Clinical trial NCT04774380
Conditions: Extensive-stage Small Cell Lung Cancer
Keywords: Chemotherapy Aggressive malignancy Programmed cell death ligand-1 Platinum-based chemotherapy
Sponsor: AstraZeneca
Start date: 2021-11-11; Completion date: 2025-01-02
Enrollment: 152 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Study to determine the safety and tolerability profile of durvalumab with platinum (cisplatin or carboplatin) plus etoposide (EP) as first-line treatment in participants with extensive-stage small-cell lung cancer.

Detailed description:
The study will be conducted in North America, Europe and Turkey.

In this single arm study participants will be treated with with durvalumab alone and concurrently with platinum-based chemotherapy and etoposide during the study period until radiological disease progression, unless there is clinical progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met, as per investigator assessment.

Arms: arm 1: Participants will receive durvalumab dose A administered via intravenous (IV) infusion concurrently with platinum-based chemotherapy and etoposide every 3 weeks (q3w). Thereafter, durvalumab monotherapy will be continued every 4 weeks post-chemotherapy unless specific treatment discontinuation criteria are met.
Interventions: intervention 1: Durvalumab intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: Etoposide
Intervention descriptions: intervention 1: Participants will receive durvalumab via IV infusion on Day 1 of each cycle. intervention 2: Participants will receive cisplatin via IV administration on Day 1 of each cycle. intervention 3: Participants will receive carboplatin via IV administration Day 1 of each cycle. intervention 4: Participants will receive etoposide via IV administration on days 1 to 3 of each cycle.

Protocol documents:
Prot_000.pdf: 


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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 2.0
06 August 2021
Version 1.0
25 November 2020
Amendment 1 (06 August 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The previous Clinical Study Protocol (CSP) version, version 1.0, dated 25 November 2020 was 
updated to implement changes requested by the regulatory authorities and other changes as per 
revised AstraZeneca CSP template. The updates are summarized below.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 1.1
Schedule of 
Activities (SoA)
In the 3rd point (For 
Durvalumab), the duration 
between 2 consecutive 
doses of durvalumab was 
modified.
For clarity
Non-substantial
In Table 1, the IMPs were 
listed in the same order as 
the order of IMP 
administration per the 
protocol. 
Footnote ‘a’ updated to 
included the duration 
between 2 consecutive 
doses of durvalumab.
Footnote ‘q’ updated to 
include details of IMP 
administration.
Footnote ‘t’ revised to 
clarify that the infusion is 
for etoposide.
To be consistent with order of 
administration as per protocol 
and for clarity
Non-substantial
Section 1.1
Schedule of 
Activities (SoA)
In Table 2, footnote g 
clarification that additional 
radiological procedures are 
not mandatory was 
included. 
This clarification was 
requested by ethics committee  
Non-substantial
Section 1.2: 
Synopsis
The estimated dates for first 
patient enrollment and last 
patient completion was 
updated.
Update on study coduct 
timelines
Non-substantial
Section 2.3.2.1: 
Durvalumab
Rash/dermatitis (including 
pemphigoid) and immune 
Updated to align with current 
approved version of the 
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
thrombocytopenia were 
added to the risks with 
durvalumab.
Investigators Brochure, 
informed consent form and 
revised protocol template
Section: 2.3.2.1: 
Durvalumab
The events cough, dyspnea 
and nausea were removed 
from the list of frequent 
AEs with durvalumab in 
monotherapy clinical 
studies.
Update of the durvalumab 
safety data
Substantial
A reference to Dosing 
Modification and Toxicity 
Management guidelines for 
durvalumab monotherapy 
or in combination with 
other products was added.
For clarity
Non-substantial
Section 4.1: 
Overall Design
Corresponding 
change to Section 
1.2: Synopsis, 
Section 1.3: 
Schema
The list of countries in 
which the study is 
conducted was updated
Study will not be conducted in 
the United Kingdom and will 
be conducted in Turkey.
Substantial
The number of platinum 
(cisplatin or carboplatin) 
plus etoposide cycles was 
changed from “4 to 6” to 
"up to 4 to 6 cycles” in 
treatments and treatment 
duration. The 
corresponding update made 
in Figure 1 and Table 8.
For clarity
Substantial
Section 4.1.1: 
Study Conduct 
Mitigation 
During Study 
Disruptions Due 
to Cases of Civil 
Crisis, Natural 
Disaster, or 
Public Health 
Crisis
Details on study conduct 
mitigation during study 
disruptions due to cases of 
civil crisis, natural disaster, 
or public health crisis were 
added.
To provide details regarding 
the conduct of the study in 
case of study disruptions due 
to cases of civil crisis, natural 
disaster, or public health crisis, 
including COVID-19 outbreak
Substantial
Section 5.1: 
Inclusion Criteria
Inclusion criterion #3 was 
revised. 
To clarify that the genetic 
analysis is optional
Non-substantial
Section 5.1: 
Inclusion Criteria
Inclusion Criteria # 10 
updated. Creatinine 
Clearance values revised 
and clarified to include 
Etoposide treatment.
As requested by regulatory 
authority
Substantial
Section 5.2: 
Exclusion 
Criteria
Exclusion criterion #14 was 
revised to extend the period 
when live vaccines are not 
allowed from 30 days to 
90 days after last dose of 
IMP.
As requested by regulatory 
authority
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 5.2: 
Exclusion 
Criteria
Exclusion criterion #16 was 
revised to state that ‘Patient 
who previously received 
immunotherapy agents 
including anti PD-1/anti 
PD-L1 are not eligible’ and 
remove sub-bullets with 
additional conditions.
For consistency with inclusion 
criterion # 9
Non-substantial
Section 5.2: 
Exclusion 
Criteria
Exclusion criterion #20 
defined the period when 
contraception is required to 
180 days after last dose of 
etoposide.
As requested by regulatory 
authority
Substantial
Section 5.3: 
Lifestyle 
Restrictions
Contraception requirements 
were updated. Highly 
effective methods of 
contraception provided in 
Table 4 updated.
For consistency with exclusion 
criterion #20 and update based 
on revised protocol template 
for safety reasons.
Substantial
Lifestyle restrictions 
regarding sun exposure 
were added.
Update based on revised 
protocol template for safety 
reasons
Substantial
Section 6.1.1.1: 
Durvalumab 
(MEDI4736)
Deleted details about 
blinding of IV bag.
To correct an error, as this is 
an open-label study.
Substantial
Infusion window of 
± 10 minutes included for 
durvalumab infusion.
Update based on revised 
protocol template for safety 
reasons
Substantial
Section 6.1.2: 
Dose and 
Treatment 
Regimens
In Table 6, an explanation 
was added that etoposide 
will be administered daily 
for three consecutive days. 
For clarity
Non-substantial 
Section 6.4
Concomitant 
Therapy
The duration of recording 
concomitant medications 
included. Text was revised 
to extend the period when 
live vaccines are not 
allowed to 90 days after last 
dose of IMP.
Tables 9 and 10 were 
deleted and a reference was 
made to Tables 17, 18 and 
19 in newly added 
Appendix H (Concomitant 
Medications). 
Refer to Appendix H
Substantial
Section 8.1.1: 
Survival 
Assessments
Incorrect reference to 
‘Table 1’ was replaced by 
reference to ‘Table 2. 
Clarification on how 
patients will be censored at 
the date cutoff.
To provide the correct 
reference and for clarification
Non-substantial




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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................3
TABLE OF CONTENTS.....................................................................................................3
1.
PROTOCOL SUMMARY .................................................................................12
1.1
Schedule of Activities (SoA)..............................................................................12
1.2
Synopsis.............................................................................................................19
1.3
Schema ..............................................................................................................24
2.
INTRODUCTION .............................................................................................25
2.1
Study Rationale..................................................................................................26
2.2
Background........................................................................................................26
2.2.1
Immunotherapies................................................................................................26
2.2.2
Durvalumab .......................................................................................................27
2.2.3
Durvalumab in Combination with Chemotherapy...............................................28
2.3
Benefit/Risk Assessment....................................................................................28
2.3.1
Potential Benefits ...............................................................................................28
2.3.1.1
Durvalumab .......................................................................................................28
2.3.1.2
Durvalumab + Chemotherapy.............................................................................29
2.3.2
Overall Risks .....................................................................................................29
2.3.2.1
Durvalumab .......................................................................................................29
2.3.2.2
Durvalumab + Chemotherapy.............................................................................30
2.3.3
Overall Benefit/Risk...........................................................................................31
3.
OBJECTIVES AND ENDPOINTS ....................................................................32
4.
STUDY DESIGN...............................................................................................33
4.1
Overall Design ...................................................................................................33
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................34
4.2
Scientific Rationale for Study Design.................................................................35
4.3
Justification for Dose .........................................................................................35
4.3.1
Durvalumab Dose and Treatment Regimen Justification.....................................35
4.3.1.1
Durvalumab Monotherapy Dose Rationale .........................................................35
4.3.1.2
Rationale for Fixed Dosing.................................................................................36
4.3.2
Rationale for Durvalumab + EP Dosing Regimen...............................................37
4.4
End of Study Definition .....................................................................................37
5.
STUDY POPULATION.....................................................................................38
5.1
Inclusion Criteria................................................................................................38
5.2
Exclusion Criteria ..............................................................................................40






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8.9
.........................................81
9.
STATISTICAL CONSIDERATIONS................................................................81
9.1
Statistical Considerations ...................................................................................81
9.2
Sample Size Determination ................................................................................81
9.3
Definitions of Analysis Sets ...............................................................................82
9.3.1
Safety Analysis Set ............................................................................................82
9.4
Outcome Measures for Analyses ........................................................................82
9.5
Statistical Analyses ............................................................................................84
9.5.1
Analysis of the Primary Variable........................................................................84
9.5.2
Analysis of the Secondary Variables ..................................................................85
9.5.2.1
Safety Variables.................................................................................................85
9.5.2.2
Efficacy Variables..............................................................................................86
9.5.2.3
................................................................................86
9.5.2.4
Baseline Demographics and Characteristics........................................................86
9.5.2.5
.......................................................................86
9.5.2.6
Subgroup Analysis .............................................................................................86
9.6
Interim Analysis.................................................................................................86
9.6.1
Steering Committee............................................................................................87
9.7
Data Management by AstraZeneca or Delegate ..................................................87
10.
REFERENCES ..................................................................................................87
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .........................................................................................93
LIST OF TABLES
Table 1
Schedule of assessments and screening for durvalumab + EP treatment............ 13
Table 2
Schedule of assessments for patients who have discontinued treatment with 
durvalumab therapy......................................................................................... 17
Table 3
Study objectives............................................................................................... 32
Table 4
Highly effective methods of contraception (< 1% failure rate).......................... 45
Table 5
Study treatments............................................................................................... 46
Table 6
Dose and treatment regimen during chemotherapy ........................................... 49
Table 7
Dose and treatment regimens post chemotherapy ............................................. 49
Table 8
Dosing schedule............................................................................................... 50
Table 9
Clinical chemistry ............................................................................................ 62
Table 10 Hematology...................................................................................................... 63
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Table 11 Urinalysis......................................................................................................... 63
Table 12 Precision around varying incidence of AE........................................................ 82
Table 13 Summary of imaging modalities for tumor assessment ................................... 116
Table 14 RECIST 1.1 evaluation of target lesions......................................................... 124
Table 15 RECIST 1.1 evaluation of non-target lesions.................................................. 125
Table 16 RECIST 1.1 overall visit response.................................................................. 125
Table 17 Restricted Medications/Therapies................................................................... 134
Table 18 Prohibited Medications/Therapies .................................................................. 134
Table 19 Supportive Medications/Therapies ................................................................. 135
LIST OF FIGURES
Figure 1 Study design: A Phase IIIb, single-arm, multi-center, international study of 
Durvalumab in combination with platinum and etoposide for the first line 
treatment of patients with extensive-stage small cell lung cancer ..................... 24
LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations............................ 94
Appendix B
Adverse Event Definitions and Additional Safety Information ................... 99
Appendix C
.................................................. 104
Appendix D
....................................................... 107
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law................................................................................. 110
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).......................... 116
Appendix G
....................................................................... 128
Appendix H
Concomitant Medications ........................................................................ 134
Appendix I
Changes Related to Mitigation of Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis, including COVID 19 
Outbreak........................................................................................................ 137
Appendix J
Abbreviations............................................................................................ 141
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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The procedures for the screening and treatment periods in this study are presented in Table 1 and 
the procedures for the follow-up period are presented in Table 2.
Whenever vital signs and blood draws are scheduled for the same nominal time, the assessments 
should occur in the following order: vital signs and then blood draws. The timing of the vital 
signs assessments should be such that it allows the blood draw to occur at the timepoints 
indicated in the schedules of activities (SoAs). Whenever electrocardiograms (ECGs), vital signs, 
and blood draws are scheduled for the same nominal time, the assessments should occur in the 
following order: ECG, vital signs, and then blood draws. The timing of the first 2 assessments 
should be such that it allows the blood draw to occur at the timepoints indicated in the SoAs.
For Durvalumab
!
Patients may delay dosing under certain circumstances. 
∀
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related adverse event (AE). 
In the event that durvalumab is discontinued or delayed as part of the toxicity 
management guidance, EP (platinum [cisplatin or carboplatin] plus etoposide) 
should still be administered as scheduled.
∀
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.
∀
Dosing intervals of subsequent cycles may be shortened as clinically feasible in 
order to gradually align treatment cycles with the schedule of tumor efficacy 
(Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]). It is 
recommended that subsequent time between 2 consecutive doses should not be 
less than 21 days, based on the half-life of durvalumab (see current Investigator 
Brochure [IB] for durvalumab).
For Chemotherapy (Platinum [Cisplatin or Carboplatin] plus Etoposide [EP])
!
Patients may delay and subsequently resume dosing per local standard clinical 
practice.
∀
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible. 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.












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d
Patients may be contacted in the week following data cutoffs to confirm survival status. Details of any 
treatment for ES-SCLC (including surgery) post the last dose of IMP must be recorded in the eCRF.
e
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.
f
 
g
See Section 6.1.3, Section 8.1, for additional details relevant to image acquisition, RECIST 1.1 assessments, 
and evaluation of scans after RECIST 1.1-defined progression. CT/MRI at baseline should consider brain scan 
due to very common involvement of central nervous system; further CT/MRI evaluations should be according 
to the schedule and brain scan when clinically indicated. Additional radiological procedures such as PET/CT, 
bone scintigraphy and other X-rays (should be applied for non-RECIST assessments) when clinically indicated 
(not mandatory).
AE: adverse event; CT: computed tomography; 
; ECOG: Eastern Cooperative 
Oncology Group; eCRF: electronic case report form; 
 
 
 
; ES-SCLC: extensive-stage small cell lung cancer; IMP: investigational medicinal product; 
MRI: magnetic resonance imaging; PD: progression of disease; 
; 
RECIST: Response Evaluation Criteria in Solid Tumours version 1.1; SAE: serious adverse event; 
T3: Triiodothyronine; T4: thyroxine; TSH: thyroid-stimulating hormone; WHO: World Health Organisation.
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1.2
Synopsis
Protocol Title: 
A Phase IIIb, single-arm, multi-center, international study of durvalumab in combination with 
platinum and etoposide for the first line treatment of patients with extensive-stage small cell lung 
cancer (LUMINANCE)
Rationale:
Extensive-stage small cell lung cancer (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 
(Horn et al 2018, Paz-Ares et al 2019). 
The Phase III, randomized open-label CASPIAN trial demonstrated a statistically significant and 
clinically meaningful improvement in overall survival with the addition of durvalumab to 
platinum (cisplatin or carboplatin) plus etoposide (EP) compared to EP alone as a first line 
treatment for patients with ES-SCLC. Consistent results were also observed for progression-free 
survival (PFS) and objective response rates, which also favored durvalumab + EP compared to 
EP alone (Paz-Ares et al 2019). These clinical benefits were observed in the context of a 
clinically relevant control arm that permitted the flexibility in platinum choice (carboplatin or 
cisplatin), up to 6 cycles of EP (consistent with routine clinical practice and compared with a 
maximum of 4 cycles in the durvalumab + EP arm) and the use of prophylactic cranial irradiation 
(PCI) at the investigator’s discretion.
ES-SCLC patients often have rapidly progressive disease and a significant proportion of patients 
will have poor prognosis (Eastern Cooperation Oncology Group [ECOG] PS2 or higher) at 
diagnosis (Foster et al 2009). As is common with registrational Phase III studies, CASPIAN 
limited recruitment to those patients with good performance status (ECOG 0 or 1) and therefore 
little is currently known regarding the safety and efficacy of durvalumab + EP in patients with 
ECOG PS2. There also remains an unmet need for additional safety and efficacy data to help 
support and inform treatment decisions on the use of durvalumab + EP for unselected patients in 
real clinical practice, including in combination with up to 6 cycles of chemotherapy and/or the 
use of PCI.
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab + EP treatment
Incidence of Grade ≥3 AE 
Incidence of imAEs


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Objectives and Endpoints
Secondary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + EP 
treatment 
PFS, ORR, DoR, DoR12, and PFS12 using site 
Investigator assessments according to RECIST 1.1
OS and OS12
To further assess the safety and tolerability profile 
of durvalumab + EP, including all AEs
Incidence of AEs, SAEs, AESIs, AE resulting in 
treatment discontinuation, and laboratory findings 
including clinical chemistry, hematology and 
urinalysis
Exploratory objective:
Endpoint/variable:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Toxicities will be classified as per NCI CTCAE grading system version 5.0. Analysis of ORR and DoR will 
be based upon Investigator assessment according to RECIST 1.1. Prior irradiated lesions may be considered 
measurable and selected as TLs providing they fulfil the other criteria for measurability. 
Note: An AESI is an AE of scientific and medical interest specific to understanding of the IMP. 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.
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AE: adverse event; AESI: adverse event of special interest; DoR: duration of response; DOR12: proportion of 
patients remaining in response 12 months from the time of first documented objective response; CTCAE: Common 
Terminology Criteria for Adverse Events; 
 
 
 
; EP: platinum (cisplatin or carboplatin) plus etoposide; 
 
; imAE: immune-mediated adverse event; 
IMP: investigational medicinal product; NCI: National Cancer Institute; ORR: objective response rate; OS: overall 
survival; OS12: proportion of patients alive at 12 months from first date of treatment; 
 
 1; PFS: progression-free survival; PFS12: proportion of patients alive and progression-free at 
12 months from first date of treatment; 
; RECIST 1.1: Response Evaluation Criteria in Solid 
Tumors version 1.1; SAE: serious adverse event; 
.
Overall Design:
This will be an open-label, single-arm, multi-center, international, Phase IIIb study to determine 
the safety and tolerability profile of durvalumab with platinum (cisplatin or carboplatin) plus 
etoposide (EP) as first-line treatment in patients with extensive-stage small-cell lung cancer. The 
study will be conducted in North America, Europe and Turkey.
Study Period:
Estimated date of first patient enrolled Q3 2021
Estimated date of last patient completed Q4 2023
Number of Patients:
Approximately 150 adult patients with ES-SCLC eligible for first line treatment with 
platinum-based chemotherapy will be enrolled for treatment.
Treatments and Treatment Duration:
All patients will receive durvalumab 1500 mg administered via intravenous (IV) infusion 
concurrently with platinum-based chemotherapy (Investigator’s choice of cisplatin or 
carboplatin) and etoposide q3w starting on Week 0 for up to 4 to 6 cycles. Durvalumab 
monotherapy will be continued q4w post-chemotherapy until confirmed radiological disease 
progression.
!
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.
!
EP: the dose of cisplatin or carboplatin plus etoposide investigated will not exceed the 
product label dose for the given indication dose (cisplatin [75 to 80 mg/m2] via IV 
infusion or carboplatin [area under the curve (AUC) 5-6 (For PS2 patients a dose of 
AUC 4 is allowed)] via IV infusion with etoposide [80 to 100 mg/m2] via IV infusion).
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!
Prophylactic cranial irradiation may be delivered per investigator discretion and local 
practice.
Duration of Treatment
Unless specific treatment discontinuation criteria are met, patients enrolled will continue 
durvalumab therapy until confirmed radiological disease progression, unless there is clinical 
progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is 
met, as per investigator assessment.
EP will be administered for up to 4 to 6 cycles for patients per investigator clinical decision.
Progression During Treatment
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined 
progression of disease (PD) may continue to receive treatment at the discretion of the 
Investigator and patient, after re-consenting for treatment through progression. A follow-up scan 
is to be collected after the initial RECIST 1.1-defined PD, preferably at the next (and no later 
than the next) scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD 
and this scan is evaluated using the Confirmation of Radiological Progression criteria are 
outlined in Appendix F. Patients with confirmed PD who continue to receive study treatment at 
the discretion of the Investigator and patient (following consultation with AstraZeneca) can 
receive treatment until no longer having clinical benefit, and tumor assessments should continue 
on their regular imaging schedule for the duration of treatment. If the subsequent scan does not 
confirm the immediate prior radiological PD, scanning should continue until the next RECIST 
1.1-defined PD which in turn will require a subsequent scan evaluated using the Confirmation of 
Radiological Progression criteria outlined in Appendix F. 
However, patients will not be permitted to continue immunotherapy if progression occurs after 
confirmed response (complete response [CR] or partial response [PR] as defined by RECIST 1.1) 
to immunotherapy treatment in the target lesions (TLs) (regardless of the appearance of new
lesions) (ie, the response and progression events both occurred in the TLs while receiving 
immunotherapy during the same treatment period).
Follow up of Patients Post Discontinuation of Study Drug
Patients who have discontinued study treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed up 
for AEs 
 for 90 days after last dose of investigational medicinal 
product (IMP), and thereafter followed up with tumor assessments until RECIST 1.1-defined 
radiological PD plus an additional follow-up scan or until death (whichever comes first).
Survival
All patients in the study should be followed up for survival at months 2, 3, 4, 6, 8, 10, and 
12 months following last dose of IMP, and then every 12 weeks until death, withdrawal of 
consent, or the end of the study.
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Steering Committee
If required, a Steering Committee (SC) will be assembled by AstraZeneca for the executive 
oversight and supervision of the study. The SC will consist of oncology experts and a statistician 
who serve their role through regular scheduled meetings or teleconferences and, if necessary, 
additional ad hoc meetings. Details of the SC remit, procedures, processes, and meeting 
frequency will be outlined in an SC Charter.
Statistical Methods
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 immune-mediated AE (imAE). A 
secondary objective of this study is to further assess the safety and tolerability of durvalumab + 
EP, in terms of all AEs, serious adverse events (SAEs), adverse events of special interest 
(AESIs) and AEs leading to treatment discontinuation. 
The primary analysis, for safety, will be conducted approximately 6 months after the last patient 
is enrolled into the study and the final statistical analysis will be conducted after the last patient 
has had the opportunity to be followed up for a minimum of 12 months or 60% overall survival 
(OS) maturity, whichever occurs first.
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. The exact 95% confidence intervals (CIs) around the incidence estimates of 
Grade ≥3 AEs and imAEs will be reported. 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 efficacy of first-line durvalumab + EP will be assessed as secondary objectives, in terms of 
OS, PFS, objective response rate (ORR), duration of response (DoR), proportion of patients alive 
at 12 months from first date of treatment (OS12), proportion of patients alive and progression-
free at 12 months from first date of treatment (PFS12) and proportion of patients remaining in 
response 12 months from the time of first documented objective response (DoR12). 
Time-to-event data will be summarized using Kaplan-Meier estimates of the median event time 
and quartiles together with their 95% CIs. ORR (based on Investigator assessment) will be 
summarized descriptively, and the exact 95% CIs will be reported. Data will be reported for 
patients overall and separately for patients based on performance status (0 to 1 and 2).
This is a safety study and no formal sample size calculation will be done. However, a total of 
approximately 150 patients will be treated with durvalumab plus platinum (cisplatin or 
carboplatin) plus etoposide. A maximum of 30% of all patients treated will have ECOG 
performance status of 2 at baseline (Cycle 1 Day 1). If the true incidence of Grade ≥3 AEs and 
imAEs in the overall population is approximately 70% and 20% respectively (rates observed in 
the CASPIAN Study were 65% and 20%, respectively), the sample size of 150 patients will 
provide a precision of ±7.6% with an exact binomial 95% CI of 62.0-77.2 for Grade ≥3 AEs, 
and a precision of ± 6.7% with an exact binomial 95% CI of 13.9, 27.3 for imAE. 


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There will be no formal interim analysis in this study.
1.3
Schema
The general study design is summarized in Figure 1.
Figure 1
Study design: A Phase IIIb, single-arm, multi-center, international study 
of Durvalumab in combination with platinum and etoposide for the first 
line treatment of patients with extensive-stage small cell lung cancer
Durvalumab 1500 mg, cisplatin (75-80 mg/m2) or carboplatin (AUC5-6 [For PS2 patients a dose of AUC 4 is 
allowed]), etoposide (80-100 mg/m2).
AE: adverse event; AUC: area under the curve; DoR: duration of response; DoR12: proportion of patients remaining 
in response 12 months from the time of first documented objective response; ES-SCLC: extensive-stage small-cell 
lung cancer; EP: platinum (cisplatin or carboplatin) plus etoposide; imAE: immune-mediated adverse event; OS: 
overall survival; OS12: proportion of patients alive at 12 months from first date of treatment; PFS: progression-free 
survival; PFS12: proportion of patients alive and progression-free at 12 months from first date of treatment; 
PD: Progression of disease; qXw: Every X weeks; PS: performance status; WHO: World Health Organization.


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2.
INTRODUCTION
Lung cancer has been the most common cancer in the world for several decades, with an
estimated 2.1 million new cases in 2018, representing 11.6% of all new cancers. It was also the
most common cause of death from cancer, with 1.76 million deaths (18.4% of the total)
(GLOBOCAN 2018).
Small cell lung cancer (SCLC) represents approximately 13-17% of all newly diagnosed lung
cancers (Oronsky et al 2017, Wang et al 2017). 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 development of widespread metastases. It is strongly associated 
with tobacco smoking and is also associated with an extremely high mutation rate
(Peifer et al 2012, Alexandrov et al 2013, Byers and Rudin 2015).
A 2-stage system dividing patients into limited and extensive-stage 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) disease was defined as any tumor that extended beyond the boundaries of a 
single radiation port. At present, limited stage (LS) disease is identified in ~30% of patients, and 
ES is identified in ~70% of patients.
For more than three decades, the standard first-line therapy for ES-SCLC consisted of four to six 
cycles of etoposide in combination with either cisplatin or carboplatin, without maintenance
therapy (Pietanza et al 2015, Früh et al 2013, Rudin et al 2015, Japan Lung Cancer Society, 
2018). Despite high initial response rates of approximately 78% (Rossi et al 2012, Fukuoka et al 
1991), it is estimated that 80% of patients with LS and almost all patients with ES-SCLC will 
relapse or experience disease progression (Clark and Ihde 1998). Therefore, the prognosis for 
patients with 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).
There are no large Phase III studies comparing cisplatin plus etoposide and carboplatin plus
etoposide. A large meta-analysis of 4 studies (including > 600 LS and ES patients), performed by 
Rossi and colleagues (Rossi et al 2012), showed similar efficacy between carboplatin- and 
cisplatin-containing regimens; median OS was 9.6 months for cisplatin and 9.4 months for 
carboplatin (hazard ratio [HR],1.08; 95% confidence interval [CI], 0.92 to 1.27; p = 0.37). ORR
was 67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to 1.16; p = 0.83).
Although the clinical efficacy between cisplatin and carboplatin may be indistinguishable, they
differ in terms of cost and toxicity profiles.
Several large Phase III studies using EP as the comparator in this setting have consistently 
reported the median PFS between 4 to 6 months and median OS between 7 to 11 months 
(Slotman et al 2015). Recently published data with EP as the control arm in randomized Phase 
III studies is consistent with earlier trials, with median PFS of 4.3 to 4.4 months and median OS 
of 10.3 to 10.9 months (Reck et al. 2016; Horn et al 2018, Paz-Ares et al 2019) as first line 
treatment of ES-SCLC.


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Recently, immunotherapy targeting the PD-1 and PD-L1 pathway has demonstrated clinical 
activity for patients with ES-SCLC, including as first-line treatment 
(Horn et al 2018, Paz-Ares et al 2019).
2.1
Study Rationale
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 PD-1 and PD-L1 pathway has demonstrated 
clinical activity for patients with ES-SCLC, including as first-line treatment. 
ES-SCLC patients often have rapidly progressive disease and a significant proportion of patients 
will have poor prognosis (ECOG PS2 or higher) at diagnosis (Foster et al 2009). As is common 
with registrational Phase III studies, CASPIAN limited recruitment to those patients with good 
performance status (ECOG 0 or 1) and therefore little is currently known regarding the safety 
and efficacy of durvalumab + EP in patients with ECOG PS2. There also remains an unmet need 
for additional safety and efficacy data to help support and inform treatment decisions on the use 
of durvalumab + EP for unselected patients in real clinical practice, including in combination 
with up to 6 cycles of chemotherapy and/or the use of PCI.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the IB.
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004). 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T cell 
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells (Keir et al 
2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (Okazaki 
and Honjo 2007). PD-1 and PD-L1/PD-L2 belong to a family of immune checkpoint proteins 
that act as co-inhibitory factors, which can halt or limit the development of T-cell response. 
When PD-L1 binds to 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.


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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 (MOA) is 
different from direct agonism of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of pre-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the 
PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Iwai et al 
2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) with responses that tend to be 
more pronounced in patients with tumors that express PD-L1 (Powles et al 2014, Rizvi et al 
2015, Segal et al 2015). In addition high mutational burden (eg, in bladder carcinoma; 
Alexandrov et al 2013) may contribute to the responses seen with immune therapy.
Pre-clinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as cytotoxic T lymphocyte associated antigen 4
(CTLA-4) and PD-L1 has promising clinical activity. Ipilimumab was first granted US Food and 
Drug Administration (FDA) approval for the treatment of metastatic melanoma and is currently 
under investigation for several other malignancies. Nivolumab and pembrolizumab, 2 anti-PD-1 
agents, and atezolizumab, an anti-PD-L1 agent, have been granted approvals by agencies for the 
treatment of a number of malignancies including metastatic melanoma, squamous and non-
squamous cell NSCLC, squamous cell carcinoma of the head and neck, and urothelial carcinoma. 
In addition there are data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a 
wide range of tumor types.
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand-2 [PD-L2]) with PD-1 on T cells 
and CD80 (B7.1) on immune cells. It is being developed by AstraZeneca/MedImmune for use in 
the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The 
proposed MOA for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 
(B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of 
immune responses, including those that may result in tumor elimination. In vitro studies 
demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T 
cells resulting in the restored proliferation of interferon-γ (Stewart et al 2015). In vivo studies 
have shown that durvalumab inhibits tumor growth in xenograft models via a T cell dependent 
mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.


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To date, durvalumab has been given to more than 8000 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 4.3.1.1. Refer to the current durvalumab IB 
for a complete summary of pre-clinical and clinical information including safety, efficacy, and 
pharmacokinetics (PK). 
2.2.3
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.
Recently, several Phase III trials have been conducted to evaluate the combination of 
immunotherapy and chemotherapy in the treatment of ES-SCLC (NCT02763579, 
NCT03043872, NCT03066778). IMpower133 was a randomized, placebo-controlled Phase III 
trial that compared atezolizumab + etoposide/carboplatin (EC) with placebo + EC in the first line 
treatment of ES-SCLC (Horn et al 2018). The study demonstrated a statistically significant 
improvement in OS with the combination of atezolizumab + EC compared to placebo + EC 
(Horn et al 2018). CASPIAN was a randomized, open-label, Phase III trial that compared 
durvalumab, with or without tremelimumab, in combination with EP versus EP alone in 
treatment naïve patients with ES-SCLC. The CASPIAN trial demonstrated a statistically 
significant improvement in OS for durvalumab + EP compared to EP alone in first line treatment 
of ES-SCLC (Paz-Ares et al 2019). Finally, KN604 was a randomized, placebo-controlled Phase 
III trial that compared pembrolizumab plus EP with placebo plus EP; while a numerical 
improvement in OS was observed, this did not reach statistical significance (Rudin et al 2020).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of durvalumab may be found in the IB.
2.3.1
Potential Benefits
2.3.1.1
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 CD-ON-MEDI4736-1108; hereafter 
referred to as Study 1108) in patients with advanced solid tumors, the study of durvalumab 
monotherapy in NSCLC (ATLANTIC Study [NCT02087432]), the study of durvalumab 
monotherapy in NSCLC following completion of platinum-based chemotherapy concurrent with 
radiation therapy (PACIFIC Study [NCT02125461]), and the study of durvalumab with or 
without tremelimumab as first line treatment for patients with advanced or metastatic NSCLC 


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(MySTIC Study [NCT02453282]). Details pertaining to these studies are provided in the current 
durvalumab IB.
2.3.1.2
Durvalumab + Chemotherapy
Studies evaluating agents targeting PD-L1 in combination with chemotherapy have yielded 
encouraging results.
The Phase III CASPIAN study demonstrated a statistically significant improvement in OS for 
durvalumab + EP compared to EP alone as first-line treatment for ES-SCLC at a pre-planned 
interim analysis with a HR of 0.73 (95% CI 0.59–0.91; p = 0.0047) (Paz-Ares et al 2019). 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 subgroups. The secondary 
endpoint of 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 ORR compared to 
EP; 67.9% vs. 57.6%, respectively. The treatment effects of durvalumab + EP were sustained 
overtime 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.
2.3.2
Overall Risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against 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 
normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ system, 
and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypo- and hyper-thyroidism.
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/dermatitis (including pemphigoid),
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, 
pancreatitis, immune thrombocytopenia, serious infections, and other rare or less frequent 


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inflammatory events including neuromuscular toxicities (eg, Guillain-Barre syndrome, 
myasthenia gravis). 
In monotherapy clinical studies, AEs at an incidence of > 20% include events such as fatigue and 
decreased appetite. Approximately 10% of patients discontinued the drug due to an AE. Please 
see the current version of the IB for a detailed summary of the monotherapy data including AEs, 
SAEs, and CTCAE Grade 3 to 5 events reported across the durvalumab program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.4).
Information on all identified and potential risks with durvalumab and a detailed summary of 
durvalumab monotherapy AE data can be found in the current version of the durvalumab IB and 
the Dosing Modification and Toxicity Management Guidelines for Durvalumab Monotherapy or 
in Combination with Other Products.
2.3.2.2
Durvalumab + Chemotherapy
The safety and tolerability of the combination of durvalumab plus chemotherapy was evaluated 
in two early 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 well tolerated with a 
manageable safety profile 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 (Paz-Ares et al 
2019). In summary, regardless of causality, rates of AE of any grade (98.1% vs 97.0%), grade 3 
or 4 AE (61.5% vs 62.4%), serious AEs (30.9% vs 36.1%), and those leading to discontinuation 
(9.4% vs 9.4%) were similar between durvalumab + EP vs EP alone. Adverse events of any 
cause leading to death occurred in 13 (5%) and 15 (6%) patients.
Immune-mediated AEs, defined as an event that is associated with drug exposure and consistent 
with an immune-mediated MOA, where there is no clear alternate aetiology and the event 
required treatment with systemic corticosteroids or other immunosuppressants and/or, for 
specific endocrine events, endocrine therapy, were reported by 19.6% of patients treated with 
durvalumab + EP compared to 2.6% of patients treated with EP alone. The majority of immune-
mediated AEs were low grade and thyroid related. 
External clinical data also supports these findings. In the randomized Phase III study 
IMpower133 demonstrated that the safety profile of atezolizumab combined with etoposide plus 
carboplatin was consistent with the previously reported safety profile of the individual agents, 
with no new findings observed.


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2.3.3
Overall Benefit/Risk
There remains a significant unmet medical need for additional treatment options for patients with 
ES-SCLC. Four to 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 PD-1 and PD-L1 pathway have 
demonstrated clinical activity across multiple lines of therapy for patients with ES-SCLC.
Durvalumab + EP demonstrated a statistically significant and clinically meaningful improvement 
in OS versus EP alone in the Phase III CASPIAN trial, reducing the risk of death by 27% for this 
challenging-to-treat disease. Consistent with the results for OS, PFS and ORR were also 
improved for durvalumab plus EP compared to EP alone. 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. The OS benefit was durable for durvalumab + EP compared with EP, as evidenced by 
the tail of the Kaplan-Meier curve; in the durvalumab + 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. 
These gains in long term clinical benefit are meaningful to patients with this recalcitrant disease.
Durvalumab + EP was associated with a well-tolerated and manageable safety profile, consistent 
with the established safety profiles of each of the drugs to date. Regardless of causality, the rates 
of AEs of any grade, AEs of grade 3 or 4, SAEs, and AEs leading to discontinuation were similar 
between the arms. Collectively, these data suggest that the addition of durvalumab to EP did not 
increase the overall treatment burden of patients with ES-SCLC over EP alone.
Taken together, the overall benefit/risk assessment supports the proposed study to further 
evaluate the safety and efficacy of durvalumab + EP as a first line treatment for ES-SCLC.


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3.
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints/variables are listed in Table 3.
Table 3
Study objectives
Primary Objective:
Endpoint/Variable:
To assess the safety and tolerability profile of 
durvalumab + EP treatment
Incidence of Grade ≥3 AE
Incidence of imAEs
Secondary Objective:
Endpoint/Variable:
To assess the efficacy of durvalumab + EP 
treatment 
PFS, ORR, DoR, DoR12, and PFS12 using site 
Investigator assessments according to RECIST 1.1
OS and OS12
To further assess the safety and tolerability profile 
of durvalumab + EP, including all AEs
Incidence of AEs, SAEs, AESIs, AE resulting in 
treatment discontinuation, and laboratory findings 
including clinical chemistry, hematology and 
urinalysis
Exploratory Objective:
Endpoint/Variable:
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table 3
Study objectives
 
 
 
 
 
 
 
 
 
Note: Toxicities will be classified as per NCI CTCAE grading system version 5.0. Analysis of ORR and DoR will 
be based upon Investigator assessment according to RECIST 1.1. Prior irradiated lesions may be considered 
measurable and selected as TLs providing they fulfill the other criteria for measurability. 
Note: An AESI is an AE of scientific and medical interest specific to understanding of the IMP. 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.
AE: adverse event; AESI: adverse event of special interest; DoR: duration of response; DoR12: proportion of 
patients remaining in response 12 months from the time of first documented objective response; CTCAE: Common 
Terminology Criteria for Adverse Events; 
 
 
 
; EP: platinum (cisplatin or carboplatin) plus etoposide; 
 
 imAE: immune-mediated adverse events; 
IMP: investigational product; NCI: National Cancer Institute; ORR: objective response rate; OS: overall survival; 
OS12: proportion of patients alive at 12 months from first date of treatment; 
 
; PFS: progression-free survival; PFS12: proportion of patients alive and progression-free at 12 months from date 
of first treatment; 
; RECIST 1.1: Response Evaluation Criteria in Solid Tumors version 1.1; 
SAE: serious adverse event; 
.
4.
STUDY DESIGN
4.1
Overall Design
This is a Phase IIIb, open-label, single-arm, multi-center, international study to evaluate the 
safety and tolerability profile of durvalumab plus platinum (cisplatin or carboplatin) plus 
etoposide (EP) in patients with ES-SCLC. An umet need remains for additional safety and 
efficacy data to help support and inform treatment decisions on the use of durvalumab + EP for 
unselected patients in real clinical practice, including patients with Eastern Cooperative 
Oncology Group (ECOG) PS of 2, in combination with up to 6 cycles of chemotherapy and/or 
the use of PCI. Patients will receive durvalumab plus EP for up to 4-6 cycles (investigators 
choice, q3w) and then durvalumab q4w until PD. 
Approximately 150 patients will be treated with the study drug in North America, Europe and 
Turkey. Patients must have histologically- or cytologically-documented ES-SCLC and be 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CC


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treatment naïve. Patients must be deemed to be eligible for etoposide and platinum-based
chemotherapy per Investigator assessment.
The primary analysis, for safety, will be conducted approximately 6 months after the last patient 
is enrolled into the study and the final statistical analysis will be conducted after the last patient 
has had the opportunity to be followed up for a minimum of 12 months or 60% OS maturity, 
whichever occurs first.
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should be 
implemented only during cases of civil crisis, natural disaster or public health crisis (eg, during 
quarantines and resulting site closures, regional travel restrictions and considerations if site 
personnel or patients become infected with severe acute respiratory syndrome coronavirus 2 
[SARS-CoV-2] or similar pandemic infection), which would prevent the conduct of study-related 
activities at study sites, thereby compromising the study site staff or the patient’s ability to 
conduct the study. The investigator or designee should contact the study sponsor to discuss 
whether the mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of patients, maintain compliance with 
Good Clinical Practice (GCP), and minimise risks to study integrity. Where allowable by local 
health authorities, ethics committees, health care provider guidelines (eg, hospital policies) or 
local government, these changes may include the following options:
!
Obtaining [consent/reconsent] for the mitigation procedures (note, in the case of verbal 
[consent/reconsent], the informed consent form [ICF] should be signed at the patient’s 
next contact with the study site).
!
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated study clinical lead. 
!
Remote visit: Performed by a site qualified health care professional (HCP) or HCP 
provided by a third-party vendor.
!
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix I. 




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shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is 
approximately 21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with PD-L1. A low level of 
immunogenicity has been observed. No patients have experienced immune-complex disease 
following exposure to durvalumab. (For further information on immunogenicity, please see the 
current durvalumab IB). 
A population PK model was developed using the data from Study 1108 (doses = 0.1 to 10 mg/kg 
q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w regimens, as represented 
by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg q4w (~1.5 fold) 
and median Ctrough,ss is expected to be higher with 10 mg/kg q2w (~1.25 fold). Clinical activity 
with the 20 mg/kg q4w dosing regimen is anticipated to be consistent with 10 mg/kg q2w with 
the proposed similar dose of 20 mg/kg q4w expected to (a) achieve complete target saturation in 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and 
clinical activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of 
anti-drug antibody impact; and (d) achieve PK exposure that yielded maximal antitumor activity 
in animal models.
Given the similar area under the serum drug concentration-time curve and modest differences in 
median peak and trough levels at steady state, the observation that both regimens maintain 
complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg q4w and 10 
mg/kg q2w regimens are expected to have similar efficacy and safety profiles, supporting further 
development with a dose of 20 mg/kg q4w. 
Clinical Data
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen.
4.3.1.2
Rationale for Fixed Dosing
A population PK model was developed for durvalumab using monotherapy data Study 1108 
(N = 292; doses = 0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population PK analysis 
indicated only minor impact of body weight (WT) on the PK of durvalumab (coefficient of 
≤0.5). The impact of body WT-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of 
durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, median, 
and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected to 
approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40 to 120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-patient variability with fixed dosing regimen. 
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang et al 
2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that fixed and 
body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang et al 2009). In addition, they investigated 18 therapeutic proteins and peptides and 


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showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in PK/pharmacodynamic parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1500 mg q4w durvalumab (equivalent to 20 mg/kg q4w) is included in the current 
study.
4.3.2
Rationale for Durvalumab + EP Dosing Regimen
The dose and schedule of durvalumab proposed for this trial is consistent with that employed in 
the Phase III CASPIAN trial: a fixed dose of 1500 durvalumab q3w while administered with 
chemotherapy followed by a fixed dose of 1500 mg durvalumab q4w while administered as 
monotherapy maintenance until disease progression (Paz-Ares et al 2019). Likewise, the dose 
and schedule of platinum (cisplatin or carboplatin) and etoposide are consistent with clinical 
practice guidelines (Paz-Ares et al 2019). 
This trial will allow up to a maximum of 6 cycles of durvalumab + EP. While the CASPIAN trial 
allowed a maximum of 4 doses of durvalumab + EP, clinical practice guidelines have 
recommended between 4-6 doses of chemotherapy for treatment of ES-SCLC (National 
Comprehensive Cancer Network 2019, ESMO Clinical Practice Guidelines). In the CASPIAN 
trial, 57% of patients in the control arm received 6 cycles of EP (Paz-Ares et al 2019), reflecting 
the importance of flexibility when determining the actual number of cycles of chemotherapy in 
clinical practice and the need to obtain safety data on the use of up to 6 cycles of durvalumab + 
EP. Therefore, this trial will allow up to 6 cycles of Durvalumab + EP.
4.4
End of Study Definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
In the event that a rollover or safety extension study is available at the time of the final data 
cut-off (DCO) and database closure, patients currently receiving treatment with durvalumab may 
be transitioned to such a study, and the current study would reach its end. The rollover or safety 
extension study would ensure treatment continuation with visit assessments per its protocol. Any 
patient who would be proposed to move to such a study would be given a new Informed 
Consent.


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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient must meet all of the inclusion criteria (Section 5.1) and none of the exclusion 
criteria (Section 5.2) for this study at the screening visits. Under no circumstances will there be 
exceptions to this rule.
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
For procedures for withdrawal of incorrectly enrolled patients see Section 6.2.2.
5.1
Inclusion Criteria
For inclusion in the study, patients should fulfill the following criteria:
Informed Consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
2.
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses. 
3.
Provision of signed and dated written Optional Genetic Research Information 
informed consent prior to collection of sample for optional genetic research that 
supports Genomic Initiative.
The ICF process is described in Appendix A 3.
Age
4.
Age ≥18 years at the time of Screening.
Type of Patient and Disease Characteristics
5.
Histologically- or cytologically-documented ES-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 
anticonvulsants for at least 1 month prior to study treatment.


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6.
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.
7.
WHO/ ECOG Performance Status of 0 to 2 at enrollment.
∀
Note: Patients with PS2 will be limited to a maximum of 30% of the total study 
population; once this limit is met, additional enrolled patients must have PS 0-1.
8.
Baseline computed tomography (CT) / magnetic resonance imaging (MRI) results of 
the brain, chest and abdomen (including liver and adrenal glands) within 28 days prior 
to the treatment initiation. 
9.
No prior exposure to immune-mediated therapy including, but not limited to, other 
anti- CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 (anti-PD-L2) antibodies, 
excluding therapeutic anticancer vaccines.
10.
Adequate organ and marrow function as defined below:
∀
Hemoglobin ≥9.0 g/dL. 
∀
Absolute neutrophil count ≥1.5 × 109/L (use of granulocyte colony-stimulating 
factor is not permitted at screening).
∀
Platelet count ≥100 × 109/L.
∀
Serum bilirubin ≤1.5 × the upper limit of normal (ULN).
∀
In patients without hepatic metastasis: alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) ≤2.5 × ULN.
∀
In patients with hepatic metastases, ALT and AST ≤5 × ULN.
∀
Measured or calculated creatinine clearance: > 60 mL/min for patients planned to 
be treated with etoposide + cisplatin and > 50 mL/min for patients planned to be 
treated with etoposide + carboplatin as determined by Cockcroft-Gault:
Males:
Creatinine CL =
Weight (kg) × (140 −age)
72 × serum creatinine (mg dL
⁄
)
Females:
Creatinine CL =
Weight (kg) × (140 −age)
72 × serum creatinine (mg dL
⁄
) × 0.85


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11.
Life expectancy ≥12 weeks at Day 1.
Weight
12.
Body weight > 30 kg.
Sex
13.
Male and/or female
Reproduction
14.
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).
5.2
Exclusion Criteria
Medical Conditions
1.
History of allogeneic organ transplantation.
2.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:


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∀
Patients with vitiligo or alopecia.
∀
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.
∀
Any chronic skin condition that does not require systemic therapy.
∀
Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician.
∀
Patients with celiac disease controlled by diet alone.
3.
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.
4.
History of another primary malignancy except for:
∀
Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of IMP and of low potential risk for recurrence.
∀
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease.
∀
Adequately treated carcinoma in situ without evidence of disease.
5.
History of leptomeningeal carcinomatosis.
6.
History of active primary immunodeficiency.
7.
Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B virus (HBV) (known positive HBV surface 
antigen [HBsAg] result), hepatitis C virus (HBC), 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 HCV antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.
8.
Any unresolved toxicity CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the 
inclusion criteria:


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∀
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician.
∀
Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the Study 
Physician.
9.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients.
Prior/Concomitant Therapy
10.
Received prior systemic therapy for ES-SCLC.
∀
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 at the time of diagnosis of ES-SCLC. 
11.
Medical contraindication to platinum (cisplatin or carboplatin)-etoposide-based 
chemotherapy.
12.
Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, 
hormone replacement therapy) is acceptable. 
13.
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.
14.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to 
90 days after the last dose of IMP. 
15.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IMP. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
16.
Patients who have received prior immunotherapy agents including anti-PD-1 or anti 
PD-L1 
17.
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab. The following are exceptions to this criterion:
∀
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection).


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∀
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent.
∀
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).
Prior/Concurrent Clinical Study Experience
18.
Participation in another clinical study with an investigational product administered in 
the last 4 weeks.
19.
Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study.
Diagnostic Assessments
Not applicable.
Other Exclusions
20.
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 and 180 days after the last dose 
of etoposide.
21.
Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements.
22.
Any condition that, in the opinion of the treating physician, would interfere with 
evaluation of the study drug or interpretation of patient safety.
For procedures for withdrawal of incorrectly enrolled patients, see Section 6.2.2.
5.3
Lifestyle Restrictions
The following restrictions apply while the patient is receiving IMP and for the specified times 
before and after:
1.
Female patient of childbearing potential.
∀
Female patients of childbearing potential who are not totally sexually abstinent 
(ie, refraining from heterosexual intercourse during the entire period of risk 
associated with study drugs) and intend to be sexually active with a non sterilized 
male partner must use at least 1 highly effective method of contraception 
(Table 4). They should have been stable on their chosen method of birth control 


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for a minimum of 90 days before entering the study and continue to use it
throughout the total duration of the drug treatment and the drug washout period 
(90 days after the last dose of durvalumab and 180 days after the last dose of 
etoposide). Non-sterilized male partners of a female patient of childbearing 
potential must use a male condom plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of contraception. Female patients should refrain from 
breastfeeding throughout this period. 
2.
Male patients with a female partner of childbearing potential.
∀
Non-sterilized male patients (including males sterilised by a method other than 
bilateral orchidectomy, eg, vasectomy) who are not abstinent and intend to be 
sexually active with a female partner of childbearing potential must use a male 
condom plus spermicide (condom alone in countries where spermicides are not 
approved) from the time of screening throughout the total duration of the drug 
treatment and the drug washout period (90 days after the last dose of durvalumab
and 180 days after the last dose of etoposide). Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Male patients should refrain from sperm donation or banking throughout this 
period.
∀
Vasectomised males are considered fertile and should still use a male condom 
plus spermicide as indicated above during the clinical study.
∀
Even if the female partner is pregnant, male patients should still use a condom 
plus spermicide (where approved), as indicated above during the clinical study, if 
there is a concern about damaging the developing foetus from drug in ejaculate.
∀
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 4). 
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post 
menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
∀
Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution.


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∀
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.
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 4. Note that 
some contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; 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 4
Highly effective methods of contraception (< 1% failure rate)
Barrier/intrauterine methods
Hormonal methods
!
Total sexual abstinence (evaluate in 
relation to the duration of the clinical 
study and the preferred and usual lifestyle 
choice of the patient)
!
Vasectomised sexual partner (with patient
assurance that partner received 
post-vasectomy confirmation of 
azoospermia)
!
Tubal occlusion
!
Intrauterine device (provided coils are 
copper banded)
!
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)a
!
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
!
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
!
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)
!
Combined pill: Normal and low dose 
combined oral contraceptive pill
!
Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, Ortho 
Evra®)
!
Mini pill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.
3.
All patients: 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.
During study treatment and for 4 weeks after the last dose of study drug, patients 
should be advised to avoid prolonged exposure to the sun, wear protective clothing 
including a hat, and seek shade from the sun as much as possible; in addition, SP30+ 


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sunscreen should be used. Exposure to other sources of ultraviolet light including sun 
beds and tanning booths, etc, should be avoided.
5.
Restrictions relating to concomitant medications are described in Appendix H 1.
5.4
Screen Failures
Screen failures are patients who do not fulfill the eligibility criteria for the study. These patients 
should have the reason for study withdrawal recorded as “screen failure” (ie, patient does not 
meet the required inclusion/exclusion criteria). This reason for study withdrawal is only valid for 
screen failures. Patients may be rescreened a single time. If a patient who has failed screening is 
rescreened, a new E-code must be assigned. Patients will reconfirm their consent to participate in 
the study by re-signing and dating their original consent form(s), next to their initial signature 
and date.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs and concomitant 
medications used due to the SAEs.
6.
STUDY TREATMENTS
6.1
Treatments Administered
6.1.1
Investigational Products
AstraZeneca will supply durvalumab (MEDI4736), whereas the EP treatments will be supplied 
locally (Table 5). Ancillary supplies required for infusion will also be locally provided (eg, saline 
bags, infusion lines).
Table 5
Study treatments
Treatment 1
Treatment 2
Treatment 3
Treatment 4
Study treatment 
name:
Durvalumab 
(MEDI4736)
Etoposide
Carboplatin
Cisplatin
Dosage 
formulation:
500-mg vial solution 
for infusion after 
dilution, 50 mg/mL
(as sourced 
locally)
(as sourced 
locally)
(as sourced 
locally)
Route of 
administration:
IV
IV
IV
IV
Dosing 
instructions:
Patients will receive 
durvalumab (1500 mg) 
via IV infusion over 
60 minutes on Day 1 of 
each cycle.


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Table 5
Study treatments
Treatment 1
Treatment 2
Treatment 3
Treatment 4
Packaging and 
labelling:
Study treatment will be 
provided in vials and 
cartons (3 × vials per 
carton)
Each vial and carton 
will be labelled in 
accordance with GMP 
Annex 13 and per 
country regulatory 
requirement a
Sourced locally 
by site
Sourced locally 
by site
Sourced locally 
by site
Provider:
AstraZeneca
Sourced locally 
by site
Sourced locally 
by site
Sourced locally 
by site
a
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or “durvalumab 
(MEDI4736)” depending upon the agreed product name used in the approved study master label document. All 
naming conventions are correct during this transitional period.
GMP: Good Manufacturing Practice; IV: intravenous.
6.1.1.1
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The 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 original packaging until use to prevent prolonged 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 IMP manager using aseptic technique. Total time from needle puncture of 
the durvalumab (MEDI4736) vial to the start of administration should not exceed: 
!
24 hours at 2°C to 8°C (36°F to 46°F)
!
4 hours at room temperature
A dose of 1500 mg (for patients > 30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of durvalumab 
[MEDI4736]) to the IV bag. The IV bag size should be selected such that the final concentration 


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is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in 
the bag.
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm filter.
Standard infusion time is one hour ± 10 minutes, however if there are interruptions during the 
infusion, the total allowed infusion time should not exceed 8 hours at room temperature with the 
infusion bag maintained at room temperature, otherwise a new dose must be prepared from new 
vials. 
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.
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any unused 
portion must be discarded.
6.1.1.2
Platinum (Cisplatin or Carboplatin) plus Etoposide
EP will be locally sourced and will be administered according to prescribing information or 
treatment guidance in general use by the Investigating site, including the sequence of drug 
administration.
6.1.1.3
Order of Administration
Patients will receive durvalumab (1500 mg) via IV infusion over 60 minutes.
A 60-minute observation period is recommended after durvalumab is administered at least for 
cycle 1.
If no issues are seen after durvalumab is given during the first cycle, it is recommended to reduce
the observation period after durvalumab administration to 30 minutes for subsequent cycles.
This will then be followed by carboplatin or cisplatin as an IV infusion, followed by etoposide 
sequentially administered by an IV infusion on Day 1 of each combination cycle; etoposide will 
also be administered on days 2, and 3 of each cycle, up until a maximum of 6 cycles has been 
reached. Duration of infusions for chemotherapy agents will be per local practice.
6.1.2
Dose and Treatment Regimens
Dose and treatment regimens during and post chemotherapy are described in Table 6 and 
Table 7, respectively. The dosing schedule is provided in Table 8.


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Table 6
Dose and treatment regimen during chemotherapy
Agent
Dose
Route
Duration
Schedule
Durvalumab
(MEDI4736)
1500 mg
IV
60 min
Up to 4 to 6 doses
with EP q3w
EP
Cisplatin (75-80 mg/m2) or 
carboplatin (AUC 5-6 [For 
PS2 patients a dose of AUC 
4 is allowed]) on Day 1 with
etoposide (80-100 mg/m2)
daily on Days 1, 2 and 3
IV
Per local
practice
Up to 4 to 6 
cycles q3w a
a
The schedule of durvalumab will be q3w while on etoposide.
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 1500 mg.
AUC: area under the curve; EP: platinum (cisplatin or carboplatin) plus etoposide; IV: intravenous; PS: performance 
status; q3w: every 3 weeks.
Table 7
Dose and treatment regimens post chemotherapy
Agent
Dose
Route
Duration
Schedule
Durvalumab
(MEDI4736)
1500 mg
IV
60 min
q4w to PD a
a
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 1500 mg.
IV: intravenous; PD: progression of disease; q4w: every 4 weeks.


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Table 8
Dosing schedule
6.1.3
Duration of Treatment and Criteria for Treatment through Progression and for 
Retreatment
Treatment with Durvalumab will be administered beginning on Day 1 until clinical progression 
or RECIST 1.1-defined radiological progression (refer to Appendix F) 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; this follow-up 
scan is evaluated using the post-progression evaluation criteria outlined in Appendix F. 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, or spinal cord compression) will not be eligible for continuing durvalumab. 
For all patients who are treated through progression, the Investigator should ensure that: 
!
The patient does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient. The patient must not 
have experienced a toxicity that required permanent discontinuation of study 
treatment. 


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!
There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG PS to > 2. 
!
There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, central nervous system metastasis, respiratory failure due to 
tumor compression, or spinal cord compression) requiring urgent alternative medical 
intervention. 
!
The patient still fulfills the eligibility criteria for this study (see Sections 5.1 and 5.2) 
with the exception of inclusion criteria 9.
Patients who AstraZeneca and the Investigator determine may not continue treatment after 
RECIST 1.1-defined PD will be followed up for survival. Patients who have discontinued 
treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent 
anticancer therapy, will be followed up with tumor assessments until RECIST 1.1-defined PD 
plus an additional follow-up scan or until death (whichever comes first) and followed for 
survival.
Post Final Data Cut-off
At the time of the final DCO, the analysis portion of the clinical study will have been completed
and all patients remaining in the study will be considered to have completed the analysis portion 
of the study. At the time of final DCO, the clinical study database will be closed to new data.
Patients in OS follow-up (progressed and have discontinued treatment) will be considered to 
have completed the study.
All patients will receive efficacy scans and follow-up care in accordance with standard local 
clinical practice. Data should be recorded on patient charts but will not otherwise be reported for 
the purposes of this study.
For patients who are continuing to receive treatment with durvalumab following the final DCO 
and database closure, it is recommended that the patients continue the scheduled site visits and 
Investigators monitor the patients’ safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab Dosing 
Modification and Toxicity Management Guidelines (See Annex to the Protocol).
Following the DCO, SAE reporting applies only to patients who are active on IMP and within 
90 days after the last dose; in all other cases, only a Statement of Death notification is to be sent 
to AstraZeneca. 
Investigators will report SAEs to AstraZeneca Patient Safety via paper case report forms (CRFs) 
until 90 days after the last dose of study drug, in accordance with Section 8.4.1. Any SAE or 
non-serious AE ongoing at the time of the DCO is to be followed up at the discretion of the 
Investigator and per local practice and in alignment with the Dosing Modification and Toxicity 
Management Guidelines (See Annex to the Protocol), unless the event is considered by the 


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Investigator to be unlikely to resolve, or the patient is lost to follow-up. Data will not be captured 
for the purposes of this study outside of being recorded in the patients’ source documents.
Different drug supply options will be available depending on the country, and these will be 
proposed to the patient when the most appropriate alternatives for continued treatment have been 
agreed between AZ and the investigator. Options may include the participation in a new rollover 
study or, if the study drug has been locally approved for use in this disease indication, patients 
may be discontinued and switched to the marketed product, in accordance with local laws. In the 
event that a rollover or safety extension study is available at the time of the final DCO and 
database closure, patients currently receiving treatment with durvalumab may be transitioned to 
such a study, and the current study would reach its end. The rollover or safety extension study 
would ensure treatment continuation with visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new ICF.
6.1.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IMP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the temperature of 
the storage area. Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection. A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage facility. 
Storage conditions stated in the IB may be superseded by the label storage.
6.2
Measures to Minimize Bias: Randomization and Blinding
6.2.1
Patient Enrollment and Randomization
This is a single-arm, open-label study; no randomization or blinding will be performed. 
If a patient withdraws from the study, then his/her enrolment code cannot be reused. Withdrawn 
patients will not be replaced.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening. 
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:
!
Obtain signed informed consent before any study specific procedures are performed. 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 be obtained within 
28 days prior to first dose of IMP (see Table 1). For patients with a single TL, if 
screening biopsy is collected prior to screening imaging for baseline tumor 
assessment, allow approximately 2 weeks before imaging scans are acquired. 
(Informed consent of study procedures may be obtained prior to the 28-day screening 
window in order to permit tumor biopsy sample acquisition).


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!
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) in the following 
format (ECCNNXXX: CC being the country code, NN being the center number, and 
XXX being the patient enrollment code at the center). This number is the patient’s 
unique identifier and is used to identify the patient on the electronic CRFs (eCRFs).
!
Determine patient eligibility (see Sections 5.1 and 5.2).
!
Obtain signed informed consent for genetic research study (optional).
If the patient is ineligible and not enrolled, the IVRS/IWRS should be contacted to terminate the 
patient in the system. 
Patients will begin treatment on Day 1. A window of up to 3 days is permitted between last 
screening assessments and first dose of IMP. Last assessments on Friday and dosing on Monday 
will be accepted. Patients must not be treated unless all eligibility criteria have been met.
6.2.2
Procedures for Handling Incorrectly Enrolled Patients
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 subsequently found not to meet all the eligibility criteria must not be initiated on treatment, 
and must be withdrawn from the study.
Where 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 a discussion 
should occur between the AstraZeneca Study Physician and the Investigator regarding whether to 
continue or discontinue the patient from treatment. The AstraZeneca Study Physician must 
ensure all decisions are appropriately documented and that the potential benefit:risk profile 
remains positive for the patient.
6.3
Treatment 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.
6.4
Concomitant Therapy
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical treatment phase of the study including the follow-up 
period following the last dose of study drug. 
Any concomitant treatment, procedure, other medication or vaccine, including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements, that the participant receives from 
the time of screening until the end of the clinical treatment phase of the study (including the 


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90-day follow-up period after the last dose of study treatment) must be recorded in the eCRF 
with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose, unit and frequency
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Restricted, prohibited, and supportive medications/therapies are described in Table 17, Table 18, 
and Table 19 of Appendix H. Refer also to the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.4 and Annex to Protocol). 
For chemotherapy agents, please refer to the local prescribing information with regards to 
warnings, precautions, and contraindications.
6.4.1
Background Medication
Not applicable.
6.4.2
Other Concomitant Treatment
Other medications considered necessary for the patient’s safety and wellbeing, may be given at 
the discretion of the Investigator and recorded in the appropriate sections of the CRF.
6.4.3
Durvalumab Drug-Drug Interactions
There is no information to date on drug-drug interactions with durvalumab either pre-clinically 
or in patients. As durvalumab is a mAb and therefore a protein, it will be degraded to small 
peptides and amino acids and will be eliminated by renal and reticuloendothelial clearance. It is 
therefore not expected that durvalumab will induce or inhibit the major drug metabolizing
cytochrome P450 pathways. As a result, there are no expected PK drug-drug interactions. The 
MOA of durvalumab involves binding to PD-L1, and therefore significant pharmacodynamic 
drug interactions with the commonly administered concomitant medications are not expected. 
Despite this, appropriate clinical monitoring in all of the planned clinical studies will be 
conducted to evaluate any potential drug-drug interactions.
6.4.4
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). AstraZeneca supply chain will be responsible 
for sourcing these 2 rescue medications to the sites if local regulations prevent the use of 
infliximab and mycophenolate in this indication, as they are considered off-label for 


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management of immunotherapy related toxicities. These rescue medications must be receipted, 
controlled, and administered by the pharmacist and stored according to the labelled storage 
conditions, with temperature excursions reported accordingly by the pharmacist.
6.5
Dose Modification
Dose delays are permitted for IO therapy (see Section 8.4.4 and Toxicity Management 
Guidelines in Annex to the Protocol). However, dose reduction is not permitted. 
Dose modifications for EP will be performed according to local guidance.
6.6
Treatment after the End of the Study
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab monotherapy up to the time that they discontinue the treatment for 
whatever reason (see Section 6.1.3).
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL
7.1
Discontinuation of Study Treatment
An individual patient will not receive any further IMP (durvalumab + EP or durvalumab 
monotherapy) if any of the following occur in the patient in question:
!
Withdrawal of consent from further treatment with IMP. 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 (eg, 
for safety and survival follow up) unless they specifically withdraw their consent to all 
further participation in any study procedures and assessments (see Section 7.3). 
!
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing.
!
Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.4 and Annex to the Protocol) or 
as defined in the local prescribing information for EP.
!
Pregnancy or intent to become pregnant.
!
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IMP (eg, refusal to adhere to 
scheduled visits).
!
Initiation of alternative anticancer therapy including another investigational agent.


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!
Clinical progression or confirmed radiological progression (refer to Appendix F) and 
Investigator determination that the patient is no longer benefiting from treatment with 
IMP.
7.1.1
Procedures for Discontinuation of Study Treatment
Discontinuation of study treatment, for any reason, does not impact the patient’s participation in 
the study. A patient who decides to discontinue IMP will always be asked about the reason(s) for 
discontinuation and the presence of any AE. The patient should continue attending subsequent 
study visits, and data collection should continue according to the study protocol. If the patient 
does not agree to continue in-person study visits, a modified follow-up must be arranged to 
ensure the collection of endpoints and safety information. This follow-up could be a telephone 
contact with the patient, a contact with a relative or treating physician, or information from 
medical records. The approach taken should be recorded in the medical records. A patient that 
agrees to modified follow-up is not considered to have withdrawn consent or to have withdrawn 
from the study.
Patients who are permanently discontinued from further receipt of IMP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs). 
All patients will be followed for survival until the end of the study. 
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative.
7.2
Lost to Follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed (see Section 4.4), such that there is insufficient information to determine 
the patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than “lost 
to follow-up.” Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. If contact with a missing patient is re-established, the 
patient should not be considered lost to follow-up and evaluations should resume according to 
the protocol.
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked, this includes those patients 
who withdrew consent or are classified as “lost to follow up.”
!
Lost to Follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable CRF modules will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 


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publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable CRF modules 
will be updated.)
7.3
Withdrawal from the Study
Patients are free to withdraw from the study at any time (IMP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any further 
IMP or further study observation, with the exception of follow-up for survival, which will 
continue until the end of the study unless the patient has expressly withdrawn their consent to 
survival follow-up. Note that the patient may be offered additional tests or tapering of treatment 
to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to:
!
All further participation in the study including any further follow up (eg, survival 
contact telephone calls).
!
Withdrawal to the use of any samples (see Section 8.8.6).
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1 and Table 2). 
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data Capture 
system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the clinical study 
agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will 
be archived at the study site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA (Table 1 and 
Table 2), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 


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Procedures conducted as part of the patient’s routine clinical management (eg, blood count and 
imaging assessments) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
8.1
Efficacy Assessments
This study will evaluate the efficacy of durvalumab + EP as secondary endpoints, in terms of OS, 
as well as PFS, PFS12, ORR, DoR, and DoR12, which will be derived from site Investigator 
assessments per RECIST1.1.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV contrast, 
of the chest and abdomen (including the entire liver and both adrenal glands), collected during 
screening/baseline and at regular (follow-up) intervals during study treatment. Pelvic imaging is 
recommended only when primary or metastatic disease in the pelvic region is likely. 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 SoAs). If an unscheduled assessment is performed (eg, to investigate clinical 
signs/symptoms of progression) and the patient has not progressed, every attempt should be 
made to perform the subsequent assessments at the next scheduled visit. Treatment continues 
until clinical progression/deterioration or confirmed radiological progression (refer to 
Appendix F), and scanning/tumor assessments 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 F) 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 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, stable disease, PD, or Not Evaluable 
[NE]).
For all patients who are treated through progression, a follow-up scan is to be collected 
4-8 weeks after the initial RECIST 1.1-defined PD; this follow-up scan is evaluated using the 
post-progression criteria outlined in 0. If the subsequent scan confirms the immediate prior 
radiological PD, no additional scans are required unless the patients are allowed to continue 
study treatment; however, if the subsequent scan does not confirm the immediate prior 
radiological PD, scanning should continue until the next RECIST 1.1-defined PD which in turn 
will require a subsequent scan evaluated using the post-progression criteria outlined in 
Appendix F.
8.1.1
Survival Assessments
Assessments for survival must be made as shown in Table 2. Survival information may be 
obtained via telephone contact with the patient or the patient’s family, or by contact with the 










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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
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
e
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system.
ALT: alanine aminotransferase; AST: aspartate aminotransferase; T3: triiodothyronine; T4: thyroxine; 
TSH: thyroid-stimulating hormone.
Table 10
Hematology
Absolute neutrophil count a
Absolute lymphocyte count a
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.
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.
Table 11
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 E for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law (HL). These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a HL case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 


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Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IMP must have further tests performed until the laboratory values have returned to Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease.
8.2.2
Physical Examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 8.3.7.
8.2.3
Vital Signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs. 
First Infusion
On the first infusion day, patients will be monitored and vital signs collected/recorded in eCRF 
prior to, during, and after infusion of IMP as presented in the bulleted list below. 
Blood pressure, pulse, temperature, and respiration rate will be collected from patients before, 
during, and after the first infusion at the following times (based on a 60 minute ± 10 minutes
infusion): 
!
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion]) 
!
Approximately 30 minutes during the infusion (halfway through infusion) 
!
At the end of the infusion (approximately 60 minutes ± 10 minutes)
If the infusion takes longer than 60 minutes, then BP, pulse, temperature, and respiration rate 
measurements should follow the principles as described above or be taken more frequently if 
clinically indicated. A 1-hour observation period is recommended after the first infusion of 
durvalumab. Infusion of chemotherapy agents per local practice. 
Subsequent Infusions 
Blood pressure, pulse, and other vital signs should be measured, collected/recorded in eCRF
prior to the start of the infusion. Patients should be carefully monitored and BP and other vital 


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signs should be measured during and post-infusion as per institution standard and as clinically 
indicated. 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 for subsequent 
cycles. Any clinically significant changes in vital signs should be entered onto an unscheduled 
vital signs CRF page. 
Situations in which vital signs results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, the vital signs values should be entered into the CRF.
8.2.4
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs). ECGs should be obtained after the patient has been in a supine position for 
5 minutes and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a corrected QT interval using 
Fridericia’s formulae (QTcF) value > 470 ms, 2 additional 12-lead ECGs should be obtained 
over a brief period (eg, 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.5
Early Patient Review for Safety
For the first 3 cycles, patients should be contacted 1 week (±1 day) after receiving the IMP to 
ensure early identification and management of toxicities. This contact should be documented in 
the medical records.
8.2.6
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.


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8.2.7
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.
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.4) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed. 
Pneumonitis (ILD) Investigation
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected.
!
Physical examination
∀
Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed.
!
SpO2
∀
Saturation of peripheral oxygen (SpO2)
!
Other items
∀
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers which are related to disease 
progression. 
(iii)
Additional Clinical chemistry: C-reactive protein, lactate 
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8.3
Collection of Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
Section 8.3.3.
8.3.1
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non 
leading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences.
8.3.2
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up 
period is completed (90 days after the last dose of durvalumab).
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 B. The Investigator will submit any updated SAE data to the Sponsor within 24 
hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the Investigator should notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All events, 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. 


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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse Event Data Collection
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
The maximum CTCAE grade reported
!
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)
!
Whether the AE is serious or not
!
Investigator causality rating against the IPs (yes or no)
!
Action taken with regard to IPs
!
Administration of treatment for the AE
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date the AE met criteria for SAE
!
Date the Investigator became aware of the SAE
!
Seriousness criteria 
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Whether an autopsy was performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication, as explained in Section 8.3.5


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!
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).
It is important to distinguish between SAEs and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but it is not an SAE unless it meets the criteria shown in Appendix 
B 2. On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke, but it would be an SAE if it satisfies the criteria shown in Appendix 
B 2.
8.3.5
Causality Collection
The Investigator will assess causal relationship between Investigational Product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study site staff: “Have you had any health problems since the previous visit/you were last 
asked?”, or revealed by observation will be collected and recorded in the CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the clinical study report (CSR). Deterioration as compared to baseline in 
protocol-mandated laboratory values should therefore only be reported as AEs if they fulfil any 
of the SAE criteria or are the reason for discontinuation of treatment with the IMP.
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 


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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.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study, see sections 8.3.9 and 8.3.10.
8.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need to be 
reported as SAEs. Please refer to Appendix E for further instruction on cases of increases in liver 
biochemistry and evaluation of HL.
8.3.9
Disease under Study
Symptoms of disease under study are those which might be expected to occur as a direct result of 
ES-SCLC. 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 IMP.
8.3.10
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.
8.3.11
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 IMP and have been identified after 
the patient’s inclusion in this study.
8.3.12
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined follow-up 
period after the administration of the last dose of study drug, must be reported as follows:
!
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF 
in the Statement of Death page. It should not be reported as an SAE.


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!
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the Statement of Death page in the 
eCRF. The report should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death.
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the post 
mortem results should be forwarded to AstraZeneca Patient Safety or its representative 
within the usual timeframes.
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started 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.
8.3.13
Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the Investigational 
Product and may require close monitoring. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this IMP.
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 imAE is defined as an AESI that is associated with drug exposure and 
is consistent with an immune-mediated MOA and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
Adverse events of special interest / 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.


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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 IBs. More specific guidelines for their evaluation and treatment are described 
in detail in the Dose Modification and Toxicity Management Guidelines (see Section 8.4.4). 
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting Investigator.
8.3.14
Safety Data to be Collected Following the Final DCO of the Study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.4). All data post the final DCO and database closure 
will be recorded in the patient notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab) post the final DCO and database closure must be reported 
as detailed in Section 8.4.1.
8.4
Safety Reporting and Medical Management
8.4.1
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day (ie, immediately but no later than 24 
hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days
of initial receipt for all other SAEs.
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 


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representatives of any follow-up information on a previously reported SAE within one calendar 
day (ie, immediately but no later than 24 hours of when he or she becomes aware of it).
Patients who are permanently discontinued from further receipt of IMP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see the 
SoAs).
8.4.2
Overdose
8.4.2.1
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. 
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
!
An overdose without associated symptoms is only reported on the Overdose CRF 
module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or 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.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.3.2. 
For other overdoses, reporting must occur within 30 days.
8.4.2.2
Platinum and Etoposide
Use of platinum (cisplatin or carboplatin) or etoposide in doses in excess of that specified in the 
protocol is considered to be an overdose. Please refer to the local prescribing information for 
treatment of cases of overdose with etoposide, cisplatin or carboplatin. If any overdose is 
associated with an AE or SAE, record the AE/SAE diagnosis or symptoms in the relevant AE 
modules in the eCRF.
8.4.3
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-


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Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE associated 
with the medication error (see Section 8.3.2) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.4.4
Management of IMP-related Toxicities
The following general guidance should be followed for management of toxicities.
!
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of the assigned IMP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted.
!
All dose modifications should be documented with clear reasoning and documentation 
of the approach taken.
!
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.
!
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. 
All toxicities will be graded according to NCI CTCAE, or version 5.0.
8.4.4.1
Specific Toxicity Management and Dose Modification Information –
Durvalumab 
Comprehensive toxicity management guidelines have been developed to assist investigators with 
the recognition and management of toxicities associated with the use of the immune-checkpoint 
inhibitor durvalumab [Medi4736] (PD-L1 inhibitor). Additionally, these guidelines are 
applicable when durvalumab is used alone or in combination and is administered concurrently or 
sequentially with other anti-cancer drugs (ie, antineoplastic chemotherapy, targeted agents), as 
part of a protocol specific treatment regimen.
The toxicity management guidelines provide information for the management of immune-
mediated reactions, infusion-related reactions, and non-immune mediated reactions that may be 
observed with checkpoint inhibitor monotherapy or combination checkpoint inhibitor regimens, 
with specific instructions for dose modifications (including discontinuations) and treatment 
interventions. Investigators are advised however to use local practice guidelines and consult local 
references for the management of toxicities observed with other cancer treatment (platinum and 
etoposide). The most current version of the toxicity management guidelines entitled “Dosing 


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Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy or in 
Combination with other Products” is provided to the investigative site as an Annex document 
and is maintained within the Site Master File. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. In addition, there are certain circumstances in which durvalumab should be 
permanently discontinued (see Section 7.1 of this protocol and the Dosing Modification and 
Toxicity Management Guidelines). Following the first dose of IMP, 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.
8.4.4.2
Specific Toxicity Management and Dose Modification Information -
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 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.
8.5
Pharmacokinetics
Not applicable.














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Table 12
Precision around varying incidence of AE
Precision of estimates of grade ≥3 or imAE for Sample Sizes using Exact Binomial 95% 
CI
Sample size
True rate of grade ≥3 AE or imAE (%) and 95% CI
20%
25%
60%
70%
150
#6.7
13.9 – 27.3
#7.3
18.6 – 33.1
#8.1
51.7 – 67.9
#7.6
62.0 – 77.2
AE: adverse event; CI: confidence interval: imAE: immune-mediated adverse event.
9.3
Definitions of Analysis Sets 
All analyses will be performed on the safety analysis set.
9.3.1
Safety Analysis Set
The Safety Analysis Set will consist of all patients who received at least 1 dose of study 
treatment. 
The safety analysis set will be used for the efficacy analysis set. 
9.4
Outcome Measures for Analyses
1 AE: Number and proportion of patients with AEs in total and by causality and severity 
2 AE: Number and proportion of patients with Grade 3 and Grade 4 AEs in total and by causality 
3 SAE: Number and proportion of patients with SAEs in total and by causality and severity 
4 AEs leading to death: Number and proportion of patients with AEs leading to death 
5 AEs leading to treatment interruption or discontinuation: Number and proportion of 
patients with AEs leading to treatment interruption and/or discontinuation 
6 AESI: Defined as an AE of scientific and medical interest specific to understanding of the 
IMP. 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. 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: 


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(a)
Number and proportion of patients with AESIs, by predefined 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 to the onset of an AESI predefined type, all 
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)
The imAEs will be assessed as a subset of AESIs. An imAE is defined as an AESI that 
is associated with drug exposure and is consistent with an immune-mediated MOA 
and where there is no clear alternate etiology. 
(f)
Laboratory findings, vital signs, and other safety parameters associated with AESIs 
will be summarized as part of the AESI outcome measures. 
7 PFS: Defined as the time from the first date of 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 IMP or receives another anticancer therapy prior to progression. 
PFS (days) = Date of event or Censor date – treatment start date +1
Patients who have not progressed or died at the time of analysis will be censored at the 
time of the latest date of assessment from their last evaluable assessment. However, if the 
patient progresses or dies after 2 or more missed visits, the patient will be censored at the 
time of the latest evaluable assessment prior to the 2 missed visits. If the patient has no 
evaluable visits or does not have baseline data, he/she will be censored at Day 1 unless 
he/she dies within 2 visits of baseline, in which case the date of death is the event date.
8 PFS12: Defined as the proportion of patients who are alive and progression free 12 months 
after first date of treatment. 
9 OS: Defined as the time from the first date of treatment until death due to any cause. 
OS (days) = Death date or Censor date - treatment start date +1 
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. 
10 OS 12: Defined as the proportion of patients who are alive 12 months after first date of 
treatment.


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11 ORR: Based on Investigator−assessed response to treatment of CR and PR, per RECIST1.1. 
12 DoR: Defined as the time from the date of first documented response per RECIST1.1 until the 
first date of documented progression per RECIST1.1 or death in the absence of disease 
progression. 
DoR (days) = Date of PFS event or censoring – Date of first response +1 
The end of response should coincide with the date of progression or death from any cause used 
for the PFS endpoint. If a patient does not progress following a response, then the patients’ DoR 
will be censored at the PFS censoring time. DoR will not be defined for those patients who do 
not have a documented response. 
13 DoR12: Defined as the proportion of patients who remain in response 12 months after first 
documented response per RECIST1.1.
14 
9.5
Statistical Analyses 
The primary analysis, for safety, will be conducted approximately 6 months after the last patient 
is enrolled into the study and the final statistical analysis will be conducted after the last patient 
has had the opportunity to be followed up for a minimum of 12 months or 60% OS maturity, 
whichever occurs first.
At the time of the DCO, the analysis portion of the clinical study will have been completed and 
all patients remaining in the study will be considered to have completed the analysis portion of 
the study. At the time of DCO, the clinical study database will be closed to new data. Patients in 
OS follow-up (progressed and have discontinued treatment) will be considered to have 
completed the study. 
Descriptive statistics will be used for all variables. Continuous variables will be summarized by 
the number of observations (n), mean, SD, median, quartiles (Q1 and Q3), minimum, and 
maximum. Categorical variables will be summarized by frequency counts and percentages for 
each category. 
For all summaries of AEs, only treatment-emergent AEs will be included. Treatment-emergent 
AEs are defined as events present at baseline that worsen in intensity after administration of IMP 
or events absent at baseline that emerge after administration of IMP, for the period extending to 
90 days after the last dose of IMP. Baseline will be the last assessment of the variable under 
consideration prior to the first IMP dose administration. 
9.5.1
Analysis of the Primary Variable 
Safety data will be summarized descriptively overall, by seriousness, by causality, and by 
maximum NCI CTCAE Grade. The exact 95% CIs around the incidence of Grade ≥3 AEs and 
imAEs will be reported for patients overall and separately by ECOG Performance Status 0-1 and 
2. 
CCI


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9.5.2
Analysis of the Secondary Variables 
9.5.2.1
Safety Variables 
Adverse Events 
Total SAEs, AESIs, AEs leading to death, and AEs leading to study drug interruption or 
discontinuation will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
by system organ class and preferred term, causality, and maximum NCI CTCAE Grade. Deaths 
from all causes will be also summarized. 
Data from all cycles of will be combined in the presentation of safety data. AEs (both in terms of 
MedDRA preferred term and CTCAE grade) will be listed individually by patient. Any AE 
occurring before treatment with IMP 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 IMP may 
be included in the AE summaries, but the majority of the AE summaries will omit the AEs 
observed after a patient has received further therapy for cancer. Further details will be provided 
in the SAP. Any AE that occurs after a patient has received further therapy for cancer (following 
discontinuation of IMP) will be flagged in the data listings. 
A separate data listing of AEs occurring more than 90 days after discontinuation of IMP will be 
produced. These events will not be included in AE summaries.
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the first IMP dose 
administration. 
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula: 
QTcF = QT/RR^(1/3) where RR is in seconds 
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) 
The denominator used in laboratory summaries will include only evaluable patients, ie, those 
who had sufficient data to have the possibility of an abnormality, for example: 
!
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a predose and at least 1 postdose value recorded. 
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable, the 
patient need only have 1 postdose value recorded. 
The denominator in vital signs data should include only those patients with recorded data. 




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statistical analysis will be conducted after the last patient has had the opportunity to be followed 
up for a minimum of 12 months or 60% OS maturity, whichever occurs first.
9.6.1
Steering Committee
If required, a SC will be assembled by AstraZeneca for the executive oversight and supervision 
of the study. The SC may consist of oncology experts and a statistician who serve their role 
through regular scheduled meetings or teleconferences and, if necessary, additional ad hoc 
meetings. Details of the SC remit, procedures, processes, and meeting frequency will be outlined 
in an SC Charter.
9.7
Data Management by AstraZeneca or Delegate 
Data management will be performed by a Contract Research Organization according to the Data 
Management Plan. 
Any data collected through third party sources will be obtained and reconciled against study 
data. Data queries will be raised for inconsistent, impossible, or missing data. All entries to the 
study database will be available in an audit trail. The data will be validated as defined in the Data 
Management Plan. Quality control procedures will be applied to each stage of data handling to 
ensure that all data are reliable and have been processed correctly. The Data Management Plan 
will also clarify the roles and responsibilities of the various functions and personnel involved in 
the data management process. When all data have been coded, validated, signed, and locked, 
clean file will be declared, and the final database will be locked.
10.
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.
Byers and Rudin 2015
Byers La, Rudin CM. Small cell lung cancer: Where do we go from here? Cancer 2015; 121:664-
672
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.








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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.
Rudin et al 2015
Rudin CM, Ismaila N, Hann CL, et al. Treatment of small-cell lung cancer: American Society of 
Clinical Oncology endorsement of the American College of Chest Physicians guideline. J Clin 
Oncol 2015;33:4106–11.
Rudin et al 2020
Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or Placebo Plus Etoposide and 
Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, 
Double Blind, Phase III KEYNOTE-604 Study. J Clin Oncol 2020;38.
Salgia and Skarin 1998
Salgia R, Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998;16(3):1207-17.
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.
Slotman et al 2015
Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, et al. Use of 
thoraci radiotherapy for extensive stage small-cell lung cancer; a phase 3 randomised controlled 
trial. Lancet 2015;345:36-2.
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.
Wang et al 2009
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012–24.
Wang et al 2017
Wang S, Tang J, Sun T, et al. Survival changes in patients with small cell lung cancer and 
disparities between different sexes, socioeconomic statuses and ages. Sci Rep 2017;7:1339.


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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.
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
!
Applicable ICH GCP Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an institutional Review Board (IRB) / (Independent 
Ethics Committee (IEC) by the Investigator and reviewed and approved by the IRB/IEC before 
the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study patients. 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO but the 
accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
!
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.
!
For all studies except those utilising medical devices investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.
!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.


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The Investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
A 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary and they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the study. 
Patients or their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 




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The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is conducted.
A 7
Data Quality Assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to
another location or party without written notification to the Sponsor. 
A 8
Source Documents


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Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study are defined as source documents. Source data are contained in source documents 
(original records or certified copies).
A 9
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multi-center studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.


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Adverse Event Definitions and Additional Safety Information
B 1
Definition of Adverse Events
An adverse event (AE) is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above.
!
AEs for malignant tumours reported during a study should generally be assessed as 
Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an 
individual event basis should be applied to clarify that the malignant tumour event 
should be assessed and reported as a Non-Serious AE. For example, if the tumour is 
included as medical history and progression occurs during the study, but the 
progression does not change treatment and/or prognosis of the malignant tumour, the 
AE may not fulfill the attributes for being assessed as serious, although reporting of 
the progression of the malignant tumor as an AE is valid and should occur. Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment 
that does not require hospitalization, may be assessed as Non-Serious; examples 
include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy.


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!
Malignant tumours that – as part of normal, if rare, progression – undergo 
transformation (eg, Richter's transformation of B cell chronic lymphocytic leukemia 
into diffuse large B cell lymphoma) should not be considered a new malignant tumour.
B 3
Life Threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
B 5
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse


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B 6
CTCAE Grade
The grading scales found in the revised NCI 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 B 2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?


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Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication Error
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. 
!
occurred
!
was identified and intercepted before the patient received the drug
!
did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error (eg, medication prepared incorrectly, even if it was not actually given 
to the patient)
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as a 
solid tablet) 
!
Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature) 


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Examples of events that do not require reporting as medication errors in clinical studies:
!
Patient accidentally missed drug dose(s) (eg, forgot to take medication)
!
Accidental overdose (will be captured as an overdose)
!
Patient failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.














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Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. 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 sections 8.2.1 and 8.3.8 of 
the Clinical Study Protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT from a central laboratory and/or elevated total bilirubin (TBL)
from a local laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than drug-induced liver injury (DILI) caused by the investigational medicinal product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
serious adverse events (SAEs) and adverse events (AEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 × Upper Limit of 
Normal (ULN) together with 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 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:
ALT ≥ 3 × ULN
AST ≥ 3 × ULN
TBL ≥ 2 × ULN
Local Laboratories Being Used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative 
!
Determine whether the subject meets PHL criteria (see Section E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not Met
If the subject does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the subject has not met PHL criteria. 
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting study treatment (See 
Appendix E)


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Notify the AstraZeneca representative who will then inform the central Study Team 
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE 
of PHL; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to clinical study protocol (CSP) process for SAE reporting.
!
For subjects that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change # in the subject’s condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study subjects’ follow-up (including any further laboratory testing) 
and the continuous review of data
!
Subsequent to this contact the Investigator will:
∀
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
∀
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
∀
Complete the three Liver CRF Modules as information becomes available 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP, to 
ensure timely analysis and reporting to health authorities within 15 calendar days from date PHL 
criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other subject matter experts as 
appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.


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Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE: update the previously submitted PHL
SAE and AE CRFs accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
!
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
!
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment 
This section is applicable to subjects with liver metastases who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment.


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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 subjects’ condition# compared with the 
last visit where PHL criteria were met# 
!
If there is no significant change no action is required
!
If there is a significant change, notify the AstraZeneca representative, who will inform 
the central Study Team, then follow the subsequent process described in Appendix E
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease or did the subject meet PHL criteria prior to starting study 
treatment and at their first on-study treatment visit as described in Section E 6 of this 
Appendix?
If No: follow the process described in Appendix E for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the subject’s condition# compared 
with when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Appendix E for 
reporting PHL as an SAE
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.


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E 8
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’


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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, 
Version 1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009). Investigator assessments will use 
the RECIST 1.1 guidelines described in this Appendix.
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of Target Lesions 
(TLs), Non-Target Lesions (NTLs), and New Lesions (NLs) is provided in Table 13.
Table 13
Summary of imaging modalities for tumor assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT: computed tomography; FDG-PET/CT: 18F-fluoro-deoxyglucose positron emission tomography/CT; 
MRI: magnetic resonance imaging.
CT/MRI at baseline should consider brain scan due to very common involvement of central nervous system; further 
CT/MRI evaluations should be according to the schedule and brain scan when clinically indicated. Additional  
radiological procedures such as PET/CT, bone scintigraphy and other X-rays (should be applied for non-RECIST 
assessments) when clinically indicated (not mandatory).
CT and MRI 
Computed tomography (CT) with intravenous (IV) contrast is the preferred imaging modality 
(although magnetic resonance imaging [MRI] with IV contrast is acceptable if CT is 
contraindicated) to generate reproducible anatomical images for tumor assessments (ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs). It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, imaging 
sequences, etc), imaging facility, tumor assessor (eg, radiologist), and method of tumor 
assessment (eg, RECIST 1.1) are used consistently for each patient throughout the study. The use 
of the same scanner for serial scans is recommended, if possible. It is important to follow the 
image collection/tumor assessment schedule as closely as possible (refer to the Schedule of 
Activities [SoA;]), and this on-study imaging schedule MUST be followed regardless of any 
delays in dosing or missed imaging visits. If an unscheduled assessment is performed (eg, to 
investigate clinical signs/symptoms of progression) and the patient has not progressed, every 
attempt should be made to perform the subsequent scan acquisitions at the next scheduled 
imaging visit.


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Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body scans 
should be performed with breath-hold scanning techniques, if possible. Therefore, CT of the 
chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. The modality used at follow-up should be the same as was used at baseline, 
and the lesions should be measured/assessed on the same pulse sequence. In general, local 
oncology diagnostic imaging parameters are applied for scan acquisition. It is beyond the scope 
of this appendix to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest abdomen 
(-pelvis). Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients. Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) at 
baseline and follow-up visits vary according to the study, and these timepoints are specified in 
the SoA. Examples include the following:
!
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis)
!
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire 
liver and both adrenal glands) (-pelvis)
!
IV contrast-enhanced CT or MRI of the head and neck
!
IV contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when patients have sensitivity to IV 
contrast or have compromised renal function:
1.
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred)
2.
Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT 
IV contrast (iodine based) is medically contraindicated at any time during the study


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3.
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the patient has compromised renal function
4.
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any
time during the study
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5-mm thickness throughout the entire 
anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this occurs, 
the minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that a 
higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the presence 
of new bone 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 NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone 
lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a bone scan 
that were not present on a previous bone scan; however, a newly observed equivocal hot-spot on 
a bone scan that cannot be verified with correlative imaging (CT, MRI, or X-ray) of the same 
anatomical region shall not be the only trigger for a progressive disease (PD) assessment at that 
time point.


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FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT (FDG-
PET/CT) scans may be used as a method for identifying new extrahepatic lesions (but not 
intrahepatic lesions) for RECIST 1.1 assessments according to the following algorithm: NLs will 
be recorded where there is positive 18F-Fluoro-deoxyglucose uptake1 not present on baseline or 
prior FDG-PET scan or in a location corresponding to a NL on a companion CT/MRI collected 
close in time to the FDG-PET scan. The PET portion of the PET/CT introduces additional data 
that may bias an Investigator if it is not routinely or serially performed. Therefore, if there is no 
baseline or prior FDG-PET scan available for comparison, and no evidence of NLs on 
companion CT/MRI scans, then follow-up CT/MRI assessments should continue as per the 
regular imaging schedule to verify the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan are 
of limited use in anatomically based efficacy assessments, and it is therefore suggested that they 
should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV contrast) 
to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used for RECIST 
1.1 tumor assessments. Caution that this is not recommended because the PET portion of the CT 
introduces additional (PET) data that may bias an Investigator if it is not routinely or serially 
performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan.
Other Tumor Assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need to be 
assessed by correlative CT or MRI anatomical scans.
                                               
1 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the 
surrounding tissue or liver is observed.


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Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.
Furthermore, an overall assessment of complete response (all other disease disappears/reverts to 
normal) would be changed to partial response if an effusion remains present radiologically.
Measurability of Tumor Lesions at Baseline
RECIST 1.1 measurable lesions at baseline:
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please see 
additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline:
!
Truly non-measurable lesions include the following:
∀
Bone lesions (see exception below for soft tissue component)
∀
Leptomeningeal disease
                                               
2 The short axis is defined as the longest in-plane axis perpendicular to the long axis.


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∀
Ascites, pleural effusion, or pericardial effusion
∀
Inflammatory breast disease
∀
Lymphangitic involvement of skin or lung
!
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10-mm to < 15-mm short axis diameter at baseline3)
!
Previously irradiated lesions4
!
Brain metastasis
Special considerations regarding lesion measurability at baseline:
!
Bone lesions
∀
Bone scan, PET scan, or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
∀
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.
∀
Blastic lesions are considered non-measurable.
!
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but 
if non-cystic lesions are present in the same patient, these should be selected over 
cystic lesions as TLs.
                                               
3 Lymph nodes with < 10-mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
4 Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.


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RECIST 1.1 TL selection at baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
identified as TLs at baseline. TLs should be selected on the basis of their size (longest diameter 
for non-nodal lesions or short axis diameter for nodal lesions), but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), a 
segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter for 
non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in whole (integer) millimeters and calculated values should be rounded to whole 
numbers. At baseline, the sum of the diameters for all TLs will be calculated and reported as the 
baseline sum of diameters. At follow-up visits, the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline:
!
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis diameter.
!
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that 
coalesce should similarly be assessed by the longest axis diameter.
!
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, 
unless imaging occurred at least approximately 2 weeks after biopsy, allowing time for 
healing.
!
If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a New 
Lesion.


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RECIST 1.1 NTL selection at baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions, not recorded 
as TLs should be identified as NTLs at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow up.
Evaluation of Tumor Response and Progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for RECIST 
1.1-defined TLs. The imaging modality, location, and scan date of each TL identified previously 
at baseline should be documented at follow-up visits with the long axis diameter for non-nodal 
lesions or short axis diameter for lymph node lesions. All measurements should be recorded in 
millimeters. The sum of the diameters for all TLs at each follow-up visit will be compared to the 
baseline sum of diameters (for response or stable disease) or to the smallest prior (nadir) sum of 
diameters (for progression).
Special cases for TL assessment at follow-up:
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
!
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.
!
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should 
be recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the 
merged TLs are non-nodal lesions, record the long axis diameter of the merged lesion.
If pathologic lymph nodes coalesce and are no longer individually separable within a 
conglomerate mass, the vector of the longest diameter of the coalesced mass should be 
used to determine the perpendicular vector for the maximal short axis diameter.
!
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.
!
If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion. The choice of “Too large to measure” in the case report form 
will trigger an overall visit response of PD.
!
When a TL has had an intervention, the following apply:
∀
TL Intervention may include radiotherapy, embolization, excisional biopsy, 
surgery, etc. that is not a part of study treatment and might adversely affect the 
size of that TL.


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∀
If an Intervention on a TL is ticked in the case report form, the diameter of the 
lesion is still recorded (0mm if no longer present) and is included in the sum of 
diameters. 
∀
If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that TL. 
∀
If a Target Lesion has an Intervention, the only Overall Visit Responses allowed 
to be recorded by the Investigator are NE or PD, with PD if the sum of diameters 
exceeds a 20% increase and at least a 5mm absolute increase in the visit sum of 
diameters compared to the previous minimum (nadir) sum of diameters. 
∀
No visit with a recorded Target Lesion Intervention can be used as the minimum 
(nadir) sum of diameters.
Table 14
RECIST 1.1 evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to < 10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters.
Stable disease 
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD.
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir)—This includes 
the baseline sum if that is the smallest on study. In addition to the relative 
increase of 20%, the sum must demonstrate an absolute increase of at least 
5 mm from nadir.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg, missing anatomy) or had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response.
Not applicable (NA)
Only relevant if no TLs present at baseline.
CR: complete response; NE: not evaluable; PD: progression of disease; PR: partial response; TL: target lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs 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.
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 unequivocal 
progression by NTLs. A modest ‘increase’ in the size of 1 or more NTLs is usually not sufficient 
to qualify for unequivocal progression status. The designation of overall progression solely on 


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the basis of change in non-target disease in the face of stable disease or progressive disease of 
target disease will therefore be extremely rare.
Table 15
RECIST 1.1 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 1 or more NTLs.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in 1 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 1 or some of the NTLs were not assessed and, in the 
Investigator’s opinion, they are not able to provide an evaluable overall 
NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any of the 
NTLs were not assessed at this visit and the progression criteria have not 
been met.
Not applicable (NA)
Only relevant if no NTLs present at baseline
CR: complete response; NE: not evaluable; NTL: non-target lesion; PD: progression of disease; TL: target lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the case report form. The presence of 1 or more NLs is assessed as progression.
The finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If a NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) new lesion has been assessed 
as unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 16.
Table 16
RECIST 1.1 overall visit response
Target Lesions
Non-Target Lesions
New Lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR


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Target Lesions
Non-Target Lesions
New Lesions
Overall visit response
PR
Non PD or NE or NA
No
PR
Stable disease
Non PD or NE or NA
No
Stable disease
NA
Non-CR/Non-PD
No
Stable disease
(non-CR/non-PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
NA
NA
No
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
a
Non-CR/Non-PD for Overall Response if only non-target lesions (no TLs) are present at baseline.
Note: An overall assessment of Complete Response (all other disease disappears/reverts to normal) would be 
changed to Partial Response if ascites remains present radiologically.
CR: complete response; NA: not applicable (only relevant if there were no target lesions at baseline or non target 
lesions at baseline); NE: not evaluable; NED: no evidence of diseases (only relevant if there were neither target 
lesions nor non-target lesions at baseline); PD: progressive disease; PR: partial response; TL: target lesion.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:
!
For patients with TLs (at baseline): complete response (CR), partial response (PR), 
stable disease, progression of disease (PD), or not evaluable (NE)
!
For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE
!
For patients with no disease at baseline: no evidence of disease (NED; available as an 
option in the electronic case report form), PD, or NE
Evaluation of scans subsequent to RECIST 1.1-defined progression
A follow-up scan is requested at least 4 weeks after a RECIST 1.1-defined radiological 
progression and no longer than the next regularly scheduled imaging visit. The follow-up scans 
provide additional information to the Investigator for patient management and further treatment 
decisions, and since the published RECIST 1.1 criteria (Eisenhauer 2009) do not provide 
guidance on how to assess scans acquired after RECIST 1.1-defined PD, supplemental 
instructions for Investigators on how to evaluate these follow-up scans are provided below. An 
immediate prior RECIST 1.1-defined radiologic PD would be considered confirmed if any of the 
following criteria are met in the subsequent follow-up scan:
!
≥20% increase and at least a 5-mm increase in the sum of diameters of TLs compared 
with the nadir sum of diameters at 2 consecutive visits, and a further increase of 
≥5 mm in the sum of diameters at the follow-up scan timepoint compared with the 
immediate prior timepoint


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!
significant progression (worsening) of NTLs at the follow-up scan timepoint compared 
with the immediate prior timepoint
!
significant progression (worsening) of previously new lesions (pre-existing new 
lesions) at the follow-up scan timepoint compared with the immediate prior timepoint
!
additional brand-new unequivocal lesions at the follow-up scan timepoint
References
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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Concomitant Medications
H 1
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted, prohibited, and supportive medications/therapies are described in Table 17, Table 18, 
and Table 19. Refer also to the dose modification guidelines for management of study drug
related toxicities in the Annex document to this protocol.
Table 17
Restricted Medications/Therapies
Medication/class of drug/therapy
Usage (including limits for duration permitted and 
special situations in which the drug/therapy is
allowed)
Hormonal therapy
For non-cancer-related conditions (eg, insulin for diabetes and 
hormone replacement therapy) only.
Bisphosphonates
For the treatment of bone metastases and osteoporosis.
Corticosteroids 
For the treatment of specific adverse drug reactions (refer to 
Toxicity Management Guidelines document).
Natural/herbal products, “folk remedies”, 
vitamins, nutritional supplements
The use of these products or other “folk remedies” should be 
discouraged, but use of these products, as well as use of all 
vitamins, nutritional supplements, and all other concomitant 
medications must be recorded in the eCRF.
Table 18
Prohibited Medications/Therapies
Prohibited medication/class of 
drug/therapy
Usage
Any investigational anticancer therapy other than those 
under investigation in this study
Must not be given concomitantly while the patient is on 
study drug.
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Must not be given concomitantly while the patient is on 
study drug.
Any concurrent treatment, including chemotherapy, 
radiotherapy, immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those under 
investigation in this study, except for those medications 
identified as “restricted,” as listed above
Must not be given concomitantly whilst the patient is 
on study drug.
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy]).
Prophylactic cranial irradiation is permitted per local 
practice at the discretion of the treating investigator.
Live attenuated vaccines
Must not be given while receiving study treatment and 
up to 90 days after the last dose of durvalumab and 
90 days after the last dose of etoposide. However, local 
guidance should be consulted to determine the 
acceptable timeframe for vaccine administration 
following chemotherapy study treatment.
Herbal and natural remedies that may have immune-
modulating effects and interfere with interpretation of 
study results
Must not be given concomitantly unless agreed by the 
sponsor.


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Table 18
Prohibited Medications/Therapies
Prohibited medication/class of 
drug/therapy
Usage
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses exceeding 
10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and tumour necrosis factor-α blockers
Must not be given concomitantly, or used for 
premedication prior to the IO infusions. The following 
are allowed exceptions:
!
Use of immunosuppressive medications for 
the management of study intervention-related 
AEs.
!
Short-term premedication for participants 
receiving combination therapy where use of a 
steroid is indicated to prevent a 
hypersensitivity or infusion reaction, or where 
a steroid is used as an anti-emetic. If used, it 
should be administered prior to chemotherapy 
and not prior to the IO infusion.
!
Use in patients with contrast allergies. 
!
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc). Consult 
with study clinical lead for prolonged therapy or need 
for a slow taper.
EGFR TKIs
Must not be given concomitantly. 
Must 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 first generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
AE: adverse event; CTLA-4: cytotoxic T-lymphocyte-associated antigen-4; CYP3A4/5: cytochrome P450 3A4/5; 
EGFR: epidermal growth factor receptor; IO: immune-oncology; PD-1: programmed cell death protein-1; PD L1:
programmed death-ligand 1; TKI: tyrosine kinase inhibitor
Table 19
Supportive Medications/Therapies
Supportive medication/class of 
drug/therapy
Usage
Concomitant medications or treatments (eg, 
acetaminophen or diphenhydramine) deemed necessary 
to provide adequate adverse event management, except 
for those medications identified as “prohibited,” as 
listed above
To be administered as prescribed by the investigator 
except for those medications identified as “prohibited,” 
as listed in Table 18.


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Table 19
Supportive Medications/Therapies
Supportive medication/class of 
drug/therapy
Usage
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy, etc]) except for those 
medications identified as “prohibited,” as listed above
Should be used, when necessary, for all patients except 
for those medications identified as “prohibited,” as 
listed in Table 18.
Vaccines limited only to non-live attenuated 
preparations (eg, influenza vaccine)
Permitted.
Natural/herbal products and “folk remedies”
Except for those medications identified as “prohibited,” 
as listed in Table 18, the use of any natural/herbal 
products or other “folk remedies” should be 
discouraged, but use of these products, as well as use 
of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the 
eCRF.


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Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health Crisis, 
including COVID 19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These changes 
should only be implemented if allowable by local/regional guidelines and following agreement 
from the sponsor.
I 1
Reconsent of Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of carrying 
out visits and assessments and should be obtained prior to performing the procedures described 
in Sections I 2 to I 5. Local and regional regulations and/or guidelines regarding reconsent of 
patients should be checked and followed. Reconsent may be verbal if allowed by local and 
regional guidelines (note, in the case of verbal reconsent the ICF should be signed at the patient’s 
next contact with the study site). Visiting the study sites for the sole purpose of obtaining 
reconsent should be avoided. 
I 2
Rescreening of Patients to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in previously 
screened patients. The investigator should confirm this with the designated study clinical lead.
In addition, during study disruption there may be a delay between confirming eligibility of a
patients and either enrolment into the study or commencing of dosing with study treatment. If 
this delay is outside the screening window specified in Section 1.1 the patient will need to be 
rescreened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to re-screen a patient in addition to that detailed in Section 5.4. The 
procedures detailed in Section 6.2 must be undertaken to confirm eligibility.
I 3
Remote Visit to Replace On-site Visit (Where Applicable)
A qualified HCP from the study site or TPV service may visit the patients at a remote location as 
per local standard operating procedures, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.
I 4
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile health 
devices.


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During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by a 
telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact with the 
patients will allow AEs, concomitant medication, and other relevant informationto be reported 
and documented.
I 5
Data Capture During Telemedicine or Remote Visits
Data collected during telemedicine or remote visits will be captured by the qualified HCP from 
the study site or TPV service in the source documents, or by the patient themselves.
I 6
COVID-19 Risk Assessment 
The safety of patients is of primary importance. Any potential risks of participating in the study, 
particularly with the added challenges due to COVID-19 outbreak, should be weighed against the 
anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised to use clinical 
judgment in determining infection prevention precautions for study patients.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. Patients 
enrolling in this study may require more frequent visits to the site for study treatment 
administration and for study assessments compared to patients receiving standard of care. 
Therefore, several risk mitigation factors have been implemented related to study conduct during 
the COVID-19 outbreak, for patient management in an event of COVID-19, and actions to be 
taken on study treatment (see Section I 9). With these measures in place, it is considered that the 
anticipated potential benefits for the patients enrolled in this study outweigh the potential risks. 
All implemented measures prioritise trial patient safety and data validity; in case these two
conflict with each other, trial patient safety should always prevail (see also European Medicines 
Agency Guidance on the management of clinical trials during the COVID-19 [coronavirus] 
pandemic [EMA 2020]). 
Notably, patients with active COVID-19 infection confirmed by local laboratory testing will not 
be eligible for study enrolment. 
I 7
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section I 10 provides a dose modification and 
management plan for patients with confirmed or suspected COVID-19 who are being treated 
with study drug durvalumab. The risk-benefit assessment should be carefully considered for each 
patient enrolling in the study based on the known safety risks related to COVID-19, individual 
needs, and local guidelines and restrictions. Investigators must continue to use their best clinical 
judgment in determining the most optimal care for patients and utmost diligence in determining 
their eligibility for study participation, continued study treatment, and overall assessment of 
benefit/risk of study treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.


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I 8
New Patient Enrolment
Study sites may continue to recruit new patients into the study provided the following activities 
to preserve study integrity can be met:
!
Upon discussion with the site monitor, the study site has confirmed the ability to enrol 
and manage new patients effectively and in compliance with the protocol.
!
Data will continue to be entered into the eCRF and queries resolved in a timely 
manner. 
Per CSP Exclusion Criteria 7, patients with uncontrolled intercurrent illness, including but not 
limited to, ongoing or active infection are not eligible for the study participation and hence such 
patients (including those who have confirmed COVID-19) should not be included for study 
participation.
I 9
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
patients’ treatment with IMP should continue, be interrupted, or be discontinued in accordance 
with the CSP.
AEs, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 along with 
logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should be 
followed, and the End of Treatment Form(s) completed.
I 10
Ongoing Patients
Patients receiving study treatment should continue to undergo safety assessments prior to dosing 
in accordance with the CSP. In case it is not feasible to perform safety assessments, study 
treatment should be interrupted until such assessments can be completed.
I 10.1
If a Patient has an Event Suspected to be COVID-19
Delay or omit study treatment as appropriate and test for COVID-19 per local health authority or 
institutional guidance. 
!
Signs and symptoms of COVID-19 include but are not limited to new onset of fever, 
new or worsening cough, shortness of breath, difficulty breathing and sometimes 
abnormal chest imaging and may be similar to those of an imAE. 
!
In accordance with the CSP and the Toxicity Management Guidelines for imAEs, 
thorough evaluation should be performed to accurately identify the underlying 
pathology in case an AE is encountered for a patient. 
!
If COVID-19 is ruled out, study treatment may be resumed per the CSP.


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!
If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
I 10.2
Patients with Confirmed COVID-19
Patients with confirmed COVID-19 (by local laboratory testing and/or combination of key 
symptoms) should have study treatment withheld and COVID-19 managed per local guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators are 
advised to apply clinical judgement regarding the use of corticosteroids as per the durvalumab 
Toxicity Management Guidelines. This includes also the consideration of alternate 
immunosuppressive agents other than corticosteroids for imAE management, depending on the 
individual patient’s presentation (Curigliano et al 2020).
I 10.3
Restarting Study Treatment
Study treatment must not be resumed until recovery from COVID-19 (eg, confirmed by imaging, 
lab testing and/or absence of symptoms) and COVID-19-specific treatment has been completed 
per local guidance.
The study clinical lead should be contacted if any additional guidance or clarification is needed.
I 10.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated COVID-
19 vaccines as well. Investigators should apply their discretion assessing the risk-benefit of other 
types of COVID-19 vaccines for patients in clinical trials. Ideally, administration of the vaccine 
should be done on a different day other than the day of study drug administration to differentiate 
any potential AEs seen from the vaccine and study drug. The administration of the vaccine and 
any potential AEs associated with the vaccine are to be documented on the concomitant 
medication and AE eCRFs, respectively.
I 11
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance on 
the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 2, 27 
March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.




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Abbreviation or special
term
Explanation
ES
Extensive stage
ES-SCLC
Extensive-stage small-cell lung cancer
FDA
Food and Drug Administration
FDG
Fluoro-deoxyglucose
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBc
Hepatitis B core
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCP
Healthcare professional
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
HRCT
High-resolution computed tomography
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
ILD
Interstitial lung disease
imAE
Immune mediated adverse event
IMP
Investigational medicinal product
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or 
activities internationally. 
IMP
Investigational medicinal product
IRB
Institutional review board
IV
Intravenous
CCI
CCI
CCI
CCI


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Abbreviation or special
term
Explanation
IVRS
Interactive voice response system
IWRS
Interactive web response system
LFT
Liver function test
LS
Limited stage
mAb
Monoclonal antibody
MOA
Mechanism of action
MRI
Magnetic resonance imaging
NA
Not applicable
NE
Not evaluable
NCI
National Cancer Institute
NED
No evidence of disease
NL
New lesion
NSCLC
Non-small-cell lung cancer
NTL
Non-target lesion
ORR
Overall response rate
OS
Overall survival
OS12
Proportion of patients alive at 12 months from first date of treatment
PCI
Prophylactic cranial irradiation
PD
Progression of disease
PD-1
Programmed cell death-1
PD-L1
Programmed cell death ligand-1
PET
Positron emission tomography
PFS
Progression-free survival
PFS12
Proportion of patients alive and progression-free at 12 months from first 
date of treatment
PHL
Potential Hy’s Law
PK
Pharmacokinetic
PR
Partial response
PS
Performance status
QTcF
Corrected QT interval using Fridericia’s formulae
qXw
Every X weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumours version 1.1
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Abbreviation or special
term
Explanation
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SCLC
Small-cell lung cancer
SD
Standard deviation
SoA
Schedule of activities
T3
Triiodothyronine
T4
Thyroxine
TBL
Total bilirubin
TL
Target lesion
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WHO
World Health Organization
WT
Weight


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D419QC00007 Clinical Study Protocol version 2
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SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D419QC00007
Edition Number
2.0
Date
07 June 2023
A Phase IIIb, Single-arm, Multi-center, International Study of Durvalumab 
in Combination with Platinum and Etoposide for the First Line Treatment 
of Patients with Extensive-stage Small Cell Lung Cancer (LUMINANCE)
Redacted
ed
ngle
gle-arm
arm
th
th
for 
Mu
latinum a
atinum
nsive
sive-stage S
stag
or Public 
P
Disclosure 


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 2 of 51
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
TABLE OF CONTENTS.....................................................................................2
LIST OF TABLES...............................................................................................5
LIST OF ABBREVIATIONS ..............................................................................6
AMENDMENT HISTORY..................................................................................9
1.
STUDY DETAILS............................................................................................. 11
1.1.1
Primary Objective .............................................................................................. 11
1.1.2
Secondary Objectives......................................................................................... 11
1.1.3
....................................................................................... 12
1.2
Study Design...................................................................................................... 12
1.2.1
Study Treatment.................................................................................................13
1.2.2
Tumor Response Assessments............................................................................ 15
1.2.3
Overall Survival Assessments ............................................................................ 15
1.3
Number of Subjects............................................................................................ 15
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of Analysis Sets................................................................................. 16
2.2
Protocol Deviations............................................................................................ 16
2.2.1
Important Protocol Deviations............................................................................ 16
2.2.2
Monitoring of Important Protocol Deviations.....................................................19
3.
ANALYSIS VARIABLES................................................................................. 19
3.1
Safety Variables................................................................................................. 19
3.1.1
Primary Safety Endpoint .................................................................................... 19
3.1.2
Secondary Safety Endpoints............................................................................... 19
3.1.3
Adverse Events ..................................................................................................20
3.1.3.1
Adverse Events of Special Interest ..................................................................... 20
3.1.3.2
Immune-Mediated Adverse Event ...................................................................... 21
3.1.4
Electrocardiograms ............................................................................................ 21
3.1.5
Vital Signs ......................................................................................................... 22
3.1.6
Laboratory Data.................................................................................................22
3.1.7
Physical Examination......................................................................................... 22
3.1.8
Exposure to IMP................................................................................................ 22
3.2
Efficacy Variables.............................................................................................. 24
3.2.1
Derivation of RECIST Visit Responses.............................................................. 25
3.2.2
Progression-Free Survival.................................................................................. 25
3.2.3
Overall Survival.................................................................................................26
CCI








Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 6 of 51
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
AJCC
American Joint Committee on Cancer
ALT
Alanine transaminase
AST
Aspartate transaminase
ATC
Anatomical therapeutic chemical
BMI
Body mass index
BoR
Best objective response
BP
Blood Pressure
CI
Confidence interval
COVID-19
Coronavirus disease 2019
CR
Complete Response
CrCl
Creatinine Clearance
CS
Clinically significant
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography 
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Event
DBL
Database lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EORTC
European Organisation for Research and Treatment of Cancer 
CCI
CCI
CCI
CCI
CCI
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Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 7 of 51
Abbreviation or 
special term
Explanation
ES-SCLC
Extensive-stage Small Cell Lung Cancer
ICH
International conference of harmonisation 
ICH 1995
ICH guidelines version dated 1995
imAE
Immune-mediated adverse event
IMP
Investigational medicinal product
IO
Immuno-Oncology
IPD
Important protocol deviations
IV
Intravenous
kg
Kilogram
LLQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MOA
Mechanism of action
MRI
Magnetic resonance imaging
msec
Milliseconds
NA
Not applicable
NCI
National Cancer Institute
NE
Not evaluable
NED
No evidence of disease
NTL
Non-target lesion
ORR
Overall response rate
OS
Overall survival
OS12
Proportion of patients alive at 12 months 
PCI
Prophylactic cranial irradiation
PD
Progressive disease
PD-L1
Programmed cell death ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PFS12
Proportion of progression-free and alive patients at 12 months 
PR
Partial response 
PS
Performance status
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 8 of 51
Abbreviation or 
special term
Explanation
PT
Preferred term
q3w
Every three weeks
q4w
Every four weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RDI
Relative dose intensity
RECIST1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
SAE
Serious adverse event 
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis software
SBP
Systolic blood pressure
SD
Stable disease
SI
International system (of units) 
SOC
System organ class
T3
Tri-iodothyronine 
T4
Thyroxine 
TEAE
Treatment-emergent adverse event
TL
Target lesion
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VAS
Visual analogue scale
WHO
World Health Organization
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 9 of 51
AMENDMENT HISTORY
Date
Brief description of change
12 July 2021
Initial version 1.0
22 September 2021
13th May 2022
Version 1.1 includes the following changes from V1.0:
!
Additions or revisions:
!
a change in the PFS unit from days to months (Section 3.2.2) 
!
addition of definition of missed visits for PFS (Section 3.2.2)
!
a change in the OS unit from days to months (Section 3.2.3)
!
a change in the DoR unit from days to months (Section 3.2.6)
!
addition of output presentation by ECOG group (Section 4.1.1)
!
!
changes to the summaries and analysis set of patient disposition 
(Section 4.2.1)
!
changes to the categories for presentation for demography and 
baseline characteristics (Section 4.2.3)
!
changes to the summaries of adverse events leading to 
discontinuation or interruption (Section 4.5.1)
!
addition of COVID-19 related adverse events analysis (Section
4.5.1)
!
changes to the presentation of adverse event by SOC and PT and 
maximum CTCAE grade. Causality removed (Section 4.5.1)
!
addition of text for most common adverse event (Section 4.5.1)
!
changes to the presentation of adverse event of special interest by 
PT, seriousness and maximum CTCAE grade. Causality removed
(Section 4.5.1.1)
!
addition of Absolute leukocytes count parameter to Haematology
(Section 4.5.4) 
!
addition of new categories for ALT, AST and ALT or AST (Section 
4.5.4.1)
!
addition of new text for Shift table for TSH test (Section 4.5.4.2)
!
Removed section 4.5.4.3 Assessment of Renal Function Test 
Abnormalities
!
Changes to summaries for overdose and medical error (Section 
4.5.6)
!
Schedule of assessment removed from Appendix
!
Section 4.5.1.1- AEPI category added
!
Section 4.5.1- The AE for etoposide+platinum are now separated 
CCI


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 10 of 51
Date
Brief description of change
02 November 2022
07 June 2023
12th June 2023
into etoposide and platinum
Section 5 – Early safety evaluation added in interim analysis 
section.
!
Section 4.5.1-The AEs for etoposide+platinum is presented together 
as per suggestion from Sponsor. 
!
Section 4.5.1-The cut-off for most common AEs with CTCAE 
Grade 3 or higher has been changed from =>2.5 to >2.5
!
Section 4.5.1-Summary of most common AEs with CTCAE Grade 
3 or higher is added for patients who had less than <=4 cycles of EP 
and >4 cycles of EP
!
3.2.5 (Best objective response definition) added 
     
Section 14.1.1 For RECIST and ECOG, baseline assessment
The timing of primary analysis is mentioned in section 5
Added ‘any study treatment’ for safely population ins section 2.1
Added ‘as per RECIST 1.1’ in progression free survival definition in 
section 3.2.2
Reference to SURVIVE AND DEAETH module removed


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 11 of 51
1.
STUDY DETAILS
This is an open-label, single-arm, multi-center, international, Phase IIIb study to determine the 
safety and tolerability profile of durvalumab with platinum (cisplatin or carboplatin) plus 
etoposide (EP) as first-line treatment in patients with extensive-stage small-cell lung cancer. 
The study will be conducted in North America and Europe.
1.1.1
Primary Objective
Primary Objective
Endpoint / Variable
To assess the safety and tolerability profile of 
durvalumab + EP treatment
Incidence of Grade ≥3 AE 
Incidence of imAEs
Note:   Toxicities will be classified as per NCI CTCAE grading system version 5.0.
Note: 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.
imAE: immune-mediated adverse event; CTCAE: Common Terminology Criteria for Adverse Event; EP: platinum (cisplatin 
or carboplatin) plus etoposide; NCI: National Cancer Institute.
1.1.2
Secondary Objectives
Secondary Efficacy Objectives
Endpoints / Variables
To assess the efficacy of durvalumab + EP 
treatment
PFS, ORR, DoR, DoR12, and PFS12 using site 
Investigator assessments according to RECIST 
1.1
OS and OS12
Secondary Safety Objectives
Endpoints / Variables
To further assess the safety and tolerability 
profile of durvalumab + EP, including all AEs
Incidence of AEs, SAEs, AESIs, AE resulting in 
treatment discontinuation, and laboratory 
findings including clinical chemistry, 
hematology and urinalysis
Note:  Toxicities will be classified as per NCI CTCAE grading system version 5.0.
Note: Analysis of ORR and DoR will be based upon Investigator assessment according to RECIST 1.1. Prior 
irradiated lesions may be considered measurable and selected as target lesions (TLs) provided they fulfil the 
other criteria for measurability.
Note: An AESI is an AE of scientific and medical interest specific to understanding of the IMP. 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.
AE: adverse event; AESI: adverse event of special interest; DoR: duration of response; DOR12: proportion of patients 
remaining in response 12 months from the time of first documented objective response; EP: platinum (cisplatin or carboplatin)
plus etoposide; ORR: objective response rate; OS: overall survival; OS12: proportion of patients alive at 12 months from first 
date of treatment; PFS: progression-free survival; PFS12: proportion of patients alive and progression-free at 12 months from 
first date of treatment; RECIST 1.1: Response Evaluation Criteria in Solid Tumors version 1.1; SAE: serious adverse event.




Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 13 of 51
Figure 1
Study design: A Phase IIIb, single-arm, multi-center, international 
study of Durvalumab in combination with platinum and etoposide for 
the first line treatment of patients with extensive-stage small cell lung 
cancer
Durvalumab 1500 mg, cisplatin (75-80 mg/m2) or carboplatin (AUC5-6 [For PS2 patients a dose of AUC 4 is allowed]), 
etoposide (80-100 mg/m2).
AE: adverse event; AUC: area under the curve; DoR: duration of response; DoR12: proportion of patients remaining in response 
12 months from the time of first documented objective response; ES-SCLC: extensive-stage small-cell lung cancer; EP: 
platinum (cisplatin or carboplatin) plus etoposide; imAE: immune-mediated adverse event; OS: overall survival; OS12: 
proportion of patients alive at 12 months from first date of treatment; PFS: progression-free survival; PFS12: proportion of 
patients alive and progression-free at 12 months from first date of treatment; PD: Progression of disease; qXw: Every X weeks; 
PS: performance status; WHO: World Health Organization.
Approximately 150 patients will be treated with the study drug in North America and Europe. 
Patients must have histologically- or cytologically-documented ES-SCLC and be treatment 
naïve. Patients must be deemed to be eligible for etoposide and platinum-based chemotherapy 
per Investigator assessment.
1.2.1
Study Treatment
All patients will receive durvalumab 1500 mg administered via intravenous (IV) infusion 
concurrently with platinum-based chemotherapy (Investigator’s choice of cisplatin or 
carboplatin) and etoposide q3w starting on Week 0 for up to 6 cycles. Durvalumab monotherapy 
will be continued q4w post-chemotherapy until confirmed radiological disease progression.
Unless specific treatment discontinuation criteria are met, patients enrolled will continue 
durvalumab therapy until confirmed radiological disease progression, unless there is clinical 
progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion 


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 14 of 51
is met, as per investigator assessment.
EP will be administered for up to 6 cycles for patients per investigator clinical decision.
For Durvalumab, Dose delays are permitted for IO (Immuno-Oncology) therapy (see CSP 
Section 8.4.4 and Toxicity Management Guidelines in Annex to the Protocol). However, dose 
reduction is not permitted. 
Dose modifications for EP will be performed according to local guidance.
The procedures for the screening and treatment periods in this study are presented in clinical 
study protocol.
Whenever vital signs and blood draws are scheduled for the same nominal time, the assessments 
should occur in the following order: vital signs and then blood draws. The timing of the vital 
signs assessments should be such that it allows the blood draw to occur at the timepoints 
indicated in the schedules of activities (SoAs). Whenever electrocardiograms (ECGs), vital 
signs, and blood draws are scheduled for the same nominal time, the assessments should occur 
in the following order: ECG, vital signs, and then blood draws. The timing of the first 2 
assessments should be such that it allows the blood draw to occur at the timepoints indicated in 
the SoAs.
For Durvalumab
!
Patients may delay dosing under certain circumstances. 
∀
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (TMG), due to either an immune or a non-immune-related adverse 
event (AE). In the event that durvalumab is discontinued or delayed as part of 
the toxicity management guidance, EP (platinum [cisplatin or carboplatin] plus
etoposide) should still be administered as scheduled.
∀
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible.
∀
Dosing intervals of subsequent cycles may be shortened as clinically feasible in 
order to gradually align treatment cycles with the schedule of tumor efficacy 
(Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) and 
 assessments. 
For Chemotherapy (Platinum [Cisplatin or Carboplatin] plus Etoposide [EP])
!
Patients may delay and subsequently resume dosing per local standard clinical 
practice.
∀
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will occur as soon as feasible. 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.
CCI


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 15 of 51
1.2.2
Tumor Response Assessments
Tumor assessments using computed tomography (CT) or magnetic resonance imaging (MRI), 
each preferably with IV contrast, will be performed at the times specified in the schedule of 
assessment (Appendix A).  RECIST 1.1 guidelines will be used to derive the secondary 
variables of PFS, OS, ORR, and DoR. The categorization of objective tumor 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.
1.2.3
Overall Survival Assessments
All patients will be followed for survival until the end of the study. 
Assessments for survival must be made as shown in Appendix A. Survival information may be 
obtained via telephone contact with the patient or the patient’s family, or by contact with the 
patient’s current physician.
In addition, patients on treatment or in survival follow-up will be contacted following the DCO
for the primary analysis and all subsequent survival analyses to provide complete survival data. 
These contacts should generally occur within 7 days of the DCO.
The survival status (including cause of death) and the date of death or last follow-up date will 
be collected.
1.3
Number of Subjects
This is a safety study and no formal sample size calculation was done. However, a total of 
approximately 150 patients will be treated with durvalumab with platinum (cisplatin or 
carboplatin) plus etoposide. A maximum of 30% of all patients treated will have ECOG 
performance status of 2 at baseline. Assuming a CTCAE grade ≥3 incidence rate of 70%, 
approximately 150 patients are needed to achieve a precision no wider than 7.6% around the 
true incidence rate (based on Clopper-Pearson exact method). For this study, incidence rate is 
defined as
푖푛푐푖푑푒푛푐푒푟푎푡푒
푛푢푚푏푒푟표푓푒푣푒푛푡푠
푛푢푚푏푒푟표푓푠푢푏푗푒푐푡푠푖푛푡푒푠푎푓푒푡푦푎푛푎푙푦푠푖푠푠푒푡
In addition, assuming an imAE incidence rate of 20%, the precision will be no wider than 6.7% 
around the true incidence rate. An illustration of the precision around the varying incidence 
rates of CTCAE grade ≥3 or imAE are provided in Table 1.


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 16 of 51
Table 1
Precision around varying incidence of AE
Precision of estimates of grade ≥3 AEs or imAE for Sample Sizes using Exact Binomial 95% CI
Sample size
True rate of grade ≥3 AE or imAE (%) and 95% CI
20%
25%
60%
70%
150
#6.7
13.9 – 27.3
#7.3
18.6 – 33.1
#8.1
51.7 – 67.9
#7.6
62.0 – 77.2
AE: adverse event; CI: confidence interval: imAE: immune-mediated adverse event.
2.
ANALYSIS SETS
2.1
Definition of Analysis Sets
With the exception of some summaries of patient disposition and particular individual patient 
data listings, which will be produced for all patients who provided informed consent and who 
were enrolled in the study, the Safety Analysis Set (SAF) will be used for listings, summaries, 
and analyses in the study.
The Enrolled Analysis Set will include all patients who signed informed consent.
The SAF will consist of all enrolled patients who received at least 1 dose of any study treatment. 
The safety analysis set will be used for the efficacy analysis set. 
2.2
Protocol Deviations
2.2.1
Important Protocol Deviations
According to ICH E3 guidelines version dated 1995 (ICH 1995), 
“Protocol deviations consist of any change, divergence or departure from the study 
design or procedures defined in the protocol. Important protocol deviations (IPDs) are 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.” 
For this study, the following 7 general categories will be considered IPDs and will be 
summarized in the CSR:
!
Deviation 1: Patients who received treatment and who deviated from the following key 
entry criteria in CSP:


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 17 of 51
!
Inclusion Criterion 5: Histologically- or cytologically-documented ES-SCLC (stage 
IV [T any, N any, M1a/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).
!
Inclusion Criterion 6: 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.
!
Inclusion Criterion 7: WHO/ ECOG Performance Status of 0 to 2 at enrollment.
Note: Patients with PS2 will be limited to a maximum of 30% of the total study 
population; once this limit is met, additional enrolled patients must have PS 0-1.
!
Inclusion Criterion 9: No prior exposure to immune-mediated therapy including, but 
not limited to, other anti- CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 (anti-
PD-L2) antibodies, excluding therapeutic anticancer vaccines.
!
Exclusion Criterion 1: History of allogeneic organ transplantation.
!
Exclusion Criterion 3: 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.
!
Exclusion Criterion 7: Active infection including tuberculosis (clinical evaluation 
that includes clinical history, physical examination and radiographic findings, and 
tuberculosis testing in line with local practice), hepatitis B virus (HBV) (known 
positive HBV surface antigen [HBsAg] result), hepatitis C virus (HBC), 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 HCV antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA.
!
Exclusion Criterion 10: Received prior systemic therapy for ES-SCLC.
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. 
!
Exclusion Criterion 11: Medical contraindication to platinum (cisplatin or 
carboplatin)-etoposide-based chemotherapy.
!
Exclusion Criterion 12: Any concurrent chemotherapy, IMP, biologic, or hormonal 
therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-
related conditions (eg, hormone replacement therapy) is acceptable. 


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 18 of 51
!
Exclusion Criterion 16: Patients who have received prior anti-PD-1 or anti PD-L1: 
•
Must not have experienced a toxicity that led to permanent discontinuation of 
prior immunotherapy. 
•
All AEs while receiving prior immunotherapy must have completely resolved or 
resolved to baseline prior to screening for this study.
•
Must not have experienced a Grade ≥3 immune-related AE or an immune-
related neurologic or ocular AE of any grade while receiving prior 
immunotherapy. Note: Patients with an endocrine AE of Grade ≤2 are 
permitted to enroll if they are stably maintained on appropriate replacement 
therapy and are asymptomatic.
•
Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence 
of an AE if re-challenged, and not currently require maintenance doses of > 10 
mg prednisone or equivalent per day.
!
Exclusion Criterion 17: Current or prior use of immunosuppressive medication 
within 14 days before the first dose of durvalumab. The following are exceptions to 
this criterion:
•
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection).
•
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent.
•
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).
!
Deviation 2: Baseline Response Evaluation Criteria in Solid Tumors (RECIST) version 
1.1 scan 42 days before enrollment. Note that the 42 days is based upon a 28-day screening 
period plus 2 weeks allowance so that only serious violators are identified.
!
Deviation 3: No baseline RECIST 1.1 assessment on or before date of enrollment.
!
Deviation 4: The patient met discontinuation criteria but did not discontinue 
investigational medicinal product (IMP) (eg, patient withdrew consent, patient became 
pregnant).
!
Deviation 5: The patient received a prohibited concomitant medication or procedure as 
detailed in Section 6.4 of the CSP or any other concomitant medication or procedure 
which, upon physician review of all medications and procedures prior to database lock 
(DBL), is considered to have a potential effect on study outcomes. 
!
Deviation 6: Missed visits, assessments, or treatments that, in the opinion of the principal 
investigator,  were due to COVID-19 global pandemic and where there was a significant 
effect on either completeness, accuracy, and/or reliability of the patient’s data, or the 
patient’s rights, safety or well-being.


Statistical Analysis Plan 
Study Code D419QC00007
Edition Number 2.0
Date 07 June 2023
Page 19 of 51
!
Deviation 7: Deviation from Good Clinical Practice (GCP) as determined by medical 
review.
2.2.2
Monitoring of Important Protocol Deviations
Programmable protocol deviations will be detected from the data recorded in the clinical 
database. The deviations will be reviewed and assessed on a case-by-case basis by AstraZeneca 
at monthly protocol deviation review meetings to determine importance of the deviation.. At 
this meeting, the programmatically-derived protocol deviations will be checked to ensure that 
they have been correctly classified as major or minor protocol deviations. 
On an ongoing basis throughout the study, monitoring notes or summaries will also be reviewed 
to determine any important post entry deviations that are not identifiable via programming. 
If the number of other deviations which are considered to have the potential to impact the 
primary analysis is considered important, sensitivity analyses may be performed on subgroups. 
This will be decided during the data review meeting and decisions will be documented prior to 
the soft database lock for primary analysis. 
The final classification of IPDs will be made prior to database lock or data cut-off for final 
analysis. Deviations considered to be important will be listed and discussed in the CSR as 
appropriate. Any other deviations from monitoring notes or reports will be reported in an 
appendix to the CSR.
3.
ANALYSIS VARIABLES
3.1
Safety Variables
Safety and tolerability will be assessed in terms of AEs (including Grade ≥3 AE, imAEs, SAEs, 
AESIs, AEs resulting in treatment discontinuation, deaths, physical examinations, laboratory 
data, vital signs, ECGs, WHO/ECOG performance status and exposure). These will be collected 
for all patients throughout the study.
3.1.1
Primary Safety Endpoint
The primary endpoint of this study is the incidence of Grade ≥3 AE and incidence of imAEs. 
Any AEs which started after the 90th day following discontinuation of IMP will be included in 
the data listings. Any AE that occurs after the start of subsequent anti-cancer therapy will be 
flagged in the data listings. These events will not be included in AE summaries.
3.1.2
Secondary Safety Endpoints
The secondary safety endpoints of this study include:
!
Treatment-emergent adverse events (TEAEs) and SAEs
!
AESI (see Section 3.1.3.1)


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!
AEs leading to death
!
AEs leading to study drug interruption or discontinuation
!
Death from all causes
!
Laboratory data including clinical chemistry, hematology, and urinalysis
!
Physical Examination
!
Vital signs including blood pressure, pulse, temperature, and respiration rate
!
ECG
3.1.3
Adverse Events
Details of all AEs and SAEs will be collected for a patient from the signing of the informed 
consent form (ICF) until the follow-up period is completed (90 days after the last dose of 
durvalumab). 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 AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) providing the System Organ Class (SOC) and Preferred Term (PT). 
In addition, all AEs will also be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for AEs (CTCAE Version 5.0) allocating grades from Grade 1 
to Grade 4 which will be used for the reporting. The meaning of these categories are as follows:  
!
Grade 1: Mild AE
!
Grade 2: Moderate AE
!
Grade 3: Severe AE
!
Grade 4: Life-threatening or disabling AE
!
Grade 5: Death related to AE
TEAEs are are defined as events present at baseline that worsen in intensity after administration 
of IMP or events absent at baseline that emerge after administration of IMP, for the period 
extending to 90 days after the last dose of IMP. Any TEAE will be included in the AE 
summaries as detailed in Section 4.5.1.
Missing start and stop dates for AEs will be imputed using the rules described in Section 4.1.4.
3.1.3.1
Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the Investigational 
Product and may require close monitoring. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this IMP. All AESIs will be programmatically 
derived.


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An AstraZeneca medically qualified expert, after consultation with the Global Patient Safety 
Physician, will review all AEs of interest and identify which PTs contribute to each AESI. A 
further review will take place prior to DBL to ensure any further terms not already included are 
captured within the categories. The final list of PTs for all AESIs will be completed before DBL 
and documented in the Study Master File.
Time to event analyses for AESIs will be performed for the following definitions: 
!
Time to first onset of AESI: Start date of first AESI episode – First dose date of 
durvalumab + 1
!
Time to first onset of AESI of Grade 3 or 4: First date of AESI episode that had CTCAE 
Grade 3 or 4 – First dose date of durvalumab + 1
!
Time to resolution of AESI: End date of AESI episode – Start date of AESI episode + 1
!
Time to resolution of Grade 3 or 4: End date of AESI episode that had 
CTCAE Grade 3 or 4 – First date AESI episode had severity of grade 3 or higher + 1
If an AESI does not resolve, then the time to resolution will be censored at earliest date of DCO, 
death date, or last dose date + 90 days. Patients who die prior to resolution of the AESI will be 
censored at the date of death.
3.1.3.2
Immune-Mediated Adverse Event
An imAE is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated MOA and where there is no clear alternate etiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the imAE. Adjudication of the imAEs will be performed by AstraZeneca
using imAE charter.
Time to event analyses for imAEs will be performed for the following definitions: 
!
Time to first onset of imAE: Start date of first imAE episode – First dose date of 
durvalumab + 1
!
Time to first onset of imAE of Grade 3 or 4: First date of imAE episode that had 
CTCAE Grade 3 or 4 – First dose date of durvalumab + 1
!
Time to resolution of imAE: End date of imAE episode – Start date of imAE episode + 1
!
Time to resolution of Grade 3 or 4: End date of imAE episode that had 
CTCAE Grade 3 or 4 – First date imAE episode had severity of grade 3 or higher + 1
If an imAE does not resolve, then the time to resolution will be censored at earliest date of DCO, 
death date, or last dose date + 90 days. Patients who die prior to resolution of the imAE will be 
censored at the date of death.
3.1.4
Electrocardiograms
These measurements are recorded as detailed in the study schedule (See Appendix A).
Whenever ECGs, vital signs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.


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At Screening, and as clinically indicated throughout the study, 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 corrected QT interval using 
Fridericia’s formulae (QTcF) value > 470 ms, 2 additional 12-lead ECGs should be obtained 
over a brief period (eg, 30 minutes) to confirm the finding. 
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula: 
QTcF = QT/RR^(1/3) where RR is in seconds 
3.1.5
Vital Signs
Vital signs measurements will be collected at the start of each treatment cycle as detailed in the 
schedule of assessment (Appendix A).
Measurements will include SBP (mmHg), DBP (mmHg), pulse rate (breaths/min), weight (kg), 
body temperature (degrees Celsius), and respiratory rate (breaths/min). Height is recorded at 
screening only.
3.1.6
Laboratory Data
Laboratory data (clinical chemistry, haematology and urinalysis) will be collected at the start of 
each treatment cycle as detailed in the schedule of assessment and as clinically indicated 
(Appendix A). Coagulation tests are only performed at baseline on Day 1 (unless performed 
within 3 days prior to Day 1) and as clinically indicated. 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.
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) 
3.1.7
Physical Examination
Physical examinations will be performed according to the assessment schedules (Appendix A).
Findings in these data will be reported as medical history at Screening and as AEs at post-
screening visits and will be included in data analyses accordingly.
3.1.8
Exposure to IMP
The total (or intended) exposure (weeks) of IMP is defined as:
!
Total treatment duration (weeks) = Total treatment duration (days) / 7
where:


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Treatment duration (days) during durvalumab + EP treatment period = [earliest of (last 
dose date where dose > 0mg + 20 days, death date, cut-off date [DCO])-first dose date of 
durvalumab + EP] +1
Treatment duration (days) during durvalumab monotherapy period = [earliest of (last 
dose date where dose > 0mg + 27 days, death date, cut-off date [DCO])-first dose date of 
durvalumab monotherapy] +1
Total treatment durations (days) = treatment duration during durvalumab + EP treatment 
period + treatment duration during durvalumab monotherapy period
The actual exposure (weeks) of IMP is defined as:
!
Actual treatment duration (weeks) = [total treatment duration (days) – total duration of 
dose delays (days)] / 7. 
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. 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. 
Dose modifications for EP treatment can be performed according to local guidance.
Patients are scheduled to receive 1500 mg via IV infusion concurrently with platinum-based 
chemotherapy (Investigator’s choice of cisplatin or carboplatin) and etoposide every 3 weeks 
(21 days) starting on Week 0 for up to 6 cycles. Durvalumab monotherapy will be continued 
every 4 weeks (28 days) post-chemotherapy until confirmed radiological disease progression. 
The duration of dose delays is the sum of all individual dose delays as follows:
!
Duration of dose delays (days) during durvalumab + EP treatment period = sum of 
MAX[0, (date of dose [x+1] – date of dose [x] - 21 days)].
!
Duration of dose delays (days) during durvalumab monotherapy period = sum of 
MAX[0, (date of dose [x+1] – date of dose [x] - 28 days)].
!
Total duration of dose delays (days) = duration of dose delays during durvalumab + EP 
treatment period + duration of dose delays during durvalumab monotherapy period
If no delays were encountered, the total duration of dose delays would sum up to 0.
Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered relative to 
the intended dose intensity through to treatment discontinuation. 
RDI is defined as follows:
RDI = 100% * d/D, where d and D are, respectively, the actual and intended cumulative doses 
delivered up to the date of durvalumab discontinuation or progressive disease or the data cut-


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off date, whichever occurs earlier. D is the total dose that would be delivered if there were no 
modification to dose or schedule.
When deriving actual dose administered the volume before and after infusion will also be 
considered.
To illustrate the calculation of RDI, Table shows an example of durvalumab dosing for 4 
patients.
Table 1
Example dose intensity scenarios
Study Day
RDI
Patient
1
29
43
64
85
106
134
155
176
181
100%
1
X
X
X
X
X
X
X
X
X
PD
100%
2
X
X
X
X
X
X
X
X[D]
PD
56%
3
X
         X                  X        O       X       X
PD
67%
4
X
X
O
X
X
X
O
X
O
PD
X: Dose of 1500mg taken; O: Dose missed; [D]: Dose discontinued; PD: Progressive Disease
In this example, all 4 Patients progressed on Day 181, and so the intended dose through to 
progression was 9 * 1500mg of durvalumab = 13500mg (13.5g).
Patient 1 received a total of 13.5g of durvalumab, whereas other patients received less 
durvalumab due to: 
!
Early stopping prior to PD (Patient 2) 
!
Dosing delays (Patient 3) 
!
Missed doses (Patient 4) 
For RDI the examples of Patients 2 and 4 illustrate that the end of actual dosing period is 
calculated based on the smallest recovery period after the last non-zero dose. 
Patient 1:
RDI = (9 * 1.5g)/ 13.5g = 100%
Patient 2:
RDI = (8 * 1.5g)/ 12g = 100% 
Patient 3:
RDI = (5 * 1.5g)/ 13.5g = 56% 
Patient 4: 
RDI = (6 * 1.5g)/ 13.5g = 67%
Exposure will also be measured by the number of cycles (doses) of durvalumab received.  If a 
cycle is prolonged due to toxicity this will still be counted as one cycle.  A cycle will be counted 
if treatment is started, even if the full dose is not delivered.  
3.2
Efficacy Variables
All RECIST assessments, whether scheduled or unscheduled, and regardless of whether a 


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patient discontinues durvalumab treatment or receives another anti-cancer therapy will be 
included in the calculation of efficacy variables.
3.2.1
Derivation of RECIST Visit Responses
This study will evaluate the efficacy of durvalumab + EP as secondary endpoints, in terms of 
OS, as well as PFS, PFS12, ORR, DoR, and DoR12, which will be derived from site Investigator 
assessments per RECIST1.1.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV 
contrast, of the chest and abdomen (including the entire liver and both adrenal glands), collected 
during screening/baseline and at regular (follow-up) intervals during study treatment. Tumor 
assessments from CT or MRI of the brain scan will be collected at baseline and when clinically 
indicated. Pelvic imaging is recommended only when primary or metastatic disease in the pelvic 
region is likely. 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 SoAs). If an unscheduled assessment is performed 
(eg, to investigate clinical signs/symptoms of progression) and the patient has not progressed, 
every attempt should be made to perform the subsequent assessments at the next scheduled visit. 
Treatment continues until clinical progression/deterioration or confirmed radiological 
progression, and scanning/tumor assessments continue throughout treatment until RECIST 1.1-
defined radiological progression plus an additional follow-up scan (if clinically feasible).
The RECIST 1.1 guidelines 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 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, stable disease, PD, or Not Evaluable [NE]).
For all patients who are treated through progression, a follow-up scan is to be collected 
4-8 weeks after the initial RECIST 1.1-defined PD; this follow-up scan is evaluated using the 
post-progression criteria outlined in CSP Appendix F. If the subsequent scan confirms the 
immediate prior radiological PD, no additional scans are required unless the patients are allowed 
to continue study treatment; however, if the subsequent scan does not confirm the immediate 
prior radiological PD, scanning should continue until the next RECIST 1.1-defined PD which 
in turn will require a subsequent scan evaluated using the post-progression criteria outlined in
Appendix F of CSP.
3.2.2
Progression-Free Survival
Progression-free survival is defined as the time from the first date of treatment until the date of 
objective disease progression as per RECIST 1.1 or death (by any cause in the absence of 
progression) regardless of whether the patient withdraws from IMP or receives another 
anticancer therapy prior to progression. 


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!
PFS (months) = (Date of event or Censor date – treatment start date +1) / (365.25/12)
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable assessment (ie, this doesn’t include NE or 
missing value).
However, if the patient progresses or dies after 2 or more missed visits, the patient will be 
censored at the time of the latest evaluable assessment prior to the 2 missed visits.
Given the scheduled visit assessment scheme (i.e. six-weekly for the first 12 weeks then eight-
weekly thereafter) the definition of 2 missed visits will change. 
1. If the previous RECIST assessment is baseline then two missing visits will equate to 13
weeks since the previous RECIST assessment, allowing for a late visit (i.e. 2 x 6 weeks 
+ 1 week for a late assessment = 13 weeks).
2. From week 13 onwards (when the scheduling changes to eight-weekly assessments), 
two missing visits will equate to 18 weeks (i.e. 2 x 8 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 18 weeks).
If the patient has no evaluable visits or does not have baseline data, he/she will be censored at 
Day 1 unless he/she dies within 2 visits of baseline, in which case the date of death is the event 
date.
If the patient has confirmed/suspected COVID-19 deaths, and has not progressed prior to death, 
he/she will be censored at the time of the latest evaluable assessment prior to the COVID-19 
death date.
A sensitivity analysis will be conducted to assess for the potential impact of COVID-19 deaths 
on PFS. This will be assessed by repeating the PFS analysis except that any patient who had 
a PFS event due to death where primary/secondary cause of death was due to COVID-19 
Infection, or a COVID-19 infection reported as a fatal AE, will be censored at their last 
evaluable assessment prior to their COVID-19 infection death date.
3.2.3
Overall Survival
The OS is defined as the time from the first date of treatment until death due to any cause.
!
OS (months) = (Death date or Censor date - treatment start date +1) / (365.25/12)
Any patient who has confirmed/suspected COVID-19 death, or 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 date that an individual patient was last known to be alive will be identified exclusively 
using the data recorded within the SURVIVE and DEATH modules of the electronic case report 
form (eCRF).
A sensitivity analysis will be conducted to assess for the potential impact of COVID-19 deaths 
on OS. This will be assessed by repeating the OS analysis except that any patient who had 
a death with primary/secondary cause as COVID-19 Infection, or a COVID-19 infection 
reported as a fatal AE will be censored at their COVID-19 infection death date.


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3.2.4
Objective Response Rate
The ORR is defined for the SAF as follows:
!
The ORR is the proportion (%) of patients with an overall response of CR or PR based on 
Investigator-assessed response. 
Data obtained up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of the ORR. Responses that occur after the start 
of subsequent anti-cancer therapy must be excluded from the derivation of ORR (ie, only 
responses that occur prior to receiving subsequent therapy will be included in the numerator).
3.2.5
Best Objective Response 
Best objective response (BoR) is the best response a patient has had after Day 1 up until 
progression, or the last evaluable assessment in the absence of progression. Responses that 
occur after the start of subsequent anti-cancer therapy must be excluded from the derivation. 
Categorization of BoR will be based on RECIST using the following response categories: CR, 
PR, SD, PD and NE.
CR or PR must be confirmed. For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used. SD should be 
recorded at least 6 weeks minus 1 week, ie, at least 35 days (to allow for an early assessment 
within the assessment window), after durvalumab initiation. For CR/PR, the initial overall visit 
assessment that showed a response will use the latest of the dates contributing towards a 
particular overall visit assessment.
For patients whose progression event is death, BoR will be calculated based upon all evaluable 
RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs <= 7 weeks 
(ie, 6 weeks + 1 week to allow for a late assessment within the assessment window) after 
durvalumab initiation, then BoR will be assigned to the progression (PD) category. For patients 
who die with no evaluable RECIST assessments, if the death occurs > 7 weeks after Day 1 then
BoR will be assigned to the NE category.
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied at 
any time following Day 1, prior to RECIST progression and prior to starting any subsequent 
cancer therapy.
3.2.6
Duration of Response
For patients who are classified as responders (see Section 3.2.4), the DoR is defined as the time 
from the date of first documented response until the first date of documented progression or 
death in the absence of disease progression.
!
DoR (months) = (Date of PFS event or censoring – Date of start of response +1) / 
(365.25/12)












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!
Characteristics of disease under investigation at diagnosis: original diagnosis date, primary 
tumor location, histology type, virology status at screening, macrovascular invasion 
(yes/no), extent of resection, primary tumor, American Joint Committee on Cancer (AJCC) 
staging.
3.4.2
Prior and Concomitant Medications and Therapies
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study will be recorded in the CRF. Details include generic and/or brand names of 
medications, WHO drug dictionary encoding, therapy reason, route, dose, dosing frequency, 
and start and stop dates. 
Prior therapies are defined as those with at least one dose/treatment taken before the date of the 
first dose of IMP.
Concomitant therapies are defined as those with at least one dose/treatment taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of IMP.
Missing start and stop dates for medications will be imputed using the rules described in Section
4.1.4.
4.
ANALYSIS METHODS
4.1
General Principles
4.1.1
General Statistical Considerations
The following general statistical considerations will be applied for the analyses and presentation 
of the data. In case of any specific deviations, methods will be specifically noted on the relevant 
output.
!
The primary analysis, for safety, will be conducted approximately 6 months after the last 
patient is enrolled into the study and the final statistical analysis will be conducted after 
the last patient has had the opportunity to be followed up for a minimum of 12 months or 
60% OS maturity, whichever occurs first. All the safety analysis will be done initially at 
6 month and then same will be repeated at the final analysis.
!
All data, demography, baseline characteristics, safety, efficacy and biomarkers, will be 
summarized using descriptive statistics, as appropriate for the type of data, for the SAF. 
!
Continuous variables will be summarized by the number of observations (n), mean, 
standard deviation, median, quartiles (Q1 and Q3), minimum, and maximum.
!
For the continuous data, the summary statistics will be displayed with the following 
accuracy (number of decimal places):
!
The minimum and maximum with same accuracy as the raw data. 
!
The mean, median and quartiles (Q1 and Q3) will be rounded to 1 additional decimal 


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place more than the number of decimal places in the raw data. 
!
The standard deviation will be rounded to 2 additional decimal places more than the 
number of decimal places in the raw data. 
!
If the number of observation is 1, then only n will be displayed in the output. Other 
summary statistics will be displayed as NE.
!
Categorical variables will be summarized by frequency counts and percentages for each 
category and percentages will be rounded to one decimal place. If the percentage is 100%, 
no decimal places will be displayed.
!
As a default, percentages will be calculated using the number of patients in the SAF as the 
denominator, with the exception of some summaries of patient disposition and particular 
individual patient data listings. If the denominator is different from this default, it will be 
explained in a footnote to the output.
!
SAS® version 9.3 or higher will be used for all analyses.
!
Exact CIs for proportions will be calculated using the Clopper-Pearson method.
!
For percentiles of survival times based on the Kaplan-Meier method (eg, median PFS, 
median OS), CIs will be calculated using the default method available in the SAS 
LIFETEST procedure (ie, the Klein and Moeschberger extension of the Brookmeyer-
Crowley method).
!
For point-estimates of survival based on the Kaplan-Meier method (eg, for PFS, OS), CIs 
will be calculated using the default method available in the SAS LIFETEST procedure 
(ie, using Greenwood’s estimate of standard error and a log-log transformation).
!
The data will be included in summaries/analyses using the following criteria:
!
All laboratory data, vital signs data that are recorded at unscheduled visits will be 
included in the summaries using the visit windows defined in Section 4.1.5.1. 
!
The tumor measurements should not be affected by any delays in treatment 
cycles/dates of start of treatment cycles as it is intended that they are only recorded 
at pre-scheduled time points. These data will be included in the summaries and 
analyses of the data using the visit windows defined in Section 4.1.5.2.
!
All data collected including scheduled, delayed and unscheduled data will be listed in the 
patient data listings which are produced for all enrolled patients. They will be ordered by 
centre, WHO/ECOG PS group, patient and visit and, if relevant, timepoint when they were 
recorded. Patients who are included in the SAF will be flagged. 
!
All adverse events will be coded using MedDRA and NCI CTCAE Grade and will be 
reported using SOC and PT, NCI CTCAE Grade, as appropriate.
!
All concomitant and previous medications will be coded using WHO drug dictionary 
and will be reported using anatomical therapeutic chemical (ATC) classification and 
generic term. 


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!
Baseline is defined as the last assessment of the variable under consideration prior to the 
first dose of IMP regardless of whether the assessment is on Day 1, Screening or 
unscheduled. For RECIST and ECOG, baseline assessment will be on or before the first 
dose of IMP.
!
All the outputs will be presented by ECOG PS 0 or 1 and ECOG PS 2.
4.1.2
Subgroup Analysis
All efficacy and safety data and some selected relevant data (eg, patient disposition, 
demography and baseline characteristics) will be summarised separately but not limited to the 
following subgroup:
o
Age at baseline (<65 versus ≥65 years)
o
Region
o
4.1.3
General Considerations for Summary of Safety Data
The following considerations are for the summary of safety data.
!
The missing values in vital signs, laboratory data, coagulation and urinalysis will not be 
imputed. 
!
If a laboratory value is reported as <LLQ (where ‘LLQ’ is the lower limit of 
quantification), then LLQ value will be used to impute ‘<LLQ’ for the summary tables. 
In the data listings, this value will be listed as reported <LLQ. 
!
Any TEAEs with missing causality data will be considered as related to the durvalumab.
!
Any TEAEs with missing assigned CTCAE grades, the criteria recommended in the 
CTCAE manual that converts severity levels into CTCAE grades should be used. If 
severity is missing, the worst case will be assumed.
!
Any partial dates will be presented as reported in the data listings. The partial dates will 
be imputed for the derivation of time to resolution, time to onset etc. using the criteria 
given in Section 4.1.4. 
4.1.4
Handling of Missing Data
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “<LLQ” (ie, below the lower limit of quantification) or >ULQ (where ‘ULQ’ is the 
upper limit of quantification) will be imputed as the LLQ value or ULQ value in the calculation 
of summary statistics but displayed as “<LLQ” or “>ULQ” in the listings.
If the start date of the concomitant medication or AE is missing, the following rules will be 
applied:
CCI


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!
If the year is missing, the year should be imputed as the year that patient received the first 
dose of durvalumab.
!
If the year is available and the month and day are missing, then impute the month as 
January and the day as 01.
!
If the year and month are available and the day is missing, impute the day as 01 (the first 
day of the month).
!
If any of the above puts the date before the date of first dose of durvalumab, a conservative 
approach is followed and, the date is imputed using the date of first dose.
If the stop date of the concomitant medication or AE is missing, the following rules will be 
applied:
!
If the year is missing, the year should be imputed as the year that patient received the last 
dose of durvalumab.
!
If the year is available and the month and day are missing, then impute the month as 
December and the day as 31.
!
If the year and month are available and the day is missing, impute the day as the last day 
of the month (eg, 28, 29, 30 or 31).
!
If any of the above puts the date after the date of the last dose of durvalumab, a 
conservative approach is followed and, the date is imputed using the data cut-off date 
(DCO).
!
It is not expected to have missing dates for unscheduled laboratory, diagnostics data. 
However, if there are missing dates, for any derivations, the dates should be imputed 
following the rules for concomitant medications and AEs
4.1.5
Definitions of Visit Windows
Time windows are defined for all summaries of vital signs, laboratory data,
 around visits 
in Section 4.1.5.1 and for tumor assessments around the scheduled RECIST assessment time in 
Section 4.1.5.2.
4.1.5.1
Visit Windows for Safety 
 Assessments
The following conventions will apply for safety
 data:
!
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.
!
All unscheduled visit data will have the potential to be included in the summaries.
!
The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the first 
post-baseline visit will be Day 2).  If an even number of days exists between two 
consecutive visits, then the upper limit will be taken as the midpoint value minus 1 day.  
CCI
CCI
CCI


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Date 07 June 2023
Page 37 of 51
If an odd number of days exists between two consecutive visits, then the upper limit will 
be taken as the midpoint value minus 0.5 day. 
For example, if a patient receives durvalumab plus EP for 4 cycles and then durvalumab 
monotherapy, the visit windows for vital signs data are:
!
Week 1; nominal day 1, visit window Day 1
!
Week 3; nominal day 22, visit window 2 – 32
!
Week 6; nominal day 43, visit window 33 – 53
!
Week 9; nominal day 64, visit window 54 – 74
!
Week 12; nominal day 85, visit window 75 – 98
!
Week 15; nominal day 106, visit window 96 – 116
!
Visits after treatment discontinuation will be assigned to the last treatment cycle
for up to 15 days only. Visits after the 15 days will contribute to the following 30 
days post treatment discontinuation interval, see below.
!
Visits up to 90 days after last dose will be assigned similarly to the definition for the visits
under treatment, but for 30 day intervals after treatment discontinuation, eg,:
!
30 days after last dose, visit window 16 – 45 
!
60 days after last dose, visit window 46 – 75
!
90 days after last dose, visit window 76 – 97
!
Data recorded after 97 days after last dose will not contribute to the analysis period 
of up to 90 days following the date of last dose, and will not be re-mapped
!
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded during treatment period will be used (regardless of where it falls in an interval), 
visits post treatment discontinuation will not be used.
!
Listings should display all values based on the scheduled or unscheduled visit specified 
on the eCRF on which the data were collected for a patient.
For visit based summaries:
!
If there is more than one value per patient within a time window then the closest value to 
the scheduled visit date should be used, or the earlier in the event the values are equidistant 
from the nominal visit date.  If there are two values recorded on the same day and the 
parameter is CTCAE gradable then the record with the highest toxicity grade should be 
used. The listings should highlight the value for that patient that went into the summary 
table, wherever feasible. Note: in summaries of extreme values all on-treatment values 
collected are used including those collected at unscheduled visits.  
!
For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit-based summary, when deriving a patient level statistic such 
as a maximum. 


Statistical Analysis Plan 
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4.1.5.2
Visit Windows for Tumor Assessments
The following conventions will apply for tumor assessment data:
!
All tumor assessments available during the study should be used for the efficacy analysis. 
A windowing rule will be applied and will follow the CSP allowed visit window; 
therefore, any RECIST assessment performed within ± 1 week of the CSP scheduled visit 
will be used for that visit.
!
If there are any assessments outside these visit windows, they will also be included in the 
closest visit window following the intent-to-treat principle.  The tumor assessments which 
are outside the visit windows will be flagged in the data listings. 
The above could result in more than one tumor assessments within a window and in that case, 
the one closest to the scheduled assessment will be used. 
4.2
Study Population
4.2.1
Patient Disposition
The following patient disposition summaries will be produced:
!
The number and percentage of patients who were screened, who were screening failures,
and who received and did not receive IMP will be summarised for all patients.
!
Discontinuation from durvalumab, discontinuation from EP , discontinuation from study, 
together with reason for discontinuation will be summarised for all patients.
!
Discontinuation of study intervention and/or withdrawal from study due to COVID-19 
will be presented separately.
The date and day of the last contact, date of informed consent, date of genetic informed consent,
date of determining eligibility for the study, treatment completion status, study completion 
status will be listed in patient disposition listings.
The number and percentage of patients with confirmed or suspected COVID-19 infection will
be presented separately, including details on COVID-19 related interruptions impacting on 
visits and investigational product administration. Listings of patients affected by the COVID-
19 pandemic will be presented detailing any affect and impact on the study. Issues reported in 
the Clinical Trial Management System will be considered for presented in listings as well.
4.2.2
Protocol deviations 
Important protocol deviations are defined in Section 2.2.1 and will be listed and summarized
for the SAF, including a summary of those identified as resulting from the COVID-19 
pandemic.
The number and percentage of patients with any IPD will be summarized for each IPD category. 
Patients with more than one deviation in the same IPD category will be counted once for that 
IPD category. Any patients who have deviations in more than one IPD category will be counted 
once in the overall summary.


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4.2.3
Demography and Baseline Characteristics
Demographic and other baseline characteristics (see Section 3.4.1) will be listed for all patients 
and summarised for the SAF, as:
!
Demographics (age, age group [<50, >=50-< 65, ≥ 65-<75, and ≥ 75 years], sex, race and 
ethnicity)
!
Patient characteristics at baseline (height, weight, body mass index (BMI), and BMI 
groups [Underweight (<18.5), Normal weight (>=18.5 - <25.0), Overweight (>=25.0 -
<30.0), Obese (>=30.0)], childbearing potential, menopausal status)
!
Nicotine use and consumption (smoking status (current, former, never), pack years)
!
Extent of disease upon entry of study (evidence of disease, sites of metastatic/locally 
advanced disease, recent progression [yes/no, date], patients ES-SCLC progressing at 
enrolment, reason tumor not amenable for resection)
!
Characteristics of disease under investigation at diagnosis (original diagnosis date, 
primary tumor location, histology type, virology status at screening, macrovascular 
invasion, extent of resection, primary tumor, AJCC staging)
!
Previous cancer therapy (number of prior chemotherapy regimens, number of cycles, 
therapy class, time from completion of chemotherapy to study treatment, best response to 
previous chemotherapy, treatment status, concomitant radiotherapy)
!
Previous radiotherapy (total dose, radiotherapy site, time from completion of radiotherapy 
to study treatment, treatment status, concomitant chemotherapy)
!
A summary and a list of patients by site and country will be provided.
Medical history and relevant surgical history are coded using MedDRA and will be summarized 
by SOC and PT.
If necessary, demographics will further be summarized separately for all patients in the SAF 
who had confirmed or suspected COVID-19 infection.
4.2.4
Previous and Concomitant Medications and Procedures
Prior and concomitant medications and procedures will be listed for all patients in the SAF.
Concomitant medications will be summarized by chemical subgroup (ATC 4th level), and 
preferred WHO name for the SAF. Patients with the same concomitant medication/procedure 
multiple times will be counted once per medication/procedure. A medication/procedure that can 
be classified into more than one chemical and/or therapeutic subgroups will be presented in 
each subgroup.
4.3
Analysis of Primary Safety Endpoint
The primary endpoint of this study is the incidence of Grade ≥ 3 AE and incidence of imAE. 
Any Grade ≥ 3 AEs or imAEs which started more than 90 days after discontinuation of IMP 
will not be included.


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The number and percentage (and exact Clopper-Pearson 95% CI) of patients with NCI CTCAE 
Grade ≥ 3 AEs will be summarized for all patients in the SAF. The number and percentages of 
patients with NCI CTCAE Grade ≥ 3 AEs will also be summarized by SOC and PT. Same tables 
will be presented for patients with imAEs.
4.4
Analysis of Secondary Efficacy Endpoints
All statistical analyses of the efficacy endpoints will be presented using the SAF. 
The tumor evaluation of target lesion and non-target lesion will be listed, and all tumor response 
will be listed.
Tumor size will also be presented graphically using waterfall plots, to present each patient’s 
month 12 percentage change in target lesion tumor size as a separate bar, with the bars ordered 
from the largest increase to the largest decrease. In this plot, the response status (CR, PR, SD, 
PD, or NE) will be distinguished.
4.4.1
Progression-Free Survival
Kaplan-Meier plots and descriptive statistics will be provided for PFS. Summaries will include 
number (%) of patients experiencing a PFS event, type of event (disease progression or death),
number of patients censored, lower and upper quartile and median PFS (months), along with 
the 95% confidence interval. The 3-month (Day 92), 6-month (Day 183), 9-month (Day 274), 
12-month (Day 365) PFS estimates will also be presented.
In addition, proportion of patients alive and progression-free at 12 months from the first date of 
treatment (PFS12) will be presented with the corresponding exact 95% CIs.
If necessary, a sensitivity analysis will be conducted to assess the potential impact of COVID-
19 related deaths on PFS. That is, patients who had a PFS event due to death where the primary 
or secondary cause of death was COVID-19 infection or COVID-19 infection was reported as 
a fatal AE, will be censored at the last evaluable RECIST 1.1 assessment prior to COVID-19 
infection related death.
4.4.2
Overall Survival
Kaplan-Meier plots and descriptive statistics will be presented for OS. Summaries will include 
number (%) of patients experiencing an OS event (overall and also at Month 12), type of event 
(death), number of patients censored, lower and upper quartile and median OS (months), along 
with the 95% confidence interval.
In addition, proportion of patients who are alive 12 months from the first date of treatment 
(OS12) will be presented with the corresponding exact 95% CIs.
If necessary, a sensitivity analysis will be conducted to assess the potential impact of COVID-
19 related deaths on OS. That is, patients who had a death event where the primary or 
secondary cause of death was COVID-19 infection or COVID-19 infection was reported as a 
fatal AE, will be censored at the date of their COVID-19 infection related death.


Statistical Analysis Plan 
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Date 07 June 2023
Page 41 of 51
4.4.3
Objective Response Rate
The ORR based on investigator-assessed response will be estimated for the SAF and will be 
presented with the corresponding exact 95% CIs.
The number (%) of patients with a CR or PR and the number (%) of patients with a single visit 
response (ie, an unconfirmed response) will also be presented.
4.4.4
Duration of Response
A Kaplan-Meier plot and descriptive statistics will be provided for the DoR for patients in the 
SAF who had responded to treatment (see Section 3.2.6). In the event of insufficient number of
events, descriptive statistics will be provided. Summaries will include: number (%) of 
responders experiencing a PFS event (overall and also at Month 12), type of event (disease
progression or death), number of patients censored, lower and upper quartile and median DoR 
with appropriate 95% CIs. The 3-month (Day 92), 6-month (Day 183), 9-month (Day 274), 12-
month (Day 365) DoR estimates will also be presented. 
In addition, proportion of patients who remain in response 12 months after first documented 
response (DoR12) will be presented with the corresponding exact 95% CIs.
Swimmer plots that clearly show the profile of each patient who responds will also be produced.
4.5
Analysis of Secondary Safety Endpoints
4.5.1
Adverse Events
All AEs reported up until 90 days following completion or discontinuation of durvalumab 
treatment or until the initiation of the first subsequent therapy (whichever occurs first) will be 
included in the summaries unless explicitly stated otherwise below.
All AEs will be summarised descriptively, in terms of number of patients (n) and percentage of 
patients (%) reporting the event by MedDRA SOC and PT. 
Listings of AEs will include the date of onset, date of resolution (if AE is resolved) and 
investigator’s assessment of severity, relationship to durvalumab, relationship to EP treatments, 
and NCI CTCAE Grade. Separate listings will be produced for all AEs, SAEs, AESIs, imAEs, 
AEs leading to treatment discontinuation, AEs leading to treatment interruption, AE leading to 
death. Listings of AESIs and imAEs will also include the additional information (eg,
intervention, dose, duration of therapy etc.) recorded for these AEs. All AEs that are not 
treatment-emergent will be flagged in the data listings and the time of onset will be flagged as 
‘pre-treatment’, ‘post-treatment and no other anti-cancer therapy’ and ‘after initiation of other
anti-cancer therapy’.
An overall summary of AE data will be presented including the number and percentage of 
patients reporting the following:
!
At least one AE
!
At least one AE of CTCAE Grade ≥ 3
o
Exact Clopper-Pearson 95% CI will be reported for patients overall and


Statistical Analysis Plan 
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Page 42 of 51
separately by ECOG PS 0 to1 and PS 2
!
At least one AE of CTCAE Grade ≥ 3, possibly related to durvalumab
!
At least one AE of CTCATE Grade≥ 3, possibly related to EP (etoposide+platinum)
!
At least one SAE
!
At least one SAE, possibly related to durvalumab
!
At least one SAE, possibly related to EP (etoposide+platinum)
!
At least one AESI
!
At least one imAE 
o
Exact Clopper-Pearson 95% CI will be reported for patients overall and 
separately by ECOG PS 0 to1 and PS 2
!
At least one AE leading to interruption or discontinuation of durvalumab
!
At least one AE leading to interruption or discontinuation of EP (etoposide+platinum)
!
(cisplatin/carboplatin)
!
At least one AE leading to interruption or discontinuation of durvalumab, possibly 
related to durvalumab
!
At least one AE leading to interruption or discontinuation of EP (etoposide+platinum), 
possibly related to EP (etoposide+platinum)
!
At least one AE leading to death
!
At least one AE associated with COVID-19
The following summaries including the number and percent of patients by SOC and PT, and 
maximum NCI CTCAE grade will be presented separately:
!
All AEs
!
All AEs of CTCAE Grade ≥ 3
!
All SAEs
!
All AEs leading to death
!
All AEs leading to death, possibly related to study treatment
!
At least one AE leading to interruption or discontinuation from study drug durvalumab
!
At least one AE leading to interruption or discontinuation from EP treatments
!
At least one AE leading to interruption from study drug durvalumab
!
At least one AE leading to discontinuation from study drug durvalumab
!
All AEs associated with COVID-19
!
All AEs excluding AEs associated with COVID-19
!
All confirmed/suspected COVID-19 AEs
!
All AEs excluding confirmed/suspected COVID-19 AEs
!
AEs leading to discontinuation of study intervention, excluding TEAEs associated with 
COVID-19 infection 
!
AEs associated with COVID-19 infection leading to discontinuation of study intervention
!
AEs with outcome of death, excluding TEAEs associated with COVID-19 infection
!
AEs associated with COVID-19 infection with outcome of death


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If multiple AEs of the same PT occur within a patient, only the maximum grade observed for 
this PT will be used in summary of AEs by grade; the patient will be counted only once in the 
number of patients for this PT and only once for the number of patients for the SOC to which 
the PT belongs.
A summary of most common AEs and another summary of most common AEs with CTCAE 
Grade 3 or higher, including all events that occur >2.5% of patients overall will be presented by 
PT, by decreasing frequency. This cut-off may be modified after review of the data. The raw 
percentage will be compared to the cut-off, without applying any rounding to the percentage 
value (ie, a TEAE with frequency of 2.5% will not appear in the table if a cut-off is 2.5%). This 
summary will also be presented for patients who received <=4 cycles and >4 cycles of EP 
(etoposide+platinum) based on etoposide.
A separate data listing of AEs occurring more than 90 days after discontinuation of IMP, and a 
data listing of AE associated with COVID-19 will be produced. 
A summary of deaths will be provided with the following information:
!
Number of deaths (related to disease under investigation, non-related, and unknown)
!
Number of deaths during the on-treatment study period up until 90-day follow-up
and prior to initiation of first subsequent therapy
!
Number of deaths occurring more than 90 days after the last dose of durvalumab or
after initiation of first subsequent therapy
Listings of key patient information for Deaths and SAEs will be provided.
4.5.1.1
Adverse Events of Special Interest and Immune-Mediated Adverse Events
The following summaries of AESIs/AEPIs will be presented by AESI category and PT, 
seriousness, causality, maximum NCI CTCAE grade, and immune-relatedness:
!
All AESIs/AEPIs
!
All serious AESIs/AEPIs
!
All AESIs/AEPIs leading to interruption or discontinuation from study drug durvalumab
!
All AESIs/AEPIs leading to interruption or discontinuation from EP treatments
!
All AESIs leading to death


Statistical Analysis Plan 
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Number and proportion of patients who received steroids, immunosuppressants, or hormone 
replacement therapy to manage AESIs will be summarized with the following time to event 
analyses for AESI/AEPI, by type of intervention:
!
Time to first onset of AESI/AEPI
!
Time to first onset of AESI/AEPI of Grade 3 or 4 
!
Time to resolution of AESI/AEPI
!
Time to resolution of AESI/AEPI of Grade 3 or 4
!
Duration of intervention with steroids, immunosuppressants, or hormone replacement 
therapy until the resolution of AESI/AEPI
Overall summaries will present the numbers and percentages of patients with at least one imAE 
by the following categories:
!
imAE
!
imAE of CTCAE Grade ≥ 3
!
imAE leading to interruption or discontinuation from study drug durvalumab
!
imAE leading to interruption or discontinuation from EP treatments
!
imAE leading to death
Using the same categories above similar summaries will be presented by preferred term, and by 
SOC and PT.
Time to event analyses for immune-mediated AE (imAE) will be performed by AESI categories, 
for: 
!
Time to first onset of imAE
!
Time to first onset of imAE of Grade 3 or 4 
!
Time to resolution of imAE
!
Time to resolution of imAE of Grade 3 or 4
For patients with imAEs having multiple PTs within an AESI category the AEs will be collapsed 
to one event if the difference between end date of an imAE and subsequent start date of the next 
imAE is <=3 days. The time to onset will be based upon the first PT, whereas time to resolution 
used for KM analysis will be based on time of the worst imAE episode from that given patient.
Summaries will include the number and percentage of patients with imAEs, lower and upper 
quartile and median time to event (days), and descriptive statistics.
At the AESI/AEPI grouped term level for time to resolution outputs the worst imAE is defined 
in the order of the following:
!
imAE with worst (highest) grade first
!
For more than one imAE with the same highest grade take imAE which did not resolve 
before imAE which did resolve
!
If multiple imAE and all resolved take imAE with longest duration
Summaries for imAEs and related data will be presented by imAE category and PT:


Statistical Analysis Plan 
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Edition Number 2.0
Date 07 June 2023
Page 45 of 51
!
All imAE
!
All serious imAE
!
All imAEs by maximum CTCAE Grade
!
All imAEs by outcome
!
All imAEs leading to interruption or discontinuation from study drug durvalumab
!
All imAEs leading to interruption or discontinuation from EP treatments
!
All imAEs leading to death
4.5.2
Electrocardiograms
Summaries of absolute and change from baseline values of each ECG parameters will be 
presented by visit. 
All individual ECG data will be listed.
4.5.3
Vital Signs
Absolute values and change from baseline for vital sign parameters (SBP, DPB, pulse rate, 
temperature, and respiration rate) will be summarised by visit.
Box plots of the vital signs results by visit will be presented.
4.5.4
Laboratory Data
Laboratory data obtained up until the 90 days after last dose of study treatment or until the 
initiation of the first subsequent anti-cancer therapy following discontinuation of study 
treatment (whichever occurs first) will be used for reporting. 
Absolute values and change from baseline for all continuous haematology and clinical 
chemistry laboratory parameters will be summarised by visit. If a patient does not have the 
baseline value of laboratory data or the value at visit, the change from baseline is considered as 
missing.
Shift tables for laboratory values by worst CTCAE Grade will be produced. The laboratory 
parameters for which CTCAE Grade shift outputs will be produced are:
!
Haematology: Absolute neutrophil count, Absolute lymphocyte count, Absolute
leukocytes count, Hemoglobin, Platelet count, Total white cell count
!
Clinical chemistry: Albumin, Alanine transaminase (ALT), Aspartate transaminase
(AST), Alkaline phosphatase (ALP), Amylase, Bicarbonate, Calcium, Chloride, 
Creatinine, Gamma glutamyl transferase, Glucose, Lactate dehydrogenase, Lipase, 
Magnesium, Potassium, Sodium, Total bilirubin, Total protein, Urea or blood urea 
nitrogen (depending on local practice)
For categorical urinalysis parameters (Bilirubin, Blood, Glucose, Protein), a shift table will be 
produced comparing baseline value to maximum on-treatment value. 
For the parameters with no CTCAE grading that are listed in the CSP the number and 
percentage of patients with laboratory values outside normal range will be summarized by 


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Page 46 of 51
shift tables from baseline to the post-baseline maximum and minimum value on-treatment.
4.5.4.1
Hy's Law
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.
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 plotted. 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. 
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 2×ULN for Total bilirubin. In each plot, total 
bilirubin will be in the vertical axis. 
Potential Hy’s law will also be summarized by liver risk factor, occurrence (yes/no), reference 
period (before/ongoing), and duration. All individual liver risk factors data and liver diagnostic 
investigation data will be listed.
4.5.4.2
Assessment of Thyroid Function Test Results
Shift table for TSH test, baseline versus maximum value on treatment will be produced for the 
categories:
!
Low
!
Normal
!
>1 to 2 x ULN
!
>2 x ULN
The following summaries will include the number and percentage of patients who have elevated 


Statistical Analysis Plan 
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Page 47 of 51
or low TSH:
!
On-treatment elevated TSH > ULN
!
On-treatment elevated TSH > ULN with TSH <= ULN at baseline
!
On-treatment elevated TSH > ULN 
!
With at least one T3 free/ T4 free < LLN
!
With all other T3 free/ T4 free >= LLN
!
With T3 free/ T4 free missing
!
On-treatment low TSH < LLN
!
On-treatment low TSH < LLN with TSH >= LLN at baseline
!
On-treatment low TSH < LLN 
!
With at least one T3 free/ T4 free > ULN
!
With all other T3 free/ T4 free <= ULN
!
With T3 free/ T4 free missing
4.5.5
Physical Examination
Full physical examinations are to be collected at baseline only. By-subject listings will be 
provided.
All individual targeted physical examination data will be listed only.
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.
4.5.6
Exposure
The following summaries will be presented for durvalumab exposure during durvalumab + EP 
treatment period, durvalumab monotherapy period, and overall:
!
Total (or intended) exposure
!
Actual exposure
!
Number of cycles received
!
Number and Reasons for dose delays of IMP
!
Relative dose intensity
Same summaries will be presented for EP treatments exposure during durvalumab + EP 
treatment period.
Individual patient data for each study drug administration (durvalumab and EP treatments) will 
be listed for all patients in the SAF.
All overdose report will be listed.
All medical error reports will be listed.
4.5.7
Pregnancy Test
Positive pregnancy test results will be listed only.








8.
APPENDIX
8.1
Appendix A:  Schedule of Assessments
The schedule of assessment is mentioned in the clinical study protocol.


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Document Name: d419qc00007-sap-ed-2
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Statistical Analysis Plan Edition 2
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