Clinical trial NCT04449861
Conditions: Small Cell Lung Carcinoma Extensive Disease
Sponsor: AstraZeneca
Start date: 2020-12-07; Completion date: 2023-03-30
Enrollment: 166 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This will be an open-label, single-arm, multicenter, Phase IIIb study to determine the safety of durvalumab + etoposide and cisplatin or carboplatin as first-line treatment in patients with extensive stage small-cell lung cancer.

Detailed description:

Arms: arm 1: Participants will receive treatment with durvalumab + etoposide and either cisplatin or carboplatin (EP) for 4 to 6 cycles. Durvalumab will be administered at a dose of 1500 mg every 3 weeks (Q3W) with first-line chemotherapy (EP) and will continue to be administered as monotherapy every 4 weeks (Q4W) post-chemotherapy until progressive disease (PD). Prophylactic cranial irradiation (PCI) is allowed at the investigators' discretion as per SoC guidance for ES-SCLC. Patients will attend a safety follow up visit 90 days after last dose of durvalumab.
Interventions: intervention 1: Durvalumab plus chemotherapy
Intervention descriptions: intervention 1: Drug: Durvalumab IV infusions every 3 weeks for 4-6 cycles and every 4 weeks thereafter until PD or other discontinuation criteria.

Drug: Carboplatin 4-6 cycles every 3 weeks

Drug: Cisplatin 4-6 cycles every 3 weeks

Drug: Etoposide 4-6 cycles every 3 weeks

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol  
 
Drug Substance 
Durvalumab 
 
Study Code 
D419BR00018 
 
Version 
2.0 
 
Date 
31 Mar 2021 
 
 
An Open Label, Multicenter Study of First-Line Durvalumab plus Platinum-
Based Chemotherapy in Chinese Patients with Extensive Stage Small-Cell 
Lung Cancer (Oriental) 
 
Sponsor: AstraZeneca Investment (China) Co., Ltd 


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VERSION HISTORY 
Version 2.0, 31 Mar 2021 
y 
Removal of “exact” and add  “using Clopper-Pearson method” to describe 95% CIs. 
Section updated: Synopsis, Section 9.5.1 and 9.5.2 
y 
Addition of “or unacceptable toxicity” in study design and Table 2. Section updated: 
Section 2.3, Table 2 
y 
Addition of inclusion criteria 8 and update of inclusion criteria 11. Section updated: 
Section 4.1 
y 
Update information of  “discontinuation of study treatment”. Section updated: Section 
4.6 
y 
Update and delete the content not applicable. Section updated: Section 4.7.1 and 4.7.2 
y 
Addition of “Cycle 1” at Baseline for clarity. Removal of Inclusion/exclusion criteria 
check at baseline. Update tumor assessment to clarify that patients who stops 
durvalumab treatment because of toxicity before PD will be required to continue tumor 
assessment during safety and survival follow-up period). Section updated: Table 2 
y 
Removal of the paragraph “Note: For coagulation parameters, activated partial 
thromboplastin time [either as a ratio or as an absolute value, in seconds]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”. Section updated: Table 4 
y 
Update the collection and follow-up of AEs and SAEs.  Section updated: Section 7.3.1 
and 7.3.2. 
y 
Removal the section of “Reporting of Non-serious Adverse Drug Reaction (Non-
serious ADR)”. Section updated: Section 7.5 (deleted) 
y 
Addition of the paragraph “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 7.4) and 
within 30 days for all other pregnancies. The same timelines apply when outcome 
information is available.” Section updated: Section 7.7.1 
y 
Addition of the underline words “The designated AstraZeneca representative works 
with the Investigator to ensure that all relevant information is completed within 1 


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(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 medication 
error (see Section 7.8) and within 30 days for all other medication errors. The 
designated AstraZeneca representative will ensure a Medication Error Report Form is 
forwarded to site, completed and sent to AZ DES.” Section updated: Section 7.8 
y 
Update of EP supply information. Section updated: Section 8.1 
y 
Addition of the underline words “Patients who continue to receive IP at the discretion 
of the Investigator can receive treatment until they are no longer deemed to be 
receiving clinical benefit or end of the study”. Section updated: Section 8.2.1 
y 
Update the tumor response as “overall tumor response”. Section updated: Section 9.4.2 
y 
Update the subgroup analysis. Section updated: Section 9.5.3 
y 
Minor administrative changes for clarification and to correct typographical errors 
Version 1.0, 27 Dec 2019 
Initial version 
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 .......................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 8 
1 
PROTOCOL SYNOPSIS ..................................................................................... 11 
Efficacy assessments ............................................................................................................... 12 
2 
INTRODUCTION ................................................................................................ 15 
2.1 
Background and rationale for conducting this study ............................................ 15 
2.1.1 
Small cell lung cancer (SCLC) ............................................................................. 15 
2.1.2 
Immunotherapies .................................................................................................. 15 
2.1.3 
Durvalumab .......................................................................................................... 17 
2.1.4 
Durvalumab in combination with chemotherapy ................................................. 18 
2.1.5 
Rationale for conducting this study ...................................................................... 19 
2.2 
Benefit/risk assessment ......................................................................................... 19 
2.2.1 
Potential Benefits .................................................................................................. 19 
2.2.1.1 
Durvalumab .......................................................................................................... 19 
2.2.1.2 
Durvalumab + chemotherapy ............................................................................... 19 
2.2.2 
Overall Risks ........................................................................................................ 20 
2.2.2.1 
Durvalumab .......................................................................................................... 20 
2.2.2.2 
Durvalumab + chemotherapy ............................................................................... 21 
2.2.3 
Overall benefit-risk assessment ............................................................................ 21 
2.3 
Study design ......................................................................................................... 22 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 22 
4 
STUDY POPULATION ....................................................................................... 23 
4.1 
Inclusion criteria ................................................................................................... 23 
4.2 
Exclusion criteria .................................................................................................. 24 
4.3 
Patient enrolment .................................................................................................. 26 
4.4 
Procedures for handling incorrectly enrolled ....................................................... 26 
4.5 
Restrictions ........................................................................................................... 27 
4.6 
Discontinuation of study treatment ....................................................................... 28 
4.6.1 
Procedures for discontinuation of patient from IP ................................................ 29 
4.7 
Criteria for withdrawal ......................................................................................... 29 
4.7.1 
Screen failures ...................................................................................................... 29 
4.7.2 
Withdrawal of the informed consent .................................................................... 29 
4.7.2.1 
Survival status for patients who withdrew consent and were lost to follow-up ... 29 
5 
STUDY PLAN AND TIMING OF PROCEDURES ........................................... 30 
5.1 
Screening/Enrollment period ................................................................................ 33 
5.2 
Treatment period ................................................................................................... 33 


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5.3 
Follow-up period .................................................................................................. 33 
6 
STUDY ASSESSMENTS .................................................................................... 34 
6.1 
Efficacy assessments ............................................................................................ 34 
6.2 
Survival assessments ............................................................................................ 35 
6.3 
Safety assessments ................................................................................................ 35 
6.3.1 
Clinical safety laboratory assessments ................................................................. 35 
6.3.2 
Physical examinations .......................................................................................... 37 
6.3.3 
Vital signs ............................................................................................................. 37 
6.3.4 
Electrocardiograms ............................................................................................... 38 
6.3.5 
WHO/ECOG performance status ......................................................................... 38 
6.3.6 
Other safety assessments ...................................................................................... 38 
7 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................. 38 
7.1 
Definition of adverse events ................................................................................. 38 
7.2 
Definitions of serious adverse event ..................................................................... 39 
7.3 
Collection of adverse events ................................................................................. 39 
7.3.1 
Time period for collection of adverse events ....................................................... 39 
7.3.2 
Follow-up of AEs and SAEs ................................................................................ 39 
7.3.3 
Adverse event data collection ............................................................................... 39 
7.3.4 
Causality collection .............................................................................................. 41 
7.3.5 
Adverse events based on signs and symptoms ..................................................... 41 
7.3.6 
Adverse events based on examinations and tests ................................................. 41 
7.3.7 
Hy’s law ................................................................................................................ 42 
7.3.8 
Disease-under-study (DUS) .................................................................................. 42 
7.3.9 
Disease progression .............................................................................................. 42 
7.3.10 
New cancers .......................................................................................................... 42 
7.3.11 
Deaths ................................................................................................................... 42 
7.4 
Reporting of serious adverse events ..................................................................... 43 
7.5 
Adverse events of special interest ........................................................................ 44 
7.6 
Overdose ............................................................................................................... 45 
7.7 
Pregnancy ............................................................................................................. 45 
7.7.1 
Maternal exposure ................................................................................................ 45 
7.7.2 
Paternal exposure .................................................................................................. 46 
7.8 
Medication Error ................................................................................................... 46 
7.9 
Management of investigational product-related toxicities ................................... 47 
7.9.1 
Specific toxicity management and dose modification information - 
Durvalumab .......................................................................................................... 48 
7.9.2 
Chemotherapy ....................................................................................................... 49 
8 
INVESTIGATIONAL PRODUCT AND OTHER STUDY ................................ 49 
8.1 
Identity of investigational products ...................................................................... 49 
8.1.1 
Order of Administration ....................................................................................... 50 
8.1.2 
Durvalumab (MEDI4736) .................................................................................... 50 
8.1.3 
EP .......................................................................................................................... 51 


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8.2 
Dose and treatment regimens ............................................................................... 51 
8.2.1 
Duration of treatment and criteria for treatment through progression .................. 52 
8.3 
Labeling ................................................................................................................ 53 
8.4 
Storage .................................................................................................................. 53 
8.5 
Compliance ........................................................................................................... 53 
8.6 
Accountability ...................................................................................................... 53 
8.7 
Concomitant medications and other treatments .................................................... 53 
8.7.1 
Other concomitant treatment ................................................................................ 55 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the physician 
and recorded appropriately. .................................................................................. 55 
8.7.2 
Durvalumab drug-drug interactions ...................................................................... 55 
8.8 
Rescue medication ................................................................................................ 56 
9 
STATISTICAL ANALYSES ............................................................................... 56 
9.1 
Statistical considerations ...................................................................................... 56 
9.2 
Sample size determination .................................................................................... 56 
9.3 
Definitions of analysis sets ................................................................................... 57 
9.3.1 
Safety analysis set (SAS) ...................................................................................... 57 
9.3.2 
Efficacy analysis set ............................................................................................. 57 
9.4 
Outcome measures for analyses ........................................................................... 57 
9.4.1 
Calculation or derivation of safety variables ........................................................ 57 
9.4.2 
Calculation or derivation of efficacy variables ..................................................... 58 
9.5 
Methods for statistical analyses ............................................................................ 59 
9.5.1 
Analysis of the primary variables ......................................................................... 60 
9.5.2 
Analysis of the secondary variables ..................................................................... 60 
9.5.3 
Subgroup analysis ................................................................................................. 60 
9.5.4 
Interim analysis ..................................................................................................... 61 
10 
STUDY MANAGEMENT BY ASTRAZENECA REPRESENTATIVE ........... 61 
10.1 
Training of study site personnel ........................................................................... 61 
10.2 
Monitoring of the study ........................................................................................ 62 
10.2.1 
Study agreements .................................................................................................. 62 
10.2.2 
Archiving of study documents .............................................................................. 62 
10.3 
Study timetable and end of study ......................................................................... 62 
11 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 63 
11.1 
Ethical conduct of the study ................................................................................. 63 
11.2 
Patient data protection .......................................................................................... 63 
11.3 
Ethics and regulatory review ................................................................................ 63 
11.4 
Informed consent .................................................................................................. 63 
11.5 
Changes to the protocol and informed consent form ............................................ 64 
11.6 
Audits and inspections .......................................................................................... 64 


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12 
REFERENCES ..................................................................................................... 65 
 
LIST OF TABLES 
Table 1 
Highly effective methods of contraception (<1% failure rate) ................... 25 
Table 2 
Schedule of assessments ............................................................................. 28 
Table 3 
Clinical chemistry  ...................................................................................... 33 
Table 4 
Hematology  ................................................................................................ 34 
Table 5 
Urinalysis  ................................................................................................... 34 
Table 6                List of investigational products for this study                                              46 
Table 7                Prohibited concomitant medications                                                            51 
Table 8                Supportive medications                                                                                52 
Table 9                Precision around varying incidence of AE                                                   53 
Table 10              Summary of methods of assessment                                                            79 
Table 11         
Evaluation of target lesions                                                                          83 
Table 12         
Evaluation of non-target lesions                                                                  84 
Table 13          
Overall visit response                                                                                  85 
 
LIST OF FIGURES 
Figure 1 
Study design ................................................................................................ 21 
LIST OF APPENDICES 
 
Appendix A 
Adverse event definitions and additional safety information ..................... 64 
Appendix B        Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s law                                                                                                                                   71 
Appendix C        Guidelines for Evaluation of Objective Tumor Response                           76 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study clinical study protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma drug concentration-time curve 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Calculated creatinine clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
Cmin 
Minimum plasma concentration 
CR 
Complete response 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen 4 
DCO 
Data Cut Off 
DCR 
Disease control rate 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 


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Abbreviation or 
special term 
Explanation 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPI 
First patient in 
GCP 
Good Clinical Practice 
Unless otherwise noted, ‘GCP’ shall mean ‘the International Council for 
Harmonisation Tripartite Guideline for Good Clinical Practise’ (ICH 
GCP) and the Japanese ‘Good Clinical Practice for Trials on Drugs 
(Ministry of Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 
March 1997, partially revised by MHLW Ordinance and their related 
notifications’ (GCP Ordinance). 
GMP 
Good Manufacturing Practice 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
HR 
Hazard ratio 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator’s Brochure 
IC 
Immune cell 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG 
Immunoglobulin 
ILD 
Interstitial lung disease 
imAE 
Immune-mediated adverse event 
IP 
Investigational product  
IRB 
Institutional Review Board, synonymous to Ethics Committee (EC) and 
Independent Ethics Committee (IEC) 
IO 
Immuno-oncology 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or 
special term 
Explanation 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non-small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
QC 
Quality Control 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SCLC 
Small-cell lung cancer 
SD 
Stable disease 
SoC 
Standard of care 
sPD-L1 
Soluble programmed cell death ligand 1 
TC 
Tumor cells 
TL 
Target lesion 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 


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1 
PROTOCOL SYNOPSIS 
An Open Label, Multicenter Study of First-Line Durvalumab plus Platinum-Based 
Chemotherapy in Chinese Patients with Extensive Stage Small-Cell Lung Cancer 
(Oriental) 
Study site(s) and number of subjects planned 
Approximately 300 extensive stage small-cell lung cancer (ES-SCLC) patients, who fulfil the 
inclusion/exclusion criteria, will be recruited by the investigational sites in China. 
Study Period: 
 
Estimated date of first patient enrolled 
Q3 2020 
Estimated date of last patient completed 
Q4 2022 
Study design:  
This will be an open-label, single-arm, multicenter, Phase IIIb study to determine the safety of 
durvalumab + etoposide and cisplatin or carboplatin as first-line treatment in patients with 
extensive stage small-cell lung cancer. Patients who fulfil all the inclusion criteria and none of 
the exclusion criteria will be enrolled and receive treatment with durvalumab + etoposide and 
either cisplatin or carboplatin (EP) for 4 to 6 cycles. Durvalumab will be administered at a 
dose of 1500 mg every 3 weeks (Q3W) with first-line chemotherapy (EP) and will continue to 
be administered as monotherapy every 4 weeks (Q4W) post-chemotherapy until progressive 
disease (PD) or intolerable toxicity. Prophylactic cranial irradiation (PCI) is allowed at the 
investigators’ discretion as per SoC guidance for ES-SCLC. Patients will attend a safety 
follow up visit 90 days after last dose of durvalumab.  
Objectives: 
All objectives will be evaluated for all patients, unless otherwise indicated. 
Primary objective: 
Endpoint/variable: 
To assess the safety and tolerability of durvalumab + EP in 
patients with performance status 0-2 
 
Incidence of Grade ≥3 AE 
Incidence of imAE 
 
AE Adverse event; EP Etoposide and platinum-based chemotherapy; imAE Immune-mediated adverse 
event. 
Secondary objective: 
Endpoint/variable: 
To assess the efficacy of durvalumab + EP in terms of PFS, ORR 
and OS 
PFS, APF12, ORR, DoR using 
site Investigator assessment 
and OS, OS12 


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To assess the safety and tolerability profile of durvalumab + EP 
Incidence of AEs, SAEs, 
AESIs, AE resulting in 
treatment discontinuation 
AESIs adverse event of special interest; DoR Duration of Response; EP Etoposide and 
platinum-based chemotherapy; ORR Objective response rate; OS Overall survival; OS12 
Overall survival at 12 months after first dose of study treatment; PFS Progression free 
survival; APF12  Proportion of patients alive and progression free at 12 months after first dose 
of study treatment. 
Target patient population 
Adult patients (aged ≥18 years) with histologically or cytologically documented extensive 
stage SCLC (stage IV  [T any, N any, M1 a/b/c], or with T3-4 due to multiple lung nodules 
that are too extensive or have tumor/nodal volume that is too large to be encompassed in a 
tolerable radiation plan according to American Joint Committee on Cancer Stage (8th edition). 
Patients must have World Health Organization/Eastern Cooperative Oncology Group 
performance status of 0-2; patients with PS2 will be limited to 20% of the total study 
population. 
Duration of treatment  
Unless specific treatment discontinuation criteria are met, patients enrolled will continue 
durvalumab therapy until disease progression or intolerable toxicity, as per investigator 
assessment.  
EP will be administered for 4 to 6 cycles for patients per investigator clinical decision 
Efficacy assessments 
Tumour assessments will be performed as per RECISTv1.1 criteria, using computed 
tomography (CT)/magnetic resonance imaging (MRI). The baseline assessment is part of the 
screening procedures and should be performed before the start of study drug. Imaging 
assessment performed according to local standard clinical practice within 28 days before the 
first dose of study drug, but prior to signing the informed consent form (ICF), can be used for 
screening purposes if the patient consents to the use of those results. Efficacy for all patients 
will be assessed per investigator using objective tumour assessments according to RECIST 
v1.1 at week 6±2 weeks, week 12±2 weeks and Q8W ±2 weeks thereafter, until confirmed 
objective disease progression as defined by RECIST 1.1 (irrespective of the reason for 
stopping study drug and/or initiation of subsequent therapy). The schedule of imaging 
radiological assessments should be followed regardless of any dose delays. 
The date, procedure, and overall response at each follow-up visit time-point will be 
documented, as well as if the patient is receiving benefit from the study medication. In case of 
disease progression, the physician will assess, date, and document the progression and 
methods (eg CT scan) used as per standard definitions and routine institutional standard of 
care.  
Follow-up of patients post discontinuation of study drug  
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 


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clinical progression, withdrawal from treatment, or patients who have started a subsequent 
anticancer therapy, will be followed up for survival.  
Survival 
All patients enrolled in the study should be followed up for survival until death, withdrawal of 
consent, or the end of the study. 
Investigational product, dosage, and mode of administration 
Durvalumab 1500 mg will be administered via intravenous infusion concurrently with 
etoposide and platinum-based chemotherapy (Investigator choice of cisplatin or carboplatin) 
q3w starting on Week 0 for 4 to 6 cycles. Durvalumab monotherapy will be continued q4w 
post-chemotherapy until disease progression.  
y 
N.B. If a patient’s weight falls to 30 kg or below, the patient should receive weight-
based dosing equivalent to 20 mg/kg of durvalumab until the weight improves to >30 
kg, at which point the patient should start receiving the fixed dosing of durvalumab 
1500 mg. 
y 
EP: the dose of etoposide + carboplatin or cisplatin investigated will not exceed the 
product label dose for the given indication dose (etoposide [80 to 100 mg/m2] via IV 
infusion with either carboplatin [area under the curve (AUC) 5-6] via IV infusion or 
cisplatin [75 to 80 mg/m2] via IV infusion) starting on Week 0, for up to a maximum 
of 6 doses/cycles. 
Statistical methods 
A comprehensive Statistical Analysis Plan (SAP) will be prepared before FPI.  
 
Approximately 300 patients will be enrolled to this study. All subjects who received at least 1 
dose of study treatment will be included in the safety analysis set, which will be the primary 
analysis set for all analyses.  
 
The primary objective of this study is to assess the safety and tolerability of durvalumab + EP, 
in terms of the incidence of Grade ≥3 AE and incidence of imAE. A secondary objective of 
this study is to further assess the safety and tolerability of durvalumab + EP, in terms of all 
AEs, SAEs, adverse events of special interest (AESI) and AEs leading to treatment 
discontinuation.  Safety data will be summarized descriptively overall, by seriousness, by 
causality, and by maximum National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Event (CTCAE) grade (v5.0) based on the safety analysis set.  Continuous 
variables will be summarised by the number of observations (n), mean, standard deviation 
(SD), median, quartiles (Q1 and Q3), minimum, and maximum. Categorical variables will be 
summarised by frequency counts and percentages for each category. The Clopper-Pearson 2-
sided 95% CIs around incidence will also be reported for Grade ≥3 Aes for each imAE, and 
where appropriate, for other AE types. 
 
The efficacy of first-line durvalumab + EP will be assessed as secondary objectives, in terms 
of PFS, APF12, ORR, DoR, OS, OS12. Time-to-event data will be summarized using Kaplan-
Meier estimates of the median event time and quartiles together with their 95% CIs; data will 
be reported for patients overall and separately for patients based on performance status (0 to 1 


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and 2). ORR (based on Investigator assessment) will be summarized descriptively, and the 
95% confidence intervals (CIs) using Clopper-Pearson method will be reported. 
As the safety of durvalumab + EP has not been previously established in ES-SCLC patients 
with PS2, a safety review committee (SRC) will be established to review the safety and 
tolerability data of the combination of Durvalumab+EP in this subset of patients at an early 
stage of enrolment. SRC will include AZ local study team member such as study physician, 
MC PV physician, PM and local medical affairs Lead, and also global clinical lead, global 
patient safety physician and GMAL. 
The SRC meeting will be held after the first 20 patients with PS2 have either completed the 
combination of durvalumab + chemotherapy (maximum of 6 cycles) or have discontinued 
treatment with durvalumab due to an AE or disease progression, whichever occurs first.    
After review of the data in patients with PS2, and patients with PS0-1, the SRC will make a 
recommendation on whether the study should continue recruitment of patients with PS2 as 
planned, or hold recruitment of this patient population, or amend the study design. In the event 
that the SRC recommends a change to the study, this will be communicated to all sites. 
There will be no formal interim analysis in this study.   
The primary analysis of the study will be conducted 6 months after LSIat which time 
secondary endpoints will also be assessed (maturity for PFS is approximately 60%).  
Additionally, final analysis will be performed at the end of the study when all patients have 
completed follow-up for safety or sufficient maturity for the secondary efficacy objectives has 
been reached.  
 
 


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2 
INTRODUCTION 
2.1 
Background and rationale for conducting this study 
2.1.1 
Small cell lung cancer (SCLC) 
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.59 million deaths (19.4% of the total 
cancer deaths; GLOBOCAN 2012). 
Small-cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung 
cancers (Puglisi et al 2010). SCLC is perhaps the most aggressive form of the disease, 
distinguishable from non-small-cell lung cancer (NSCLC) by its rapid doubling time, high 
growth fraction, and early dissemination. It is strongly associated with tobacco smoking and is 
also associated with an extremely high mutation rate. Inactivation of TP53 and RB1 occurs 
frequently, and in a recent study in which sequencing of SCLC tumors was carried out, 
recurrent mutations were identified in the CREBBP, EP300, and MLL genes that encode 
histone modifiers (Peifer et al 2012). Furthermore, mutations in PTEN, SLIT2, and EPHA7(as 
well as focal amplifications of the FGFR1 tyrosine kinase gene) were observed. 
A 2-stage system dividing patients into limited and extensive disease was developed in 1973 
by the United States (US) Veteran’s Administration Lung Cancer Study Group. Limited 
disease was defined as tumor tissue that could be encompassed in a single radiation port, and 
extensive-stage (ES) was defined as any tumor that extended beyond the boundaries 
of a single radiation port. At present, limited disease is identified in ~30% of patients, and ES 
is identified in ~70% of patients. 
Four to six cycles of platinum based chemotherapy, etoposide in combination with either 
cisplatin or carboplatin, without maintenance therapy has been the standard care (SoC) for 
patients with ES SCLC for the past 25 years (Pignon et al 1992, Roth et al 1992), and are 
recommended by major worldwide oncology treatment guidelines, ie, ASCO, NCCN, ESMO. 
Despite high initial response rates of up to 70% (Rossi et al 2012), it is estimated that 80% of 
patients with limited stage and almost all patients with ES SCLC will relapse or experience 
disease progression (Clark and Ihde 1998). Therefore, the prognosis for patients with SCLC in 
general and particular ES SCLC is poor; the reported 2-year survival is only 5% and 5 years 
survival rate is less than 2% (Rossi et al 2012). 
2.1.2 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells 
(Hirano et al 2005 


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Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
2005;65(3):1089-96. 
Horn et al 2018 
L.Horn, A.S. Mansfield, A.Szczesna, L.Havel, M.Krzakowski, M.J.Hochmair, F.Huemer, 
G.Losonczy, M.L Johnson, M.Nishio, M.Reck, T.Mok, S.Lam, D.S Shames, J.Liu, B.Ding, 
A.Lopez-Chavez, F.Kabbinavar,W.Lin, A.Sandler. and S.V.Liu for the Impower 133 Study 
Group First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung 
Cancer NEJM 2018 Sept, 25. 
Iwai et al 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99:12293-7. 
Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; 
CD273) (Paz-Ares 2019 
Luis Paz-Ares, Mikhail Dvorkin, Yuanbin Chen, Niels Reinmuth, et al. Durvalumab plus 
platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage 
small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 
LANCET. 2019 Oct 4. pii: S0140-6736(19)32222-6 
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 PD-1, an inhibitory signal is transmitted into the T cell, which 
reduces cytokine production and suppresses T-cell proliferation. Tumor cells exploit this 
immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed 
cells in the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells 
binds to PD-1 receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. 
These deactivated T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 
pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in 
response to endogenous 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 CD80 receptors expressed 
on immune cells. This activity overcomes PD-L1-mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is 
different from direct agonism of a stimulatory receptor such as CD28. 


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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 monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance antitumor immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Horn et al 2018 
L.Horn, A.S. Mansfield, A.Szczesna, L.Havel, M.Krzakowski, M.J.Hochmair, F.Huemer, 
G.Losonczy, M.L Johnson, M.Nishio, M.Reck, T.Mok, S.Lam, D.S Shames, J.Liu, B.Ding, 
A.Lopez-Chavez, F.Kabbinavar,W.Lin, A.Sandler. and S.V.Liu for the Impower 133 Study 
Group First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung 
Cancer NEJM 2018 Sept, 25. 
Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Topalian et al 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366:2443-54. 
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. 
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 SCLC, as well as metastatic melanoma, squamous and non-squamous cell non-
small-cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial 
carcinoma.  
2.1.3 
Durvalumab 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-
1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those 
that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes 
the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation 
of IFN-γ (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor 


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growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 2015). Based on 
these data, durvalumab is expected to stimulate the patient’s antitumor immune response by 
binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has 
been engineered to reduce antibody-dependent cellular cytotoxicity and complement-
dependent cytotoxicity.  
To date, durvalumab has been given to more than 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 Section 7.5 Refer to the current 
durvalumab IB for a complete summary of pre-clinical and clinical information including 
safety, efficacy, and pharmacokinetics (PK).  
2.1.4 
Durvalumab in combination with chemotherapy 
Nonclinical and clinical studies have indicated that blockade of immune checkpoints (PD-
1/PD-L1) can have a positive effect on antitumor immunity. Patients with SCLC may be 
particularly susceptible to these immunotherapies given the high mutational burden of this 
disease (Salgia and Skarin 1998). The use of combination chemotherapy is a mainstay of 
oncology therapy. The goal of combination chemotherapy is to utilize agents that affect cancer 
cells by different mechanisms, thus reducing the risk of developing resistance. Current 
investigations are now adding immunotherapeutics to chemotherapeutics to broaden antitumor 
responses.  
Checkpoint inhibitors have been tested in SCLC, either used alone or in combination with 
chemotherapy. The IMpower133 study was presented at the World Congress on Lung Cancer 
(Horn et al 2018). IMpower133 was a randomized placebo-controlled phase III study, 
comparing atezolizumab + etoposide/carboplatin (EC) with placebo + EC in first line 
treatment of ES-SCLC. The study demonstrated a statistically significant improvement in OS 
with the combination of atezolizumab + etoposide/carboplatin compared to placebo + EC. 
Meanwhile, the CASPIAN study which was presented at the World Congress on Lung Cancer 
(Paz-Ares et al 2019) demonstrated a statistically significant improvement in OS of 
durvalumab plus etoposide/platinum (EP) compared to etoposide/platinum (EP) in first-line 
SCLC as well. CASPIAN was a randomised, open-label, phase 3 trial, to assess durvalumab, 
with or without tremelimumab, in combination with etoposide plus either cisplatin or 
carboplatin (EP) in treatment-naive patients with ES-SCLC. CASPIAN met its primary 
endpoint of overall survival for durvalumab plus EP versus EP at the planned interim analysis, 
with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 
months (95% CI 11·5–14·8) in the durvalumab plus EP group versus 10·3 months (9·3–11·2) 
in the EP group. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 
treated patients in the durvalumab plus EP group and 166 (62%) of 266 in the EP group; 
adverse events leading to death occurred in 13 (5%) and 15 (6%) patients in the two groups, 
respectively. Immune-mediated adverse events (imAEs) were reported in 52 (20%) of 265 
patients treated with durvalumab plus EP and seven (3%) of 266 patients treated with EP 
alone, Most of these events were grade 1 or 2; grade 3 or 4 imAEs occurred in 12 patients 
(5%) in the durvalumab plus EP group and one patient (<1%) in the EP group. Deaths due to 
imAEs occurred in one (<1%) patient in each group; causes of death were hepatotoxicity in 


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the durvalumab plus EP group and pneumonitis in the EP group. The most common imAEs 
were hypothyroid events (occurring in 24 [9%] patients in the durvalumab plus EP group and 
two [1%] patients in the EP group) and hyperthyroid events (occurring in 14 [5%] and none in 
the two groups, respectively), which were all grade 1 or 2 in severity. 
2.1.5 
Rationale for conducting this study 
ES-SCLC is an aggressive malignancy and the prognosis remains poor despite favorable 
initial response to platinum-based chemotherapy, which has been the standard treatment for 
over 3 decades. Recently, immunotherapy targeting the programmed cell death-1 (PD-1) and 
programmed cell death ligand-1 (PD-L1) pathway has demonstrated clinical activity for 
patients with ES-SCLC, including as first-line treatment. While the CASPIAN study 
demonstrated improved OS with the addition of durvalumab to carboplatin or cisplatin plus 
etoposide (Paz-Ares 2019), there remains unmet needs for improved treatments in first line 
ES-SCLC in China, particularly more safety data for patients who would not have been 
included in CASPIAN study, including the ECOG PS=2 population and for those patients for 
whom flexible number of chemotherapy cycles is important in treatment decision making. 
2.2 
Benefit/risk assessment 
The following sections include summaries of the potential benefits and risks associated with 
durvalumab prior to the overall benefit-risk assessment. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of durvalumab 
may be found in the Investigator’s Brochure. 
2.2.1 
Potential Benefits 
2.2.1.1 
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab monotherapy 
are based on the first-in-human, single-agent study (Study 1108) in patients with advanced 
solid tumors. Overall, as of 7 May 2015, 456 of 694 patients treated with durvalumab 10 
mg/kg Q2W were evaluable for response (defined as having ≥24 weeks follow-up, measurable 
disease at Baseline, and ≥1 follow-up scan or discontinued because of disease progression or 
death without any follow-up scan). Data from patients with SCLC in this study, although 
limited (n=19), showed a favorable disease control rate (DCR) of 26.3% when durvalumab 
was given 10 mg/kg Q2W. 
 
 
2.2.1.2 
Durvalumab + chemotherapy 
Studies evaluating agents targeting PD-L1 or CTLA-4 in combination with chemotherapy 
have yielded encouraging results.   
The Phase III CASPIAN study demonstrated a statistically significant improvement in OS for 
durvalumab plus etoposide/platinum (EP) compared to EP alone as first-line treatment for ES-
SCLC at a pre-planned interim analysis with a hazard ratio of 0·73 (95% CI 0·59–0·91; 
p=0·0047]).  The median overall survival was 13·0 months (95% CI 11·5–14·8) in the 
durvalumab plus EP group versus 10·3 months (95% CI 9·3–11·2) in the EP alone group. The 
OS improvement with durvalumab plus EP was demonstrated across all pre-specified 


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subgroups. The secondary endpoint of progression free survival (PFS) was also improved with 
durvalumab plus EP versus EP (PFS HR: 0.78 [95% CI, 0.645‒0.936]; median PFS, 5.1 vs. 
5.4 months); the 12-month PFS rate was 17.5% vs. 4.7%, respectively. Durvalumab plus EP 
showed a 10% improvement in confirmed objective response rate (ORR) compared to EP; 
67.9% vs. 57.6%, respectively.  The treatment effects of durvalumab + EP were sustained over 
time compared to EP alone, as supported by the estimates of the 18 month OS rate, as well as 
the 12-month OS, PFS, and Duration of Response rates: 53.7% vs 39.8% of patients were 
alive at 12 months; an estimated 33.9% vs 24.7% of patients were alive at 18 months; and the 
12-month PFS rate was 17.5% vs 4.7%, across the two groups, respectively.  
2.2.2 
Overall Risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1), aim 
to boost endogenous immune responses directed against tumor cells. By stimulating the 
immune system however, there is the potential for adverse effects on other tissues.  
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune-mediated effects can occur in 
nearly any organ system, and are most commonly seen as gastrointestinal AEs such as colitis 
and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and 
liver enzyme elevations, skin events such as rash and dermatitis, and endocrinopathies 
including hypo- and hyper-thyroidism. 
2.2.2.1 
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 
transaminases, nephritis/increases in creatinine, , rash/dermatitis, myocarditis, 
myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, pancreatitis, 
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 ı 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program. 


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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 7.9.1). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 
2.2.2.2 
Durvalumab + chemotherapy 
The safety and tolerability of the combination of durvalumab plus chemotherapy was 
evaluated in two studies evaluating different chemotherapy regimens in patients with solid 
tumors: AZ study D419SC00001 and CCTG study NCT02537418. In general, the 
combination of durvalumab plus tremelimumab with chemotherapy appeared tolerable and 
manageable. On all dose levels, dose delays of durvalumab were mostly for administrative 
reasons/patient request and neutropenia related to chemotherapy. 
 
In the randomized phase III CASPIAN study, durvalumab + EP was tolerable and manageable 
as first line treatment for ES-SCLC.  The safety profile was consistent with the known profile 
of all the agents and no new safety signals were identified.  In summary,  any-cause adverse 
events of any grade were reported in 98.1% vs 97.0% of patients in the durvalumab +EP and 
EP alone groups, respectively.  Rates of grade 3 or 4 occurred in 163 (62%) of 265 treated 
patients in the durvalumab plus EP group and 166 (62%) of 266 in the EP group; serious 
adverse events (SAEs) occurred in 30.9% of patients treated in the durvalumab plus EP group 
and 36.1% of patients treated in the EP group; adverse events leading to death occurred in 13 
(5%) and 15 (6%) patients. Adverse events of any cause leading to discontinuation of study 
treatment occurred in 9.4% of the patients treated in both the durvalumab + EP and the EP 
alone groups.  Immune-mediated adverse events (imAEs) were reported in 52 (20%) of 265 
patients treated with durvalumab plus EP and seven (3%) of 266 patients treated with EP, 
Most of these events were grade 1 or 2 and were endocrine related; grade 3 or 4 imAEs 
occurred in 12 patients (5%) in the durvalumab plus EP group and one patient (<1%) in the EP 
group. 
External clinical data also supports these findings. In the randomized Phase III study 
IMpower133 demonstrated that the safety profile of atezolizumab plus EC was consistent with 
the previously reported safety profile of the individual agents, with no new findings observed. 
2.2.3 
Overall benefit-risk assessment 
There remains a significant unmet medical need for additional treatment options for patients 
with ES-SCLC. Four or six cycles of platinum-based chemotherapy has been considered the 
standard treatment regimens for the last several decades; however, OS remains poor with a 2-
year survival rate of 5% despite favorable initial responses. The vast majority of ES-SCLC 
patients will relapse with a median time to progression of 4 to 6 months and a median OS of 7 
to 11 months. The poor prognosis reflects the limited treatment options available, highlighting 
the need for the development of newer therapeutic options. 
 
Recently, immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) and 
programmed cell death ligand-1 (PD-L1) pathway have demonstrated clinical activity across 


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multiple lines of therapy for patients with ES-SCLC. 
 
In the Phase III CASPIAN study, durvalumab + EP demonstrated a statistically significant and 
clinically meaningful improvement in OS versus EP alone, reducing the risk of death by 27% 
for this challenging-to-treat disease. Importantly, these clinical benefits were observed in the 
context of a clinically relevant control arm that permitted up to 6 cycles of EP (compared with 
4 cycles in the durvalumab + EP arm) and PCI at the investigator’s discretion. Median OS was 
13.0 versus 10.3 months for durvalumab plus EP versus EP alone and the OS benefit was 
observed across all clinically relevant patient subgroups. Consistent with the results for OS, 
PFS was also improved for durvalumab plus EP versus EP, as was confirmed ORR, with an 
incremental improvement of 10.3% between arms (67.9% vs. 57.6%). OS benefit was durable 
for durvalumab plus EP compared with EP, as evidenced by the tail of the Kaplan-Meier 
curve; in the durvalumab plus EP arm, an estimated 53.7% of patients were alive at 12 months 
and 33.9% of patients were alive at 18 months, compared to an estimated 39.8% and 24.7% of 
patients on the EP alone arm, respectively, at these landmarks. Sustained clinical benefit was 
also observed across PFS and tumor response with durvalumab plus EP versus EP, with 12-
month PFS rates of 17.5% versus 4.7%, and 22.7% versus 6.3% of patients remaining in 
response at 12 months, respectively. These gains in long term clinical benefit are meaningful 
to patients with this recalcitrant disease. 
2.3 
Study design 
This will be an open-label, single-arm, multicenter, Phase IIIb study to determine the safety of 
durvalumab + etoposide and cisplatin or carboplatin as first-line treatment in patients with 
extensive stage small-cell lung cancer. Patients who fulfil all the inclusion criteria and none of 
the exclusion criteria will be enrolled and receive treatment with durvalumab + etoposide and 
either cisplatin or carboplatin (EP) for 4 to 6 cycles. Durvalumab will be administered at a 
dose of 1500 mg every 3 weeks (Q3W) with first-line chemotherapy (EP) and will continue to 
be administered as monotherapy every 4 weeks (Q4W) post-chemotherapy until progressive 
disease (PD) or unacceptable toxicity. Prophylactic cranial irradiation (PCI) is allowed at the 
investigators’ discretion as per SoC guidance for ES-SCLC. Patients will attend a safety 
follow up visit 90 days after last dose of durvalumab. 
Figure 1                Overall study design 
 
ES-SCLC: Extensive-stage small-cell lung cancer; EP: etoposide + cisplatin or carboplatin; 
PD: Progressive disease 
3 
OBJECTIVES AND ENDPOINTS 
All objectives will be evaluated for all patients, unless otherwise indicated. 


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Primary objective: 
Endpoint/variable: 
To assess the safety and tolerability of durvalumab + EP in 
patients with performance status 0-2 
 
Incidence of Grade ≥3 AEs 
Incidence of imAEs 
 
AE Adverse event; EP Etoposide and platinum-based chemotherapy; imAE Immune-mediated adverse 
event. 
Secondary objective: 
Endpoint/variable: 
To assess the efficacy of durvalumab + EP in patients with 
performance status 0-2 
PFS, APF12, ORR, DoR using 
site Investigator assessment and 
OS, OS12 
To further assess the safety and tolerability profile of 
durvalumab + EP 
Incidence of AEs, SAEs, AESIs, 
AE resulting in treatment 
discontinuation 
AESIs adverse event of special interest; DoR Duration of Response; EP Etoposide and 
platinum-based chemotherapy; ORR Objective response rate; OS Overall survival; OS12 
Overall survival at 12 months after first dose of study treatment; PFS Progression free 
survival; APF12 Proportion of patients alive and progression free at 12 months after first dose 
of study treatment. 
4 
STUDY POPULATION 
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion 
criteria (Section 4.2) for this study at the screening visits. Under no circumstances will there 
be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study, patients should fulfill the following criteria: 
1. Male or female ≥18 years at the time of Screening.  
2. Written informed consent obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations. 
3. Histologically or cytologically documented extensive stage SCLC (stage IV [T any, N 
any, M1 a/b], or with T3-4 due to multiple lung nodules that are too extensive or have 
tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan, 
according to American Joint Committee on Cancer Stage 8th edition). 
− 
Brain metastases; must be asymptomatic or treated and stable off steroids and anti-
convulsants for at least 1 month prior to study treatment. Patients with suspected 
brain metastases at screening should have a CT/MRI of the brain prior to study entry. 
4. Patients must be considered suitable to receive a platinum-based chemotherapy regimen as 
1st line treatment for the ES-SCLC. Chemotherapy must contain either cisplatin or 
carboplatin in combination with etoposide. 
5. Life expectancy ≥12 weeks at Day 1. 
6. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0 to 2 at enrollment. 


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− 
Note: Patients with PS2 will be limited to a maximum of 20% of the total study 
population; once this limit is met, additional enrolled patients must have PS 0-1.  
7. Body weight >30 kg. 
8. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 
mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with 
computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for 
accurate repeated measurements as per RECIST 1.1 guidelines.  
9. Baseline CT/MRI results of the chest and abdomen (including liver and adrenal glands) 
within 28 days prior to the treatment initiation. 
10. No prior exposure to immune-mediated therapy including, but not limited to, other anti-
CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) 
antibodies, excluding therapeutic anticancer vaccines. 
11. Adequate organ and marrow function as defined below (test can be repeated once if 
necessary): 
− 
Hemoglobin ≥9.0 g/dL. 
− 
Absolute neutrophil count ≥1.5 × 10^9/L (use of granulocyte colony-stimulating 
factor is not permitted within 7 days before  testing). 
− 
 Platelet count ≥100 × 10^9/L. 
− 
Serum bilirubin ≤1.5 × the upper limit of normal (ULN). 
− 
In patients without hepatic metastasis: ALT and AST ≤2.5 × ULN. 
− 
In patients with hepatic metastases, ALT and AST ≤5 × ULN. 
− 
Measured or calculated creatinine clearance: >60mL/min for patients planned to be 
treated with cisplatin and >40mL/min for patients planned to be treated with 
carboplatin  
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they have 
been amenorrheic for 12 months without an alternative medical cause. 
The following age-specific requirements apply: 
− 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
− 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
 
4.2 
Exclusion criteria  
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Previous IP assignment in the present study. 
2. Medical contraindication to etoposide-platinum (carboplatin or cisplatin)-based 


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chemotherapy. 
3. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an 
interventional study. 
4. Received prior systemic therapy for ES-SCLC. 
y 
Patients who have received prior chemoradiotherapy for limited-stage SCLC 
must have been treated with curative intent and experienced a treatment-free 
interval of at least 6 months since last chemotherapy, radiotherapy, or 
chemoradiotherapy cycle from diagnosis of ES-SCLC 
5. Any condition that, in the opinion of the treating physician, would interfere with evaluation 
of the study drug or interpretation of patient safety. 
6. Planned consolidation chest radiation therapy. Radiation therapy outside of the chest for 
palliative care (ie, bone metastasis) is allowed but must be completed before first dose of the 
study medication. 
7. Major surgical procedure (as defined by the investigator) within 28 days prior to the 
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
8. History of allogeneic organ transplantation. 
9. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment 
(systemic steroids or immunosuppressive agents) or has a clinical symptomatology suggesting 
worsening of PNS. 
10. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis with the exception 
of diverticulosis, systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and 
uveitis, etc]). The following are exceptions to this criterion: 
x Patients with vitiligo or alopecia 
x Patients with hypothyroidism (eg, following Hashimoto syndrome) and stable on 
hormone replacement 
x Any chronic skin condition that does not require systemic therapy  
x Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician 
x Patients with celiac disease controlled by diet alone 
11. 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 interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that 
would limit compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent. 
12. History of active primary immunodeficiency. 
13. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 


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practice), hepatitis B (known positive HBV surface antigen [HbsAg] result), hepatitis C, or 
human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence 
of HbsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only 
if polymerase chain reaction is negative for HCV RNA.  
14. Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab. The following are exceptions to this criterion: 
x Intranasal, inhaled, topical steroids or local steroid injections (eg, intra articular 
x injection). 
x Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent. 
x Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication). Premedication with steroids for chemotherapy is acceptable. 
15. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after 
the last dose of IP. 
16. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from Screening to 
90 days after the last dose of durvalumab. 
For procedures for withdrawal of incorrectly enrolled patients, see Section 4.4. 
4.3 
Patient enrolment 
At Screening (Days -28 to -1), the investigator(s) or suitably trained delegate(s) will perform 
the following: 
1. Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
2. Determine patient eligibility. See Section 4.1 and Section 4.2. 
3. Choose platinum agent that the patient would receive in cycle 1 (based on the most 
appropriate option for the patient). 
 
The above does not list the exact sequence of study related procedures but provides the steps 
that should be taken during the screening period prior to baseline of the patient. 
 
Patients must not be treated unless all eligibility criteria have been met. 
 
Patients should begin treatment with durvalumab on Day 1 of Cycle 1 of EP. 
 
4.4 
Procedures for handling incorrectly enrolled 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who 
are enrolled but found to not meet all the eligibility criteria must not be initiated on treatment 
and must be withdrawn from the study as a screen failure. 


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When a patient does not meet all the eligibility criteria but is incorrectly started on treatment, 
the investigator should inform the AstraZeneca Study Physician immediately, and the Study 
Physician and the investigator should discuss whether to continue or discontinue the patient 
from treatment. The Study Physician must ensure that all decisions are appropriately 
documented. 
4.5 
Restrictions 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
1. Female patient of childbearing potential 
激 
Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception (Table ) from the 
time of Screening and must agree to continue using such precautions for 90 days after 
the last dose of durvalumab. Non-sterilized male partners of a female patient must use 
male condom plus spermicide throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period is an 
acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. Female patients 
should also refrain from breastfeeding throughout this period. 
2. Male patients with a female partner of childbearing potential 
激 
Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from Screening through 90 days 
after receipt of the final dose of durvalumab. Not engaging in sexual activity is an 
acceptable practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. Male patients should 
refrain from sperm donation throughout this period.  
激 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table ). 
Note: Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
y 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy). 
y 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 


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chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
Highly effective methods of contraception, defined as those that result in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 1. Note 
that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper-containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel, which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
Table  1      Highly effective methods of contraception (<1% failure rate) 
Barrier/intrauterine methods 
Hormonal methods 
Copper T intrauterine device 
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) a 
Etonogestrel implants: eg, Implanon or Norplan 
Intravaginal device: eg, ethinylestradiol and 
etonogestrel 
Medroxyprogesterone injection: eg, Depo-
Provera 
Normal and low-dose combined oral 
contraceptive pill 
Norelgestromin/ethinylestradiol transdermal 
system 
Cerazette (desogestrel) 
a This is also considered a hormonal method. 
3. Patients should not donate blood or blood components while Participating in this study and 
through 90 days after receipt of the final dose of durvalumab or until alternate anticancer 
therapy is started. 
4. Restrictions relating to concomitant medications are described in Section 8.7. 
4.6 
Discontinuation of study treatment 
An individual patient will not receive any further IP (durvalumab + EP or durvalumab 
monotherapy) if any of the following occur in the patient in question: 
 
y 
Withdrawal of consent from further treatment with IP. The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment. A patient who discontinues 
treatment is normally expected to continue to participate in the study unless they 
specifically withdraw their consent to further participation in any study procedures and 
assessments (see Section 4.7.2). 
y 
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing. 
y 
An AE that meets criteria for discontinuation of durvalumab as defined in the Dosing 
Modification and Toxicity Management Guidelines (see section 7.9 and Annex to 
Protocol). 
y 
Evidence of a new paraneoplastic syndrome(s) or worsening of an existing paraneoplastic 


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syndrome(s). 
y 
Pregnancy or intent to become pregnant 
y 
Noncompliance with the study protocol that, in the opinion of the investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits). 
y 
Initiation of alternative anticancer therapy including another investigational agent. 
y 
Clinical progression or confirmed radiological progression per Investigator assessment 
(refer to Appendix C) and Investigator determination that the patient is no longer 
benefiting from treatment with IP. 
y 
EP treatment should be discontinued after a maximum of 6 cycles  
y 
EP treatment İ 2 cycles  
y 
Durvalumab treatment delayed > 12 weeks 
y 
EP will not be provided by study if permanently discontinuation of durvalumab 
 
4.6.1 
Procedures for discontinuation of patient from IP 
At any time, patients are free to discontinue IP without prejudice to further treatment. A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs. If possible, they will be seen and assessed by an 
investigator(s). AEs will be followed up (see Section 7).  
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. 
All patients will be followed for survival until the end of the study. 
4.7 
Criteria for withdrawal 
4.7.1 
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not enter treatment. This reason for study withdrawal is only valid for screen failures (ie, 
not enrolled patients). 
4.7.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment. 
Patients who withdraw treatment in the study will not receive further IP, 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.  
4.7.2.1 
Survival status for patients who withdrew consent and were lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed, 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 


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“lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is re-
established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol. 
At the time of PFS and OS analyses, the survival status of all patients should be re-checked; 
this includes those patients who withdrew consent or are classified as “lost to follow-up.” 
y 
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.  
y 
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws to 
obtain a current survival status. (The applicable CRF modules will be updated.) 
5 
STUDY PLAN AND TIMING OF PROCEDURES 
This study has been subject to an internal review according to AstraZeneca standard 
procedures.  
 
The latest version of the IB and any subsequent updates will be supplied to the investigator. 
Investigators need to become familiar with the content of the IB and appendices associated 
with this protocol.  
Patients may delay dosing under certain circumstances. 
y 
Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-related AE. 
 
y 
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible. 
 
y 
For subsequent cycles the time between 2 consecutive doses cannot be less than 21 
days, based on the half-lives of durvalumab. If there is a dosing delay while on the 
q3w schedule, all future dosing days should be delayed to ensure that the intervals 
between dosing study treatment are always at least 21 days.  
 
Table 2 below outlines data collection measures that are considered for this study. 
 


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Table  2           Schedule of assessments 
Visit 
Screening 
Treatment period 
Safety 
follow-up 
visit 
Survival 
follow-up 
phone 
calls/emails 
Baseline 
(Day1, 
Cycle 1) 
During 
Chemotherapy 
1 cycle = 21 days 
Post-
Chemotherapy 
1 cycle = 28 days 
window 
Day-28 to 
Day-1 
0 
±3 days 
±3 days 
±7 days 
±14 days 
Week 
Weeks-4 
to Week-
1 
Week 0  
Week 3, 6, 9;  
Weeks 12, 15 at 
investigator 
discretion 
3 weeks after 
last dose of 
chemotherapy 
(either Week 
12, 15 or 18), 
then every  
weeks until PD 
or unacceptable 
toxicity 
90 days 
after last 
dose 
Every 3 
months 
Written informed 
consenta 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Demographics, 
including baseline 
characteristics  
X 
 
 
 
 
 
Medical history, 
including cancer 
treatment history 
X 
 
 
 
 
 
ECG recordingb 
X 
As clinically indicated 
Physical 
examination, weight, 
and vital signs 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
 
Laboratory Assessments 
Clinical chemistryc 
X 
Xd 
X 
X 
X 
 
Hematologyc 
X 
Xd 
X 
X 
X 
 
TSH, (reflex free T3 
or free T4f) 
X 
Xe 
X 
X 
X 
 


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Visit 
Screening 
Treatment period 
Safety 
follow-up 
visit 
Survival 
follow-up 
phone 
calls/emails 
Baseline 
(Day1, 
Cycle 1) 
During 
Chemotherapy 
1 cycle = 21 days 
Post-
Chemotherapy 
1 cycle = 28 days 
window 
Day-28 to 
Day-1 
0 
±3 days 
±3 days 
±7 days 
±14 days 
Week 
Weeks-4 
to Week-
1 
Week 0  
Week 3, 6, 9;  
Weeks 12, 15 at 
investigator 
discretion 
3 weeks after 
last dose of 
chemotherapy 
(either Week 
12, 15 or 18), 
then every  
weeks until PD 
or unacceptable 
toxicity 
90 days 
after last 
dose 
Every 3 
months 
Hepatitis B, C, HIV 
virology 
X 
 
 
 
 
 
Pregnancy testg 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
As clinically indicated 
 
Monitoring 
AE 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
X 
X 
X 
X 
 
IP Administration 
Durvalumab h 
 
X 
X 
X 
 
 
Etoposide i 
 
X 
X k 
 
 
 
Carboplatin or 
cisplatin i,j 
 
X 
X k 
 
 
 
Tumor assessment 
per Investigator -
report (according to 
RECIST1.1)l 
X 
 
On study tumor assessments should occur at Week 6±2 weeks, at Week 
12±2 weeks then every 8±2 weeksm until PD 
 
Subsequent 
anticancer therapy 
 
 
 
 
X 
X 
Survival status 
 
 
 
 
X 
X 
a. 
Written informed consent and any locally required privacy act document authorization must be obtained prior to 
performing any protocol-specific procedures, including screening/baseline evaluations. If laboratory or imaging 
procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with 


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consent of the patient. However, all screening laboratory and imaging results must have been obtained within 28 days of 
first dose. 
b. 
Any clinically significant abnormalities detected require triplicate ECG results. 
c. 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if 
clinically indicated. 
d. 
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to 
be repeated at day 1.  
e. 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 
f. 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the 
endocrine system. 
g. 
Pregnancy test will be performed in women of childbearing potential only. A urine or serum pregnancy test is 
acceptable. Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose 
of study drug and then every 3 weeks during chemotherapy and every 4 weeks post-chemotherapy. 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. 
h. 
Results for liver function tests, electrolytes, full blood count, and creatinine must be available before commencing an 
infusion (samples taken within 3 days prior to infusion) and reviewed by the treating physician or Investigator prior to 
dosing.  
i. 
Durvalumab will be administered first, followed by the etoposide + cisplatin/carboplatin regimen. 
j. 
If cisplatin, infuse over 1 to 2 hours. If carboplatin, infuse over 0.5 to 1 hour. 
k. 
Chemotherapy regimen (etoposide plus either cisplatin or carboplatin) to be administered Q3W for 4 to 6 cycles, per 
investigator clinical decision. 
l. 
See Section 6.1 and Appendix C for additional details relevant to image acquisition, RECIST 1.1 assessments, and 
evaluation of scans after RECIST 1.1-defined progression. 
m. 
Patients will have scans done Q6W for the first 12 weeks, and then Q8W thereafter or per institutional standard at 
investigator discretion. 
 
5.1 
Screening/Enrollment period 
All screening and enrollment procedures will be performed according to the assessment 
schedules in Table 2. Demographic data and other characteristics will be recorded including 
date of birth, gender and smoking history, etc, according to local regulations.  A standard 
medical and surgical history will be obtained. 
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening 
evaluations. If laboratory or imaging assessments were performed for alternate reasons prior 
to signing consent, these can be used for screening purposes with consent of the patient. 
Screening and baseline evaluations may be performed over more than 1 visit if required. 
5.2 
Treatment period 
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2). 
Whenever vital signs, electrocardiograms (ECGs), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: ECG, vital signs and 
then blood draws.  
5.3 
Follow-up period 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up. 
Patients who permanently discontinue drug for reasons other than objective disease 


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progression should continue to have tumor assessment until disease progression as per 
investigator assessment. 
All patients will be followed for survival until the end of the study. 
6 
STUDY ASSESSMENTS  
The investigator will ensure that data are recorded on the eCRFs as specified in this study 
protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the clinical study agreement (CSA). The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
6.1 
Efficacy assessments 
This study will evaluate the efficacy of durvalumab + EP as secondary endpoints, in terms of 
OS, as well as PFS, APF12, ORR, and DoR, which will be derived from site Investigator 
assessments per RECIST1.1.  
Tumor assessments should 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 study 
treatment. Any other areas of disease involvement 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 SoA, Table 2). Treatment continues until clinical 
progression/deterioration or confirmed radiological progression (refer to Section 8.2.1), and 
scanning/tumor assessments should continue throughout treatment until RECIST 1.1-defined 
radiological progression plus an additional follow-up scan (if clinically feasible). 
The RECIST 1.1 guidelines (Appendix C) provide a method of assessment of change in tumor 
burden in response to treatment. Screening/Baseline imaging should be performed no more 
than 28 days before start of study treatment, and ideally should be performed as close as 
possible to and prior to the start of study treatment. The RECIST 1.1 assessments of baseline 
images identify Target Lesions (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 timepoint responses (CR, PR, 
SD, PD, or Not Evaluable [NE]). 
The date, procedure, and overall response should be documented at each follow-up visit time-
point as well as if the patient is taking benefit from the study medication. In case of disease 
progression, the physician will assess, date, and document the progression and methods (eg 
CT scan) used as per standard definitions and routine institutional standard of care.  


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6.2 
Survival assessments  
The survival status of the patient will be collected during the study. After discontinuation of 
study treatment, patients will continue to be followed for survival via phone calls or email 
every 3 months to study end. The survival status (including cause of death) and the date of 
death or last follow-up date will be collected. 
6.3 
Safety assessments  
6.3.1 
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 
Clinical laboratory safety tests, will be performed in a licensed clinical laboratory according to 
local standard procedures.  Urine 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 and according to standard medical practice.  The date, time of collection, and 
results (values, units, and reference ranges) will be recorded. The Investigator should make an 
assessment of the available results with regard to clinically relevant abnormalities. The 
laboratory results should be signed and dated and retained at center as source data for 
laboratory variables. For information on how AEs based on laboratory tests should be 
recorded and reported, see Section 7.3.6. 
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies and HIV antibodies. T-spot TB test will be performed when 
determined to be essential by investigator. 
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site. Clinically significant (as assessed by the Investigator) laboratory 
abnormalities will be recorded as AEs. Laboratory results relevant to / associated with imAE 
will be recorded. will be 
The laboratory variables to be measured are presented in Table 3 (clinical chemistry), Table 4 
(hematology), and Table 5 (urinalysis). 
Table  3 
Clinical chemistry 
Albumin 
Lipaseb 
Alkaline phosphatase 
Magnesiumc 
ALTa 
Potassium 
Amylaseb 
Sodium 
ASTa 
Total bilirubina 


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Bicarbonatec 
Total protein 
Calcium  
TSHe 
Chloridec 
T3 freef (reflex only) 
Creatinined  
T4 freef (reflex only) 
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 
1 of these parameters is routinely measured, either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, 
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 
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using 
actual body weight).  
e 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to 
be repeated at Day 1. 
f 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical 
suspicion of an AE related to the endocrine system. 
ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid-stimulating 
hormone. 
 
Table  4 
Hematology 
Absolute neutrophil counta 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
 
 
a 
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated 
by Data Management if entered as percentage. Total white cell count therefore has to be 
provided. 
 


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Table  5 
Urinalysis 
Bilirubin 
Ketones 
Blood 
pH 
Color and appearance 
Protein 
Glucose 
Specific gravity 
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated. 
Note: Microscopy is preferred to investigate white blood cells, with use of high power field 
for red and white blood cells; dipstick can be used as well.  
 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix B 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.  
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 7.3.6. 
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. 
6.3.2 
Physical examinations 
At screening and each visit during the treatment period, a complete physical examination will 
be performed and include an assessment of the following: general appearance, respiratory, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, musculo-skeletal (including spine and extremities) and neurological systems. 
Physical examination information will only be reported in the CRF if abnormalities are 
reported as AEs. 
6.3.3 
Vital signs 
Vital signs will be monitored at screening and at every visit during the study. During 
durvalumab infusions, vital signs should be monitored as per institutional care 
recommendations for the administration of monoclonal antibodies. Vital signs will be reported 
if abnormalities are reported as AEs. 


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6.3.4 
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. 
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.  
6.3.5 
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) 
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. 
6.3.6 
Other safety assessments 
Safety findings supporting the monitoring and evaluation of imAEs, including radiographic or 
pathologic findings, or pulmonary function tests (in case of pneumonitis or ILD), should be 
reported.  
7 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
7.1 
Definition of adverse events 
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product. An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver), or the abnormal results of an investigation (eg, 


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laboratory findings). In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered. 
The term AE is used to include both SAEs and non-serious AEs. 
7.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow
up), that fulfils one or more of the following criteria: 
y 
results in death 
y 
is immediately life-threatening 
y 
requires in-patient hospitalization or prolongation of existing hospitalization 
y 
results in persistent or significant disability/incapacity 
y 
is a congenital abnormality or birth defect 
y 
is an important medical event that may jeopardize the patient or may require medical 
y 
intervention to prevent one of the outcomes listed above 
All SAEs (ie, those occurring after the AE and SAE collection period) considered to be 
reasonably related to the study treatments or to the research must be notified to the sponsor 
with no time limit. 
7.3 
Collection of adverse events 
7.3.1 
Time period for collection of adverse events 
Adverse events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period up to 90 days after the last dose of 
durvalumab treatment. If an event that starts post the defined safety follow up period noted 
above is considered to be due to a late onset toxicity to study drug then it should be reported 
as an AE or SAE as applicable. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix A. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
7.3.2 
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/SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the 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. 
7.3.3 
Adverse event data collection 
The following variables will be collected for each AE: 


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y 
AE (verbatim) 
y 
The date when the AE started and stopped 
y 
The maximum CTCAE grade reported 
y 
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar day) 
y 
Whether the AE is serious or not 
y 
Investigator causality rating against the IPs (yes or no) 
y 
Action taken with regard to IPs 
y 
Administration of treatment for the AE 
y 
Outcome 
In addition, the following variables will be collected for SAEs: 
y 
Date the AE met criteria for SAE 
y 
Date the Investigator became aware of the SAE 
y 
Seriousness criteria  
y 
Date of hospitalization 
y 
Date of discharge 
y 
Probable cause of death 
y 
Date of death 
y 
Whether an autopsy was performed 
y 
Causality assessment in relation to study procedure(s) 
y 
Causality assessment in relation to other medication, as explained in Section 7.3.4   
y 
Description of the SAE 
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).  


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It is important to distinguish between SAEs and severe AEs. Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 7.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but it is not an SAE unless it meets the criteria 
shown in Section 7.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Section 7.2. 
7.3.4 
Causality collection 
The investigator will assess the causal relationship between the IPs and each AE and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?” 
For SAEs, causal relationship will also be assessed for other medications and study 
procedures. Note that, for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes.” 
7.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to questions from the 
study site staff, 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. 
7.3.6 
Adverse events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values should only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the investigational product. 
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, 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, which 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. 
7.3.7 
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 B for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law. 
7.3.8 
Disease-under-study (DUS) 
Symptoms of DUS are those which might be expected to occur as a direct result of extensive-
stage small cell lung cancer. Events which are unequivocally due to disease under study 
should not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of the investigational product. 
7.3.9 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease. 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, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
7.3.10 
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. 
7.3.11 
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: 
x 
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented. It should 
not be reported as an SAE. 
x 
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. 


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x 
Deaths with an unknown cause should always be reported as an SAE.  It should also 
be documented in the Statement of Death page. A post mortem may be helpful in the 
assessment of the cause of death, and if performed, a copy of the post-mortem results 
should be forwarded to AstraZeneca Patient Safety or its representative within the 
usual timeframes. 
Deaths occurring after the protocol defined safety follow up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow up period and the 
event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE. 
7.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to durvalumab, or to 
the study procedure(s).  
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca study representatives (or designees) within one day i.e., 
immediately but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca study representative (or designee) 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. 
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 
study representatives of any follow-up information on a previously reported SAE within one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it. 
The reference documents for definition of expectedness are the IBs for durvalumab, as 
applicable to the tumor specific Module.  
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such. 
 


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7.5 
Adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for durvalumab 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 aetiology. 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. 
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab 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 and rare/less 
frequent imAEs including neuromuscular toxicities such as myasthenia gravis and Guillain-
Barre syndrome. 
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment are 
described in detail in the Dose Modification and Toxicity Management Guidelines (see 
Section 7.9.1 and Annex to the Protocol). 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. 


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7.6 
Overdose 
Durvalumab 
Use of durvalumab 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, and 
possible symptoms of overdose are not established.  
x 
An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the eCRF and in the Overdose eCRF 
module. 
x 
An overdose without associated symptoms will only be reported in the Overdose 
eCRF module. 
If an overdose of an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply.  For other 
overdoses, reporting must occur within 30 days. 
Chemotherapy 
Please refer to the local prescribing information for treatment of cases of overdose with 
etoposide, cisplatin or carboplatin. 
7.7 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
y 
Pregnancy discovered before the study patient has received any study drugs. 
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. 
7.7.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, durvalumab should be 
discontinued immediately. 


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Pregnancy itself is not regarded as an AE unless there is a suspicion that durvalumab 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 study representatives within 1 day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 7.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.7.2 
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, whichever is the longer time period. Please follow 
the local prescribing information relating to contraception and the time limit for such 
precautions for SoC agents.  
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose of durvalumab 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.   
7.8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient. 
Medication error includes situations where an error: 


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y 
occurred 
y 
was identified and intercepted before the patient received the drug 
y 
did not occur, but circumstances were recognized that could have led to an error 
  
Examples of events to be reported in clinical studies as medication errors: 
y 
Drug name confusion 
y 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient 
y 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
y 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a solid 
tablet 
y 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 
y 
Wrong patient received the medication  
y 
Wrong drug administered to patient  
 
Examples of events that do not require reporting as medication errors in clinical studies: 
y 
Patient accidentally missed drug dose(s) eg, forgot to take medication 
y 
Accidental overdose (will be captured as an overdose) 
y 
Patient failed to return unused medication or empty packaging 
y 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (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 medication error (see Section 7.8) and within 30 days for all other 
medication errors. The designated AstraZeneca representative will ensure a Medication Error 
Report Form is forwarded to site, completed and sent to AZ DES 
7.9 
Management of investigational product-related toxicities 
The following guidance should be followed for management of toxicities.  


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x Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
x 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. 
x All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 
x  Patients should be thoroughly evaluated to rule out any alternative etiology (eg, 
disease progression, concomitant medications, and infections). This includes EP 
induced toxicity. In the event that toxicities are clearly attributed to chemotherapy, 
both EP and durvalumab should be delayed.  
x  In the absence of a clear alternative etiology, all events should be considered 
potentially immune related and the toxicity management guidelines detailed in the 
Annex to Protocol should be followed. 
x In the event that durvalumab is temporarily discontinued or delayed as part of the 
toxicity management guidance, EP should still be administered as scheduled; every 
effort should be made to ensure patients receive at least 4 cycles of EP in the study, if 
conditions allow. 
All toxicities will be graded according to NCI CTCAE, Version 5.0. 
7.9.1 
Specific toxicity management and dose modification information - 
Durvalumab 
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 inhibitor durvalumab [Medi4736] (PD-L1 inhibitor).  These guidelines 
are applicable when durvalumab 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, 


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immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.  In addition, there are certain circumstances in which durvalumab 
should be permanently discontinued (see Section 4.6 of this protocol and the Dosing 
Modification and Toxicity Management Guidelines).  Following the first dose of IP, 
subsequent administration of durvalumab can be modified based on toxicities observed as 
described in the Dosing Modification and Toxicity Management Guidelines. These guidelines 
have been prepared 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 regimen by the reporting Investigator. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician. 
7.9.2 
Chemotherapy 
Chemotherapies are associated with a number of unwanted effects. EP-related toxicity 
management, dose adjustment, including dose delays and reductions should be performed as 
indicated in the local prescribing information for the relevant agent. In the event of 
unfavorable tolerability, patients can switch between cisplatin and carboplatin therapy at any 
point on study (assuming eligibility for the switched therapy is met). 
 
EP is the SoC and is expected to cause hematologic non-immune-related AEs for which the 
non-immune-related Toxicity Management Guidelines should not be applied. Sites should 
utilize dose delays, dose modifications, G-CSF or component transfusions (eg, platelet 
transfusions) as necessary per local standards to maintain the dose and schedule of EP 
treatment to optimize tolerability for individual patients.  
 
In the event that an AE can reasonably be attributed to EP, dose adjustment of EP should be 
attempted before modifying the administration of durvalumab. 
 
In the event that EP is delayed, durvalumab should also be delayed and to be resumed as soon 
as feasible. Every effort should be made to ensure patients receive at least 4 cycles of EP, if 
conditions allow. 
8 
INVESTIGATIONAL PRODUCT AND OTHER STUDY 
TREATMENTS 
8.1 
Identity of investigational products 
AstraZeneca will supply durvalumab (MEDI4736)and EP treatments (Table ) 
 
Table  6 
List of investigational products for this study  
Investigational product 
Dosage form and strength 


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Durvalumab 
500 mg vial solution for infusion after 
dilution, 50 mg/mL, IV 
Etoposide 
IV (as sourced locally) 
Carboplatin 
IV (as sourced locally) 
Cisplatin 
IV (as sourced locally) 
8.1.1 
Order of Administration 
Patients will receive durvalumab (1500 mg) via IV infusion over 60 minutes on Day 1 of each 
cycle. 
We recommend a 60-minute observation period after durvalumab is administered at least for 
cycle 1. 
If no issues are seen after durvalumab is given during the first cycle, we recommend reducing 
the observation period after durvalumab administration to 30 minutes.  
Durvalumab will then be followed by carboplatin or cisplatin as an IV infusion over 60 
minutes on Day 1 of each cycle, for a maximum of 6 cycles, followed by etoposide 
sequentially administered by a 60-minute IV infusion on Days 1, 2, and 3 of each cycle, for a 
maximum of 6 cycles. 
8.1.2 
Durvalumab (MEDI4736) 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10.0 mL. Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product 
should be kept in secondary packaging until use to prevent excessive light exposure. 
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag 
 The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique. Total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration should not exceed: 
y 
24 hours at 2°C to 8°C (36°F to 46°F) 
y 
4 hours at room temperature 
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration. 
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of 
durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 


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concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.  
If weight falls to ӊ 30 kg weight-based dosing at 20 mg/kg will be a administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter 
Standard infusion time 1 hour. In the event that there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded. 
Preparations are to be in accordance with the study-specific drug handling instructions. 
8.1.3 
EP 
EP will be supplied by AstraZeneca and will be administered according to prescribing 
information or treatment guidance in general use by the Investigating site. 
8.2 
Dose and treatment regimens 
During Chemotherapy 
Agent 
Dose 
Route 
Duration 
Schedule 
Durvalumab 
(MEDI4736) 
1500 mg 
IV 
60 mins 
4 to 6 doses 
with EP Q3W 
EP 
Etoposide (80-100 mg/m2) 
with either carboplatin (area 
under the curve 5-6) or 
cisplatin (75-80 mg/m2) 
IV 
Per local 
practice 
4 to 6 doses 
Q3W 
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab Q3W until the weight improves to >30 kg, at which point the patient should 
start receiving the fixed dosing of durvalumab 1500mg. 
EP Etoposide and platinum-based chemotherapy; IV Intravenous; Q3W Every 3 weeks. 


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Post-Chemotherapy: 
Agent 
Dose 
Route 
Duration 
Schedule 
Durvalumab 
(MEDI4736) 
1500 mg 
IV 
60 mins 
Q4W               
to PD* 
   Patients are treated until PD unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met 
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab Q4W until the weight improves to >30 kg, at which point the patient should 
start receiving the fixed dosing of durvalumab 1500mg. 
IV Intravenous; PD Progressive disease; Q4W Every 4 weeks. 
8.2.1 
Duration of treatment and criteria for treatment through progression 
All treatment will be administered beginning on Day 1. 
Treatment with SoC chemotherapy (EP) will be limited to 6 cycles on a Q3W schedule, at the 
investigators’ discretion. 
Durvalumab will be administered beginning on Day 1 until PD unless there is unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met. 
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-
defined PD may continue to receive study treatment at the discretion of the Investigator and 
patient as long as they are deemed to be receiving clinical benefit. A follow-up scan is to be 
collected after the initial RECIST 1.1-defined PD, 4-8 weeks after the prior assessment of PD. 
Patients who continue to receive IP at the discretion of the Investigator can receive treatment 
until they are no longer deemed to be receiving clinical benefit or end of the study, unless 
there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is 
met.  Image acquisitions and tumor assessments should continue on their regular imaging 
schedule for the duration of treatment. 
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) will not be eligible for continuing durvalumab. 
For all patients who are treated through progression, the investigator should ensure patients do 
not have any significant, unacceptable or irreversible toxicities that indicate continuing 
treatment would not further benefit the patient. 
Patients who AstraZeneca and the investigator determine may not continue treatment after PD 
will be followed up for survival. Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
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Following confirmed disease progression, standard chemotherapy can be offered by the 
investigator per local practice. 
8.3 
Labeling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labeling. Label 
text will be translated into local language.  
Labels will be provided as a single panel label. 
8.4 
Storage 
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2rC to 8rC) and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the temperature 
of the storage area. Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection. A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage 
facility. Storage conditions stated in the IB may be superseded by the label storage. 
The package inserts for etoposide/carboplatin/cisplatin specifies the appropriate storage for 
these agents. 
8.5 
Compliance 
The administration of each study drug should be recorded in the appropriate sections of the 
eCRF. 
Treatment compliance will be assured by reconciliation of site drug accountability logs. 
8.6 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. The 
study personnel will account for all study drugs. 
Drug accountability should be performed until the patient stops study treatment completely. 
Study site personnel will account for all study drugs received at the site, for all unused study 
drugs, and for appropriate destruction of study drugs. Certificates of delivery, destruction, and 
return should be signed. 
8.7 
Concomitant medications and other treatments 
The investigator must be informed as soon as possible about any medication taken from the 
time of Screening until the end of the clinical treatment phase of the study (final study visit), 
including the Follow-up period following the last dose of study drug. Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF. 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
Restricted, prohibited, and permitted concomitant medications are described in Table 7 and 


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Table 8. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
section 7.9.1 and Annex to Protocol). 
Table 7 
Prohibited concomitant medications 
Prohibited medication/class of drug: 
Usage: 
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.  Local 
treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, 
by local surgery or radiotherapy]) 
Live attenuated vaccines  
Should not be given through 30 days after the 
last dose of IP 
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 immuno-oncology 
infusions.  The following are allowed 
exceptions: 
x 
Use of immunosuppressive medications 
for the management of IP-related AEs.  
x 
Short-term premedication for patients 
receiving combination agents SoC, in 
which the prescribing information for the 
agent requires the use of steroids for 
documented hypersensitivity reactions. 
x 
Use in patients with contrast allergies.   
x 
In addition, use of inhaled, topical, and 
intra-nasal 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). 


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Prohibited medication/class of drug: 
Usage: 
EGFR TKIs  
Should not be given concomitantly.  
Should be used with caution in the 90 days 
post-last dose of durvalumab.  
Increased incidences of pneumonitis (with 
third generation EGFR TKIs) and increased 
incidence of transaminase increases (with 1st 
generation EGFR TKIs) has been reported 
when durvalumab has been given 
concomitantly. 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless 
agreed by the Sponsor 
AE Adverse event; CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4; EGFR Epidermal growth factor 
receptor; IP Investigational product; PD-1 Programmed cell death 1; PD-L1 Programmed cell death ligand 
1; SoC Standard of care; TKI Tyrosine kinase inhibitor. 
 
Table  8 
Supportive medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator 
Best supportive care (including antibiotics, G-
CSF and other hematopoietic factors, nutritional 
support, correction of metabolic disorders, 
optimal symptom control, and pain management 
[including palliative radiotherapy to non-target 
lesions, etc]) 
Should be used, when necessary, for all patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
8.7.1 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the physician and recorded 
appropriately. 
8.7.2 
Durvalumab drug-drug interactions 
There is no information to date on drug-drug interactions with durvalumab either preclinically 
or in patients. As durvalumab is a monoclonal antibody and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance. It is therefore not expected that durvalumab will induce or 
inhibit the major drug metabolising cytochrome P450 pathways. As a result, there are no 
expected pharmacokinetic drug-drug interactions. The mechanism of action of durvalumab 


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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. 
8.8 
Rescue medication 
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids 
and other immunosuppressant rescue medication has to be made available to this patient 
population. The 2 products that fall into the category of immunosuppressants are infliximab 
(eg, for colitis) and mycophenolate (eg, for hepatitis). Rescue medications will be sourced per 
local practice. 
9 
STATISTICAL ANALYSES  
9.1 
Statistical considerations  
All statistical analyses will be performed by AstraZeneca or its representatives.   
A comprehensive statistical analysis plan (SAP) will be prepared and finalized before first 
patient in (FPI) and any subsequent amendments will be documented, with final amendments 
completed prior to reporting of the data. The primary aim of the study is to assess the safety 
and tolerability of 'urvalumab + EP in patients with performance status 0-2. 
9.2 
Sample size determination 
This is a safety study and no formal sample size calculation will be done.  However, assuming 
AE of CTCAE grade ≥3 with an incidence of 60%, approximately 300 patients are needed to 
achieve the estimation precision no wider than 5.7% based on exact method (Clopper-
Pearson).  In addition, assuming the imAE with an incidence of 20%, the estimation precision 
will be no wider than 4.7% using the same method.  An illustration of the precision around the 
varying incidences of AE for the patients enrolled is provided in Table 9. 
Table  9 
Precision around varying incidence of AE 
Sample Size 
Precision achieved with different assumed incidence of AE  
20% 
40% 
50% 
60% 
70% 
200 
5.8% 
7.0% 
7.1% 
7.0% 
6.6% 
300 
4.7% 
5.7% 
5.8% 
5.7% 
5.3% 
500 
3.6% 
4.4% 
4.5% 
4.4% 
4.1% 


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9.3 
Definitions of analysis sets 
9.3.1 
Safety analysis set (SAS) 
The safety analysis set will include all subjects who received at least one dose of study 
treatment.  
9.3.2 
Efficacy analysis set 
The safety analysis set will be used for the efficacy analysis set. 
9.4 
Outcome measures for analyses 
9.4.1 
Calculation or derivation of safety variables 
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs, 
ECG and exposure. These will be collected for all patients.  
 
Adverse events 
Adverse events will be summarized as follows in terms of both Medical Dictionary for 
Regulatory Activities [MedDRA] preferred terms and CTCAE grade: 
AE: Number and proportion of patients with AEs in total and by causality and severity 
AE with Grade ≥3: Number and proportion of patients with Grade ≥3 AEs 
SAE: Number and proportion of patients with SAEs in total and by causality and severity 
AEs leading to death: Number and proportion of patients with AEs leading to death 
AEs leading to treatment discontinuation: Number and proportion of patients with AEs 
leading to treatment discontinuation 
AESIs: An adverse event of special interest (AESI) is one of scientific and medical interest 
specific to understanding of the Investigational Product and may require close monitoring and 
rapid communication by the investigator to the sponsor. An AESI may be serious or non-
serious. Please refer to Section 7.5.  In order to further characterize safety objectives related to 
AESIs, outcome measures will be assessed, which may include (and are not necessarily limited to) 
the following:  
(a) Number and proportion of patients with AESIs, by pre-defined type (or newly defined by 
this study) in total and by seriousness, severity and causality, including immune-relatedness;  
(b) Number and proportion of patients who received steroids, immunosuppressants and/or 
hormone replacement therapy to manage AESIs;  
(c) Time from start of durvalumab (MEDI4736) to the onset of an AESI pre-defined type, all 


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interventions of AESIs by type of intervention (including intervention with steroids, 
immunosuppressants and/or hormone replacement therapy), and time from onset of an AESI 
type to resolution;  
 
(d) Duration of the intervention with steroids, immunosuppressants and/or hormone 
replacement therapy until the resolution of AESI;  
 
(e) Laboratory findings, vital signs and other safety parameters associated with AESIs will be 
summarized as part of the AESI outcome measures.  
 
imAEs: The imAEs will be assessed as a subset of AESIs. Please refer to Section 7.5. 
Any AE occurring before treatment with study drug will be included in the data listings but 
will not be included in the summary tables of AEs. Any AE occurring within 90 days of 
discontinuation of durvalumab will be included in the AE summaries.  
9.4.2 
Calculation or derivation of efficacy variables 
Investigator assessments 
At each visit, patients will be programmatically assigned a response of CR, PR, SD, or PD 
depending on the status of their disease compared with baseline and previous assessments (by 
investigator assessment according to RECIST v1.1 criteria). If a patient has had a tumour 
assessment which cannot be evaluated, then the patient will be assigned a visit response of not 
evaluable (NE) unless there is any evidence of progression in which case the response will be 
assigned as PD. Please refer to Appendix C for the definitions of CR, PR, SD, and PD. The 
investigator assessments will be used in the calculation of PFS,  APF12, ORR and DoR. 
 
Progression free survival 
Progression-free survival is defined as the time from first dose of study treatment until the 
date of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from study therapy or receives another anti-cancer  
therapy prior to progression. Patients who have not progressed or died at the time of analysis 
will be censored at the time of the latest date of assessment of investigator. However, if the 
patient progresses or dies after 2 or more missed visits, the patient will be censored at the time 
of the latest assessment. If the patient has no evaluable visits or does not have baseline data, 
they will be censored at the day of first dose unless they die within 2 visits of baseline. 
The PFS time will always be derived based on scan/assessment dates not visit dates.  
 
The following rules will be applied: 
x Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression. 
x When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
Proportion of patients alive and progression free at 12 months  


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The APF12 will be defined as the Kaplan-Meier estimate of PFS (per investigator assessment 
according to RECIST v1.1 criteria) at 12 months. 
 
Objective Response Rate 
Objective Response Rate is defined as the number (%) of patients with measurable disease 
with at least 1 visit response of CR or PR. Data obtained up until progression or last evaluable 
assessment in the absence of progression will be included in the assessment of ORR. If any 
patients do not have measurable disease at baseline then the analysis of ORR will exclude 
these patients, so that the denominator is a subset of the SS who have measurable disease at 
baseline. 
However, any CR or PR which occurred after a further anti-cancer therapy was received will 
not be included in the numerator for the ORR calculation. 
 
Duration of Response 
Duration of response is only calculated for patients who have a best overall tumor response of 
CR or PR before subsequent anti-cancer therapy. Duration of response will be defined as the 
time from the date of first documented response until the date of documented progression or 
death in the absence of disease progression. The end of response should coincide with the date 
of progression or death from any cause used for the PFS endpoint. The time of the initial 
response will be defined as the latest of the dates contributing towards the first visit response 
of PR or CR.  
 
If a patient does not progress following a response, then his/her duration of response will use 
the PFS censoring time. 
 
Overall survival 
Overall survival is defined as the time from the date of first dose of study treatment 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. 
 
Proportion of patients alive at 12 months 
The OS12 will be defined as the Kaplan-Meier estimate of OS at 12 months. 
 
9.5 
Methods for statistical analyses 
Analysis for this study will mostly be descriptive. Continuous variables will be summarised 
by the number of observations (n), mean, standard deviation (SD), median, quartiles (Q1 and 
Q3), minimum, and maximum. Categorical variables will be summarised by frequency counts 
and percentages for each category. Two-sided 95% CIs will be provided as appropriate. 
Approximately, 300 patients will be enrolled to this study. All subjects who received at least 1 
dose of study treatment will be included in the safety analysis set, which will be the primary 
analysis set for all analyses. 
 


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9.5.1 
Analysis of the primary variables 
One of the primary outcome measures for the study is the frequency and percentage of patients 
with AEs of CTCAE grade ≥3, and it will be summarized by System Organ Class and preferred 
term. The same summary table will be generated by maximum CTCAE grade and by 
relationship to the treatment. AEs of CTCAE grade ≥3 (both in terms of MedDRA preferred 
terms and CTCAE grade) will be listed individually by patient. The Clopper-Pearson 95% CIs 
around the incidence rate will also be reported.  
 
Similar analyses will be conducted for imAEs. 
 
9.5.2 
Analysis of the secondary variables 
One of the secondary objectives is to assess the efficacy of first-line durvalumab + EP in 
terms of PFS, ORR, DoR and OS. PFS (by investigator assessment according to RECIST v1.1 
criteria) is defined as the time from first dose of treatment until the date of objective PD 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. ORR is defined as 
the percentage of patients with a best response of CR (complete response) or PR (partial 
response) by investigator assessment according to RECIST v1.1 criteria. DoR will be defined 
as the time from the date of first documented response until the date of documented 
progression or death in the absence of disease progression. OS is defined as the time from first 
dose of treatment until death due to any cause. Time-to-event data (PFS, OS) will be 
summarized using Kaplan-Meier estimates of the median event time and quartiles together 
with their 95% CIs, given the anticipated maturity of 60%. The Kaplan-Meier curves will be 
provided. The proportion of patients alive and progression free at 12 months (APF12), the 
proportion of patients alive at 12 months (OS12) will be summarized (using the Kaplan-Meier 
curve). ORR will be summarized descriptively, and the Clopper-Pearson 95% confidence 
intervals (CIs) will be provided. A median duration of response and associated 95% 
confidence interval will be calculated for responding patients.  
 
Analyses similar to the primary endpoints will be conducted for overall AEs, SAEs, AESIs and 
AEs leading to discontinuation of study treatment. In addition, the number and percentage of 
patients with AEs will be presented by PT. Time to event endpoints will be analysed using 
Kaplan-Meier estimates of the median event time. 
 
9.5.3 
Subgroup analysis 
Subgroup analysis of safety and efficacy will be conducted for the cohorts of patients with PS 
0 to 1 and 2 at baseline. For time to event analysis, each subgroup must have at least 20 events 
per subgroup level in order for that subgroup level to be included in the subgroup analysis. 
Additional subgroup analyses may be conducted for safety and efficacy parameters based on 
the following and will be defined in the SAP as appropriate: 
x Platinum received in Cycle 1 (cisplatin versus carboplatin) 
x Sex (male versus female) 
x Age (<65 versus ≥65 years of age) 


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x Smoking status (current versus former versus never smoker) 
x Number of cycles of EP (İ4 versus >4) 
x Use of PCI (yes versus no) 
 
Other baseline variables may also be assessed pending clinical justification.  The purpose of 
the subgroup analyses is to assess the consistency of effect across expected prognostic and/or 
predictive factors. Forest plot(s) will be generated. 
 
9.5.4 
Interim analysis 
There will be no formal interim analysis in this study.   
 
As the safety of durvalumab + EP has not been previously established in ES-SCLC patients 
with PS2, a safety review committee (SRC) will be established to review the safety and 
tolerability data of the combination of Durvalumab+EP in this subset of patients at an early 
stage of enrolment. SRC will include AZ local study team member such as study physician, 
PV physician, PM and local medical affairs Lead, and also global clinical lead, global patient 
safety physician and GMAL. 
The SRC will meet after the first 20 patients with PS2 have either had the opportunity to 
complete the combination of durvalumab + chemotherapy (maximum of 6 cycles) or have 
discontinued treatment with durvalumab due to an AE or disease progression, whichever 
occurs first.    
After review of the data in patients with PS2, and patients with PS0-1, the SRC will make a 
recommendation on whether the study should continue recruitment of patients with PS2 as 
planned, or hold recruitment of this patient population, or amend the study design. In the event 
that the SRC recommends a change to the study, this will be communicated to all sites. 
 
The primary analysis of the study will be conducted 6 months after LSIat which time 
secondary endpoints will also be assessed (maturity for PFS is anticipated to be approximately 
60%).   
 
Additionally, final analysis will be performed at the end of the study when all patients have 
completed follow-up for safety or sufficient maturity for the secondary efficacy objectives has 
been reached. 
10 
STUDY MANAGEMENT BY ASTRAZENECA 
REPRESENTATIVE 
10.1 
Training of study site personnel 
Before the first patient is enrolled in the study, an AstraZeneca representative or delegate will 
review and discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and train them in any study-specific procedures. 


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The Principal Investigator will ensure that appropriate training relevant to the study is given to all 
of these staff and that any new information relevant to the performance of this study is forwarded 
to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study (medical, 
nursing, and other staff). 
10.2 
Monitoring of the study 
During the study, an AstraZeneca representative or delegate will have regular contacts with the 
study site, including visits to  
y 
Provide information and support to the investigator(s) 
y 
Confirm that facilities remain acceptable 
y 
Confirm that the investigational team is adhering to the protocol, data are being accurately 
and timely recorded in the eCRFs, biological samples are handled in accordance with the 
Laboratory Manual, and study drug accountability checks are being performed 
y 
Perform source data verification (a comparison of the data in the eCRFs with the patient’s 
medical records at the hospital or practice and other records relevant to the study), including 
verification of informed consent of participating patients. This will require direct access to all 
original records for each patient (eg, clinic charts). 
The AstraZeneca representative will be available between visits if the investigators or other staff 
at the centers need information and advice about the study conduct. 
10.2.1 
Study agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA for this study. In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of the Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients. In all other respects not relating to study 
conduct or treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before any patients are enrolled. 
10.2.2 
Archiving of study documents 
The investigator follows the principles outlined in the CSA. 
10.3 
Study timetable and end of study 
After patients have discontinued from durvalumab treatment, other available treatment options 
will be at the discretion of the physician. 
Enrolment will be closed as soon as the product receives China marketing authorization as first 
line treatment for ES-SCLC or total 300 sample size is achieved, whichever comes first. 
Treatment will continue to be provided to all patients who are already enrolled to the study and 
who are still deriving benefit, until disease progress or study end. 
The end of the study is defined as “the last visit of the last patient undergoing the 
study”. The study will be end when all patients have completed follow-up for safety or sufficient 
maturity for the secondary efficacy objectives has been reached, which will estimate to be end by 
Q4, 2022. 
The study may be terminated at individual centers if the study procedures are not being performed 


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according to GCP.  
11 
ETHICAL AND REGULATORY REQUIREMENTS 
11.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics. 
11.2 
Patient data protection 
The Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and privacy 
legislation.  
AstraZeneca or its representative will not provide patient information to patients, any insurance 
company, any employer, their family members, general physician or to any other third party, 
unless required to do so by law.  
Precautions are taken to preserve confidentiality and prevent data being linked to the identity of 
the patient. Also Regulatory authorities may require access to the relevant files. 
11.3 
Ethics and regulatory review 
An Independent Review Board (IRB)/Ethics Committee (EC) must approve the final study 
protocol, including the final version of the ICF and any other written information and/or materials 
to be provided to the patients, as per local regulations. The opinion of the IRB/EC must be given 
in writing. 
AstraZeneca or its representative must approve any modifications to the ICF that are needed to 
meet local requirements.  
Before enrollment of any patient into the study, the final protocol, including the final version of 
the ICF, is to be approved by the national regulatory authority or a notification to the national 
regulatory authority is to be done, according to local regulations.  
AstraZeneca or its representative will provide Regulatory Authorities, IRB/EC, and investigators 
with safety updates/reports according to local requirements.  
Each investigator is responsible for providing the IRB/EC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the IP. AstraZeneca or its 
representative will provide this information to the investigator so that he/she can meet these 
reporting requirements. 
11.4 
Informed consent 
The investigator at each site will:  
y 
Ensure each patient is given full and adequate oral and written information about the nature, 
purpose, possible risk, and benefit of the study.  
y 
Ensure each patient is notified that they are free to discontinue from the study at any time.  
y 
Ensure that each patient is given the opportunity to ask questions and allowed time to 


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consider the information provided.  
y 
Ensure each patient or legally acceptable representative provides signed and dated ICF before 
conducting any procedure specifically for the study.  
y 
Ensure the original, signed ICF(s) is/are stored in the investigator’s study file.  
y 
Ensure a copy of the signed ICF is given to the patient.  
y 
Ensure that any incentives for patients who participate in the study as well as any provisions 
for patients harmed as a consequence of study participation are described in the informed 
consent form that is approved by an IRB/EC.  
11.5 
Changes to the protocol and informed consent form 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a protocol amendment and where required in a new version of the study 
protocol (Revised Study Protocol). 
The amendment is to be approved by the relevant IRB/EC and if applicable, the national 
regulatory authority needs also to be notified or has to provide approval, before 
implementation. Local requirements are to be followed for revised protocols. 
AstraZeneca or its representative will distribute any subsequent amendments and new versions 
of the protocol to each participating investigator. For distribution to IRB/EC, see Section 11.3. 
If a protocol amendment requires a change to a site’s ICF, AstraZeneca (or its representative) 
and the site’s IRB/EC are to approve the revised ICF before the revised form is used. 
If required by local regulations, any administrative change will be communicated to or 
approved by each IRB/EC. 
11.6 
Audits and inspections 
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB/EC may perform 
audits or inspections at the study site, including source data verification.  The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, ICH guidelines, and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the study site. 


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12 
REFERENCES 
Alexandrov et al 2013 
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature 2013;500:415-21. 
Brahmer et al 2012 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-
65. 
Clark and Ihde 1998 
Clark R, Ihde DC. Small-cell lung cancer: treatment progress and prospects. Oncology 
(Williston Park) 1998;12:647–58; discussion 661-3. 
Dunn et al 2004 
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60. 
GLOBOCAN 2012 
GLOBOCAN. Lung cancer, estimated incidence, mortality and prevalence worldwide in 
2012. International Agency for Research on Cancer, World Health Organization; Lyon, 2012. 
Available from: URL: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on 
16 April 2015孱季
Hirano et al 2005 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
2005;65(3):1089-96. 
Horn et al 2018 
L.Horn, A.S. Mansfield, A.Szczesna, L.Havel, M.Krzakowski, M.J.Hochmair, F.Huemer, 
G.Losonczy, M.L Johnson, M.Nishio, M.Reck, T.Mok, S.Lam, D.S Shames, J.Liu, B.Ding, 
A.Lopez-Chavez, F.Kabbinavar,W.Lin, A.Sandler. and S.V.Liu for the Impower 133 Study 
Group First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung 
Cancer NEJM 2018 Sept, 25. 
Iwai et al 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99:12293-7. 
Keir et al 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704.季


Clinical Study Protocol - 2.0 
AstraZeneca 
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CONFIDENTIAL AND PROPRIETARY 
 66 of 87 
 
Paz-Ares 2019 
Luis Paz-Ares, Mikhail Dvorkin, Yuanbin Chen, Niels Reinmuth, et al. Durvalumab plus 
platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage 
small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 
LANCET. 2019 Oct 4. pii: S0140-6736(19)32222-6 
Okazaki and Honjo 2007 
PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007;19(7):813-
24. 
Okudaira et al 2009 
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-
H1 or B7-DC induces an antitumor effect in a mouse pancreatic cancer model. Int J Oncol 
2009;35(4):741-9. 
Pardoll 2012 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12:252-64. 
Peifer et al 2012 
Peifer M, Ferneandes-Cuesta L, Sos ML, Seidel D, Kasper LH, Plenker D, et al. Integrative 
genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 
2012;44(10):1104-10. 
Pignon et al 1992 
Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, et al. A metaanalysis 
of thoracic radiotherapy for small cell lung cancer. N Engl J Med 1992;327:1618-24. 
Powles et al 2014 
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558-
62. 
Puglisi et al 2010 
Puglisi M, Dolly S, Faria A, Myerson JS, Popat S, O’Brien ME. Treatment options for small 
cell lung cancer: Do we have more choice? Br J Cancer 2010;102(4):629-38. 
Qin et al 2016 
Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell 
lung cancer. Cancer Med 2016; 9:2169–70. 
Rizvi et al 2015 
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with 
nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032 


Clinical Study Protocol - 2.0 
AstraZeneca 
Durvalumab - D419BR00018 
 
CONFIDENTIAL AND PROPRIETARY 
 67 of 87 
 
Rossi et al 2012 
Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. Carboplatin- or 
cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS 
meta-analysis of individual patient data. J Clin Oncol 2012;30:1692-98. 
Roth et al 1992 
Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. Randomized 
study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus 
alternation of these two regimens in extensive small-cell lung cancer: a Phase III trial of the 
Southeastern Cancer Study Group. J Clin Oncol 1992;10(2):282-91. 
Salgia and Skarin 1998 
Salgiia, Skarin A. Molecular abnormalities in lung cancer. J Clin Onc 1998,16:1207-1217. 
Segal et al 2015 
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma 
of the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011. 
Stewart et al 2015 
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification 
and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3(9):1052-62. 
Topalian et al 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366:2443-54. 
Zhang et al 2008 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Antitumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9. 
 


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Appendix A Adverse event definitions and additional safety information 
A 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. 
A 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: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalization or prolongation of existing hospitalization  
x 
Results in persistent or significant disability or incapacity.  
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardize the patient or may require 
medical treatment to prevent one of the outcomes listed above. 
x 
Adverse Events (AEs) for malignant tumours reported during a study should 
generally be assessed as Serious AEs if not the same as the primary tumour under 
investigation. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical bjudgement 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-


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Serious; examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical 
cancer removed via cone biopsy. 
x 
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.  
A 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). 
A 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. 
A 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. 
x 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
x 
Development of drug dependency or drug abuse 


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A 6 
CTCAE grade 
The grading scales found in the revised National Cancer Institute CTCAE latest version 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 A2. 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 A2. 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 A2. 
A 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. 
x 
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? 
x 
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? 
x 
De-challenge experience. Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
x 
No alternative cause. The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x 
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. 
x 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship. 
In difficult cases, other factors could be considered such as: 


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x 
Is this a recognized feature of overdose of the drug? 
x 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
A 8 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the 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.  
x 
occurred 
x 
was identified and intercepted before the participant received the drug 
x 
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: 
x 
Drug name confusion 
x 
Dispensing error (eg, medication prepared incorrectly, even if it was not actually 
given to the participant) 
x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 


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x 
Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as 
a solid tablet)  
x 
Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature)  
x 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
x 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
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  
x 
Participant accidentally missed drug dose(s) (eg, forgot to take medication) 
x 
Accidental overdose (will be captured as an overdose) 
x 
Participant failed to return unused medication or empty packaging 
x 
Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
 
 
 


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Appendix B Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law 
B 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. 
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. 
B 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.  
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. 


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B 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: 
x 
ALT Ӌ3 × ULN 
x 
AST Ӌ3 × ULN 
x 
TBL Ӌ2 × ULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x 
Determine whether the patient meets PHL criteria (see Appendix B2 for definition) 
by reviewing laboratory reports from all previous visits 
x 
Promptly enter the laboratory data into the laboratory CRF 
B 4 
Follow-up 
B 4.1 
Potential Hy’s law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
B 4.2 
Potential Hy’s law criteria met 
If the patient does meet PHL criteria the Investigator will: 
x 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section 7.4 Safety Reporting) 
x 
Notify the AstraZeneca representative who will then inform the central Study Team  
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
x 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  


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x 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  
x 
If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
B 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. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP. 
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: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow 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: 
x 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 


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x 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
x 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined. 
B 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. 
x 
If there is no significant change, no action is required 
x 
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 A 5. 
x 
*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. 
B 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) 


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If No: Follow the process described in Appendix B4.1 
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 B4. 
*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. 
 
 
 


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Appendix C 
Guidelines for Evaluation of Objective Tumor Response 
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 the study with regards to Investigator 
assessment of tumor burden including protocol-specific requirements for this study. 
Definition of measurable, non-measurable, target and non-target lesions 
Only patients with measurable target disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been previously irradiated.  
Tumor lesions selected for screening biopsy should not be selected as target lesions, unless 
imaging occured at least 2 weeks after biopsy, allowing time for healing. 
Measurable: 
A lesion, not previously irradiated or biopsied per the protocol prior to randomisation, that can 
be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes 
which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) and which is suitable for accurate repeated measurements. 
Non-measurable: 
x 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 mm to <15 mm short axis at baseline1). 
x 
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 that is not measurable by CT or 
MRI. 
x 
Tumour lesions selected for screening biopsy 
x 
Previously irradiated lesions2 
 
1 The short axis is defined at the longest axis perpendicular to the long axis of the tumour. Nodes with <10 mm 
short axis are considered non-pathological and should not be recorded or followed as non-target lesions 
(NTLs). 
2 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated will not be considered measurable and must be selected as NTL at baseline and followed 
up as part of the NTL assessment. 


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x 
Skin lesions assessed by clinical examination 
x 
Brain metastasis 
Special cases: 
x 
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. 
x 
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 as target lesions (TLs). 
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. Lymph nodes, in any location, are collectively considered as a single organ, with a 
maximum of 2 lymph nodes as TLs. A bilateral organ is considered as a single organ. 
Non-target lesions: 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. 
Methods of assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits. 
A summary of the methods to be used for RECIST assessment is provided in Table 10 , and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided. 
Table  10  
Summary of methods of assessment 
Target lesions  
Non-target lesions 
New lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Clinical examination  
X-ray, Chest X-ray 
CT (preferred) 
MRI 
Clinical examination  
X-ray, Chest X-ray 
Ultrasound 
Bone scan 
FDG-PET 


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   CT  Computed tomography; FDG-PET  18-Fluoro-deoxyglucose positron emission tomography; MRI  
Magnetic resonance imaging. 
CT and MRI  
CT and MRI, each preferably with intravenous contrast, are generally considered to be the 
best currently available and reproducible methods to measure TL selected for response 
assessment and to assess NTL and identification of any new lesions.  
It is recommended that intravenous contrast-enhanced CT examinations of the chest and 
abdomen (including liver and adrenal glands) are used to assess tumour burden at baseline and 
follow-up visits. Any other areas of disease involvement 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 contrast 
of the abdomen and pelvis is appropriate. In patients with severely compromised renal 
function a non-contrast CT examination of the chest, abdomen and pelvis is appropriate. For 
brain lesion assessment, MRI with intravenous contrast is the preferred method over 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 timepoints per patient.季
Clinical examination  
Clinical examination will not be used for assessment of TL.  Clinically detected lesions can be 
selected as TLs if they are assessed by CT or MRI scans.  Clinical examination can be used to 
assess NTL and to identify the presence of new lesions. 
X-ray 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL as they will be assessed by CT 
examination or MRI examination.  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 assessment of TL and NTL as it is not a 
reproducible method, does not provide an accurate assessment of tumor size, and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 


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Tumor markers  
Tumor markers will not be used for tumor response assessments as per RECIST 1.1. 
Cytology and histology  
Histology will not be used as part of the tumor response assessment as per RECIST 1.1.  
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary for the Investigator to 
differentiate between response/stable disease (an effusion may be a side effect of the 
treatment) and progressive disease (if the neoplastic origin of the fluid is confirmed). Where 
cytology findings are not available, any effusion that significantly worsens (from trace to 
large) or appearance of clinically significant effusion (requiring change in drug therapy) 
during the study treatment will be considered to be progression of NTL, or disease progression 
due to new lesions.  
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 will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion.  Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal. 
FDG-PET scan 
18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 
be recorded where there is positive 18-Fluoro-deoxyglucose uptake3 not present on baseline 
FDG-PET scan or in a location corresponding to a new lesion on CT/MRI at the same follow-
up visit. If there is no baseline FDG-PET scan available, and no evidence of new lesions on 
CT/MRI scans then follow-up CT/MRI assessments should be continued, scheduled as per 
protocol or clinical indicated, in order to confirm new lesions. 
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT are of 
limited use in anatomically-based efficacy assessments, and it is therefore suggested that they 
 
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed. 


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should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST measurements. However, this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed. 
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 liver and 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, e.g., new lesions at follow up. 
Baseline assessments should be performed no more than 28 days before start of study 
treatment, and ideally should be performed as close as possible to the start of investigational 
product.  Efficacy for all patients will be assessed by objective tumor assessments every 
6 weeks for the first 12 weeks, then every 8 weeks thereafter until confirmed objective disease 
progression as defined by RECIST 1.1 (irrespective of the reason for stopping treatment/or 
subsequent therapy).  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 visits.   
For patients who discontinue study drug due to toxicity in the absence of confirmed objective 
progression, objective tumor assessments should be continued every 6±2 weeks for  weeks 
(relative to the date of randomization) then every 8±2 weeks until confirmed objective disease 
progression.  
Radiologic progression (PD by RECIST 1.1) requires confirmation; the confirmatory scan 
should occur no earlier than 4 weeks after the prior assessment of PD in the absence of 
clinically significant deterioration.  
If progression is not confirmed then the patient should continue on study treatment continue 
with imaging assessments on their regular schedule. 
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients. 


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Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on IMT treatment, re-treatment, or until subsequent cancer therapy 
according to the clinical study protocol. 
Target lesions 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis 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: 
x 
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.  
x 
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. 
x 
If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm. 
x 
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts.  
x 
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).   
x 
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. 
x 
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion.  


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x 
When a TL has had any intervention e.g., radiotherapy, embolization, surgery, 
during the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST case report form. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 11). 
Table 11  
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 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 shrinkage 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 sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.  Note: if the sum of 
diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a TL response 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable 
disease; TL  Target lesion. 
 
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 12). 


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Table 12  
Evaluation of non-target lesions 
Complete response (CR) 
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
Non CR/Non PD 
Persistence of one or more NTL. 
Progression (PD) 
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy. 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met. 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion. 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to qualify for unequivocal progression status. 
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.  
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. 
The finding of a new lesion should be unequivocal: i.e., 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 new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 
Symptomatic deterioration 
Symptomatic 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 evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed. 
Evaluation of overall visit response 
The overall visit response will be derived using the algorithm shown in Table 13. 
Table  13  
Overall visit response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NE 
Non PD or NE 
No 
NE 
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 non-target lesions at baseline) 
 
Confirmation of Progression 
Radiologic progression (PD by RECIST 1.1) requires confirmation with a subsequent scan, 
and the confirmatory scan should occur no earlier than 4 weeks after the prior assessment of 
progression of disease (PD) in the absence of clinical deterioration. 
Radiologic progression would be considered confirmed if the following criteria are met: 
x 
≥ 20% increase in sum diameters of target lesions compared to the nadir at 
2 consecutive visits (with an absolute increase of at least 5 mm) 
x 
And/or significant progression (worsening) of NTLs and/or pre-existing new lesions at 
the confirmatory scan time-point compared with the prior time-point (Note: Pre-
existing new lesions from earlier time-points are evaluated as NTLs at the 
confirmatory scan time-point) 
x 
And/or additional new unequivocal lesions at the confirmatory scan time-point. 
In the absence of significant clinical deterioration, the Investigator should continue study 
treatment until radiologic progression is confirmed.  


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If radiologic progression is not confirmed, then the patient should continue on study treatment 
and continue with regularly scheduled imaging assessments.  
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression. 
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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Statistical Analysis Plan 
Study Code 
D419BR00018 
Edition Number 
2.0 
Date 
6 Apr 2022 
An Open Label, Multicenter Study of First-Line Durvalumab plus 
Platinum-Based Chemotherapy in Chinese Patients with 
Extensive Stage Small-Cell Lung Cancer (Oriental) 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
TABLE OF CONTENTS ...................................................................................................... 3 
LIST OF ABBREVIATIONS ............................................................................................... 6 
AMENDMENT HISTORY ................................................................................................... 9 
1 
STUDY DETAILS ........................................................................................... 14 
1.1 
Study objectives ................................................................................................ 14 
1.2 
Study design ..................................................................................................... 14 
1.3 
Number of patients ........................................................................................... 15 
2 
ANALYSIS SETS ............................................................................................ 16 
2.1 
Definition of analysis sets ................................................................................. 16 
2.1.1 
Safety set (SS) .................................................................................................. 16 
2.1.2 
Efficacy analysis set.......................................................................................... 16 
2.2 
Violations and deviations .................................................................................. 16 
3 
PRIMARY AND SECONDARY VARIABLES ............................................... 16 
3.1 
Primary endpoints ............................................................................................. 16 
3.2 
Secondary endpoints ......................................................................................... 17 
3.2.1 
Derivation of RECIST visit responses ............................................................... 17 
3.2.2 
Site Investigator Assessments Using RECIST 1.1 ............................................. 18 
3.2.2.1 
Target Lesions .................................................................................................. 18 
3.2.2.2 
Non-Target Lesions and New Lesions. .............................................................. 18 
3.2.2.3 
New Lesions ..................................................................................................... 18 
3.2.2.4 
Overall Visit Response ..................................................................................... 19 
3.2.3 
PFS ................................................................................................................... 19 
3.2.4 
APF12 .............................................................................................................. 21 
3.2.5 
ORR ................................................................................................................. 21 
3.2.6 
DoR .................................................................................................................. 21 
3.2.7 
OS .................................................................................................................... 22 
3.2.8 
OS12 ................................................................................................................ 22 
3.2.9 
Incidence of AEs, SAEs, AESIs and AEs leading to treatment discontinuation . 22 
3.3 
Other safety variables ....................................................................................... 23 
3.3.1 
Exposure ........................................................................................................... 23 
3.3.2 
Lab test ............................................................................................................. 24 
3.3.3 
Vital signs, weight and BMI ............................................................................. 24 
3.3.4 
Physical examinations ....................................................................................... 25 
3.3.5 
ECGs ................................................................................................................ 25 
3.3.6 
ECOG PS ......................................................................................................... 25 
3.3.7 
Pregnancy test ................................................................................................... 25 
3.3.8 
Potential Hy’s law case ..................................................................................... 25 
3.3.9 
Concomitant medication ................................................................................... 26 
4 
ANALYSIS METHODS ................................................................................... 26 


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4.1 
General principles ............................................................................................. 26 
4.1.1 
Analysis software ............................................................................................. 26 
4.1.2 
General analysis methods .................................................................................. 26 
4.1.3 
Hypothesis test.................................................................................................. 27 
4.1.4 
Baseline ............................................................................................................ 27 
4.1.5 
Unscheduled visits ............................................................................................ 27 
4.1.6 
Data derivation rules ......................................................................................... 27 
4.1.7 
Handling of missing data and incomplete date .................................................. 28 
4.2 
Analysis methods .............................................................................................. 29 
4.2.1 
Disposition of patients ...................................................................................... 29 
4.2.2 
Demographics and baseline characteristics ........................................................ 30 
4.2.2.1 
Demographics ................................................................................................... 30 
4.2.2.2 
Pathology at screening ...................................................................................... 30 
4.2.2.3 
Extent of SCLC upon entry to study .................................................................. 30 
4.2.2.4 
Medical and surgical history ............................................................................. 30 
4.2.2.5 
Previous and current anti-cancer therapy ........................................................... 30 
4.2.2.6 
Previous and current radiotherapy ..................................................................... 31 
4.2.2.7 
Use of nicotine .................................................................................................. 31 
4.2.3 
Prior and concomitant medications ................................................................... 31 
4.2.4 
Primary endpoints ............................................................................................. 31 
4.2.5 
Secondary endpoints ......................................................................................... 32 
4.2.5.1 
PFS ................................................................................................................... 32 
4.2.5.2 
APF12 .............................................................................................................. 32 
4.2.5.3 
ORR ................................................................................................................. 32 
4.2.5.4 
DoR .................................................................................................................. 33 
4.2.5.5 
OS .................................................................................................................... 33 
4.2.5.6 
OS12 ................................................................................................................ 33 
4.2.5.7 
Incidence of AEs, SAEs, AESIs and AEs leading to treatment discontinuation . 33 
4.2.6 
Other safety variables ....................................................................................... 33 
4.2.6.1 
Adverse Events ................................................................................................. 33 
4.2.6.2 
Exposure ........................................................................................................... 34 
4.2.6.3 
Lab tests ........................................................................................................... 34 
4.2.6.4 
Vital signs, weight and BMI ............................................................................. 35 
4.2.6.5 
Physical examinations ....................................................................................... 35 
4.2.6.6 
ECGs ................................................................................................................ 35 
4.2.6.7 
ECOG PS ......................................................................................................... 35 
4.2.6.8 
Pregnancy test ................................................................................................... 35 
4.2.6.9 
Potential Hy’s Law case .................................................................................... 36 
4.2.7 
Subsequent anti-cancer therapy ......................................................................... 36 
4.2.8 
Subgroup analysis ............................................................................................. 36 
4.2.9 
Sensitivity analysis ........................................................................................... 37 
5 
INTERIM ANALYSES .................................................................................... 37 
6 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................ 38 
7 
REFERENCES ................................................................................................. 38 
8 
APPENDIX ...................................................................................................... 38 


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Appendix A Schedule of assessments .................................................................................. 38 
Appendix B TFL mock shells .............................................................................................. 41 
Appendix C SDTM and ADaM specifications ..................................................................... 41 
 
LIST OF TABLES 
Table 1 Precision around varying incidence of AE .............................................................. 15 
Table 2 Overall Visit Responses.......................................................................................... 19 
Table 3 Criteria of at least 2 missing tumor assessments ...................................................... 20 
Table 4 PFS calculation under various cases ....................................................................... 20 
Table 5 Variable derivation rules ........................................................................................ 27 
 
LIST OF FIGURES 
Figure 1 Overall study design .............................................................................................. 15 
 


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LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AJCC 
American joint committee on cancer 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APF 
Alive and progression free 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma drug concentration-time curve 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BMI 
Body mass index 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Calculated creatinine clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
Cmin 
Minimum plasma concentration 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen 4 
DBP 
Diastolic blood pressure 
DCO 
Data cut off 
DCR 
Disease control rate 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


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Abbreviation or special 
term 
Explanation 
EGFR 
Epidermal growth factor receptor 
ES-SCLC 
Extensive stage small-cell lung cancer 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
HR 
Hazard ratio 
IASLC 
International Association for the Study of Lung Cancer 
IC 
Immune cell 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG 
Immunoglobulin 
ILD 
Interstitial lung disease 
imAE 
Immune-mediated adverse event 
IP 
Investigational product  
IO 
Immuno-oncology 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NE 
Not evaluable 
nmiss 
No. of missing patients 
no. 
Number 
NSCLC 
Non-small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PCI 
Prophylactic cranial irradiation 
PK 
Pharmacokinetic(s) 
PLT 
Platelet 
PR 
Partial response 


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Abbreviation or special 
term 
Explanation 
PT 
Preferred term 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
QC 
Quality control 
5', 
Relative dose intensity 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SBP 
Systolic blood pressure 
SCLC 
Small-cell lung cancer 
SD 
Stable disease 
SI 
International system 
SoC 
Standard of care 
SOC 
System organ class 
SS 
Safety set 
Std 
Standard deviation 
TBil 
Total bilirubin 
TC 
Tumor cells 
TFL 
Table, figure and listing 
TL 
Target lesion 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WNL 
Within normal limits 
 


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AMENDMENT HISTORY 
Date 
Category*: 
Change refers to 
Description of change 
In line with 
the CSP? 
Rationale 
2 Apr 2022 
Other 
Page 2  
Statisticians from Tigermed were added on signature 
pages. AZ statistician was changed from Wenhan 
Jiang to Li Luo. AZ medical advisor was changed 
from Min Gao to Ziyi Huang. AZ global product 
statistician were added on signature page. 
NA 
Team member change in AZ. 
Tigermed SOP require signature of 
statistician from Tigermed for SAP. 
2 Apr 2022 
Other 
Section 2.2, page 13 
4 general categories of IPD were deleted and 
replaced by the sentence ‘Several IPDs could be 
identified with programming to assist locating 
potential IPDs.’ 
Yes 
The specification of IPD will be 
written in the external file of PD 
log but not in SAP. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 3.2.3, page 17 
‘(2 x 6 weeks for tumor assessments + 2 x 2 weeks 
for permitted visit window)’ were added. 
Yes 
This sentence was added to explain 
clearly what the 2 visit after 
baseline means. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 3.2.3, page 18 
In table 4, ‘Patients without PD and death’ was 
replaced by ‘Patients without PD and death but had 
post-treatment tumor assessment’. 
Yes 
To be more clear. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 3.2.3, page 18 
In table 4, for the case of patient died after treatment 
without tumor assessment, 12 weeks was modified to 
16 weeks. 
Yes 
Since 2 x 6 weeks for tumor 
assessments + 2 x 2 weeks for 
permitted visit window was defined 
for this case of censoring. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 3.2.4, page 19 
Section 3.2.8, page 20 
The sentence ‘which is the point estimate of PFS/ OS 
at the latest event İ 365 day from first dose of study 
treatment’ were removed. 
Yes 
These sentences were used to 
specify the rules for programming. 
They could be written in ADaM 
specification instead of in SAP. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 3.2.5, page 19 
It is emphasized that the denominator of ORR should 
be patients with measurable disease. 
Yes 
In CSP 2.0, inclusion criteria 8 was 
added to require that only patients 
with measurable disease at 
screening could be enrolled. And 


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the definition of ORR was modified 
accordingly.
2 Apr 2022
Derivation of primary 
or secondary endpoints
Section 3.2.7, page 20
The domain of possible last recorded date that an 
individual patient was known to be alive was clearly 
stated.
Yes
This clarification was to avoid 
ambiguous code in programming.
2 Apr 2022
Other
Section 3.3.1, page 21
Yes
The derivation rules were modified 
according to the data actually 
collected in EDC.
2 Apr 2022
Data presentations
Section 3.3.2, page 22
The sentence ‘Laboratory data will be from local 
laboratories and will be converted to AZ preferred 
units, and AZ project reference ranges will be used 
for the primary interpretation of laboratory data’ was 
deleted.
Yes
AZ will not provide preferred units 
and reference ranges. 
2 Apr 2022
Data presentations
Section 3.3.8, page 23 
and page 24
ALT and AST category added >8x - İ10x, >10x -
İ20x.
Sentence ‘Plots of post-baseline ALT and AST vs. 
post-baseline total bilirubin will also be produced 
with reference lines at 3×ULN for ALT, AST, and 
Yes
These categories were added to 
show more information.
Plots of potential Hy’s law case 
were not needed.


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2×ULN for Total bilirubin. In each plot, total 
bilirubin will be in the vertical axis’ was deleted. 
2 Apr 2022 
Other 
Section 3.3.9, page 24 
Section 4.2.3, page 28 
Prior medication was defined as any medication that 
ended prior to the first dose of the study treatment 
Yes 
The definition of both prior and 
concomitant medication was 
deleted. 
2 Apr 2022 
Other 
Section 3.3.10, page 24 
A new section about the definition of class of anti-
cancer therapy was added. 
Yes 
To clearly distinguish previous, 
concurrent and subsequent anti-
cancer therapy. 
2 Apr 2022 
Other 
Section 4.1.2, page 24 
The sentence ‘In addition, all efficacy and safety data 
and some selected relevant data (eg, patient 
disposition, demography and baseline characteristics) 
will be summarised separately for the WHO/ECOG 
PS 0 to 1 and 2 subgroups’ was modified to ‘In 
addition, some efficacy and safety data will be 
summarised separately for the WHO/ECOG PS 0 to 1 
and 2 subgroups’. 
Yes 
Not all efficacy and safety data 
were needed to be analyzed for PS 
subgroup. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 4.1.6, page 26 
In table 5 some derivation rules were added, 
including: time from original diagnosis to the first 
dose of study treatment, time from the latest 
assessment to the first dose of study treatment, time 
to first AE, and duration of AE. 
Yes 
These rules were added as needed. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 4.1.7, page 26 
The sentence ‘Imputation will be done only in the 
context of identifying treatment emergent adverse 
event (TEAE)’ was deleted. 
Yes 
The imputation of date of AE will 
not only be used to identify TEAE, 
but also for other calculations, such 
as time to first AE. 
2 Apr 2022 
Data presentations 
Section 4.2.2.2, page 
28 
Variables of pathology of SCLC at screening include 
time from original diagnosis to the first dose of study 
treatment, time from the latest assessment date to the 
first dose of study treatment, pathology at diagnosis 
with primary tumor, regional lymph nodes and 
Yes 
This section was modified 
according to actual data collected. 


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distant metastases TNM classification, and 
stage/AJCC stage. 
2 Apr 2022 
Data presentations 
Section 4.2.2.4, page 
28 
It was added that ‘The event recorded in medical 
history page will be classified as medical history and 
current disease for summary. Any event that ended 
prior to the first dose of the study treatment will be 
considered as medical history. While those which 
ended after the first dose or are still ongoing will be 
considered as current disease’. 
Yes 
This sentence was added as 
demanded. 
2 Apr 2022 
Data presentations 
Section 4.2.2.5, page 
28 
The methods, how concurrent anti-cancer therapy and 
subsequent anti-cancer therapy would be analyzed, 
were added. 
Yes 
This sentence was added as 
demanded. 
2 Apr 2022 
Data presentations 
Section 4.2.2.6, page 
28 
The definition of concurrent and subsequent PCI was 
added.  
Yes 
This sentence was added as 
demanded. 
2 Apr 2022 
Derivation of primary 
or secondary endpoints 
Section 4.2.4, page 29 
Time to event will be censored at the date of DCO, 
death, 90 days after the last dose of durvalumab 
treatment or the date of initiation of the first 
subsequent therapy, whichever occurs first. K-M 
curve will be presented. 
Yes 
The rules of censoring was more 
clear and involve date of DCO into 
consideration. K-M curve was 
required. 
2 Apr 2022 
Data presentations 
Section 4.2.5.4, page 
30 
DoR will be analysed in the same methods as PFS. 
Yes 
This sentence was modified to 
avoid unnecessary repeat. 
2 Apr 2022 
Data presentations 
Section 4.2.6.1, page 
30 and page 31 
The information of summary of AE and death was 
modified. 
Yes 
The section was modified as 
demanded. 
2 Apr 2022 
Data presentations 
Section 4.2.6.3, page 
32 
Shift tables for lab tests were added. 
Yes 
The section was modified as 
demanded. 


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2 Apr 2022 
Other 
Section 4.2.8, page 33 
Definition of subgroups were modified. 
Yes 
The section was modified as 
demanded. 
* Pre-specified categories are  
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other 
All the section and page no. in the second column corresponded to the location in SAP v1.0 which was finalized on 30 Oct 2020. 


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1
STUDY DETAILS
1.1
Study objectives
All objectives will be evaluated for all patients, unless otherwise indicated.
Primary objective:
Endpoint/variable:
To assess the safety and tolerability of durvalumab + EP in 
patients with performance status 0-2
Incidence of Grade ≥3 AEs
Incidence of imAEs
AE Adverse event; EP Etoposide and platinum-based chemotherapy; imAE Immune-mediated 
adverse event.
Secondary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + EP in patients with 
performance status 0-2
PFS, APF12, ORR, DoR
using site Investigator 
assessment and OS, OS12
To further assess the safety and tolerability profile of 
durvalumab + EP
Incidence of AEs, SAEs, 
AESIs, AE resulting in 
treatment discontinuation
AESIs adverse events of special interest; DoR Duration of Response; EP Etoposide and 
platinum-based chemotherapy; ORR Objective response rate; OS Overall survival; OS12 
Overall survival at 12 months after first dose of study treatment; PFS Progression free 
survival; APF12 Proportion of patients alive and progression free at 12 months after first dose 
of study treatment.
1.2
Study design
This will be an open-label, single-arm, multicenter, Phase IIIb study to determine the safety of 
durvalumab + etoposide and cisplatin or carboplatin as first-line treatment in patients with 
extensive stage small-cell lung cancer. Patients who fulfil all the inclusion criteria and none of 
the exclusion criteria will be enrolled and receive treatment with durvalumab + etoposide and 
either cisplatin or carboplatin (EP) for 4 to 6 cycles. Durvalumab will be administered at a 
dose of 
every 3 weeks (Q3W) with first-line chemotherapy (EP) and will continue to 
be administered as monotherapy every 4 weeks (Q4W) post-chemotherapy until progressive 
disease (PD). Prophylactic cranial irradiation (PCI) is allowed at the investigators’ discretion 
as per standard of care (SoC) guidance for extensive stage small-cell lung cancer (ES-SCLC).
Patients will attend a safety follow up visit 90 days after last dose of durvalumab. The study 
flowchart is shown below in Figure 1 Overall study design.


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Figure 1 Overall study design 
 
ES-SCLC Extensive-stage small-cell lung cancer; EP etoposide + cisplatin or carboplatin; PD 
Progressive disease 
The schedule of assessments including safety, tolerability, and efficacy using RECIST version 
1.1 are detailed in the study assessment schedule in Appendix A. 
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) 
will be performed at the times specified in the schedule of assessment (Appendix A).  
RECIST 1.1 measurements as assessed by the Investigator will be used to derive the 
secondary variables of PFS, APF12, ORR, and DoR. The categorisation of objective tumour 
response assessment into complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD) or not evaluable (NE) will be based on RECIST 1.1. 
Patients will be followed for survival status every 3 months (q3m) following treatment 
discontinuation, until death, withdrawal of consent or the end of the study. These contacts may 
be conducted by phone and the survival data collected will be reported in the clinical database. 
1.3 
Number of patients 
This is a safety study and no formal sample size calculation will be done.  However, assuming 
AE of CTCAE grade ≥3 with an incidence of 60%, approximately 300 patients are needed to 
achieve the estimation precision no wider than 5.7% based on exact method (Clopper-
Pearson).  In addition, assuming the imAE with an incidence of 20%, the estimation precision 
will be no wider than 4.7% using the same method.  An illustration of the precision around the 
varying incidences of AE for the patients enrolled is provided in Table 1 Precision around 
varying incidence of AE. 
Table 1 Precision around varying incidence of AE 
Sample Size 
Precision achieved with different assumed incidence of AE  
20% 
40% 
50% 
60% 
70% 
200 
5.8% 
7.0% 
7.1% 
7.0% 
6.6% 
300 
4.7% 
5.7% 
5.8% 
5.7% 
5.3% 
500 
3.6% 
4.4% 
4.5% 
4.4% 
4.1% 
 


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2 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
2.1.1 
Safety set (SS) 
The safety analysis set will include all patients who received at least one dose of study 
treatment. 
2.1.2 
Efficacy analysis set 
The safety set will be used as the efficacy analysis set. 
2.2 
Violations and deviations 
Protocol deviations are defined as any change, divergence or departure from the study design 
or procedures defined in the protocol. Important protocol deviations (IPDs) are defined as a 
subset of protocol deviations that may significantly affect the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a patient's rights, safety, or well-
being. 
Categories of protocol deviations and IPDs will be documented by clinical operation team. 
Protocol deviations and IPDs will be recorded accordingly throughout the study by clinical 
investigators. Several IPDs could be identified with programming to assist locating potential 
IPDs. 
These IPDs identified by programming will be reported to clinical operation team and be 
combined with clinical PD findings. The final combined PDs from clinical operation team will 
be used for statistical analyses. 
A complete list of anticipated protocol deviations (including important protocol deviations) 
will be compiled separately and finalised prior to database lock. 
3 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Primary endpoints 
Primary endpoints include incidence of grade ≥3 AEs and incidence of imAEs. 
Incidence of grade ≥3 AEs: Number and proportion of patients in SS with CTCAE (version 
5.0) grade ≥3 AEs. 
Incidence of imAEs: Number and proportion of patients in SS with imAEs. 
imAEs: ImAEs will be identified from AEs of special interest (AESIs) based on programmatic 
rules that consider interventions involving systemic steroid therapy, immunosuppressant use, 
and/or endocrine therapy. Endocrine therapies include standard endocrine supplementation, as 


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well as treatment of symptoms resulting from endocrine disorders (for example, therapies for 
hyperthyroidism include beta blockers [e.g., propranolol], calcium channel blockers [e.g., 
verapamil, diltiazem], methimazole, propylthiouracil, and sodium perchlorate).    
3.2 
Secondary endpoints 
Secondary endpoints include some variables regarding the efficacy of durvalumab + EP, such 
as PFS, APF12, ORR, DoR using site investigator assessment and OS, OS12 and some 
variables regarding the safety and tolerability of durvalumab + EP, such as incidence of AEs, 
SAEs, AESIs and AEs resulting in treatment discontinuation. 
3.2.1 
Derivation of RECIST visit responses 
For all patients, the RECIST tumour response data will be used to determine each patient’s 
visit response according to RECIST version 1.1.  It will also be used to determine, if and when 
a patient’s disease has progressed in accordance with RECIST and their best objective 
response to study treatment.  
The baseline radiological tumour assessment is part of the screening procedure and should be 
performed no more than 28 days before the start of treatment, and ideally as close as possible 
to the start of study treatment.  Tumour assessments will be at 6 weeks ± 2 weeks after study 
treatment initiation, at 12 weeks ± 2 weeks after study treatment initiation and then continue 
every 8 weeks ± 2 weeks thereafter until disease progression. An additional follow-up scan 
will be performed if clinically feasible.  
If an unscheduled assessment is performed, and the patient’s disease has not progressed, every 
attempt should be made to perform the subsequent assessments at patients’ scheduled 
visits.  This schedule is to be followed to minimise any unintentional bias caused by some 
patients being assessed at a different frequency than other patients. 
Additional scans can be completed per standard practice post-disease progression. 
From the investigator’s review of the imaging scans, the RECIST tumour response data will 
be used to determine each patient’s visit response according to RECIST version 1.1. At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD 
or PD, using the information from target lesions (TLs), non-target lesions (NTLs) and new 
lesions and depending on the status of their disease compared with baseline and previous 
assessments. If a patient has had a tumour assessment which 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).  
RECIST outcomes (ie, PFS and ORR etc.) will be calculated programmatically from site 
investigator data from overall visit responses. 


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3.2.2 
Site Investigator Assessments Using RECIST 1.1 
Site investigator will record their assessment of overall response, and response in target lesions, 
non-target lesions, new lesions on the CRF form.  Instructions to the investigator regarding 
selection of target and non-target lesions are included in Appendix C of the Clinical Study 
Protocol. 
 
3.2.2.1 
Target Lesions  
Measurable disease is defined as having at least one measurable lesion, not previously irradiated, 
which is ≥ 10 mm in the longest diameter (LD), (except lymph nodes which must have short axis 
≥ 15 mm) with CT or MRI and which is suitable for accurate repeated measurements.  
 
All other measurable lesions not recorded as TL, and all non-measurable lesions (or sites of 
disease) should be identified as non-target lesions (NTLs) at baseline and their response should be 
followed at subsequent visits.  
For patients who do not have measurable disease at entry (ie, no TLs) but have non-measurable 
disease, evaluation of overall visit responses will be based on the overall NTL assessment and the 
absence/presence of new lesions. If a patient does not have measurable disease at baseline, then 
the TL visit response will be not applicable (NA).  
 
Missing TL Data  
 
If all TL measurements are missing, then the TL visit response is NE. Overall visit response will 
also be NE, unless there is a progression of non-TLs or new lesions, in which case the response 
will be PD.  
 
3.2.2.2 
Non-Target Lesions and New Lesions.  
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.  
 
To achieve ‘unequivocal progression’ based on NTLs, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or PR in TLs, the overall 
tumor burden has increased sufficiently to merit a discontinuation of therapy. A modest ‘increase’ 
in the size of one or more NTLs is usually not sufficient to qualify for unequivocal progression 
status.  
 
3.2.2.3 
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.  
 
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.  
 
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.  
 


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New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses.  
 
A new lesion indicates progression, so the overall visit response will be PD irrespective of the TL 
and NTL response.  
 
Symptomatic deterioration is not a descriptor for progression of NTLs: it is a reason for stopping 
study therapy and will not be included in any assessment of NTLs.  
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without objective 
evidence of disease progression at that time should continue to undergo tumor assessments where 
possible until objective disease progression is observed.  
 
3.2.2.4 
Overall Visit Response  
Table 2 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give an overall visit response.  
 
Table 2 Overall Visit Responses 
Target  
Non-target  
New Lesions  
Overall Visit 
Response  
CR  
CR (or NA)  
No (or NE)  
CR  
CR  
Non-CR/Non-PD or 
NE  
No (or NE)  
PR  
PR  
Non-PD or NE or NA  
No (or NE)  
PR  
SD  
Non-PD or NE or NA  
No (or NE)  
SD  
PD  
Any  
Any  
PD  
Any  
PD  
Any  
PD  
Any  
Any  
Yes  
PD  
NE  
Non-PD or NE or NA  
No (or NE)  
NE  
NA  
CR  
No (or NE)  
CR  
NA  
Non-CR/Non-PD  
No (or NE)  
SD  
NA  
NE  
No (or NE)  
NE  
NA  
NA  
No (or NE)  
NED  
CR complete response; PR partial response; SD stable disease; PD progression of disease; NE not evaluable; NA not 
applicable (only relevant if there were neither target nor non-target lesions at baseline); NED no evidence of disease. 
3.2.3 
PFS 
PFS is defined as the time from first dose of study treatment until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from study therapy or receives another anti-cancer therapy prior to 
progression. Patients who have not progressed or died at the time of analysis will be censored 
at the time of the latest date of tumor 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 assessment. 
If the patient has no evaluable visits or does not have baseline data, they will be censored at 
the day of first dose unless they die within 2 visits of baseline (2 x 6 weeks for tumor 
assessments + 2 x 2 weeks for permitted visit window). 


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The PFS time will always be derived based on assessment dates not visit dates. 
 PFS (months) = (Date of event or censoring – Date of first dose + 1) /30.4375, results round 
to 1 decimal place. The cases of event and censoring are listed in Table 4 PFS calculation 
under various cases. 
Given the scheduled visit assessment scheme (ie, q6w ± 2w for the first 12 weeks then q8w ± 
2w thereafter) the definition of 2 missed visits will change. To evaluate the no. of missing 
tumor assessments between the first PD/death and the last non-missing tumor assessment 
before, following rules will be used. 
Table 3 Criteria of at least 2 missing tumor assessments 
Cases 
Conditions when considered as at least 
2 missing tumor assessments 
There is 2 consecutive missed tumor assessments 
before first PD/death since first dose. 
Time interval between first dose and 
first PD/death is >16 weeks (ie. 2 * 6 
+ 4 weeks, 112 days) 
If the 2 consecutive missed tumor assessments 
occur over the period(Week 12) when the 
scheduled assessments changes from q6w to q8w季
Time interval between the last tumor 
assessment and first PD/death is >18 
weeks (ie. 6 + 8 + 4 weeks, 126 days) 
If the 2 consecutive missed tumor assessments 
occur after Week 12 onwards 
Time interval between the last tumor 
assessment and first PD/death is >20 
weeks (ie. 2 * 8 + 4 weeks, 140 days) 
 
Table 4 PFS calculation under various cases 
Cases 
Date used as the end of 
PFS 
Event or 
Censoring 
Patients with PD or death, and first PD or 
death are within 2 assessments after last 
tumor assessment before PD/death 
Date of first PD or death 
Event 
Patients with PD or death, and first PD or 
death are after 2 or more missing 
assessments from last tumor assessment 
before PD/death 
Date of the last non-PD 
tumor assessment after 
first dose 
Censoring 


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Patients without PD and death but had post-
treatment tumor assessment 
Latest date of tumor 
assessment after first dose 
Censoring 
Patient is alive and has no tumor 
assessments after first dose or does not have 
baseline tumor data 
Date of first dose 
Censoring 
Patient has died >16 weeks after start of 
treatment and has no tumor assessments 
after first dose or does not have baseline 
tumor data 
Date of first dose 
Censoring 
3.2.4 
APF12 
The APF12 will be defined as the Kaplan-Meier estimate of PFS (per investigator assessment 
according to RECIST v1.1 criteria) at 12 months. 
3.2.5 
ORR 
ORR is defined as the proportion of patients with measurable disease at baseline who have at 
least 1 visit response of CR or PR. If any patients do not have measurable disease at baseline 
then the analysis of ORR will exclude these patients, so that the denominator is a subset of the 
SS who have measurable disease at baseline. Data obtained up to progression or last evaluable 
assessment in the absence of progression will be included in the assessment of ORR. 
However, any CR or PR which occurred after a further anti-cancer therapy was received will 
not be included in the numerator for the ORR calculation (where the SS with measurable 
disease will be the denominator).  
ORR (%) = No. of patients with CR or PR before further anti-cancer therapy after first dose 
/No. of a subset of SS patients with measurable disease *100, results round to 1 decimal place. 
3.2.6 
DoR 
Duration of response is only calculated for patients who have a best overall tumor response of 
CR or PR before further anti-cancer therapy after first dose.  
Duration of response will be defined as the time from the date of first documented response 
until the date of PD or death in the absence of disease progression. The end of response should 
coincide with the date of PD or death from any cause used for the PFS endpoint. The time of 
the initial response will be defined as the date of tumor assessment for the first response of PR 
or CR.  


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If a patient does not progress following a response, then his/her duration of response will use 
the PFS censoring time. 
DoR (months) = (Date of event or censoring – Date of first documented CR or PR before 
further anti-cancer therapy after first dose + 1) /30.4375, results round to 1 decimal place.  
3.2.7 
OS 
Overall survival is defined as the time from the date of first dose of study treatment 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. The possible last 
recorded date could be found from visits, AEs, concomitant medication, cancer therapy, vital 
signs, physical examination, lab test, study drug exposure, survival status survey and 
disposition of patient. 
OS (months) = (Date of death or last recorded date on which the patient was known to be alive 
- date of first dose of study treatment + 1) /30.4375, results round to 1 decimal place. 
3.2.8 
OS12 
The OS12 will be defined as the Kaplan-Meier estimate of OS at 12 months. 
3.2.9 
Incidence of AEs, SAEs, AESIs and AEs leading to treatment 
discontinuation 
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product. An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver), or the abnormal results of an investigation (eg, 
laboratory findings). In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered. 
The term AE is used to include both SAEs and non-serious AEs. 
AEs will be collected from time of signing of informed consent throughout the treatment 
period and including the follow-up period up to 90 days after the last dose of durvalumab 
treatment. 
An SAE is an AE occurring during any study phase (i.e. treatment, follow-up), that fulfils one 
or more of the following criteria: 
z results in death 


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z
is immediately life-threatening
z
requires in-patient hospitalization or prolongation of existing hospitalization
z
results in persistent or significant disability/incapacity
z
is a congenital abnormality or birth defect
z
is an important medical event that may jeopardize the patient or may require medical
z
intervention to prevent one of the outcomes listed above
An AESI is one of scientific and medical interest specific to understanding of the 
Investigational Product and may require close monitoring and rapid communication by the 
investigator to the sponsor.
The AESIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs that 
have a likely inflammatory or immune-mediated pathophysiological basis resulting from the 
mechanism of action of durvalumab and requiring more frequent monitoring and/or 
interventions such as corticosteroids, immunosuppressants, and/or endocrine therapy. 
Endocrine therapies include standard endocrine supplementation, as well as treatment of 
symptoms resulting from endocrine disorders (for example, therapies for hyperthyroidism 
include beta blockers [e.g., propranolol], calcium channel blockers [e.g., verapamil, 
diltiazem], methimazole, propylthiouracil, and sodium perchlorate, infusion-related reactions 
and hypersensitivity/anaphylactic reactions). 
An AstraZeneca medically qualified expert after consultation with the Global Patient Safety 
Physician has reviewed the AEs of interest and identified which MedDRA preferred terms 
contribute to each AESI. A further review will take place prior to Database lock (DBL) to 
ensure any further terms not already included are captured within the categories. Specific 
terms(PT and SOC) will be defined in an external file.
AEs leading to treatment discontinuation including AEs leading to durvalumab permanently 
discontinuation and AEs leading to EP permanently discontinuation.
The incidence rate of AEs/SAEs/AESIs/AEs leading to treatment discontinuation (%) = No. of 
patients with at least one AEs/SAEs/AESIs/AEs leading to treatment discontinuation / No. of 
patients in SS *100, results round to 1 decimal place.
3.3
Other safety variables


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季
.
3.3.2
Lab test
Lab test will be measured at screening and every visit during the study. The parameters to be 
measured are variables in hematology, clinical chemistry and urinalysis.
Hematology parameters include absolute neutrophil count (ANC), absolute lymphocyte count
(ALC), haemoglobin, platelet count (PLT) and total white cell count (WBC).
Clinical chemistry parameters include albumin, lipase, alkaline phosphatase (ALP), 
magnesium, alanine transaminase (ALT), potassium, amylase, sodium, aspartate transaminase
(AST), total bilirubin (TBil), bicarbonate, total protein, calcium, TSH, free T3 and free T4
(reflex testing only if TSH is abnormal), chloride, creatinine, gamma glutamyl transferase
(GGT), urea or blood urea nitrogen (depending on local practice), glucose and lactate 
dehydrogenase.
Corrected calcium product will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – Albumin (g/L)] × 0.02)
Urinalysis parameters include bilirubin, ketones, blood, pH, colour and appearance, protein,
glucose and specific gravity.
3.3.3
Vital signs, weight and BMI
Vital signs will be monitored at screening and at every visit during the study. Parameters 
include pulse rate, respiratory rate, systolic blood pressure (SBP), diastolic blood pressure
(DBP), height, weight, BMI and body temperature.


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3.3.4 
Physical examinations 
At screening and each visit during the treatment period, a complete physical examination will 
be performed and include an assessment of the following: general appearance, respiratory, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, musculo-skeletal (including spine and extremities) and neurological systems. 
3.3.5 
ECGs 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study. The results include overall evaluation and its clinical significance. 
3.3.6 
ECOG PS 
ECOG PS will be assessed at screening and at every visit during the study. The result will 
range from 0 to 5, while higher score represents a severer case / worse performance status.  
3.3.7 
Pregnancy test 
Pregnancy test will be performed in 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. The 
result will be negative or positive. 
3.3.8 
Potential Hy’s law case 
Patients experiencing a Hy’s Law incident will be tabulated and details will be included in by-
patient listings. Hy’s Law incidents are those cases where a patient shows an AST or ALT 
≥3 × ULN together with total bilirubin ≥2 × ULN. Please refer to Appendix B of the CSP for 
further instructions.  
The following summaries (n, %) of the laboratory data will be used to identify cases of Hy’s law:  
Elevated ALT, AST, and total bilirubin during the study  
• 
ALT ≥ 3x – ≤ 5x, > 5x – ≤8x, > 8x - ≤10x, >10x - ≤20x, and >20x upper limit of normal 
(ULN) during the study  
• 
AST ≥ 3x – ≤ 5x, > 5x – ≤8x, > 8x - ≤10x, >10x - ≤20x, and >20x ULN during the study  
• 
Total bilirubin ≥2x – ≤3x, >3x – ≤5x, >5x ULN during the study  
• 
ALT or AST ≥3x – ≤5x, >5x – ≤8x, >8x - ≤10x, >10x - ≤20x, and >20x ULN during the 
study  
• 
ALT or AST ≥3x ULN and total bilirubin ≥2x ULN during the study (Potential Hy’s law): The 
onset date of ALT or AST elevation should be prior to or on the date of total bilirubin 
elevation  
 
Narratives will be provided in the CSR for patients who have ALT ≥ 3x ULN plus Total bilirubin 
≥ 2x ULN or AST ≥ 3x ULN plus Total bilirubin ≥ 2x ULN at any visit.  


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Liver biochemistry test results over time for patients with elevated ALT or AST (ie, ≥ 3x ULN), 
and elevated Total bilirubin (ie, ≥ 2x ULN) (at any time) will be summarized. Individual patient 
data where ALT or AST (ie, ≥ 3x ULN) plus Total bilirubin (ie, ≥ 2x ULN) are elevated at any 
time will also be listed.  
3.3.9 
Concomitant medication 
Any medications taken by the patient at any time between the date of the first dose (including 
the date of the first dose) of study treatment up to the date of last dose of study treatment + 90 
days in the study will be considered as concomitant medication. Any medication that ended 
prior to the first dose of the study treatment will be considered as prior medication. 
3.3.10 
Anti-cancer therapy 
Anti-cancer therapy in the study will be classified as previous, concurrent and subsequent 
anti-cancer therapy. Previous anti-cancer therapy is the anti-cancer therapy which start before 
the first dose of study drug. Concurrent anti-cancer therapy is the anti-cancer therapy which 
start after the first dose of study drug and before the last dose of study drug. Subsequent anti-
cancer therapy is the anti-cancer therapy which start after the last dose of study drug. 
4 
ANALYSIS METHODS 
4.1 
General principles 
4.1.1 
Analysis software 
SAS® v9.4 or above version will be used for statistical analysis. 
4.1.2 
General analysis methods 
All data, demography, baseline characteristics, safety, and efficacy, will be summarized using 
descriptive statistics, as appropriate for the type of data, for the SS. In addition, some efficacy 
and safety data will be summarised separately for the WHO/ECOG PS 0 1 and 2 subgroups. 
For continuous variable, no. of non-missing patients, no. of missing patients (nmiss), mean, 
standard deviation (Std), median, interquartile range (Q1 and Q3), maximum and minimum 
values will be used to descriptive the variable. The minimum and maximum will keep the 
same decimal place with the raw data, while mean, median, Q1 and Q3 will keep one more 
decimal place, and Std will keep two more decimal places. The decimal place of above 
statistics will not exceed four regardless of the decimal place of raw data. 
For category variable, no. of patients and proportions will be adopted. “0” will be displayed 
when the count was zero. The proportions are all based on the non-missing data and will keep 
one decimal place unless otherwise specified. Two-sided 95% confidence intervals (CIs) will 
be provided as appropriate. 


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All patients who received at least one dose of study treatment will be included in SS, which 
will be the primary analysis set for all analyses unless otherwise specified. 
4.1.3 
Hypothesis test 
No hypothesis test is required for the primary endpoints, which are descriptive. 
4.1.4 
Baseline 
The baseline of all measurements and tests will use the latest valid records before first dose of 
study treatment. 
4.1.5 
Unscheduled visits 
The records in unscheduled visits will be aligned with predefined terms of measurements and 
tests in the study. The results will be included in the shift table of these laboratory tests and 
measurements. The records in unscheduled visits will also be presented in listings but not 
summarized by visit. 
4.1.6 
Data derivation rules 
The data derivation rules are describe as follows: 
Table 5 Variable derivation rules 
Variable (unit) 
Definition 
Derivation rules 
Age (years) 
Years from birth date to 
informed consent  
Integer part of ((date of informed 
consent – date of birth) / 365.25) 
Time from first dose 
of study treatment to 
the date of disposition 
event (months) 
Months from the date of 
first dose of study treatment 
to the start date of 
disposition event  
(Start date of disposition event – 
date of first dose of study treatment 
+ 1) / 30.4375, round to 2 decimal 
place 
Time from original 
diagnosis to informed 
consent 
Months from the date of 
original diagnosis to the 
date of informed consent 
(Date of informed consent – date of 
original diagnosis) / 30.4375, round 
to 2 decimal place 
BMI at each visit 
(kg/m^2) 
Weight over squared height 
Weight at each visit (kg) / height at 
screening (m)^2, round to 2 decimal 
place 
Time from original 
diagnosis to the first 
Months from the date of 
original diagnosis of SCLC 
(Date of first dose of study 
treatment –  date of original 


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dose of study 
treatment (months) 
to the date of first dose of 
study treatment  
diagnosis of SCLC + 1) / 30.4375, 
round to 2 decimal place 
Time from the latest 
assessment to the first 
dose of study 
treatment (months) 
Months from the date of 
latest assessment of SCLC 
to the date of first dose of 
study treatment  
(Date of first dose of study 
treatment –  date of latest 
assessment of SCLC + 1) / 30.4375, 
round to 2 decimal place 
Time to first AE 
(days) 
Days from the date of first 
dose of study treatment to 
the date of first AE 
occurrence or censoring 
Date of first AE or censoring – date 
of first dose of study treatment +1 
Duration of AE (days) 
Days from the AE start date 
to the AE stop date or date 
of DCO. The date used 
should not be imputed. 
AE stop date or date of DCO – AE 
start date +1 
4.1.7 
Handling of missing data and incomplete date 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “<x” (i.e. below the lower limit of quantification) or >x (i.e. above the upper limit of 
quantification) will be imputed as “x” in the calculation of summary statistics but displayed as 
“<x” or “>x” in the listings.  
Additionally, adverse events that have missing causality (after data querying) will be assumed 
to be related to study drug, with the exception of causality assessments that are not applicable 
for the patient. The original incomplete or missing dates will be presented in the listings. 
x 
Adverse events: all AEs will be considered as treatment-emergent unless the opposite can 
be clearly stated.  
x 
Concomitant medications: all medications will be considered as concomitant unless the 
opposite can be clearly stated. 
The original incomplete or missing start dates will be imputed as below: 
x 
Missing day: impute the 1st of the month unless month is same as month of first dose of 
study drug then impute first dose date 
x 
Missing day and month: impute 1st January unless year is the same as first dose date then 
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x 
Completely missing – impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end date. 
When imputing a start date, ensure that the new imputed date is sensible i.e. is prior to the end 
date of the AE or study. 
Partial AE or medication end dates will be imputed as follows: 
x 
If only day is missing: impute day as the earlier of either the date of DCO or the last day 
of the month; 
x 
If day and month are missing: impute day and month as the earlier of either the date of 
DCO or the last day of the year; 
x 
If the end date is missing, then the analysis end date will not be imputed. 
Imputed dates will not be used for deriving duration of events or treatment. 
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive +1 from the database and 
the death date using the available information provided: 
x 
For missing day only – using the 1st of the month 
x 
For missing day and month – using the 1st of January 
If there is evidence of death but the date is entirely missing, it will be treated as missing, i.e. 
censored at the last known alive date. 
 
4.2 
Analysis methods 
4.2.1 
Disposition of patients 
The summary table of disposition will include no. of patients screened and enrolled, and the 
distribution of disposition events. Reason for screening failure will also be presented. 
Important protocol deviations recorded by clinical operation team will be summarized 
according to predefined categories. All protocol deviations will also be listed. 
The number and proportion of patients included and excluded from SS will be summarized. 
For those excluded from SS, reasons for exclusion will be summarized. 


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The excluded patients will be identified on data review meeting. The reasons will be imported 
to analysis dataset from an external document. 
4.2.2 
Demographics and baseline characteristics 
All the variables below will be summarized using descriptive statistics for continuous and 
categorical variable accordingly. Specific of other category in each variable will not be 
presented in summary tables but listed. Variables which are not presented in the following 
statements but collected in EDC will not be summarized but listed. 
4.2.2.1 
Demographics 
Demographics includes age, age group (<65 years, ≥65 years), sex, race, ethnicity, height, 
weight and body mass index (BMI) at screening. 
4.2.2.2 
Pathology at screening 
Variables of pathology of SCLC at screening include time from original diagnosis to the first 
dose of study treatment, time from the latest assessment date to the first dose of study 
treatment, pathology at diagnosis with primary tumor, regional lymph nodes and distant 
metastases TNM classification, and stage/AJCC stage.  
4.2.2.3 
Extent of SCLC upon entry to study 
Variables of extension of disease upon entry to study include whether the patient had 
recurrence of earlier cancer and sites of local/metastatic disease. 
4.2.2.4 
Medical and surgical history 
Variables to describe medical history include no. of patients with any medical history and 
coded terms of medical history. The terms of medical history will be coded using the latest 
version of MedDRA before database lock. The coded terms will be sorted according to the 
descending order of occurrence rate of system organ class (SOC) and preferred term (PT) 
within each SOC. 
The event recorded in medical history page will be classified as medical history and current 
disease for summary. Any event that ended prior to the first dose of the study treatment will 
be considered as medical history. While those which ended after the first dose or are still 
ongoing will be considered as current disease. 
Surgical history will be summarized in the same way as medical history. 
4.2.2.5 
Anti-cancer therapy 
Number and percentage of patients had previous cancer therapy will be summarized. The 
therapy class, therapy agent and with or without concomitant chemoradiotherapy will be 
listed. 


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Concurrent and subsequent anti-cancer therapy will be summarized separately in the same 
way as previous anti-cancer therapy. 
4.2.2.6 
Radiotherapy  
Number and percentage of patients had previous radiotherapy will be summarized. Other 
variables including site, start date, end date, etc. will be listed.  
Concurrent and subsequent radiotherapy will be summarized separately in the same way as 
previous radiotherapy. 
Number and percentage of patients receiving concurrent/ subsequent PCI will be summarized 
and listed. Other concurrent/ subsequent  radiotherapy will be summarized in the same way as 
PCI. Concurrent/ subsequent PCI is the concurrent/ subsequent radiotherapy whose site or 
region is brain and treatment status is prophylaxis. 
4.2.2.7 
Use of nicotine 
Nicotine use, category (never, former, current) and number of pack years used will be 
summarized. 
4.2.3 
Prior and concomitant medications 
Any medications taken by the patient at any time between the date of the first dose (including 
the date of the first dose) of study treatment up to the date of last dose of study treatment + 90 
days in the study will be considered as concomitant medication. Any medication that ended 
prior to the first dose of the study treatment will be considered as prior medication. 
No. of patients with any prior or concomitant medications will be presented. Medications will 
be presented and coded using WHO Drug dictionary (WHO DD) and sorted by descending 
order of occurrence rate. 
4.2.4 
Primary endpoints 
Adverse events, which start after first dose of study drug up to 90 days after the last dose of 
durvalumab treatment or the date of initiation of the first subsequent therapy, whichever 
occurs first, will be analysed in summary table. Other AEs recorded in the study will only be 
listed. This rule applies to all analysis of AE. 
Frequency of AEs of CTCAE grade ≥3, no. and percentage of patients with AEs of CTCAE 
grade ≥3 will be presented. These AEs will also be summarized by System Organ Class 
(SOC) and preferred term (PT). The exact 95% CIs around the incidence estimates will also 
be reported.  
Time to event endpoints will be analysed using Kaplan-Meier method to estimate the median 
event time to the first AE of CTCAE grade 3 or higher. If a patient has no AE of CTCAE 
grade 3 or higher, the time to event will be censored at the date of DCO, death, 90 days after 


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the last dose of durvalumab treatment or the date of initiation of the first subsequent therapy, 
whichever occurs first. K-M curve will be presented. 
Similar analyses will be conducted for imAEs. 
An 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. In 
general, imAEs will include AESIs that are managed using steroids, immunosuppressants 
and/or hormone replacement therapy. 
The identification of imAEs will be made following the AstraZeneca imAE characterization 
charter. 
1. The selection of preferred term,  
2. Programmatic identification of those potential imAEs requiring medication such as steroids, 
immunosuppressants and/or hormone replacement therapy 
All imAEs which are identified by the investigator (as recorded in CRF Adverse Events (AE)) 
will undergo a review by medical monitor. In addition, imAEs will be checked 
programmatically as described in the imAE charter on the clinical database to ensure the 
recording of imAEs are complete and unambiguous. If any discrepancies found, those will be 
resolved as an on-going basis and before DBL. 
All above AEs will be listed. 
4.2.5 
Secondary endpoints 
4.2.5.1 
PFS 
PFS will be summarized using Kaplan-Meier estimates of the median event time and quartiles 
together with their 95% CIs, given the anticipated maturity of 60%. The Kaplan-Meier curves 
will be provided. The no. and proportion of cases of events (e.g. PD, death) and censorings 
will be summarized. 
4.2.5.2 
APF12 
APF12 will be estimated using the Kaplan-Meier curve. The estimate along with confidence 
intervals using Greenwood’s estimate of standard error and a log-log transformation will be 
presented. 
4.2.5.3 
ORR 
ORR will be summarized descriptively, and the exact 95% CIs will be provided. Best overall 
response before a further anti-cancer therapy in the study will be summarized. No. and 
proportion of patients with each kind of best overall response will be presented. 


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4.2.5.4 
DoR 
Kaplan-Meier plot will be produced using the same methods as PFS whenever appropriate. 
Otherwise, descriptive statistics will be presented. 
4.2.5.5 
OS 
OS will be analysed in the same methods as PFS. 
4.2.5.6 
OS12 
OS12 will be analysed in the same methods as APF12. 
4.2.5.7 
Incidence of AEs, SAEs, AESIs and AEs leading to treatment discontinuation 
Analyses similar to the primary endpoints will be conducted for overall AEs, SAEs, AESIs 
and AEs leading to discontinuation of study treatment. In addition, the no. and percentage of 
patients with AEs will be presented by PT.  
All above AEs will be listed. Detailed statement of death will be listed. 
4.2.6 
Other safety variables 
4.2.6.1 
Adverse Events 
The following AE summaries will be summarized similar to the primary endpoints: 
x All AEs causally related to any study treatment 
x All AEs by CTCAE grade 
x Any CTCAE grade ı3 causally related to any study treatment 
x All SAEs causally related to any study treatment 
x All AESIs causally related to any study treatment 
x AEs leading to discontinuation of any study treatment, causally related to any study 
treatment 
x AEs that resulted in death 
x AEs that resulted in death causally related to any study treatment 
x Other significant AEs 
 
AE, AE with CTCAE grade ≥3, AESI and imAE will be summarized by SOC, PT and most 
severe outcome. The severity of outcome is Fatal> Not Recovered/Not Resolved> 
Recovered/Resolved with Sequelae> Recovering/Resolving> Recovered/Resolved.  
Most common AEs (≥2%), most common AEs of CTCAE grade 3 or 4, causally related AEs, 
causally related AEs of CTCAE grade 3 or 4, AEs leading to interruption of 
durvalumab/EP/study treatment, SAEs, SAEs causally related to study treatment will also be 
summarized for PT and maximum CTCAE grade. 
A summary of deaths will be provided with the following information: 


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x 
Total number of deaths (regardless of date and reason of deaths) 
x 
Death related to disease under investigation only, as determined by the investigator 
x 
  Deaths related to disease under investigation, as determined by the investigator, and with 
an AE with outcome of death (with further subcategories for AEs with onset/worsening 
date prior to 90 days after the last dose of study treatment and initiation of subsequent 
anticancer therapy)  
x 
 AEs with outcome of death only (with further subcategories for AEs with 
onset/worsening date prior to 90 days after the last dose of study treatment and initiation 
of subsequent anticancer therapy) 
x 
Other deaths 
 
A list of all deaths will also be produced. 
 
Any AE with a relatedness to study treatment of possible or probable will be considered to be 
causally related to study treatment for purposes of the data summaries.  Relatedness should be 
assigned by the investigator to each study treatment individually on the eCRF.  When the 
relatedness of an AE is missing on the eCRF, all efforts will be taken to ensure that the 
Investigator assigns his/her assessment of relatedness prior to database lock.  
If relatedness of an AE is missing at the DBL, the AE will be considered as related to study 
treatment and related to durvalumab. 
4.2.6.2 
Exposure 
The exposure for durvalumab and each kind of drug of EP will be summarized respectively.  
x intended exposure for durvalumab  
x actual exposure for durvalumab  
x total number of cycles of each molecule received 
x number of patients receiving 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, >12 cycles of 
durvalumab 
x number of patients receiving 1, 2, 3, 4, 5, 6,  >6 cycles of each drug of EP 
x number of, and reasons for, dose delays and interruptions 
  
Additionally, for durvalumab, relative dose intensity will also be summarized.  
Dose reductions are not permitted per the CSP for durvalumab and the actual exposure 
calculation makes no adjustment for any dose reductions that may have occurred. 
All these variables will be listed. Overdose report will also be listed. 
4.2.6.3 
Lab tests 
Baseline and post-baseline hematology, clinical chemistry and urinalysis results will be 
summarized descriptively by visit according to the general principles. For continuous 
laboratory assessments, absolute value and change from baseline will be summarized using 
descriptive statistics at each scheduled assessment time. These data summaries will be 


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provided in international system (SI) of units whenever applicable. The frequency and 
percentage for each clinical evaluation category (e.g., ‘normal’ and ‘abnormal with/without 
clinical significance’, ‘Unchecked’) will be summarized by visit. Shift table will be provided 
to show the change in CTC (V 5.0) grades between baseline and the worst post-baseline case 
if applicable. For the tests in clinical chemistry without CTC grade, shift table will be 
provided to show the change from baseline to maximum and minimum value during treatment 
respectively. For the tests in urinalysis, shift table will be provided to show the change from 
baseline to the worst value on treatment. Only when there is no post-baseline CTC grades or 
values, the worst post-baseline/ maximum value/ minimum value of lab test will be considered 
as unchecked in shift table. For the lab tests in clinical chemistry which have no CTC grades, 
normal range (low, normal, and high) will be used to evaluate the maximum or minimum 
value.  
 
Listings will be provideG for those whose results are normal at baseline and abnormal in post-
baseline evaluations, or abnormal both at baseline and in post-baseline evaluations. 
4.2.6.4 
Vital signs, weight and BMI 
Baseline and post-baseline vital signs, weight and BMI will be summarized descriptively by 
visit. Change from baseline at each visit will also be summarized. Box plots of the vital signs 
results by visit will be presented. 
All baseline and post-baseline vital signs, weight and BMI will be listed. 
4.2.6.5 
Physical examinations 
Patient with PE in the study will be listed. 
4.2.6.6 
ECGs 
The change from baseline ECG evaluation to post-baseline ECG evaluation will be 
summarized using shift table. The worst case will be used as post-baseline result for analysis. 
Only when there is no post-baseline clinical evaluation, the worst post-baseline of ECG 
evaluation will be considered as unchecked in shift table. 
Patient with abnormal ECG results in the study will be listed. 
4.2.6.7 
ECOG PS 
A summary of ECOG performance status at each scheduled time point will be provided. 
ECOG PS in the study will be listed. 
4.2.6.8 
Pregnancy test 
Patients with positive baseline or post-baseline pregnancy test results will be listed. 


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4.2.6.9 
Potential Hy’s Law case 
Liver diagnosis, liver risk factors and liver signs and symptoms regarding PHL case will be 
listed by patient and PHL case. 
4.2.7 
Subsequent anti-cancer therapy 
Subsequent anti-cancer therapy is the anti-cancer therapy which start after the last dose of 
study drug. Variables of subsequent anti-cancer therapy will include no. of patients with 
anticancer therapy post IP, therapy class, therapy agent and no. of cycles. These variables will 
be summarized using descriptive statistics for continuous and categorical variable accordingly. 
4.2.8 
Subgroup analysis 
Subgroup analysis of safety and efficacy (i.e. primary and secondary endpoints) will be 
conducted for the cohorts of patients with PS 0, 1, and 2 at baseline. For time to event 
analysis, each subgroup must have at least 20 events per subgroup level in order for that 
subgroup level to be included in the subgroup analysis. 
Additional subgroup analyses may be conducted for primary and/or secondary endpoints 
based on the following: 
z Platinum therapy administered in cycle 1 (cisplatin vs carboplatin) 
z Sex (male versus female) 
z Age (<65 versus ≥65 years of age) 
z Smoking status (current DQG former versus never smoker) 
z Number of cycles of EP (≤4 versus >4, based on etoposide exposure) 
z Use of PCI (yes versus no) 
z Brain metastases (yes versus no) 
z Liver metastases (yes versus no) 
z AJCC stage (stage III versus stage IV) 
Patients with missing data for a subgroup variable will be excluded from the analysis for that 
subgroup only 


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4.2.9 
Sensitivity analysis 
Considering the IPDs which could significantly affect the evaluation of efficacy endpoints 
may occur in the study, sensitivity analysis will be performed for PFS and OS excluding the 
patients with such IPDs. 
These IPDs will be determined in the date review meeting before database lock and clearly 
documented.  
 
5 
INTERIM ANALYSES 
There will be no formal interim analysis in this study.   
As the safety of durvalumab + EP has not been previously established in ES-SCLC patients 
with PS2, a safety review committee (SRC) will be established to review the safety and 
tolerability data of the combination of durvalumab+EP in this subset of patients at an early 
stage of enrolment. SRC will include AZ local study team member such as study physician, 
PV physician, PM and local medical affairs Lead, and also global clinical lead, global patient 
safety physician and GMAL. 
The SRC will meet after the first 20 patients with PS2 have either had the opportunity to 
complete the combination of durvalumab + chemotherapy (maximum of 6 cycles) or have 
discontinued treatment with durvalumab due to an AE or disease progression, whichever 
occurs first.  
After review of the data in patients with PS2, and patients with PS0-1, the SRC will make a 
recommendation on whether the study should continue recruitment of patients with PS2 as 
planned, or hold recruitment of this patient population, or amend the study design. In the event 
that the SRC recommends a change to the study, this will be communicated to all sites. 
The primary analysis of the study will be conducted 6 months after LSI, at which time 
secondary endpoints will also be assessed (maturity for PFS is anticipated to be approximately 
60%).   
Additionally, final analysis will be performed at the end of the study when all patients have 
completed follow-up for safety or sufficient maturity for the secondary efficacy objectives has 
been reached. 
 


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6 
CHANGES OF ANALYSIS FROM PROTOCOL 
No change of analysis from protocol is made. 
 
7 
REFERENCES 
None. 
 
8 
APPENDIX 
Appendix A Schedule of assessments 
Visit 
Screening 
Treatment period 
Safety 
follow-up 
visit 
Survival 
follow-up 
phone 
calls/emails 
Baseline 
(Day1) 
During 
Chemotherapy 
1 cycle = 21 days 
Post-
Chemotherapy 
1 cycle = 28 days 
Visit window 
Day-28 to 
Day-1 
0 
±3 days 
±3 days 
±7 days 
±14 days 
Week 
Weeks-4 
to Week-
1 
Week 0 
Week 3, 6, 9;  
Weeks 12, 15 at 
investigator 
discretion 
3 weeks after 
last dose of 
chemotherapy 
(either Week 
12, 15 or 18), 
then every  
weeks until PD 
90 days 
after last 
dose 
Every 3 
months 
Written informed 
consenta 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Demographics, 
including baseline 
characteristics  
X 
 
 
 
 
 
Medical history, 
including cancer 
treatment history 
X 
 
 
 
 
 


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Visit 
Screening 
Treatment period 
Safety 
follow-up 
visit 
Survival 
follow-up 
phone 
calls/emails 
Baseline 
(Day1) 
During 
Chemotherapy 
1 cycle = 21 days 
Post-
Chemotherapy 
1 cycle = 28 days 
Visit window 
Day-28 to 
Day-1 
0 
±3 days 
±3 days 
±7 days 
±14 days 
Week 
Weeks-4 
to Week-
1 
Week 0 
Week 3, 6, 9;  
Weeks 12, 15 at 
investigator 
discretion 
3 weeks after 
last dose of 
chemotherapy 
(either Week 
12, 15 or 18), 
then every  
weeks until PD 
90 days 
after last 
dose 
Every 3 
months 
ECG recordingb 
X 
As clinically indicated 
Physical 
examination, weight, 
and vital signs 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
 
Laboratory Assessments 
Clinical chemistryc 
X 
Xd 
X 
X 
X 
 
Hematologyc 
X 
Xd 
X 
X 
X 
 
TSH, (reflex free T3 
or free T4f) 
X 
Xe 
X 
X 
X 
 
Hepatitis B, C, HIV 
virology 
X 
 
 
 
 
 
Pregnancy testg 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
As clinically indicated 
 
Monitoring 
AE 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
X 
X 
X 
X 
 
IP Administration 
Durvalumab h 
 
X 
X 
X 
 
 
Etoposide i 
 
X 
X k 
 
 
 
Carboplatin or 
cisplatin i,j 
 
X 
X k 
 
 
 


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Visit 
Screening 
Treatment period 
Safety 
follow-up 
visit 
Survival 
follow-up 
phone 
calls/emails 
Baseline 
(Day1) 
During 
Chemotherapy 
1 cycle = 21 days 
Post-
Chemotherapy 
1 cycle = 28 days 
Visit window 
Day-28 to 
Day-1 
0 
±3 days 
±3 days 
±7 days 
±14 days 
Week 
Weeks-4 
to Week-
1 
Week 0 
Week 3, 6, 9;  
Weeks 12, 15 at 
investigator 
discretion 
3 weeks after 
last dose of 
chemotherapy 
(either Week 
12, 15 or 18), 
then every  
weeks until PD 
90 days 
after last 
dose 
Every 3 
months 
Tumor assessment 
per Investigator -
report (according to 
RECIST1.1)l 
X 
 
On study tumor assessments should occur at Week 6±2 weeks, at Week 
12±2 weeks then every 8±2 weeksm until PD 
 
Subsequent 
anticancer therapy 
 
 
 
 
X 
X 
Survival status 
 
 
 
 
X 
X 
a. 
Written informed consent and any locally required privacy act document authorization must be obtained prior to 
performing any protocol-specific procedures, including screening/baseline evaluations. If laboratory or imaging 
procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with 
consent of the patient. However, all screening laboratory and imaging results must have been obtained within 28 days of 
first dose. 
b. 
Any clinically significant abnormalities detected require triplicate ECG results. 
c. 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if 
clinically indicated. 
d. 
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to 
be repeated at day 1.  
e. 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 
f. 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the 
endocrine system. 
g. 
Pregnancy test will be performed in 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. 
h. 
Results for liver function tests, electrolytes, full blood count, and creatininemust be available before commencing an 
infusion (samples taken within 3 days prior to infusion) and reviewed by the treating physician or Investigator prior to 
dosing.  
i. 
Durvalumab will be administered first, followed by the etoposide + cisplatin/carboplatin regimen. 
j. 
If cisplatin, infuse over 1 to 2 hours. If carboplatin, infuse over 0.5 to 1 hour. 
k. 
Chemotherapy regimen (etoposide plus either cisplatin or carboplatin) to be administered Q3W for 4 to 6 cycles, per 
investigator clinical decision. 
l. 
See protocol Section 6.1 and Appendix C for additional details relevant to image acquisition, RECIST 1.1 assessments, 
and evaluation of scans after RECIST 1.1-defined progression. 
m. 
Patients will have scans done Q6W for the first 12 weeks, and then Q8W thereafter or per institutional standard at 
investigator discretion. 


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Appendix B TFL mock shells 
Please refer to the independent appendix document containing all TFL mock shells. 
Appendix C SDTM and ADaM specifications 
Please refer to the independent appendix documents for the specifications.