and Janssen 2013). In 
addition to the descriptive system, respondents also assess their health on the day of assessment 
on a visual analog scale, ranging from 0 (worst imaginable health) to 100 (best imaginable 
health). This score is reported separately. 
9.4.7
Calculation or derivation of pharmacokinetic variables
9.4.7.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modelling approach. 
The impact of physiologically-relevant patient characteristics (covariates) and disease on PK will 
be evaluated. The relationship between the PK exposure and the effect on safety and efficacy 
endpoints will be evaluated. The results of such an analysis will be reported in a separate report. 
The PK, pharmacodynamics, 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.
9.4.7.2
Pharmacokinetic analysis
The actual sampling times will be used in the PK calculations. PK concentration data and 
summary statistics will be tabulated. Individual and mean blood concentration-time profiles will 
be generated. Samples below the lower limit of quantification will be treated as missing in the 
analyses.
9.4.7.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADA to durvalumab and to tremelimumab. ADA 
titer and the presence of nAb will be reported for samples confirmed positive for the presence of 

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ADA. The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated, if the data allow.
9.4.8
Calculation or derivation of biomarker variables
Biomarker status, as defined in the secondary and exploratory objectives, will be assessed for 
evaluable patients in each treatment group according to prespecified criteria that will be detailed 
in the SAP.
9.4.9
Calculation or derivation of pharmacogenetic variables (Not Applicable for 
China)
In the case of genetic data, only the date that the patient gave consent to participation in the 
genetic research and the date the blood sample was taken from the patient will be recorded in the 
eCRF and database. The genetic data generated from the study will be stored in the AstraZeneca 
Laboratory Information Management System (LIMS) database or other appropriate system. This 
database is a secure database, which is separate from the database used for the main study. Some 
or all of the dataset from the main study may be duplicated within the AstraZeneca LIMS 
database for exploratory genetic analysis. Data will be reported outside the CSR (please see 
Appendix D).
9.5
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will be 
developed and finalized before database lock and will describe the patient populations to be 
included in the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. Any deviations from this plan will be reported in the clinical study report.
If this study achieves statistical significance for either of the dual primary endpoints of PFS 
and/or OS at one of the planned interim analyses, then that will be considered the primary 
analysis for that endpoint. Further analyses for that particular endpoint may still occur depending 
on the need to have long-term follow up or more mature data. The final analysis of the study will 
then be the last assessment of long-term benefit. 
9.5.1
Efficacy analyses
The primary aim of the study is to assess the efficacy of durvalumab monotherapy versus 
placebo in terms of PFS (per RECIST 1.1 as assessed by BICR) and OS.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group. 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 group. 
In general, baseline will be the last observed assessment of the variable under consideration prior 
to the intake of the first dose of IP, except for efficacy variables. For efficacy variables 
(including PRO), baseline is defined as the last observed measurement prior to randomization.

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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 on the SAS.
All outputs will be summarized by treatment group for all randomized patients (FAS). However, 
for analyses involving the durvalumab and tremelimumab combination treatment group, only 
those patients randomized up to and including the date of the 600th patient will be included in the 
analyses (combination analysis set, approximately 200 patients per arm).
Results of all statistical analyses will be presented using a 95% CI and p-value, unless otherwise 
stated.
Table 13 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 monotherapy and durvalumab and 
tremelimumab combination therapy versus placebo in all randomized patients (FAS), unless 
otherwise indicated.
Table 13
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank tests for:

Primary analysis using BICR RECIST 1.1 assessments 
(durvalumab monotherapy versus placebo)

Sensitivity analyses using BICR RECIST 1.1 assessments 
1) Interval censored analysis – evaluation time bias
2) Analysis using alternative censoring rules – attrition bias

Sensitivity analysis using site Investigator RECIST 1.1 
assessments  – ascertainment bias

Secondary analysis using BICR RECIST 1.1 assessments 
(durvalumab + tremelimumab versus placebo and durvalumab + 
tremelimumab versus durvalumab monotherapy)
Subgroup analysis using Cox proportional hazards models
Additional analysis using Cox proportional hazards models to 
determine the effect of covariates on the HR estimate
Additional analysis using Cox proportional hazards models to 
determine the consistency of treatment effect between subgroups

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Endpoints analyzed
Notes
Overall survival
Stratified log-rank tests for:

Primary analysis (durvalumab monotherapy versus placebo)

Secondary analysis (durvalumab + tremelimumab versus 
placebo and durvalumab + tremelimumab versus durvalumab 
monotherapy)
Sensitivity analysis using a Kaplan-Meier plot of time to censoring 
where the censoring indicator of the primary analysis is reversed –
attrition bias
Subgroup analysis using Cox proportional hazards models
Additional analysis using Cox proportional hazards models to 
determine the effect of covariates on the HR estimate
Additional analysis using Cox proportional hazards models to 
determine the consistency of treatment effect between subgroups
Objective response rate
Cochran-Mantel-Haenszel test for difference in proportions (using 
Investigator RECIST 1.1 assessments) adjusting for the same factors 
as the primary endpoint for:

Secondary analysis (durvalumab monotherapy and durvalumab 
+ tremelimumab combination therapy versus placebo and 
durvalumab + tremelimumab versus durvalumab monotherapy)
PFS at 18 months and 
24 months
Kaplan-Meier estimates
Time to death or distant 
metastasis
Stratified log-rank test using BICR tumor data (RECIST 1.1)
Time from randomization to 
second progression 
Stratified log-rank test using site Investigator RECIST 1.1 
assessments
OS at 24 and 36 months
Kaplan-Meier estimates of survival at 24 months and 36 months and 
analyses following the method described by Klein et al (Klein et al 
2007)
Change from baseline in key 
symptoms (EORTC QLQ-C30 
and QLQ-LC13)
Mixed-model repeated measures analysis
GHSQoL/Function 
improvement rate (EORTC 
QLQ-C30 endpoints)
Presented using summaries and descriptive statistics
Symptom improvement rate 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Logistic regression
Time to GHSQoL/Function 
deterioration (EORTC 
QLQ-C30 endpoints)
Stratified log-rank test

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Endpoints analyzed
Notes
Time to symptom deterioration 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Stratified log-rank test
Treatment-related symptoms 
(PRO-CTCAE and PGIS)
Presented using summaries and descriptive statistic
BICR  Blinded Independent Central Review; CMH  Cochran–Mantel–Haenszel; CTCAE Common Terminology 
Criteria for Adverse Event; EORTC  European Organisation for Research and Treatment of Cancer; 
GHS/QoL Global health score/Health-related quality of life; ORR  Objective response rate; OS  Overall 
survival; PCI  Prophylactic cranial irradiation; PFS  Progression-free survival; PGIS Patient’s Global 
Impression of Severity; PRO Patient-reported outcome; QLQ-C30  30-Item core quality of life questionnaire; 
QLQ-LC13  Lung cancer module; SAP Statistical analysis plan.
9.5.1.1
Progression-free survival
The primary PFS analysis will be based on the programmatically derived RECIST 1.1 using 
BICR tumor assessments. The analysis will be performed in the FAS using a stratified log-rank 
test adjusting for TNM stage (I/II versus III) and receipt of PCI (yes versus no). The effect of 
durvalumab monotherapy and durvalumab and tremelimumab combination therapy versus 
placebo treatment will be estimated by the hazard ratio (HR) together with its corresponding 
confidence interval (CI) (95% and [1-adjusted alpha] × 100%) from a stratified Cox proportional 
hazards model.
In order to ensure there are at least 5 events within each strata; if there are too few events in the 
Stage I/II stratification level, TNM stage may be excluded from the models leaving receipt of 
PCI as the sole stratification factor. 
Secondary PFS analyses will be performed using the same methodology as for the primary 
analysis.
Kaplan-Meier plots of PFS will be presented by treatment group. Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each treatment group.
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be analyzed 
using a log-rank test. For patients whose death was treated as PFS event, the date of death will be 
used to derive the PFS time used in the analysis. This approach has been shown to be robust even 
in highly asymmetric assessment schedules (Sun and Chen 2010). 
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following 2 or more non-evaluable tumor assessments will be included. 
In addition, patients who take subsequent therapy prior to progression or death will be censored 
at their last evaluable assessment prior to taking the subsequent therapy. This analysis will be 

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supported by a Kaplan-Meier plot of the time to censoring where the censoring indicator of the 
PFS analysis is reversed.
Ascertainment bias will be assessed by analyzing the site Investigator data. The stratified log-
rank test will be repeated on PFS using the site Investigator data based on RECIST. 
Disagreements between Investigator and central reviews of RECIST progression will be 
presented for each treatment group.
The assumption of proportionality will be assessed 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. In addition, the Kaplan-Meier curve along with 
landmark analyses (eg, 1-year PFS rate) will also help in understanding the treatment benefit.
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using BICR assessments) 
between durvalumab monotherapy and durvalumab and tremelimumab combination therapy 
versus placebo in the following subgroups of the FAS (but not limited to): 

TNM stage (Stage I/II versus III)

Receipt of PCI (yes versus no)

Time from end date of cCRT to randomization in this study (<14 days, ≥14 to <28 
days, ≥28 days)

Time from last dose of radiotherapy to randomization in this study (<28 days, ≥28 to 
<56 days, ≥56 to <84 days, ≥84 days)

Prior platinum chemotherapy (carboplatin versus cisplatin)

Prior radiotherapy regimen (daily versus twice daily)

Best response to CRT (CR versus PR versus SD)

Sex (male versus female)

Age (<65 versus ≥65 years of age)

PD-L1 status (< 1% versus ≥1%)

Smoking status (smoker versus non-smoker [never smoker])

Race/ethnicity

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
Geographic region

WHO/ECOG PS (0 versus 1)
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 PFS.
Cox proportional hazards modeling will be employed to assess the effect of covariates on the HR 
estimate. A model will be constructed, containing the treatment and the stratification factors, to 
ensure that any output from the Cox modeling is likely to be consistent with the results of the 
stratified log-rank test.
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985 (Gail and Simon 1985).
Additionally, for each subgroup, the HR (durvalumab monotherapy or durvalumab and 
tremelimumab combination therapy: placebo) and 95% CI will be calculated from a Cox 
proportional hazards model with treatment as the only covariate. These will be presented on a 
Forest plot including the HR and 95% CI from the overall population. 
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 PFS will not be formally analyzed. In this case, only 
descriptive summaries will be provided.
9.5.1.2
Overall survival
The primary analysis of OS in the FAS will be analyzed using a stratified log-rank test, using the 
same methodology as described for the PFS endpoint. The treatment effect will be estimated by 
the HR together with its corresponding CIs (95% and [1-adjusted alpha] × 100%) from a 
stratified Cox proportional hazards model. Kaplan-Meier plots will be presented by treatment 
group. 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.
9.5.1.3
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using BICR tumor data, 
for unconfirmed and confirmed responses. The analysis will be performed using a Cochran-
Mantel-Haenszel (CMH) test, stratified using the same stratification factors as for the primary 
endpoint. The effect of treatment will be estimated by the difference in proportions between 
treatment groups, together with its corresponding 95% CI and p-value (2-sided). The CI for the 
difference in proportions between the treatment groups will be computed using Miettinen and 

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Nurminen's (MN) stratified confidence limits. This analysis will be performed in the FAS, 
including all patients with measurable disease at baseline. 
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 group, BoR will be summarized by n (%) for each category (CR, PR, SD, PD, and 
NE). No formal statistical analyses are planned for BoR.
Analyses will be repeated using the site Investigator data as per RECIST 1.1, for unconfirmed 
and confirmed responses.
9.5.1.4
Progression-free survival at 18 months and 24 months
The proportion of patients alive and progression free at 18 months and 24 months (ie, PFS18 and 
PFS24) and corresponding 95% CIs will be summarized (using the Kaplan-Meier curve) and 
presented by treatment group.
9.5.1.5
Time to death or distant metastasis
TTDM will be analyzed using identical methods as outlined for the analysis of PFS and adjusting 
for the same set of covariates, but no subgroup analysis will be performed. Medians and Kaplan-
Meier plots will be presented to support the analysis. 
9.5.1.6
Proportion of patients alive at 24 and 36 months
The proportion of patients alive at 24 and 36 months (ie, OS24 and OS36) and corresponding 
95% CIs will be summarized (using the Kaplan-Meier curve) and presented by treatment group. 
9.5.1.7
Time from randomization to second progression
Second progression (PFS2) in the FAS will be analyzed using a stratified log-rank test, using the 
same methodology as described for the primary PFS endpoint. The treatment effect will be 
estimated by the HR together with its corresponding CI and p-value. Kaplan-Meier plots will be 
presented by treatment group. Summaries of the number and percentage of patients who have an 
event as well as who were censored will be provided along with the medians for each treatment.
For supportive purposes, the time to the start of subsequent therapy will be analyzed using the 
same methodology and model. The HR for the treatment effect together with its 95% CI will be 
presented. In addition, a Kaplan-Meier plot of the time to the start of subsequent therapy will be 
presented by treatment group. No multiplicity adjustment will be applied, as these are viewed as 
supportive endpoints.
A summary table of first subsequent therapies by treatment group will be provided, as well as the 
response to first subsequent therapy by treatment group.
9.5.1.8
Duration of response
Descriptive data will be provided for the duration of response in responding patients, including 
the associated Kaplan-Meier curves and the estimated medians (without any formal comparison 
of treatment groups or p-value attached). This analysis will be performed in the FAS.

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9.5.1.9
Patient-reported outcomes: EORTC QLQ-C30 and QLQ-LC13
Five symptoms have been identified as primary: 

Dyspnea: multi-item scale based on 3 questions (“Were you short of breath when you 
rested; walked; climbed stairs?” – QLQ-LC13),

Cough: 1 item (“How much did you cough?” – QLQ-LC13),

Chest pain: 1 item (“Have you had pain in your chest?” – QLQ-LC13).

Fatigue: multi-item based on 3 questions (“Did you need rest?; Have you felt weak?; 
Were you tired?” – QLQ-C30)

Appetite loss: 1 item (“Have you lacked appetite?” – QLQ-C30)
The physical functioning, role functioning and overall health status domains (GHS/QoL) of the 
EORTC QLQ-C30 are furthermore pre-specified endpoints of interest.
Mixed-model repeated measures analysis
Change from baseline in dyspnea, cough, and chest pain scores as assessed by the EORTC 
QLQ-LC13 GHS/QoL, physical functioning, role functioning, and 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. No multiplicity 
adjustment will be applied, as these are viewed as supportive secondary endpoints.
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 QLQLC13. 
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.
Improvement rate
A summary of the symptom improvement rate for all symptom scales/items in EORTC 
QLQ-C30 and QLQ-LC13 will be produced. Similarly, a summary of function/HRQoL 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced. 

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Symptom improvement rates will be analyzed by comparing between treatment groups using a 
logistic regression model. The odds ratio and 95% CI for each scale/item will be presented 
graphically on a Forest plot. If there are very few responses in 1 treatment group, a Fisher’s exact 
test will be considered.
Change from baseline
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 assessment time point for each 
treatment group. Graphical presentations may also be produced as appropriate. Summaries of the 
number and percentage of patients in each response category at each assessment time point for 
each ordinal item (in terms of the proportion of patients in the categories of improvement, stable, 
and deterioration as defined in Table 12) will also be produced for each treatment group.
9.5.1.10
Health care resource use
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalization, outpatient, and day case), reason, length of stay by ward type (including 
intensive care unit), and procedures and tests may be undertaken to examine the impact of 
disease and treatment on resource use to primarily support the economic evaluation of 
durvalumab monotherapy and the durvalumab and tremelimumab combination therapy. This 
would include providing descriptive statistics as appropriate, including means, median, and 
ranges.
9.5.2
Safety analyses
Safety and tolerability data will be presented by treatment group using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data. AEs (both 
in terms of Medical Dictionary for Regulatory Activities preferred terms and CTCAE grade) will
be listed individually by patient. The number of patients experiencing each AE will be 
summarized by treatment group 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 clinical laboratory findings (including chemistry, 
hematology, and urinalysis), physical examinations, vital signs, and ECGs. Exposure to 
durvalumab monotherapy, durvalumab and tremelimumab combination therapy, and placebo will 
be summarized. Time on study; durvalumab monotherapy, durvalumab and tremelimumab 
combination therapy, and placebo dose delays will also be summarized. At the end of the study, 
appropriate summaries of all safety data will be produced, as defined in the SAP.
A listing of all subjects affected by the COVID-19 pandemic, and subjects with reported issues 
in the Clinical Trial Management System due to COVID-19 pandemic will be generated. In 
addition, all COVID-19 related non-important PDs and issues will be summarized and listed. 
Additional analyses might be conducted to investigate the impact of COVID-19 on study 
endpoints.

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9.5.3
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.
9.5.4
Immunogenicity data
Immunogenicity results will be listed by patient, and a summary will be provided by the number 
and percentage of patients who develop detectable ADA to durvalumab and to tremelimumab. 
ADA titer and nAb data will be listed for samples confirmed positive for the presence of ADA. 
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow. 
9.5.5
Pharmacokinetic/pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters may 
be investigated graphically or using an appropriate data modeling approach.
9.5.6
Biomarker data
The relationship of PD-L1 expression (secondary endpoint) and, if applicable, of exploratory 
biomarkers to clinical outcomes (including but not restricted to) of PFS, OS, and ORR will be 
presented. TMB related testing or analysis is not applicable in China.
PD-L1 expression determined by validated SP263 IHC assay will be reported in the CSR. The 
relationship between tissue- and blood-based secondary and exploratory biomarkers to clinical 
outcomes (PFS, OS, and ORR) will be assessed. Summaries and analyses for secondary and 
exploratory biomarkers will be documented in a separate analysis plan and will be reported 
outside the CSR in a separate report.
9.5.7
Methods for multiplicity control
The MTP shown in Figure 3 will be used to strongly control the family-wise type I error rate 
(alpha) at 5% (2-sided) for testing the following primary and key secondary endpoints: 

Primary endpoints: PFS and OS for durvalumab monotherapy versus placebo

Key secondary endpoints: PFS and OS for durvalumab in combination with 
tremelimumab versus placebo
The testing procedure is hierarchical starting with testing the 2 dual primary endpoints of PFS 
(per BICR) and OS as outlined in Figure 3. The overall 5% type I error (2-sided) is split among 
the 2 dual primary endpoints. An alpha level of 0.5% is allocated to PFS and an alpha level of 
4.5% is allocated to OS. For PFS, 1 interim analysis plus 1 primary analysis is planned (2 total). 
For OS, 2 interim analyses plus 1 primary analysis (3 total) are planned. The 0.5% alpha level for 
PFS will be split between 2 potential analysis timepoints, and the 4.5% alpha level for OS will be 
split between 3 potential analysis timepoints, even if all planned tests are not performed (if the 
prior MTP levels do not pass at an interim). The 0.5% alpha level for PFS, and the 4.5% alpha 
level for OS, are controlled at the time of the interim and primary analyses using the 

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Lan-DeMets spending function that approximates an O’Brien Fleming approach, as described in 
Section 9.6.
If any of the PFS analyses are significant, then the allocated test mass (0.5%) can be recycled to 
OS giving a total test mass of 5% for OS. If neither of the PFS analyses are significant, but OS is 
significant at the 4.5% level, at either an interim or primary analysis (where the alpha was 
controlled by the Lan-DeMets spending function), then the 4.5% can be recycled to test PFS at 
5%. If OS is significant at either an interim or primary analysis, and the alpha recycled to re-test 
PFS, then PFS can only be tested using the information available at the time of that original PFS 
analysis. 
If both PFS and OS are statistically significant for the primary analyses comparing durvalumab 
monotherapy versus placebo, then the 5% alpha can be carried down to test durvalumab in 
combination with tremelimumab versus placebo. OS will be tested at 5% and then, if significant 
PFS will be tested at a 5% alpha level. Further details will be provided in the SAP.
Figure 3
Multiple testing procedure
D durvalumab; OS overall survival; PFS progression-free survival; T tremelimumab.
9.6
Interim analyses
Three interim analyses are planned: 1 for PFS and 2 for OS. 
PFS has the potential to be analyzed on 2 occasions, once at the interim analysis (PFS-IA) and 
then at the primary PFS analysis. OS has the potential to be analyzed on 3 occasions: once at the 
PFS interim analysis (OS-IA1), then at an interim analysis (OS-IA2), and for the primary OS 
analysis.

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The planned PFS-IA will occur when approximately 308 PFS BICR events have occurred in the 
durvalumab monotherapy and placebo treatment groups (58.8% maturity). OS-IA1 will occur at 
the same time when it is anticipated that approximately 242 death events in the durvalumab 
monotherapy and placebo treatment groups (46.2% maturity) will have occurred. 
The planned OS-IA2 will occur when approximately 299 death events have occurred in the 
durvalumab monotherapy and placebo treatment groups (57.1% maturity). 
The interim analyses will be assessed by an IDMC (further details are given in the IDMC 
charter). The recommendations from the IDMC will not reveal the results of the analysis but will 
take the form of “Continue/Modify/Recommend Early Submission/Stop”.
PFS interim analysis
For the comparison of durvalumab monotherapy versus placebo, approximately 308 PFS BICR 
events (58.8% maturity) will be available for the interim analysis. The Lan-DeMets spending 
function that approximates an O’Brien Fleming approach will be used to account for multiplicity 
introduced by including an interim analysis for superiority (Lan and DeMets 1983).
At the time of the PFS-IA, the significance level will be calculated by the IDMC based on the 
actual number of events observed as a proportion of the planned primary number of events 
(n = 370). If for example 83.2% of the number of PFS BICR events required at the time of the 
primary PFS analysis are available at the time of PFS-IA (ie, 308/370), the 2-sided significance 
level to be applied for the PFS-IA would be 0.184%, and the 2-sided significance level to be 
applied for the primary PFS analysis would be 0.444% (controlled at an overall alpha level of 
0.5%). 
OS interim analyses
For the comparison of durvalumab monotherapy versus placebo, approximately 242 and 
299 death events (46.2% and 57.1% maturity) will be available for the first and the second 
interim OS analyses, respectively. The Lan-DeMets spending function that approximates an 
O’Brien Fleming approach will be used to account for multiplicity introduced by including an 
interim analysis for superiority (Lan and DeMets 1983).
At the time of each interim analysis, the significance level will be calculated by the IDMC based 
on the actual number of events observed as a proportion of the planned primary number of events 
(n = 348). If for example 69.5% and 85.9% of the number of death events required at the time of 
the primary OS analysis are available at the time of each interim analysis respectively (ie, 
242/348 and 299/348), the 2-sided significance level to be applied for the first and second OS 
interim analyses would be 1.243% and 2.398%, respectively, and the 2-sided significance level 
to be applied for the primary OS analysis would be 3.616% (controlled at an overall alpha level 
of 4.5%). 
If both the PFS interim and OS interim analysis results do not meet the efficacy boundary for 
superiority, the study will remain blinded and continue to be followed for PFS and survival. The 

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recommendations from the IDMC will not reveal the results of the analysis but will take the form 
of “Continue/Modify/Recommend Early Submission/Stop.”
The key secondary comparison of durvalumab in combination with tremelimumab versus 
placebo will similarly use a Lan-DeMets spending function to define significance boundaries for 
PFS and OS. These will be based on the number of events for the comparison and are therefore 
distinct from those defined for the boundaries for the primary comparison of durvalumab 
monotherapy versus placebo. Further details will be provided in the SAP. 
9.6.1
Data monitoring committee
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.
A data monitoring committee will be utilized for this study. Appendix A 5 provides more details 
on the rationale for and the remit of the committee.
An IDMC comprised of independent experts will be convened to confirm the safety and 
tolerability of the proposed dose and schedule and for the planned interim analyses. The safety 
review will take place after the first 20 patients have been randomized into each of the 
3 treatment groups (ie, after a total of 60 patients have been randomized to the study). In 
addition, the IDMC will review planned interim analyses and inform the Sponsor whether the 
interim boundaries specified in Section 9.6 are met. 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.”  
The study may also be stopped based on the findings of the interim safety analysis conducted by 
the IDMC. 
Full details of the IDMC procedures, processes, and interim analyses can be found in the IDMC 
Charter. 

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10.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

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Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

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
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and will notify the IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach 
of the protocol or regulations is essential so that legal and ethical obligations are met.
o
A ‘serious breach’ means a breach likely to affect to a significant degree the 
safety and rights of a participant or the reliability and robustness of the data 
generated in the clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about such breaches.
o
AstraZeneca will comply with country-specific regulatory requirements relating 
to serious breach reporting to the regulatory authority, IRB/IEC, and 
investigators. If EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is 
required to enter details of serious breaches into the EMA CTIS. It is important to 
note that redacted versions of serious breach reports will be available to the public 
via CTIS.

The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are able 
to identify the occurrence of a (potential) serious breach
o
A (potential) serious breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (e-mail address or telephone number) provided by 
AstraZeneca.
A 2
Financial disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.

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A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of the 
study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded 
from other aspects of the study (Not Applicable for China).
If a patient’s partner becomes pregnant during or within 90 days after the last dose of 
durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab 
combination therapy, the partner is asked to sign the "Adult Study Informed Consent Form for 
Pregnant Partners of Study Patients" and provide information about the pregnancy accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research (Not Applicable for China). The Investigator or authorized 
designee will explain to each patient the objectives of the exploratory research. Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will indicate this in the ICF. If a patient withdraws consent to the use of 
donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca will 
not be obliged to destroy the results of this research.
A 4
Data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, their 
general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.

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Precautions are taken to preserve confidentiality and prevent genetic data from 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 might also have access to his or her genetic data. Also, regulatory authorities may require 
access to the relevant files. Even so, the patient’s medical information and the genetic files 
would remain physically separate.
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data sets 
transferred to the Sponsor will contain only the identifier; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of clinical study data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS within 
a year from global End of Trial Date in all participating countries, due to scientific reasons, as 
otherwise statistical analysis is not relevant.
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or summary 
of main study results may also be available on other websites according to the regulations of the 
countries in which the main study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

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The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of the study 
which includes clinical reviews of study data in accordance with the currently approved protocol. 
Monitoring details describing clinical reviews of study data from a medical perspective are 
included in more detail in the Medical Oversite Plan.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study, including interactive voice response system printouts, are defined as source 
documents. Source data are contained in source documents (original records or certified copies).
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.

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Appendix B
Authorship will be determined by mutual agreement and in line 
with International Committee of Medical Journal Editors 
authorship requirements. Adverse event definitions and 
additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event 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 or incapacity. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above.
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; 

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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.
B 3
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).
B 4
Hospitalization
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.
B 5
Important medical event or medical treatment
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, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment 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 anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
B 6
CTCAE grade

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The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the criteria 
recommended in the CTCAE manual that converts severity levels into CTCAE grades should be 
used. A copy of the CTCAE can be downloaded from the Cancer Therapy Evaluation Program 
website (http://ctep.cancer.gov). The applicable version of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 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 not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 7
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 etiology 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?

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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.
B 8
Medication error, Drug abuse, Drug misuse
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the participant 
or has the potential to cause harm to the participant. 
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 participant.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error (eg, medication prepared incorrectly, even if it was not actually given 
to the participant)

Drug not administered as indicated, for example, wrong route, dose (error greater than 
+/- 10%), 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 participant received the medication (excluding IVRS/IWRS errors)

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
Wrong drug administered to participant (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 

Participant accidentally missed drug dose(s) (eg, forgot to take medication)

Accidental overdose (will be captured as an overdose)

Participant 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.
Drug abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, non-
therapeutic excessive use of IMP/study intervention or AstraZeneca NIMP for a perceived 
reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Abuse Report Form. This form should be used both if the drug abuse 
happened in a study participant or if the drug abuse regards a person not enrolled in the study
(such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or a 
person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of getting 
high.
Drug misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorised product 
information, or for unauthorised IMPs/study interventions or AstraZeneca NIMPs, outside the 

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intended use as specified in the protocol, and includes deliberate administration of the product by 
the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to the 
DES using the Drug Misuse Report Form. This form should be used both if the drug misuse 
happened in a study participant or if the drug misuse regards a person not enrolled in the study 
(such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that they were feeling 
better when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
Handling of human biological samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of sample 
shipment.
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 AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end of 
a specified period as described in the informed consent.
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 
The Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented.

Ensures that the patient and AstraZeneca are informed about the sample disposal.

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AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented and the 
site informed.

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Appendix D
Genetics (Not applicable for China)
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting patients.
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 studies and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA (ie, the entire 
genome). 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on durvalumab continues but no longer than 
15 years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All 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 fulfill 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.

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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
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 study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined Appendix C 2.
Not applicable for China.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients pre-dose at the first 
dosing visit. 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 
at the first dosing visit, 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.
Not applicable for China.
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 only by the second, unique number. 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 enrollment/randomization 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 
permit tracing of samples for destruction in the case of withdrawal of consent.

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Not applicable for China.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Not applicable for China.
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 center. The Principal 
Investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely withdrawal from the genetic aspect of the study at any time.
Not applicable for China.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician 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. In addition, 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 analyses the samples.
AstraZeneca and its designated organizations 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 organizations 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.

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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 may be prepared where appropriate.

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Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law
E 1
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 managing liver abnormalities can be found in the 
Dosing Modification and Toxicity Management Guidelines.
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.
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT from a central laboratory and/or elevated TBL from a local 
laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
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 product 
(IP). 
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.
E 2
Definitions
Potential Hy’s law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥2 × ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP). 
Hy’s law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the IP, 
can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
E 3
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 ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s law criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
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 8.4 Safety Reporting and Appendix E, Section 6. Actions 
Required When Potential Hy’s Law Criteria are Met Before and After Starting Study 
Treatment)

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.

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
For subjects that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change# in the subject’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study patients’ follow-up (including any further laboratory testing) 
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. Complete follow-up SAE Form as required.

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 
# - A ‘significant’ change in the subject’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.
E 5
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.
As soon as possible 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 IP to ensure 
timely analysis and reporting to health authorities within 15 calendar days from date PHL criteria 
was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other patient matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

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
If the alternative explanation is an AE/SAE, update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:

Send updated 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.

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 previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
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 Appendix E, 
Section 4.2.

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
# - 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.
E 7
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 starting study treatment and at first on-
study treatment visit, as described in Appendix E 6?
If No: Follow the process described in Appendix E, Section 4.2 for reporting PHL as an SAE
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 Appendix E, Section 4.2 for 
reporting PHL as an SAE.
# - 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.
E 8
Laboratory tests
Recommended Hy’s Law lab kit for laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 

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IgM and IgG anti-HBc
HBsAg
HBV DNA#
IgM and IgG anti-HCV
HCV RNA* 
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)**
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal antibody 
(Anti-LKM)
Anti-Smooth Muscle antibody (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
# HBV DNA is only recommended when IgG anti-HBc is positive. 
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. 

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Appendix F
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for this study with regard to Investigator 
assessment of tumor burden including protocol-specific requirements for this study. 
Definitions of measurable, non-measurable, target and non-target lesions
Measurable:
A lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter (except 
lymph nodes which must have short axis1diameter of ≥15 mm) with computed tomography (CT) 
or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination (manual palpation) that is not 
measurable by CT or MRI.

Brain metastasis
Special cases:

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable.

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 
                                               
1 The short axis is defined as the longest axis perpendicular to long axis
2 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as non-target lesions (NTLs).

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baseline. Lymph nodes, in any location (local/regional and distant), are collectively considered 
as a single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal 
glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a 
single organ.
A previously irradiated lesion may be selected as a Target Lesion provided it fulfils the criteria 
for reproducible measurability and is the only lesion available. 
Tumor lesions selected for fresh screening biopsy should not be selected as Target Lesions, 
unless imaging occurred at least ~2 weeks after biopsy, allowing time for healing.
Non-Target Lesions (NTLs):
All additional measurable lesions not recorded as TLs and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline.
Imaging Modalities
A summary of the imaging modalities to be used for RECIST 1.1 assessment of Target Lesions, 
Non-Target Lesions, and New Lesions is provided in Table 14.
Table 14
Summary of imaging modalities for tumor assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET/CT
CT  Computed tomography; FDG-PET/CT  18F-Fluoro-deoxyglucose positron emission tomography/CT; MRI  
Magnetic resonance imaging. 
CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
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 intravenous CT contrast, a non-contrast CT examination of the chest and an MRI 
with intravenous MRI contrast of the abdomen is appropriate. In patients with severely 
compromised renal function a non-contrast CT examination of the chest and abdomen is 
appropriate. For brain lesion assessment, MRI with IV contrast is the preferred method over IV 

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contrast-enhanced CT. It is strongly recommended to maintain use of the same imaging modality 
(CT or MRI), acquisition protocol, facility and scanner across all imaging time points per patient.
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST assessments. Tumors identified by clinical examination will need to be 
assessed by correlative CT or MRI anatomical scans.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence of 
new bone lesions. 
Ultrasound 
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may not 
provide an accurate assessment of true tumor size. Tumors identified by ultrasound will need to 
be assessed by correlative CT or MRI anatomical scan.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.
Tumor markers 
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1.
Histology and Cytology
Histology on tumor biopsy samples will not be used as part of the tumor response assessment as 
per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (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.
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 

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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. 
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new lesions, according to the 
following algorithm:  New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake3 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 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with intravenous
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used for 
RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET portion 
of the CT introduces additional (PET) data that may bias an Investigator if it is not routinely or 
serially performed.
Tumor response evaluation 
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including the entire liver and both adrenal glands) must be used at each subsequent 
follow-up assessment. Additional imaging may be performed based on the signs and symptoms 
of the patient, eg, new lesions at follow-up.
Baseline assessments should be performed post-CRT and no more than 42 days before the date 
of randomization and the first dose of IP, and ideally should be performed as close as possible to 
the date of randomization. Efficacy by RECIST 1.1 for all patients will be assessed according to 
the schedules of assessment. If an unscheduled assessment is performed, and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled imaging visits. 
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the 
surrounding tissue or liver is observed.

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identified as TL at baseline. Target lesions should be selected on the basis of their size (longest 
diameter for non-nodal lesions or short axis diameter for nodal lesions), but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as the 
baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be calculated 
and reported as the follow-up sum of diameters.
Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis diameter. 

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a New 
Lesion.

If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 

If two or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s). 

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion. 

When a TL has had any intervention eg, definitive radiotherapy, embolization, 
surgery, etc. during the study, the size of the TL should still be provided where 
possible and the intervention recorded in the RECIST case report form. If a TL has 
been completely removed (surgery), the longest diameter should be recorded as 0 mm.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 15).

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Table 15
Evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient decrease in sum of diameters to qualify for PR 
nor sufficient increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – this 
includes the baseline sum if that is the smallest on study. In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm from nadir.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
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
Not applicable (NA)
Only relevant if there were no Target Lesions at baseline
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NA Not applicable; 
SD  Stable disease; TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded by 
the Investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit (see Table 16).

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Table 16
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.
Not applicable (NA)
Only relevant if there were no Non-Target Lesions at baseline
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NA Not applicable; 
NTL  Non-target lesion; TL  Target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or partial 
response in TLs, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify 
for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of one 
or more new lesions is assessed as progression. The finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor. If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should be 
continued until the previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
Symptomatic deterioration
Symptomatic (clinical) deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.

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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.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 17.
Table 17
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 or NA
No
PR
SD
Non PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/non-PD*)
NE
Non PD or NE or NA
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  Progression of disease, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no target and/or non-target lesions at baseline), NED No Evidence 
of Disease (only relevant if there were neither target nor non-target lesions at baseline).
* Non-CR/Non-PD for Overall Response if only non-target lesions (no TLs) are present at baseline.
Central Review
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization (CRO) for QC and storage. Guidelines 
for image acquisition, de-identification, storage at the investigative site as source data, and 
transfer to the imaging CRO will be provided in a separate document. Results of these 
independent reviews will not be communicated to Investigators, and results of Investigator 
RECIST 1.1 assessments will not be shared with the central reviewers. The management of 
patients will be based, in part, upon the results of the RECIST 1.1 assessment conducted by the 
Investigator. Further details of the BICR will be documented in the Independent Review Charter 
(also referred to as “Imaging Charter”).

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Specifications for anatomical 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.
CT scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous throughout 
all the anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and reconstruction 
interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, abdomen 
and pelvis. Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients. Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease.
b. IV contrast administration: Optimal visualization 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 optimized 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. Care must be 
taken in measurement of target lesions on a different modality and interpretation of non-target 
disease or new lesions, since the same lesion may appear to have a different size using a new 
modality. Oral contrast is recommended to help visualize 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.

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c. Slice thickness and reconstruction interval: It is recommended that CT scans be performed 
at 5 mm contiguous slice thickness and this guideline presumes a maximum 5 mm thickness in 
recommendations for measurable lesion definition. Exceptionally, particular institutions may 
perform medically acceptable scans at slice thicknesses greater than 5 mm. If this occurs, the 
minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
All window settings should be included in the assessment, particularly in the thorax where lung 
and soft tissue windows should be considered. When measuring lesions, the TL should be 
measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” images 
of the apparent lesion.
MRI Scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality used 
at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis (and other anatomies [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 optimized 
for the specific body part being imaged as well as the scanner utilized. CT of the chest is 
typically recommended over MRI due to significant motion artifacts (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.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix G
International Airline Transportation Association (IATA) 6.2 
guidance document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (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 eg, 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 eg, Hepatitis A, B, C, D, and E viruses, 
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 study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix H
Patient-reported outcomes

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Patient Global Impression of Severity for Cancer Symptoms
Overall, how would you rate the severity of your cancer symptoms today?
No symptoms
Very mild
Mild
Moderate
Severe
Very Severe

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Appendix I
Abbreviations
Abbreviation or 
special term
Explanation
ADA
anti-drug antibody(s)
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUCss
area under the concentration versus time curve at steady state
B7-H1
B7 homolog 1
BICR
Blinded Independent Central Review
BID
twice daily
BoR
best objective response
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
CL
creatinine clearance
Cmax,ss
maximum drug concentration at steady state
CR
complete response
CRF
case report form
CRO
Contract Research Organization
CRT
chemoradiation therapy
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
Ctrough,ss
median trough concentration at steady state
DCO
data cut-off
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor

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Abbreviation or 
special term
Explanation
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
electronic patient reported outcome
ES-SCLC
extensive stage small-cell lung cancer
EQ-5D-5L
EuroQoL 5 dimension, 5-level health state utility index
FAS
full analysis set
FDA
Food and Drug Administration
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography/computed 
tomography
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
HBV surface antigen
HBV
hepatitis B
HCV
hepatitis C
HIV
human immunodeficiency virus
HR
hazard ratio
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life
IA
interim analysis
IB
Investigator Brochure
IC
immune cell
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
Ig
immunoglobulin
ILD
interstitial lung disease 
imAE
immune-mediated adverse event
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IP
investigational product
irAE
immune-related adverse event

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Abbreviation or 
special term
Explanation
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria In Solid Tumors
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LDH 
lactate dehydrogenase
LFT
liver function test
LIMS
laboratory information management system
LS-SCLC
limited stage small-cell lung cancer
mAb
monoclonal antibody
MOA
mechanism of action
MRI
magnetic resonance imaging
MTP
multiple testing procedure
nAb
neutralizing antibody
NCI
National Cancer Institute
NE
not evaluable
NED
no evidence of disease
NIMP
Non-Investigational Medicinal Product
NL
New Lesion
NSCLC
non-small cell lung cancer
NTL(s)
non-target lesion(s)
OAE
other significant adverse event
ORR
objective response rate
OS
overall survival
OS24
proportion of patients alive at 24 months from randomization
OS36
proportion of patients alive at 36 months from randomization
OS-IA1
first interim analysis of OS
OS-IA2
second interim analysis of OS
PCI
prophylactic cranial irradiation
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1

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Abbreviation or 
special term
Explanation
PFS
progression-free survival
PFS18
Progression-free survival at 18 months following randomization
PFS2
time from randomization to second progression
PFS24
Progression-free survival at 24 months following randomization
PGIS
Patient’s Global Impression of Severity
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PS
performance status
QD
once daily
QLQ-C30
30-item core quality of life questionnaire
QLQ-LC13
lung cancer module
QoL
quality of life
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
qXw
every X weeks
RECIST
Response Evaluation Criteria In Solid Tumors
RT
radiotherapy
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
safety analysis set
SCLC
small-cell lung cancer
SD
stable disease
SNP
single-nucleotide polymorphism
SoA
schedule of activities
sPD-L1
soluble programmed cell death ligand 1
SpO2
saturation of peripheral oxygen
T3
triiodothyronine
T4
thyroxine
T-cell
T lymphocyte
TCs
tumor cells
TKI
tyrosine kinase inhibitor

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185 (185)
Abbreviation or 
special term
Explanation
TL(s)
target lesion(s)
TMB
tumor mutational burden
TMG
Toxicity Management Guidelines
TNF-α
tumor necrosis factor alpha
TSH
thyroid-stimulating hormone
TTDM
time to death or distant metastasis
ULN
upper limit of normal
US
United States
WHO
World Health Organization
WT
body weight

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: d933qc00001-csp-v5
Document Title:
D933QC00001 Clinical Study Protocol version 5
Document ID:
Doc ID-003781249
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14-Jan-2023 01:26 UTC
Content Approval
13-Jan-2023 20:08 UTC
Content Approval
13-Jan-2023 17:43 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.