Conditions: Small Cell Lung Carcinoma Extensive Disease
Keywords: Extensive-Stage ICI SCLC Durvalumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 101
Healthy volunteers: yes

Brief summary:
This is a Phase IIIb, interventional, single arm, multicentre study to evaluate safety, effectivenees, use of resources and patient reporting outcomes in patients with ES-SCLC treated with durvalumab in combination with platinum-etoposide as first-line treatment in Spain.

Detailed description:
This trial will provide an opportunity to further evaluate the safety profile and efficacy of durvalumab + EP in patient population that is reflective of real-world clinical practice, Durvalumab will be concurrently administered with first-line chemotherapy (EP) on an every 3 week (q3w) schedule for 4 to 6 cycles, and will continue to be administered as monotherapy post-chemotherapy on an every 4 week (q4w) schedule until confirmed progressive disease (PD) or unacceptable toxicity.

Prophylactic cranial irradiation (PCI) is allowed in patients showing complete or partial responses after the durvalumab + EP combination cycles, at the discretion of the investigator according to their local clinical practice.

Arms:
arm 1: Durvalumab 1500 mg via IV infusion will be concurrently administered with first-line chemotherapy (EP) on an every 3 week (q3w) schedule for 4 to 6 cycles, and will continue to be administered post-chemotherapy on an every 4 week (q4w) schedule until confirmed progressive disease (PD) or unacceptable toxicity.

Interventions: intervention 1: Durvalumab intervention 2: Cisplatin intervention 3: Etoposide intervention 4: Carboplatin
Intervention descriptions: intervention 1: Durvalumab 1500 mg via IV infusion over 60 minutes on Day 1 of each cycle. intervention 2: Cisplatin as an IV infusion per local standards (usually over 60 to 120 minutes on Day 1) of each cycle. intervention 3: Etoposide sequentially administered per local standards (usually over 30 to 60 minutes IV infusion) on Days 1, 2, and 3 of each cycle. intervention 4: Carboplatin as an IV infusion per local standards (usually over 30 to 60 minutes on Day 1) of each cycle.

Protocol document:
Prot_004.pdf: 
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Clinical Study Protocol  
Drug Substance 
Durvalumab  
Study Code 
D419QC00005 
Version 
3.0 
Date 
02 Feb 2021 
A Phase IIIB Study in Untreated Patients with Extensive-Stage Small Cell 
Lung Cancer 
A Phase IIIB, Single Arm Study, of Durvalumab in Combination with 
Platinum-Etoposide for Untreated Patients with Extensive-Stage Small Cell 
Lung 
Cancer 
reflecting 
Real 
World 
Clinical 
Practice 
in 
Spain 
(CANTABRICO) 
Sponsor: 
AstraZeneca Farmacéutica Spain, S.A 
Serrano Galvache, 56 
28033 Madrid (Spain)  
 
 
 
 
Regulatory Agency Identifying Number(s): EudraCT number  2020-002328-35 


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VERSION HISTORY 
Version 2.0, 25 September 2020 
Section 6.4, table 6: Prohibited concomitant medications, has been updated with anti-
epileptics, according to clarifications requested by AEMPS. 
Version 3.0, 02 February 2021 
Table 1 Schedule of assessments for durvalumab therapy treatment: New rows have been 
added in relation with the blood samples for biomarker analysis and for an optional tumor 
biopsy at progression disease. Minimun time between cycles has been clarified. 
2.3.1.1 Durvalumab: Safety information of durvalumab has been added due to the update of 
the investigational brochure of durvalumab. 
Table 5  Study treatments: Duration of etoposide, cisplatin and carboplatin infusion has 
been modified according to the summary of product characteristics. 
5.1 Inclusion criteria: Inclusion criteria 4b has been updated to allow the inclusion of 
patients with treated brain metastases treated with steroids and anti convulsants. 
6.1.3. Order of Administration: Duration of etoposide, cisplatin and carboplatin infusion has 
been modified according to the summary of product characteristics. 
8.8 Biomarkers: Information related with the additional blood samples and a tumor sample at 
progression disease have been added. 
Table 11: Information related with biomarkers has been added due to the addition of 2 new 
substudies (See appendix D and E). 
Appendices J & K: 2 new appendices has been added due to the addition of 2 new 
biomarkers substudies.  
Appendix L: Dosing Modification and Toxicity Management Guidelines for Durvalumab has 
been also added as anappendix.   
 
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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RESPONSIBLE PARTIES 
 
Name 
Professional title 
Role in study 
Affiliation 
Email address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................... 1 
VERSION HISTORY ............................................................................................. 2 
TABLE OF CONTENTS ........................................................................................ 4 
1. 
PROTOCOL SUMMARY .................................................................................... 10 
1.1 
Schedule of activities (SoA) .................................................................................. 10 
1.2 
Synopsis................................................................................................................. 16 
1.3 
Schema .................................................................................................................. 22 
2. 
INTRODUCTION ................................................................................................. 22 
2.1 
Study rationale ....................................................................................................... 23 
2.2 
Background ........................................................................................................... 24 
2.2.1 
Immunotherapies ................................................................................................... 24 
2.2.2 
Durvalumab ........................................................................................................... 26 
2.2.3 
Durvalumab in combination with chemotherapy .................................................. 26 
2.3 
Benefit/risk assessment ......................................................................................... 27 
2.3.1 
Potential benefits ................................................................................................... 27 
2.3.1.1 
Durvalumab ........................................................................................................... 27 
2.3.1.2 
Durvalumab + chemotherapy ................................................................................ 27 
2.3.2 
Overall risks .......................................................................................................... 28 
2.3.2.1 
Durvalumab ........................................................................................................... 28 
2.3.2.2 
Durvalumab + chemotherapy ................................................................................ 29 
2.3.3 
Overall benefit/risk ................................................................................................ 29 
3. 
OBJECTIVES AND ENDPOINTS....................................................................... 30 
4. 
STUDY DESIGN .................................................................................................. 34 
4.1 
Overall design........................................................................................................ 34 
4.2 
Scientific rationale for study design ...................................................................... 35 
4.3 
Justification for dose ............................................................................................. 35 
4.3.1.1 
Durvalumab dose rationale .................................................................................... 35 
4.3.1.2 
Rationale for fixed dosing ..................................................................................... 36 
4.3.1.3 
Rationale for durvalumab + EP  dosing regimen .................................................. 37 
4.4 
End of study definition .......................................................................................... 37 
5. 
STUDY POPULATION........................................................................................ 37 
5.1 
Inclusion criteria .................................................................................................... 38 
5.2 
Exclusion criteria ................................................................................................... 40 
5.3 
Lifestyle restrictions .............................................................................................. 42 


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5.4 
Screen failures ....................................................................................................... 44 
6. 
STUDY TREATMENTS ...................................................................................... 44 
6.1 
Treatments administered ....................................................................................... 45 
6.1.1 
Investigational products ........................................................................................ 45 
6.1.1.1 
Durvalumab (MEDI4736) ..................................................................................... 45 
6.1.1.2 
Etoposide + platinum ............................................................................................ 46 
6.1.1.3 
Order of Administration ........................................................................................ 47 
6.1.2 
Dose and treatment regimens ................................................................................ 47 
6.1.2.1 
Durvalumab (MEDI4736) ..................................................................................... 47 
6.1.2.2 
Etoposide + platinum ............................................................................................ 47 
6.1.3 
Duration of treatment and criteria for treatment through progression and for 
retreatment ............................................................................................................. 48 
6.1.4 
Storage ................................................................................................................... 49 
6.1.5 
Medical devices ..................................................................................................... 49 
6.2 
Measures to minimize bias .................................................................................... 49 
6.2.1 
Patient enrollment.................................................................................................. 49 
6.2.2 
Procedures for handling incorrectly enrolled patients ........................................... 50 
6.2.3 
Methods for assigning treatment groups ............................................................... 50 
6.2.4 
Methods for ensuring blinding .............................................................................. 50 
6.3 
Treatment compliance ........................................................................................... 50 
6.4 
Concomitant therapy ............................................................................................. 50 
6.4.1 
Background medication ......................................................................................... 53 
6.4.2 
Other concomitant treatment ................................................................................. 53 
6.4.3 
Durvalumab drug-drug interactions ...................................................................... 53 
6.4.4 
Rescue medication ................................................................................................. 53 
6.5 
Dose modification ................................................................................................. 54 
6.6 
Treatment after the end of the study ...................................................................... 54 
7. 
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL .. 54 
7.1 
Discontinuation of study treatment ....................................................................... 54 
7.1.1 
Procedures for discontinuation of study treatment ................................................ 55 
7.2 
Lost to follow-up ................................................................................................... 55 
7.3 
Withdrawal from the study .................................................................................... 56 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 56 
8.1 
Efficacy assessments ............................................................................................. 57 
8.1.1 
Central reading of scans ........................................................................................ 58 
8.1.2 
Survival assessments ............................................................................................. 58 
8.2 
Safety assessments ................................................................................................ 58 
8.2.1 
Clinical safety laboratory assessments .................................................................. 58 
8.2.2 
Physical examinations ........................................................................................... 60 
8.2.3 
Vital signs .............................................................................................................. 61 


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8.2.4 
Electrocardiograms ................................................................................................ 61 
8.2.5 
Early patient review for safety .............................................................................. 62 
8.2.6 
WHO/ECOG performance status .......................................................................... 62 
8.2.7 
Patient reported outcomes (PRO) .......................................................................... 62 
8.2.7.1 
EORTC QLQ-C30 ................................................................................................. 62 
8.2.7.2 
EORTC QLQ-LC13 .............................................................................................. 63 
8.2.7.3 
PRO-CTCAE ......................................................................................................... 63 
8.2.7.4 
Administration of the patient-reported outcome questionnaires ........................... 63 
8.2.8 
Health care resource use ........................................................................................ 64 
8.2.9 
Other safety assessments ....................................................................................... 64 
8.3 
Collection of adverse events.................................................................................. 65 
8.3.1 
Method of detecting AEs and SAEs ...................................................................... 66 
8.3.2 
Time period and frequency for collecting AE and SAE information .................... 66 
8.3.3 
Follow-up of AEs and SAEs ................................................................................. 66 
8.3.4 
Adverse event data collection................................................................................ 66 
8.3.5 
Causality collection ............................................................................................... 67 
8.3.6 
Adverse events based on signs and symptoms ...................................................... 68 
8.3.7 
Adverse events based on examinations and tests .................................................. 68 
8.3.8 
Hy‘s law ................................................................................................................ 68 
8.3.9 
Disease-under study (DUS) ................................................................................... 68 
8.3.10 
Disease progression ............................................................................................... 69 
8.3.11 
New cancers .......................................................................................................... 69 
8.3.12 
Deaths .................................................................................................................... 69 
8.3.13 
Adverse events of special interest ......................................................................... 69 
8.3.14 
Safety data to be collected following the final DCO of the study ......................... 70 
8.4 
Safety reporting and medical management ........................................................... 71 
8.4.1 
Reporting of serious adverse events ...................................................................... 71 
8.4.2 
Pregnancy .............................................................................................................. 71 
8.4.2.1 
Maternal exposure ................................................................................................. 72 
8.4.2.2 
Paternal exposure .................................................................................................. 72 
8.4.3 
Overdose ................................................................................................................ 73 
8.4.3.1 
Durvalumab ........................................................................................................... 73 
8.4.3.2 
EP treatment .......................................................................................................... 73 
8.4.4 
Medication error .................................................................................................... 73 
8.4.5 
Management of IP-related toxicities ..................................................................... 73 
8.4.5.1 
Specific toxicity management and dose modification information – 
Durvalumab ........................................................................................................... 74 
8.4.5.2 
Specific toxicity management and dose modification information – EP 
treatment ................................................................................................................ 75 
8.5 
Pharmacokinetics................................................................................................... 75 
8.6 
Pharmacodynamics ................................................................................................ 75 
8.7 
Genetics ................................................................................................................. 75 
8.8 
Biomarkers ............................................................................................................ 75 
8.8.1 
Exploratory biomarkers ......................................................................................... 76 


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8.8.1.1 
Collection of tumor samples for exploratory tumor biomarkers ........................... 76 
8.8.1.2 
Collection of samples for exploratory peripheral biomarkers ............................... 77 
8.8.2 
Management of biomarker data ............................................................................. 78 
8.8.3 
Storage, re-use and destruction of biomarker samples .......................................... 79 
8.8.4 
Labeling and shipment of biological samples ....................................................... 79 
8.8.5 
Chain of custody of biological samples ................................................................ 79 
8.8.6 
Withdrawal of informed consent for donated biological samples ......................... 79 
8.9 
Medical Resource Utilization and Health Economics ........................................... 80 
9. 
STATISTICAL CONSIDERATIONS .................................................................. 81 
9.1 
Statistical hypotheses ............................................................................................ 81 
9.2 
Sample size determination..................................................................................... 81 
9.3 
Populations for analyses ........................................................................................ 82 
9.3.1 
Safety analysis set ................................................................................................. 82 
9.3.2 
Biomarker analysis evaluable population .............................................................. 82 
9.4 
Outcome measures for analyses ............................................................................ 82 
9.5 
Statistical analyses ................................................................................................. 85 
9.5.1 
Analysis of the primary variables .......................................................................... 85 
9.5.2 
Analysis of the secondary variables ...................................................................... 85 
9.5.2.1 
Safety variables ..................................................................................................... 85 
9.5.2.2 
Efficacy variables .................................................................................................. 86 
Progression-free survival ....................................................................................................... 87 
Objective response rate .......................................................................................................... 87 
Duration of response .............................................................................................................. 87 
Overall survival ...................................................................................................................... 87 
9.5.2.3 
Patient reported outcomes ..................................................................................... 88 
(a) 
EORTC QLQ-C30 ................................................................................................. 88 
(b) 
EORTC QLQ-LC13 .............................................................................................. 90 
(c) 
PRO-CTCAE ......................................................................................................... 91 
9.5.2.4 
Healthcare resource use ......................................................................................... 91 
9.5.3 
Biomarker data ...................................................................................................... 91 
9.6 
Interim analyses ..................................................................................................... 91 
10. 
REFERENCES ...................................................................................................... 92 
11. 
SIGNATURES ...................................................................................................... 97 
 
LIST OF TABLES 
Table 1 
Schedule of assessments for durvalumab therapy treatment ................................ 11 
Table 2 
Schedule of assessments for patients who have discontinued treatment with 
durvalumab + EP therapy .................................................................................... 15 


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Table 3 
Study objectives ................................................................................................... 30 
Table 4 
Highly effective methods of contraception (<1% failure rate) ............................. 44 
Table 5 
Study treatments ................................................................................................... 45 
Table 6 
Prohibited concomitant medications .................................................................... 51 
Table 7 
Supportive medications ........................................................................................ 53 
Table 8 
Clinical chemistry ................................................................................................. 59 
Table 9 
Hematology .......................................................................................................... 60 
Table 10 Urinalysis .............................................................................................................. 60 
Table 11: Biomarker analysis ............................................................................................... 78 
Table 12.  Precision around varying incidence of AE .......................................................... 81 
Table 13 Summary of outcome variables and analysis populations .................................... 82 
Table 14 Pre-planned statistical and sensitivity analyses to be conducted ......................... 86 
 
LIST OF FIGURES 
 
Figure 1 Study design ......................................................................................................... 22 
 
LIST OF APPENDICES 
Appendix A Regulatory, ethical and study oversight considerations ................................ 99 
Appendix B Adverse event definitions and additional safety information ...................... 104 
Appendix C Handling of human biological samples ....................................................... 109 
Appendix D  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy‘s Law ..................................................................................... 112 
Appendix E Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors) .................................. 118 
Appendix F Durvalumab weight-based dose calculation ................................................. 130 
Appendix G Abbreviations............................................................................................... 131 
Appendix H EORTC QLQ-C30 questionnaire ................................................................ 135 
Appendix I  EORTC QLQ-LC13 questionnaire .............................................................. 137 
Appendix J  Discovery of biomarkers to predict benefit from chemoimmunotherapy in 
SCLC using digital spatial profiling .................................................................. 138 


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Appendix K  Determination of circulating leukocyte-platelet complexes & PD-L1 
expression on circulating cells in patients with advanced SCLC patients 
receiving durvalumab in combination with platinum and etoposide. ................ 141 
Appendix L   Dosing Modification and Toxicity Management Guidelines (TMGs) for 
Durvalumab Monotherapy, Durvalumab in Combination with other Products, 
or Tremelimumab Monotherapy – 17 November 2020. .................................... 143 
 
 


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1. 
PROTOCOL SUMMARY 
1.1Schedule of activities (SoA) 
The procedures for the screening and treatment periods in this study are presented in Table 1 and 
Table 2, and the procedures for the follow-up period are presented in Table 2. Patients who 
continue beyond Cycle 13 will continue with all Cycle 13 assessments until termination of 
treatment (Table 1). 
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 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 
AE. 
 
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible. 
 
Dosing intervals of subsequent cycles (during chemotherapy interval is 21 
days, post chemotherapy interval is 28 days) may be adapted +/-3 days as 
clinically feasible in order to gradually align treatment cycles with the 
schedule of tumor efficacy (RECIST) and PRO assessments.  
For EP treatment  
 
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. 


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Table 1 
Schedule of assessments for durvalumab therapy treatment  
 
 
During Chemotherapy 
1 cycle = 21 days 
Post-Chemotherapy 
1 cycle = 28 days 
 
For 
details, 
see Section 
 
Screening 
C1 
C2 
C3 
C4-C6 
C5-C7 to PD 
End of treatment 
Week 
-4 to -1 
0 
Q3w ±3 days during chemotherapy and q4w ±3 days post-
chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Day 
-28 to -1 
1a 
Q21days ±3 days during chemotherapy and q28days ±3 days 
post-chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Informed Consent 
Informed consent: study proceduresb 
X 
 
 
 
 
 
 
5.1 
Consent: sample for biomarker analysis 
(optional) 
X 
 
 
 
 
 
 
5.1 
Study procedures 
Physical exam (full) 
X 
 
 
 
 
 
 
8.2.2 
Targeted physical exam (based on 
symptoms) 
 
X 
X 
X 
X 
X 
X 
8.2.2 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
8.2.3 
ECGd 
X 
As clinically indicated 
8.2.4 
Concomitant medications 
<-----------------------------------------------------------------------------------------------------------------------------> 
6.4 
Demography, 
including 
baseline 
characteristics and tobacco use 
X 
 
 
 
 
 
 
5.1 
Eligibility criteria 
X 
 
 
 
 
 
 
5.1, 5.2 
Laboratory Assessments 
Clinical chemistrye 
X 
Xf 
X 
X 
X 
X 
X 
Table 8 
Hematologye 
X 
Xf 
X 
X 
X 
X 
X 
Table 9 
TSHg, (reflex free T3 or free T4h) 
X 
X 
X 
X 
X 
X 
X 
Table 8 
Urinalysis 
X 
As clinically indicated 
Table 10 
Hepatitis B and C and HIV 
X 
 
 
 
 
 
 
8.2.1 


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During Chemotherapy 
1 cycle = 21 days 
Post-Chemotherapy 
1 cycle = 28 days 
 
For 
details, 
see Section 
 
Screening 
C1 
C2 
C3 
C4-C6 
C5-C7 to PD 
End of treatment 
Week 
-4 to -1 
0 
Q3w ±3 days during chemotherapy and q4w ±3 days post-
chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Day 
-28 to -1 
1a 
Q21days ±3 days during chemotherapy and q28days ±3 days 
post-chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Pregnancy testi 
X 
X 
X 
X 
X 
X 
X 
8.2.1 
 
Monitoring 
WHO/ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
8.2.6 
AE/SAE assessment k 
<------------------------------------------------------------------------------------------------------------> 
8.3 
Patient follow up contact / Patient 
review for safety 
 
Midway through Cycles 1, 2, 
and 3: days 14 of C1, 2, and 3 
 
8.2.5 
IP administration (Interval between 2 consecutive doses: 21 (+/-3) days during chemotherapy and 28 (+/-3) days after chemotherapy) 
Durvalumab l 
 
X 
X 
X 
X 
X 
X 
6.1.1.1  
Etoposide n,o 
 
X 
X 
X 
X 
 
 
6.1.2.1 
Carboplatin or cisplatin n,p 
 
X 
X 
X 
X 
 
 
6.1.2.1 
Other assessments and assays 
EORTC QLQ-C30 v3, EORTC QLQ-
LC13 and PRO CTCAE r,  
 
X 
X 
X 
X 
X 
X 
8.2.7 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
resource uset 
 
X 
X 
X 
X 
X 
X 
8.2.8 
Archival tumor biopsy (if available) 
X 
 
 
 
 
 
 
8.8 
Fresh tumor biopsy (optional) 
 
 
 
 
 
 
X (at PD) 
 


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During Chemotherapy 
1 cycle = 21 days 
Post-Chemotherapy 
1 cycle = 28 days 
 
For 
details, 
see Section 
 
Screening 
C1 
C2 
C3 
C4-C6 
C5-C7 to PD 
End of treatment 
Week 
-4 to -1 
0 
Q3w ±3 days during chemotherapy and q4w ±3 days post-
chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Day 
-28 to -1 
1a 
Q21days ±3 days during chemotherapy and q28days ±3 days 
post-chemotherapy, unless dosing needs to be held for toxicity 
reasons 
 
Efficacy evaluations 
Tumor assessments (RECIST 1.1) q 
X 
On-study tumor assessments will be performed following local standard practice, but at least with a 
maximun interval of 12 weeks. It is recommended that on-study tumor assessments occur q9w ± 1w 
for the first 12-18 weeks (relative to the C1D1, during chemotherapy treatment), and then, at least 
with a maximum interval of 12 weeks if signs or symptoms of progression do not happen before, if it 
is the standard procedure at study site, until RECIST 1.1-defined radiological progression plus an 
additional follow-up scan 4-8 weeks later.g 
8.1, E 
 
 
 
 
 
 
 
 
 
a 
Every effort should be made to minimize the time between inclusion and starting treatment (ie, within 1 day of inclusion). 
b 
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. All patients will be required to provide consent to supply a sample of their tumor (archived biopsy) for entry into this study. This consent is 
included in the main patient ICF. Informed consent of study procedures archival tumor sample may be obtained prior to the 28-day screening window. If laboratory or 
imaging procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient. However, all 
screening laboratory and imaging results must have been obtained within 28 days of inclusion. 
c 
Body weight is recorded at each visit along with vital signs. 
d 
Normal ECG basal mandatory (28 days maximum before first treatment). Other ECG will be performed under investigator criteria.  
e 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated. 
f 
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.  
g 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 
h 
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. 
i 
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then every 3weeks during chemotherapy and every 4 weeks during durvalumab monotherapy. Pregnancy test may occur on 
Day 1, but results must be available and reviewed by the treating physician or Investigator prior to commencing an infusion  
 
k 
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed  
l 
Results for LFTs, electrolytes, full blood count (during chemotherapy) and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing. 
n  
Durvalumab  is infused first followed by the etoposide + cisplatin/carboplatin regimen 
o  
Etoposide should be infused as local clinical practice, usually over 0.5 to 1 hour. 
p  
Cisplatin and carboplatin should be infused as local clinical practice. If cisplatin, usually over 1 to 2 hours. If carboplatin, usually over 0.5 to 1 hour. 


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q 
See Section 6.1.3, Section 8.1, and E for additional details relevant to image acquisition, RECIST 1.1 assessments, and evaluation of scans after RECIST 1.1-defined 
progression. 
r  
For the PRO collection, the research nurse or study coordinator should ensure that the patient completes the questionnaire prior to any other study procedures and before 
discussion of PD to avoid introducing bias to the patient‘s responses to the questions. The EORTC QLQ-C30 should always be completed prior to the EORTC QLQLC13 
module.  
 
 
t  
The site should complete the hospital resource use form at every scheduled and unscheduled clinic visit up to and including the study treatment discontinuation follow-up 
visit. If the patient discontinues study treatment for reasons other than RECIST 1.1 assessed PD, the hospital resource use form should continue to be completed until PD has 
been confirmed. 
 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. 
C  Cycle; ECG  Electrocardiogram; IM  Intramuscular; LFT  Liver function test; qXw  Every X weeks; qXdays  Every X days; T3  Triiodothyronine; T4  Thyroxine; 
TSH  Thyroid-stimulating hormone. 
 
 


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Table 2 
Schedule of assessments for patients who have discontinued treatment with durvalumab + EP therapy  
 
Time since last dose of IP 
Evaluation 
Day (±3) 
Months (±1 week) 
12 months and 
every 6 months 
(±2 weeks) 
For details, see 
Section 
30 
2 
3 
4 
6 
8 
10 
Physical examination (full) 
X 
 
 
 
 
 
 
 
8.2.2 
Vital signs (temperature, respiratory 
rate, blood pressure, and pulse) 
X 
 
 
 
 
 
 
 
8.2.3 
Weight 
X 
X 
X 
 
 
 
 
 
8.2.3 
Pregnancy testa 
X 
As clinically indicated 
8.2.1 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
8.3 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
6.4 
WHO/ECOG performance status 
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at initiation of subsequent 
anticancer therapyb 
8.2.6 
Subsequent anticancer therapyc  
<------------------------------------------------------------------------------------------------------------------------------------> 
8.1 
Survival statusf 
 
X 
X 
X 
X 
X 
X 
X 
(every 
2 months) 
8.1 
Hematology 
X 
X 
X 
 
 
 
 
 
Table 9 
Clinical chemistry 
X 
X 
X 
 
 
 
 
 
Table 8 
TSH (reflex free T3 or free T4g) 
X 
X 
X 
 
 
 
 
 
Table 8 
Tumor assessment (RECIST 1.1)i 
On-study tumor assessments will be performed following local standard practice, but at least with a maximun 
interval of 12 weeks, until RECIST 1.1-defined radiological progression plus an additional follow-up scan 4-8 
weeks later.g 
8.1 
a 
For women of childbearing potential only. A urine or serum pregnancy test is acceptable.  
b 
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such information. In addition, 
WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where possible. 
c 
Details of any treatment for ES-SCLC (including surgery) post the last dose of IP must be recorded in the eCRF. At minimum, collect the start date and description of the subsequent 
anticancer therapy.  
f 
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 IP must be 
recorded in the eCRF. 
g 
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. 
i 
See Section 6.1.3, Section 8.1, and E for additional details relevant to image acquisition, RECIST 1.1 assessments, and evaluation of scans after RECIST 1.1-defined progression. 
 
NA  Not applicable; qXw  Every X weeks; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-stimulating hormone. 


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1.2Synopsis 
National Co-ordinating Investigator 
Dr M Dolores Isla Casado 
Jefe de Servicio de Oncología Médica  
Hospital Clínico Universitario Lozano Blesa 
Avda. San Juan Bosco, 15  
50009 Zaragoza (Spain) 
e-mail: lola.isla@gmail.com 
 
Protocol Title:  
A Phase IIIB, Single Arm Study, of Durvalumab in Combination with Platinum-Etoposide 
for Untreated Patients with Extensive-Stage Small Cell Lung Cancer reflecting Real World 
Clinical Practice in Spain (CANTABRICO) 
A Phase IIIB Study in Untreated Patients with Extensive-Stage Small Cell Lung Cancer 
Rationale:  
Recent data indicate that in 2018 lung cancer has been the leading cause of death from tumors in 
Spain (22,153 deaths). Small-cell lung cancer (SCLC) represents approximately 13% of all 
newly diagnosed lung cancers (Puglisi et al 2010). SCLC is perhaps the most aggressive form of 
the disease. Extensive-stage disease (ES) was defined as any tumor that extended beyond the 
boundaries of a single radiation port and is identified in ~70% of patients with SCLC. 
Four to six cycles of platinum based chemotherapy, etoposide in combination with either 
cisplatin or carboplatin has been the standard care (SoC) for patients with ES SCLC for the past 
25 years (Pignon et al 1992, Roth et al 1992). Despite high initial response rates of up to 70% 
(Rossi et al 2012), it is estimated that 80% of patients with limited stage and almost all patients 
with ES SCLC will relapse or experience disease progression (Clark and Ihde 1998). Therefore 
prognosis for patients with SCLC in general and particular ES SCLC is poor; the reported 2-year 
survival is only 5% and 5 years survival rate is less than 2% (Rossi et al 2012). 
The phase III, randomised, open-label CASPIAN study showed a statistically significant 
improvement in overall survival (primary study endpoint) with first-line durvalumab and 
etoposide plus either cisplatin or carboplatin (platinum–etoposide) versus platinum–etoposide 
alone in patients with ES-SCLC at a planned interim analysis.  


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Despite the positive results, there remains limited information about the effectiveness and safety 
of durvalumab plus platinum-etoposide in ECOG PS 2 patients, as well as in patients having 
received CRT as a definitive treatment for a limited stage (LS)-SCLC and with progressive and 
platinum-sensitive disease at least 6 months after treatment; there is also limited information in 
patients with some stable comorbidities, controlled autoimmune diseases, or even in those 
patients where the investigator can expect benefit from a prophylactic cranial irradiation. 
Therefore, there remains an unmet need for additional data to help support and inform the health-
care decisions in the use of durvalumab in combination with platinum–etoposide as first-line 
treatment for unselected patients with ES-SCLC in real clinical practice.  
In the treatment of lung cancer, it is important to both increase survival and palliate symptoms 
because disease symptoms have negative impacts on health-related quality of life (HRQoL) 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004). In this study, the 
validated EORTC QLQ-C30 and EORTC QLQ-LC13 will be used to assess HRQoL, physical 
functioning, and symptom severity. 
The present study will assess the safety and effectiveness of durvalumab plus platinum-etoposide 
in a real world ES-SCLC population until P&R approval of durvalumab in ES-SCLC based on 
CASPIAN results.  
This trial will generate clinically relevant safety and efficacy data with durvalumab in 
combination with EP under conditions that reflect a real-world setting... 
 
 
 
 
 
 


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Objectives and Endpoints 
 
Primary objective: 
Endpoint/variable: 
To describe safety  profile of durvalumab in 
combination with platinum–etoposide as first-
line treatment for patients with ES-SCLC  
Incidence of grade ≥ 3 AEs 
Incidence of imAE  
 
Secondary objective: 
Endpoint/variable: 
To describe effectiveness of durvalumab in 
combination with platinum–etoposide as first-
line treatment for patients with ES-SCLC. 
 
Progression Free Survival (PFS). 
PFS rate at 6 months and at 1 year (PFS6, PFS12).  
Objetive Response Rate (ORR): using site 
investigator assessments according to RECIST 1.1. 
Duration of Response (DoR). 
DoR at 1 year (DoR12) 
Time to Treatment Discontinuation (TTD). 
Overal Survival (OS). 
The OS rate at 6, 12 and 18 months. 
Time to event endpoints measured as time from first 
Durvalumab dose. 
To describe the impact of durvalumab in 
combination with platinum–etoposide as first-
line treatment for patients with ES-SCLC on 
patients‘ disease-related symptoms and Health 
Related Quality of Life (HRQoL) and (PROs). 
Changes in vital signs, physical findings, and 
clinical laboratory results during and following 
study treatment administration. 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 items (EORTC QLQ-C30). 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life. 
Questionnaire-Lung Cancer 13 (EORTC QLQ-
LC13).   
Changes from baseline in PRO-CTCAE. 
To describe health care resources use related to 
management of ES-SCLC patients treated with 
durvalumab in combination with platinum–
etoposide as first-line treatment.  
- 
Number and length of hospitalizations 
- 
Number of visits to oncology service 
- 
Number of emergency visits 
- 
Number of outpatient visits 
- 
Number of imaging tests 
- 
Number of biopsy-related procedures 
- 
Treatment dose, duration, number of cycles 
 


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Objectives and Endpoints 
 
Exploratory objective: 
Endpoint/variable: 
 
  
 
 
 
 
 
 
 
 
Overall design: 
Phase IIIb, interventional, single arm, multicentre study to evaluate safety, effectiveness, use of 
resources and patient reporting outcomes in patients with ES-SCLC treated with durvalumab in 
combination with platinum–etoposide as first-line treatment in Spain. 
Prophylactic cranial irradiation (PCI) is allowed in patients showing complete or partial 
responses after chemo-Durvalumab treatment under investigator criteria. 
Study Period: 
Estimated date of first patient enrolled: Q4 2020 
Estimated date of last patient enrolled*: Q2 2021 
Estimated date of last patient completed: Q2 2022 
*Recruitment duration may be reduced or extended, until P&R approval of durvalumab in ES-
SCLC based on CASPIAN results. 
Number of patients: 
This is a safety study, and given the real-world setting, there is no formal predefined statistical 
hypothesis and no formal sample size calculation will be done. 
A convenience sample size of  approximately 85 patients was estimated based on the expected 
accrual potential during 6 months in 30 sites, although the recruitment duration may be reduced 
or extended, until P&R approval of durvalumab in Spain for ES-SCLC based on CASPIAN 
results, and the number of patients recruited could be higher.  A maximum of 30% of recruited 
patients will have ECOG performance status of 2 at baseline.  


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Treatments and treatment duration: 
Durvalumab will be concurrently administered with first-line chemotherapy (EP) on an every 3 
week (q3w) schedule for 4 to 6 cycles, and will continue to be administered post-chemotherapy 
on an every 4 week (q4w) schedule until confirmed progressive disease (PD) or unacceptable 
toxicity.  
Durvalumab + chemotherapy combination 
 
Durvalumab 1500 mg via IV infusion q3w concurrently with chemotherapy, starting 
on Week 0, for 4-6 cycles. Please note, if a patient‘s weight falls to 30 kg or below 
(≤30 kg), then the patient should receive weight-based dosing equivalent to 20 mg/kg 
of durvalumab after consultation between the Investigator and Study Physician, until 
the weight improves to above 30 kg (>30 kg), at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg. 
 
EP: the dose of etoposide + carboplatin or cisplatin investigated will not exceed the 
product label dose for the given indication dose (etoposide [80 to 100 mg/m2] via IV 
infusion with either carboplatin [area under the curve (AUC) 5-6] via IV infusion or 
cisplatin [75 to 80 mg/m2] via IV infusion), starting on Week 0, for 4-6 cycles. 
Durvalumab monotherapy 
 
Durvalumab 1500 mg via IV infusion q4w, starting 3 weeks after the last infusion of 
the combination, until confirmed progressive disease (PD) or unacceptable toxicity. 
Please note, if a patient‘s weight falls to 30 kg or below (≤30 kg), then the patient 
should receive weight-based dosing equivalent to 20 mg/kg of durvalumab q4w after 
consultation between Investigator and Study Physician, until the weight improves to 
above 30 kg (>30 kg), at which point the patient should start receiving the fixed dosing 
of durvalumab 1500 mg q4w.  
Duration of treatment 
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
clinical progression or confirmed radiological progression (defined in Appendix E).  
Progression during treatment 
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. 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 E. 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 E. 


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Follow up of patients post discontinuation of study drug 
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, clinical 
progression, or who have commenced subsequent anticancer therapy will be followed up 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.  
Survival 
All patients in the study should be followed up for survival. 
Statistical methods 
All statistical analyses will be performed by AstraZeneca or its representatives (e.g. CRO). 
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 3 months 
of the first enrolled patient, and any subsequent amendments will be documented, with final 
amendments completed prior to reporting of the data.  
All analyses will be descriptive in nature. Categorical (e.g., gender) study measures will be 
reported using frequency and proportions and continuous measures (e.g., age) will be reported 
using mean, median, standard deviation and range. Additionally, Kaplan-Meier curves will be 
presented for time-to-event outcomes such as overall and progression free survival.  
All analyses will be based on the intention to treat (ITT) population consisted of all enrolled 
patients who had received at least 1 dose of study drug (chemotherapy or Durvalumab). For the 
overall study population and for any subpopulation, estimated 95% CIs for various event rates 
will be calculated.  
The incidence of common, or uncommon (<1%) serious adverse events will be estimated. 
Serious adverse events, grade 3/4 AEs, AE leading to death, AE leading to discontinuation, 
imAE and adverse events of special interest will be summarised by preferred term and incidence 
rates. 
Baseline will be the last assessment of the variable under consideration prior to the intake of the 
first study drug (Durvalumab) dose. 
Planned subgroup analyses of safety and effectiveness according to baseline characteristics 
include: ECOG status, gender, , presence of brain or liver metastases, smoking status, age of 65 
years or older, and use of prophylactic cranial irradiation. 
 


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1.3Schema 
The general study design is summarized in Figure 1. 
Figure 1 
Study design 
 
SCLC Small cell lung cancer; IV intravenous; AUC area under the curve; PD Progressive disease. 
 
2. INTRODUCTION 
Cancer is the second leading cause of death globally, and is responsible for an estimated 9.6 
million deaths in 2018. According to population predictions, it is estimated that the number of 
deaths caused by tumors will increase to more than 16 million in the year 2040 (Ferlay et al 
2012). 
Also in Spain, cancer is one of the main causes of morbidity and mortality. The number of 
cancers diagnosed in Spain in 2020 is estimated to reach 277,394 cases according to REDECAN 
calculations, a number very similar to the year 2019. 
Lung cancer will be the 4th tumor most frecuently diagnosed in Spain with 29,638 cases in 2020. 
Recent data indicate that in 2018 lung cancer has continued to be the leading cause of death from 
tumors in Spain (22,153 deaths): 17,194 deaths in men, although it has experienced a 0.4% 
reduction compared to 2017; while in women 4,959 deaths were documented, which reflects an 
increase of 2.2% since 2017 (SEOM 2020). 


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Small-cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung 
cancers (Puglisi et al 2010). SCLC is perhaps the most aggressive form of the disease, 
distinguishable from non-small-cell lung cancer (NSCLC) by its rapid doubling time, high 
growth fraction, and early dissemination. It is strongly associated with tobacco smoking and is 
also associated with an extremely high mutation rate. Moreover, inactivation of TP53 and RB1 
occurs frequently, and in a recent study in which sequencing of SCLC tumors was carried out, 
recurrent mutations were identified in the CREBBP, EP300, and MLL genes that encode histone 
modifiers (Peifer et al 2012). Furthermore, mutations in PTEN, SLIT2, and EPHA7 (as well as 
focal amplifications of the FGFR1 tyrosine kinase gene) were also observed. 
A 2-stage system dividing patients into limited and extensive disease was developed in 1973 by 
the United States (US) Veteran‘s Administration Lung Cancer Study Group. Limited stage was 
defined as tumor tissue that could be encompassed in a single radiation port, and extensive-stage 
disease (ES) was defined as any tumor that extended beyond the boundaries of a single radiation 
port. At present, limited stage is identified in ~30% of patients, and ES is identified in ~70% of 
patients. 
Four to six cycles of platinum based chemotherapy, etoposide in combination with either 
cisplatin or carboplatin, without maintenance therapy has been the standard care (SoC) for 
patients with ES SCLC for the past 25 years (Pignon et al 1992, Roth et al 1992), and are 
recommended by major worldwide oncology treatment guidelines, ie, ASCO, NCCN, ESMO. 
Despite high initial response rates of up to 70% (Rossi et al 2012), it is estimated that 80% of 
patients with limited stage and almost all patients with ES SCLC will relapse or experience 
disease progression (Clark and Ihde 1998). Therefore prognosis for patients with SCLC in 
general and particular ES SCLC is poor; the reported 2-year survival is only 5% and 5 years 
survival rate is less than 2% (Rossi et al 2012). 
2.1Study rationale 
The phase III, randomised, open-label CASPIAN study showed a statistically significant 
improvement in overall survival (primary study endpoint) with first-line durvalumab and 
etoposide plus either cisplatin or carboplatin (platinum–etoposide) versus platinum–etoposide 
alone in patients with ES-SCLC at a planned interim analysis. To our knowledge, this was the 
first phase 3 study with published data of anti-PD-1 or anti-PD-L1 in patients with ES-SCLC that 
permitted the use of investigator‘s choice of either cisplatin or carboplatin as the platinum 
component in platinum–etoposide and that allowed up to six cycles of platinum–etoposide 
(consistent with routine clinical practice) in the control group, compared with four cycles in the 
durvalumab plus platinum–etoposide group. 


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In CASPIAN, the addition of durvalumab to platinum–etoposide as first-line treatment for 
patients with ES-SCLC resulted in consistent and durable clinical benefit across overall survival, 
progression-free survival, and objective response, compared with a clinically relevant control 
group that is reflective of current global clinical practice for this challenging-to-treat disease. Our 
results align with those from the IMpower133 trial of atezolizumab plus carboplatin–etoposide, 
while providing significant progress in offering the flexibility of platinum choice in combination 
with immunotherapy, expanding treatment options for patients and physicians (Paz-Ares et al 
2019). 
In spite of the fact that the control arm in CASPIAN is quite close to real clinical practice, ES-
SCLC patients have a rapidly progressive disease, symptomatic and some of them will be 
evaluated as PS 2 at diagnosis. We have quite limited information about the  effectiveness and 
safety of durvalumab plus platinum-etoposide in this kind of patients, as well as in patients 
having received CRT as a definitive treatment for a limited stage (LS)-SCLC and with 
progressive and platinum-sensitive disease at least 6 months after treatment; there is also limited 
information in patients with some stable comorbidities, controlled autoimmune diseases, or even 
in those patients where the investigator can expect benefit from a prophylactic cranial irradiation. 
Therefore, there remains an unmet need for additional data to help support and inform the health-
care decisions in the use of durvalumab in combination with platinum–etoposide as first-line 
treatment for unselected patients with ES-SCLC in real clinical practice.  
In the treatment of lung cancer, it is important to both increase survival and palliate symptoms 
because disease symptoms have negative impacts on health-related quality of life (HRQoL) 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004). This is especially true 
for studies that use PFS as a relevant endpoint, where it is important to better understand in what 
regard the delay in disease progression is meaningful to patients. In this study, the validated 
EORTC QLQ-C30 and EORTC QLQ-LC13 will be used to assess HRQoL, physical functioning, 
and symptom severity. 
The present study will assess the safety and effectiveness of durvalumab plus platinum-etoposide 
in a real world ES-SCLC population.  
2.2Background 
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the Investigator‘s Bochure. 
2.2.1Immunotherapies 
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).  


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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 (Puglisi et al, Qin 
et al 2016 ). Importantly, PD-L1 is commonly over-expressed on tumor cells or on 
non-transformed cells in the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the 
tumor cells binds to PD-1 receptors on the activated T cells, leading to the inhibition of cytotoxic 
T cells. These deactivated T cells remain inhibited in the tumor microenvironment. The 
PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by 
tumor cells in response to endogenous antitumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells. This activity overcomes PD-L1-mediated inhibition of antitumor immunity. While 
functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different 
from direct agonism of a stimulatory receptor such as CD28. 
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, Hopwood 
et al 1995, Horn et al 2018, Hyde et al 1974, Iwai et al 2002, Paz-Ares et al 2019, Peifer et al 
2012, Pignon et al 1992, 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 United States 
(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 non-small-cell lung cancer, small cell lung cancer, 
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. 


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2.2.2Durvalumab 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 
and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that 
may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the 
inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of 
IFN-γ (SEOM 2020, Sprangers and Aaronson 1992, Stewart et al 2015). In vivo studies have 
shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism (SEOM 2020, Sprangers and Aaronson 1992, Stewart et al 2015). Based on these 
data, durvalumab is expected to stimulate the patient‘s antitumor immune response by binding to 
PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered 
to reduce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.  
To date, durvalumab has been given to more than 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 and Section 8.3.13. Refer to the 
current durvalumab IB for a complete summary of pre-clinical and clinical information including 
safety, efficacy, and pharmacokinetics (PK).  
2.2.3Durvalumab 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 
study that compared atezolizumab + etoposide/carboplatin (EC) with placebo + EC in the first 
line treatmet of ES-SCLC (Horn 2018). The study demonstrated a statistically significant 
improvement in OS with the combination of atezolizumab + EC compared to placebo + EC 
(Horn 2018). CASPIAN was a randomized, open label phase III trial that compared durvalumab, 
with or without tremelimumab, in combination with either cisplatin or carboplatin plus etoposide 
(EP) versus EP alone in treatment naïve patients with ES-SCLC. The CASPIAN trial 
demonstrated a statistically significant improvement in OS of durvalumab plus EP compared to 


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EP alone in first line treatment of ES SCLC (Paz-Ares 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 2020). 
2.3Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of durvalumab may be found in the Investigator‘s Brochure. 
2.3.1Potential benefits 
2.3.1.1Durvalumab 
More than 8000 patients have been treated across a large number of studies with durvalumab 
given as either a single agent or in combinations with a number of other anti-cancer therapies. 
The studies are being conducted across various tumour indications and stages of disease, 
including solid tumours and haematologic malignancies.  
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 
(MYSTIC Study [NCT02453282]).  Details pertaining to these studies are provided in the 
current durvalumab IB. 
2.3.1.2Durvalumab + chemotherapy 
Studies evaluating agents targeting PD-L1 in combination with chemotherapy have yielded 
encouraging results. 
CASPIAN is a randomised, open-label, multi-centre, global, Phase III trial in the first line 
treatment of 805 patients with ES-SCLC. The trial compared durvalumab in combination with 
etoposide and either carboplatin or cisplatin chemotherapy, or durvalumab  and chemotherapy 
with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the 
experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the 
control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial 
irradiation. The trial was conducted in more than 200 centres across 23 countries.  
Durvalumab plus platinum–etoposide demonstrated a statistically significant and clinically 
meaningful improvement in overall survival versus platinum–etoposide alone, with an HR of 
0.73 (95% CI 0.59–0.91; p=0.0047) (Paz-Ares 2019). Median overall survival was 13.0 months 
(95% CI 11.5–14.8) with durvalumab plus platinum– etoposide versus 10.3 months (9.3–11.2) 
with platinum– etoposide; the 12-month overall survival rates were 54% (47.4–59.5) versus 40% 
(33.7–45.8); and the 18-month overall survival rates were 34% (26.9–41.0) versus 25% (18.4–
31.6). Overall survival benefit was observed across all clinically relevant patient subgroups. 
Consistent with the results for overall survival, progression-free survival (assessed without 


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formal statistical significance testing) was also in favour of durvalumab plus platinum–etoposide, 
as were objective response. Importantly, adding durvalumab to platinum-etoposide demonstrated 
significant and durable improvements in overall survival while maintaining quality of life, by 
delaying worsening of patient-reported symptoms, functioning, and HRQoL compared to 
platinum-etoposide alone.  
Patients receiving durvalumab plus platinum–etoposide experienced reduced symptom burden 
over 12 months for pre-specified symptoms of fatigue, appetite loss, cough, dyspnea, and chest 
pain; a statistically significant difference over 12 months was observed for appetite loss in favor 
of durvalumab plus platinum–etoposide compared to platinum–etoposide alone. Patients in the 
durvalumab plus platinum–etoposide group experienced longer time to deterioration in a broad 
range of patient-reported symptoms, functioning and HRQoL compared to platinum–etoposide. 
2.3.2Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against tumor cells. By stimulating the immune system, however, there is the potential for 
adverse effects on normal tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ system, 
and are most commonly seen as gastrointestinal 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.  
2.3.2.1Durvalumab 
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, thyroiditis,  type I diabetes mellitus and diabetes insipidus), hepatitis/increases 
in transaminases, nephritis/increases in creatinine, rash/dermatitis (incluiding pemphigoid), 
myocarditis, myositis/polymyositis, inmune thrombocytopenia, infusion-related reactions, 
hypersensitivity reactions, pancreatitis, serious infections, and other rare or less frequent 
inflammatory events including neuromuscular toxicities (e.g. Guillain Barre syndrome, 
myasthenia gravis).  
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB. 
In monotherapy clinical studies, AEs at an incidence of > 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued the 
drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program. 


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The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, with the use of 
established treatment guidelines for immune-mediated toxicity (see Section 8.4.5). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB.  
2.3.2.2Durvalumab + 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 
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. The most common adverse 
events were haematological toxicities. Immune-mediated adverse events, defined as an event that 
is associated with drug exposure and consistent with an immune-mediated mechanism of action, 
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, consistent with the known safety profile of durvalumab.  
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 (Horn 2018). 
 
2.3.3Overall benefit/risk 
There remains a significant unmet medical need for additional treatment options for patients with 
ES-SCLC. Four or six cycles of platinum-based chemotherapy has been considered the standard 
treatment regimens for 2 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. 


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Treatment with durvalumab has shown activity in several tumor types in a subset of patients 
deriving meaningful and durable benefit. Efficacy data for patients treated with durvalumab 
monotherapy have shown clinical activity across several tumor types.  
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 SCLCover EP alone. 
 
Taken together, the overall benefit/risk profile of durvalumab + EP remains favourable for 
continued development and supports the proposed study to further evaluate this combination for 
untreated patients with extensive-stage small cell lung cancer (SCLC) in a real-world setting. 
3. OBJECTIVES AND ENDPOINTS 
 
Table 3 
Study objectives 
 
Primary Objective: 
Endpoint/Variable: 
To describe safety  profile of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC and also as 
monotherapy maintenance treatment. 
Incidence of grade ≥ 3 AEs 
Incidence of imAE  
 
 
 


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Secondary Objective: 
Endpoint/Variable: 
To describe effectiveness of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC. 
Progression Free Survival (PFS). 
PFS rate at 6 months and at 1 year (PFS6, PFS12).  
Objetive Response Rate (ORR): using site 
investigator assessments according to RECIST 1.1. 
Duration of Response (DoR) 
DoR at 1 year (DoR12). 
Time to Treatment Discontinuation (TTD). 
Overal Survival (OS). 
The OS rate at 6, 12 and 18 months. 
Time to event endpoints measured as time from first 
Durvalumab dose. 
To describe the impact of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC on patients‘ 
disease-related symptoms and Health Related 
Quality of Life (HRQoL) and (PROs). 
Changes in vital signs, physical findings, and 
clinical laboratory results during and following 
study treatment administration 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 items (EORTC QLQ-C30). 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life. 
Questionnaire-Lung Cancer 13 (EORTC QLQ-
LC13).   
Changes from baseline in PRO-CTCAE. 
To describe health care resources use related to 
management of ES-SCLC patients treated with 
durvalumab 
in 
combination 
with 
platinum–
etoposide as first-line treatment.  
- 
Number and length of hospitalizations 
- 
Number of visits to oncology service 
- 
Number of emergency visits 
- 
Number of outpatient visits 
- 
Number of imaging tests 
- 
Number of biopsy-related procedures 
- 
Treatment dose, duration, number of cycles 


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Secondary Objective: 
Endpoint/Variable: 
To describe effectiveness of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC. 
Progression Free Survival (PFS). 
PFS rate at 6 months and at 1 year (PFS6, PFS12).  
Objetive Response Rate (ORR): using site 
investigator assessments according to RECIST 1.1. 
Duration of Response (DoR) 
DoR at 1 year (DoR12). 
Time to Treatment Discontinuation (TTD). 
Overal Survival (OS). 
The OS rate at 6, 12 and 18 months. 
Time to event endpoints measured as time from first 
Durvalumab dose. 
To describe the impact of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC on patients‘ 
disease-related symptoms and Health Related 
Quality of Life (HRQoL) and (PROs). 
Changes in vital signs, physical findings, and 
clinical laboratory results during and following 
study treatment administration 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 items (EORTC QLQ-C30). 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life. 
Questionnaire-Lung Cancer 13 (EORTC QLQ-
LC13).   
Changes from baseline in PRO-CTCAE. 
To describe health care resources use related to 
management of ES-SCLC patients treated with 
durvalumab 
in 
combination 
with 
platinum–
etoposide as first-line treatment.  
- 
Number and length of hospitalizations 
- 
Number of visits to oncology service 
- 
Number of emergency visits 
- 
Number of outpatient visits 
- 
Number of imaging tests 
- 
Number of biopsy-related procedures 
- 
Treatment dose, duration, number of cycles 
Exploratory Objective: 
Endpoint/Variable: 


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Secondary Objective: 
Endpoint/Variable: 
To describe effectiveness of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC. 
Progression Free Survival (PFS). 
PFS rate at 6 months and at 1 year (PFS6, PFS12).  
Objetive Response Rate (ORR): using site 
investigator assessments according to RECIST 1.1. 
Duration of Response (DoR) 
DoR at 1 year (DoR12). 
Time to Treatment Discontinuation (TTD). 
Overal Survival (OS). 
The OS rate at 6, 12 and 18 months. 
Time to event endpoints measured as time from first 
Durvalumab dose. 
To describe the impact of durvalumab in 
combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC on patients‘ 
disease-related symptoms and Health Related 
Quality of Life (HRQoL) and (PROs). 
Changes in vital signs, physical findings, and 
clinical laboratory results during and following 
study treatment administration 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 items (EORTC QLQ-C30). 
Change from baseline in European Organisation for 
Research and Treatment of Cancer Quality of Life. 
Questionnaire-Lung Cancer 13 (EORTC QLQ-
LC13).   
Changes from baseline in PRO-CTCAE. 
To describe health care resources use related to 
management of ES-SCLC patients treated with 
durvalumab 
in 
combination 
with 
platinum–
etoposide as first-line treatment.  
- 
Number and length of hospitalizations 
- 
Number of visits to oncology service 
- 
Number of emergency visits 
- 
Number of outpatient visits 
- 
Number of imaging tests 
- 
Number of biopsy-related procedures 
- 
Treatment dose, duration, number of cycles 
  
 
 
 
 
 
 
 
 
 


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Once the elegible participant has given the informed consent to be included at the program, study 
variables apart from those that will be used to assess the objectives, will include at least the 
following: 
 Demographic characteristics: age, gender, race/ethnicity, smoking status, family history 
of cancer.  
 
 Clinical characteristics: SCLC stage, tumor site and histology, number and location of 
metastases including brain metastases, presence of other primary malignancy at diagnosis, 
performance status according to the ECOG scale. 
4. STUDY DESIGN 
4.1Overall design 
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.  
This is a Phase IIIb, interventional, single arm, multicentre study to evaluate safety, 
effectivenees, use of resources and patient reporting outcomes in patients with ES-SCLC treated 
with durvalumab in combination with platinum–etoposide as first-line treatment in Spain. 
This study will include approximately 85 eligible patients at participating Spanish sites.  
Durvalumab will be concurrently administered with first-line chemotherapy (EP) on an every 3 
week (q3w) schedule for 4 to 6 cycles, and will continue to be administered as monotherapy 
post-chemotherapy on an every 4 week (q4w) schedule until confirmed progressive disease (PD) 
or unacceptable toxicity.  
Prophylactic cranial irradiation (PCI) is allowed in patients showing complete or partial 
responses after the durvalumab + EP combination cycles,  at the discretion of the investigator 
according to their local clinical practice. 
Assessments will be conducted as indicated in Table 2 and Table 3. 
Tumor assessments will be performed at Screening as baseline with follow-ups following local 
standard practice, but at least with a maximun interval of 12 weeks. It is recommended that on-
study tumor assessments occur at Week 9 ±1 week from the date of inclusion for the first 12-18 
weeks (during durvalumab + EP, relative to the C1D1), and then every 8 ±1 weeks until 
confirmed objective disease progression (please refer to Appendix E). 


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4.2Scientific rationale for study design 
CASPIAN was a randomized, open-label, multi-centre, global, Phase III trial in the first line 
treatment of patients with ES-SCLC (NCT03043872). Durvalumab + EP demonstrated a 
statistically significant and clinically meaningful improvement in overall survival versus EP 
alone, with an HR of 0.73 (95% CI 0.59–0.91; p=0.0047). Overall survival benefit was observed 
across all clinically relevant patient subgroups.  
The overall safety profile in CASPIAN was similar between the two groups, with similar 
frequencies of grade 3 or 4 adverse events, adverse events leading to discontinuation, and 
adverse events leading to death. The most common adverse events were haematological 
toxicities. Immune-mediated adverse events were mostly low grade and manageable with 
standard treatment guidelines and were numerically higher in the durvalumab plus platinum–
etoposide group, and consistent with the known safety profile of durvalumab.  
This phase IIIb single arm study, is supported by the available clinical safety and efficacy data 
provided by CASPIAN randomized, open-label, phase 3 trial compared to other currently 
available treatment options that offer a limited life expectancy. It is expected that durvalumab in 
combination with etoposide and either carboplatin or cisplatin chemotherapy followed by 
durvalumab monotherapy, will be approved by the EMA during 2020. This trial will provide an 
opportunity to further evaluate the safety profile and efficacy of durvalumab + EP in patient 
population that is reflective of real-world clinical practice, including patients with ECOG 
performance status 2 who have not been included in pivotal studies of immunotherapy in this 
disease setting. 
4.3Justification for dose 
4.3.1.1Durvalumab dose rationale 
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, pre-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study CD-ON-MEDI4736-1108 
(hereafter referred to as Study 1108) in patients with advanced solid tumors and from a Phase I 
study performed in Japanese patients with advanced solid tumor (D4190C00002). 
PK/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg q2w or 15 mg/kg q3w, durvalumab exhibited non-linear (dose-dependent) 
PK consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg 
q2w, suggesting near complete target saturation (membrane-bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is 
approximately 21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with PD-L1. A low level of 


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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 
ADA impact; and (d) achieve PK exposure that yielded maximal antitumor activity in animal 
models. 
Given the similar area under the serum drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
q4w and 10 mg/kg q2w regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg q4w.  
Clinical data 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen. 
4.3.1.2Rationale 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 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012).  


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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. 
4.3.1.3Rationale 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 2019).  Likewise, the dose and 
schedule of etoposide and either carboplatin or cisplatin are consistent with those employed in 
the phase III CASPIAN trial as well as clinical practice guidelines (Paz-Ares 2019). 
This trial will allow up to a maximum of 6 cycles of durvalumab + EP to be administered Q3W.  
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 
(NCCN, ESMO). In the CASPIAN trial, 57% of patients in the control arm received 6 cycles of 
EP (Paz-Ares 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.  
4.4End 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. 
See Appendix A 6 for guidelines for the dissemination of study results. 
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 should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screening 
failures, refer to section 5.4. 


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In this protocol, ―enrolled‖ patients are defined as those who sign informed consent.  
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3. 
5.1 
Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
Informed consent 
1. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and this protocol. 
2. Provision of signed and dated, written informed consent obtained from the patient/legal 
representative prior to performing any protocol-related procedures. The ICF process is 
described in Appendix A 3. 
Age 
3. Male or female ≥18 years at the time of screening. 
 
Type of patient and disease characteristics 
4. Patients must have histologically- or cytologically-documented extensive-stage SCLC 
(stage IV [T any, N any, M1a/b/c] or with T3-4 due to multiple lung nodules that are too 
extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable 
radiation plan, according to American Joint Committee on Cancer Stage, 8th edition).  
a. Patients who had received chemoradiotherapy for LS-SCLC and have experienced 
a treatment-free interval of at least 6 months since last chemotherapy, 
radiotherapy, or chemoradiotherapy cycle, can be included under investigator 
criteria. 
b. Patients may be included if they either do not have brain metastases, or have brain 
metastases that are asymptomatic, or have brain metastases that have been treated 
at least 2 weeks prior to study treatment and are currently receiving 10 mg/day or 
less of prednisone or equivalent. Patients with suspected brain metastases at 
screening should have a CT/MRI of the brain prior to enrollment. 
5. Patients must be considered suitable to receive a platinum-based chemotherapy regimen 
as 1st line treatment for ES-SCLC. Chemotherapy must contain either cisplatin or 
carboplatin in combination with etoposide. 
6. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0-2 at enrolment/ 


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a. Note: a maximun of 30% of total patients with PS2 will be allowed; once this 
limit is met, additional enrolled patients must have PS 0-1. 
7. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as 
≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 
mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is 
suitable for accurate repeated measurements as per RECIST 1.1 guidelines. 
8. No prior exposure to immune-mediated therapy for cancer including, but not limited to, 
other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 
(anti-PD-L2) antibodies.  
9. Adequate hematologic and organ function, defined by the following laboratory results 
obtained within 14 days prior to first Durvalumab dose: 
a. ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support 
b. Platelet count ≥ 100,000/μL without transfusion 
c. Hemoglobin ≥ 9.0 g/dL 
d. INR or aPTT ≤ 1.5 × upper limit of normal (ULN); This applies only to patients 
who are not receiving therapeutic anticoagulation; patients receiving therapeutic 
anticoagulation should be on a stable dose. 
e. AST and ALT ≤ 2.5 × ULN, with the following exceptions: Patients with 
documented liver metastases: AST and/or ALT ≤ 5 × ULN; Patients with 
documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN.  
f. Serum bilirubin ≤ 1.5 × ULN; Patients with known Gilbert disease who have 
serum bilirubin level ≤ 3 × ULN may be enrolled. 
g. Measured or calculated creatinine clearance: >60mL/min for patients on cisplatin 
and >45mL/min for patients on carboplatin, as determined by Cockcroft-Gault 
(using actual body weight): 
Males 
Creatinine CL =  
Weight (kg) × (140 - Age) 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
 
Females: 
Creatinine CL =  
Weight (kg) × (140 - Age)  
 × 0.85 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
 
10. 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 


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been amenorrheic for 12 months without an alternative medical cause. For women of 
childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive methods that result in a failure rate of < 1% per year 
during the treatment period and for at least 90 days after the last dose of study 
treatment.For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures. 
11. Life expectancy of at least 12 weeks. 
Weight 
12. Body weight >30 kg. 
 
5.2 
Exclusion criteria  
1. History of allogeneic organ transplantation. 
2. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., 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: 
a. 
Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement 
c. 
Any chronic skin condition that does not require systemic therapy 
d. Patients with celiac disease controlled by diet alone 
Note:  Patients without active disease in the last 5 years may be included but only after 
consultation with AstraZeneca. 
3. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan 
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit 


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compliance with treatment requirements or compromise the ability of the patient to give 
written informed consent. 
5. Malignancies other than SCLC within 3 years prior to screening if the patient has no 
evidence of disease, with the exception of those with a negligible risk of metastasis or 
death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, 
localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ   
treated surgically with curative intent). 
6. History of leptomeningeal carcinomatosis. 
7. History of active primary immunodeficiency. 
8. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, 
or human immunodeficiency virus (positive HIV 1 / 2 antibodies).  
a. NOTE: Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
9. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic 
treatment (systemic steroids or immunosuppressive agents) or has a clinical 
symptomatology suggesting worsening of PNS. 
10. Known allergy or hypersensitivity to Durvalumab (IMFINZI), etoposide, carboplatin, 
cisplatin, or any of their excipients. 
11. Medical contraindication to etoposide-platinum (carboplatin or cisplatin)-based 
chemotherapy 
Prior/concomitant therapy 
12. Has received prior systemic treatment for ES-SCLC. 
13. Planned consolidation chest radiation therapy. 
14. Receipt of live attenuated vaccination within 30 days prior to the first dose of 
Durvalumab (IMFINZI). Note: Patients, if enrolled, should not receive live vaccine 
whilst receiving Durvalumab (IMFINZI) and up to 30 days after the last dose of 
Durvalumab (IMFINZI). 
15. Major surgical procedure (as defined by the treating physician) within 28 days prior to 
the first dose of Durvalumab (IMFINZI). Note: Local surgery of isolated lesions for 
palliative intent is acceptable.  


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16. Prior exposure to any immune-mediated therapy, including, but not limited to, anti-
CTLA-4, 
anti-PD-1, 
anti-PD-L1, 
or 
anti-PD-L2 
antibodies, 
including 
Durvalumab/(IMFINZI). 
17. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of Durvalumab (IMFINZI). The following are exceptions to this criterion: 
a. 
Intranasal, inhaled, topical steroids or local steroid injections 
b. 
Systemic corticosteroids at physiological doses, which are not to exceed 10 
mg/day of prednisone, or its equivalent  
c. 
Systemic steroid administration required as premedication for hypersensitivity 
reactions (eg, CT scan premedication), or as premedication for chemotherapy is allowed. 
Prior/concurrent clinical study experience 
18. Participation in another clinical study with an IP during the last 4 weeks. 
19. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional study. 
20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
Other exclusions 
21. Female patients who are pregnant or breast-feeding, or male or female patients of 
reproductive potential who are not willing to employ an effective method of birth control 
from screening to 90 days after the last dose of Durvalumab (IMFINZI). 
22. Any condition that, in the opinion of the treating physician, would interfere with 
evaluation of the Program drug or interpretation of patient safety. 
 
5.3 
Lifestyle restrictions 
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after: 
1. 
Female patient of child-bearing potential 
 
Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 4) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period 90 days after 


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the last dose of durvalumab. Non-sterilized male partners of a female patient of 
childbearing potential must use a male condom plus spermicide throughout this 
period. Cessation of birth control after this point should be discussed with a 
responsible physician. Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. Female patients 
should refrain from breastfeeding throughout this period.  
2. 
Male patients with a female partner of childbearing potential 
 
Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 
spermicide from the time of screening throughout the total duration of the drug 
treatment and the drug washout period 90 days after the last dose of durvalumab. 
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm 
donation throughout this period. 
 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 4).  
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral 
salpingectomy, 
bilateral 
oophorectomy, 
or 
complete 
hysterectomy) 
or 
post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution. 
 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago. 
 
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, 
or complete hysterectomy) are eligible.  
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 4. Note 
that some contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
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). 


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Table 4 
Highly effective methods of contraception (<1% failure rate) 
Barrier/intrauterine methods 
Hormonal methods 
 
Copper T intrauterine device 
 
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®)a 
 
 
Implants: 
Etonogestrel-releasing 
implants 
(eg, 
Implanon® or Norplant®) 
 
Intravaginal Devices: Ethinylestradiol/etonogestrel-
releasing intravaginal devices (eg, NuvaRing®)  
 
Injection: Medroxyprogesterone injection (eg, Depo-
Provera®) 
 
Combined Pill: Normal and low dose combined oral 
contraceptive pill 
 
Patch: 
Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) 
 
Minipill: Progesterone based oral contraceptive pill 
using desogestrel: Cerazette® is currently the only 
highly effective progesterone based pill  
a 
This is also considered a hormonal method 
 
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. 
Restrictions relating to concomitant medications are described in Section 6.4. 
5.4Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be included. These patients should have the reason for study withdrawal recorded as 
―eligibility criteria not fulfilled‖ (ie, patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (ie, not included 
patients). Patients may be rescreened a single time.  
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAE). 
6. STUDY TREATMENTS 
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to platinum (carboplatin or 
cisplatin), etoposide and durvalumab.  


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6.1Treatments administered 
6.1.1Investigational products 
AstraZeneca will supply durvalumab (MEDI4736). SoC agents platinum (carboplatin or cisplatin) 
and etoposide will be supplied locally, as it is the standard treatment for these patients according 
usual clinical practice.  
Table 5 
Study treatments 
 
 
Durvalumab 
Etoposide 
Cisplatin  
Carboplatin 
Study treatment name: 
 
Durvalumab 
(MEDI4736) 
Etoposide  
Cisplatin 
Carboplatin 
Dosage formulation: 
 
500-mg vial 
solution for 
infusion after 
dilution, 
50 mg/mL 
Sourced 
locally 
by site 
Sourced locally 
by site 
Sourced 
locally by site 
Route of administration  
IV 
IV   
IV   
IV  
Dosing instructions: 
 
Durvalumab 
1500 mg via IV 
infusion over 60 
minutes on Day 
1 of each cycle. 
Etoposide 
sequentially 
administered per 
local 
standards 
(usually over 30 
to 60 minutes IV 
infusion) 
on 
Days 1, 2, and 3 
of each cycle. 
Cisplatin as an 
IV infusion per 
local standards 
(usually over 60 
to 120 minutes 
on Day 1) of 
each cycle. 
Carboplatin as 
an IV infusion 
per 
local 
standards 
(usually over 
30 
to 
60 
minutes 
on 
Day 1) of each 
cycle. 
Packaging and labelling 
 
500-mg 
vial 
solution for 
infusion 
after 
dilution.b 
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. Each vial will be labelled in accordance with 
Good Manufacturing Practice (GMP) Annex 13 and per country regulatory requirement.  
 
6.1.1.1Durvalumab (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) 


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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 IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab (MEDI4736) vial to the start of administration should not exceed:  
 
24 hours at 2°C to 8°C (36°F to 46°F) 
 
4 hours at room temperature 
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 
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, however if  there are interruptions during the infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used, after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered. 
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.  
6.1.1.2Etoposide + platinum 
Etoposide + platinum (cisplatin or carboplatin) will be locally sourced and will be administered 
according to prescribing information or treatment guidance in general use by the Investigating 
site.  


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6.1.1.3Order of Administration 
Patients will receive durvalumab (1500 mg) via IV infusion over 60 minutes. 
We recommend a 60-minute observation period after durvalumab is administered at least for 
cycle 1. 
If no issues are seen after durvalumab is given during the first cycle, we recommend reducing the 
observation period after durvalumab administration to 30 minutes. 
Durvalumab infusion will then be followed by administration following local standards of an IV 
infusion of carboplatin usually over 30 to 60 minutes or cisplatin usually over 60 to 120 minutes 
, followed by etoposide sequentially administered usuallyover 30 to 60 minutes infusion on Day 
1 of each combination cycle;  etoposide will also be administered as an IV infusion on days 2 
and 3 of each cycle up until a maximum of 6 cycles has been reached. 
6.1.2Dose and treatment regimens 
6.1.2.1Durvalumab (MEDI4736)  
Patients will receive 1500 mg durvalumab via IV infusion q3w in combination with EP and q4w 
in monotherapy until clinical progression or RECIST 1.1-defined radiological progression unless 
there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. 
(Please note, 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 q4w after consultation between Investigator and 
Study Physician, until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg q4w). 
6.1.2.2Etoposide + platinum 
Patients will receive, according to SoC, 4-6 cycles of: 
- Etoposide: 80 to 100 mg/m2 daily on Days 1 to 3 (total dose 300 mg/m2) given q3w plus 
- Carboplatin: AUC 5-6 on Day 1 given q3w, or 
- Cisplatin: 75 to 80 mg/m2 intravenous (IV) on Day 1 given q3w 
Cisplatin and carboplatin have indistinguishable clinical efficacy but are different in terms of 
cost and toxicity profiles. The selection of cisplatin or carboplatin in combination with etoposide 
is at the investigator‘s discretion. These agents are commonly used in ES-SCLC and will be 
given as per the product label for the indication and the NCCN and ESMO guidelines. 
Prophylactic cranial irradiation (PCI) will be permitted; this will be at the investigators‘ 
discretion as per SoC guidance for ES-SCLC. 


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6.1.3Duration of treatment and criteria for treatment through progression and for 
retreatment 
Durvalumab will be administered beginning on Day 1 until clinical progression or RECIST 1.1-
defined radiological progression (refer to 0E), 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 durvalumab 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, and this follow-up 
scan is evaluated using the post-progression evaluation criteria outlined in 0E. 
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 may not 
have experienced a toxicity that required permanent discontinuation of study 
treatment. 
 
There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG performance status 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, with the execption of 
inclusion criterion 8  
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 (DCO) 
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure may continue to receive their assigned treatment for as long as they and their 
physician considers they are gaining clinical benefit. Different drug supply options may be 
available and these will be proposed to the patient when the most appropriate alternatives for 


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continued treatment have been agreed between AZ and the Investigator.  Options may incude 
participation in a new rollover study, or if durvalumab has been locally approved for use in this 
disease indication, patients may be discontinued from study treatment and transitioned to the 
marketed product, in accordance with local laws.  For patients continuing to receive durvalumab 
treatment following the final DCO and database closure, it is recommended that the patients 
continue the scheduled site visits and Investigators monitor the patients‘ safety laboratory results 
prior to and periodically during treatment with durvalumab in order to manage AEs in 
accordance with the durvalumab Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5).  
6.1.4Storage 
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is stored 
in a secured area, in refrigerated temperatures (2°C to 8°C), if needed, 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. 
6.1.5Medical devices 
Not applicable.  
6.2Measures to minimize bias 
6.2.1Patient enrollment  
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.   
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 have been obtained within 
28 days of inclusion.  
 
Obtain a unique enrollment number (E-code), through the Interactive Web Response 
System (IWRS). This number is the patient‘s unique identifier and is used to identify 
the patient on the electronic case report forms (eCRFs). 
 
Determine patient eligibility (see Sections 5.1 and 5.2) 


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If the patient is ineligible and not included, the IWRS should be contacted to terminate the 
patient in the system.  
Patients will begin treatment on Day 1. Treatment should start no more than 3 working days after 
being included. Patients must not be included and treated unless all eligibility criteria have been 
met.  
If a patient withdraws from participation in the study, then his or her enrollment code cannot be 
reused.  
6.2.2Procedures 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 included in error, or incorrectly 
started on treatment, the Investigator should inform the Study Medical Monitor immediately, and 
a discussion should occur between the Study Medical Monitor and the Investigator regarding 
whether to continue or discontinue the patient from treatment. The Study Medical Monitor must 
ensure all decisions are appropriately documented and that the potential benefit:risk profile 
remains positive for the patient.   
6.2.3Methods for assigning treatment groups 
Not applicable. This is a single arm study. 
6.2.4Methods for ensuring blinding 
Not applicable. This is a single arm study. 
 
6.3 Treatment compliance 
Any change from the dosing schedule, dose delays/interruptions, dose reductions and dose 
discontinuations should be recorded in eCRF. 
The Investigational Product Storage Manager is responsible for managing the IP from receipt by 
the study site until the destruction or return of all unused IP. 
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.  


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Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose, unit and frequency 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5).  
Table 6 
Prohibited concomitant medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy other 
than those under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [eg, by local surgery or radiotherapy]) 
PCI is allowed in patients showing complete or 
partial responses after chemo-durvalumab treatment 
under investigator criteria. 
Live attenuated vaccines  
Should not be given through 30 days after the last 
dose of IP 


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Prohibited medication/class of drug: 
Usage: 
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
 
Use of immunosuppressive medications for 
the management of IP-related AEs. 
 
Short-term 
premedication 
for 
patients 
receiving combination agents EP where the 
prescribing information for the agent requires 
the 
use 
of 
steroids 
for 
documented 
hypersensitivity reactions. 
 
Use in patients with contrast allergies. 
 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy 
related events experienced by the patient (eg, 
chronic obstructive pulmonary disease, radiation, 
nausea, etc). 
EGFR TKIs 
Should not be given concomitantly. 
Should be used with caution in the 90 days post 
last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence 
of transaminase increases (with 1st generation 
EGFR TKIs) has been reported when durvalumab 
has been given concomitantly. 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concurrently unless agreed by 
the sponsor 
Anti-epileptics 
New treatment with phenytoin should not be started if 
patient is on treatment with cisplatin/carboplatin.  
If patient started taking phenytoin previously, 
monitor the levels of phenytoin in plasma while 
patient is on treatment with cisplatin/carboplatin and 
adjust the dose accordingly. There is a risk of 
exacerbation of convulsions due to the decrease of 
phenytoin digestive absorption and/or increased 
metabolism by the cytotoxic drug. 
 


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Table 7 
Supportive medications 
Supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed 
necessary 
to 
provide 
adequate 
prophylactic or supportive care, except for 
those medications identified as ―prohibited,‖ as 
listed above  
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc]) 
Should be used, when necessary, for all patients 
Inactivated viruses, such as those in the 
influenza vaccine 
Permitted 
 
6.4.1Background medication 
6.4.2Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the patient‘s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form. 
6.4.3Durvalumab drug-drug interactions 
There is no information to date on drug-drug interactions with durvalumab either pre-clinically 
or in patients. As durvalumab is a monoclonal antibody and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance. It is therefore not expected that durvalumab will induce or inhibit 
the major drug metabolizing cytochrome P450 pathways. As a result, there are no expected 
pharmacokinetic drug-drug interactions. The mechanism of action of durvalumab involves 
binding to PD-L1, and therefore significant pharmacodynamic drug interactions with the 
commonly administered concomitant medications are not expected. Despite this, appropriate 
clinical monitoring in all of the planned clinical studies will be conducted to evaluate any 
potential drug-drug interactions. 
6.4.4Rescue 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).  These medications will be sourced locally 
as needed. 


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6.5Dose modification 
Dose delays are permitted for IO therapy (see Dosing Modification and Toxicity Management 
Guidelines).  However, dose reduction is not permitted.  
Chemotherapy dose modifications will be performed according SmPC guidelines.  
6.6Treatment 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 6.1.2). 
7. DISCONTINUATION 
OF 
TREATMENT 
AND 
SUBJECT 
WITHDRAWAL  
7.1Discontinuation of study treatment  
An individual patient will not receive any further durvalumab or EP dose if any of the following 
occur in the patient in question: 
 
Withdrawal of consent from further treatment with IP. The patient is, at any time, free 
to discontinue treatment, without prejudice to further treatment. A patient who 
discontinues treatment is normally expected to continue to participate in the study 
(eg, for safety and survival follow up) unless they specifically withdraw their consent 
to all further participation in any study procedures and assessments (see Section 7.3).  
 
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing 
 
Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5) or as defined in the local 
prescribing information for the EP treatment.  
 
Pregnancy or intent to become pregnant 
 
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits) 
 
Initiation of alternative anticancer therapy including another investigational agent 
 
Clinical progression or confirmed radiological progression (refer to 0E) and 
Investigator determination that the patient is no longer benefiting from treatment with 
IP 


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 
Completion of the study by the sponsor for obtaining the indication for ES-SCLC in 
combination with etoposide + platinum 
7.1.1Procedures for discontinuation of study treatment 
Discontinuation of study treatment, for any reason, does not impact the patient‘s participation in 
the study. A patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE. The patient should continue attending subsequent 
study visits, and data collection should continue according to the study protocol. If the patient 
does not agree to continue in-person study visits, a modified follow-up must be arranged to 
ensure the collection of endpoints and safety information. This follow-up could be a telephone 
contact with the patient, a contact with a relative or treating physician, or information from 
medical records. The approach taken should be recorded in the medical records. A patient that 
agrees to modified follow-up is not considered to have withdrawn consent or to have withdrawn 
from the study. 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs).  
Patients who permanently discontinue drug for reasons other than objective RECIST disease 
progression should continue to have RECIST scans performed according usual clinical practice, 
at least q12w ±1w (relative to the date of inclusion), until RECIST 1.1-defined radiological PD 
plus an additional follow-up scan or death (whichever comes first) as defined the SoAs. 
If a patient is discontinued for RECIST 1.1-defined progression, then the patient should have 
1 additional follow-up scan performed 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. 
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.  
7.2Lost 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.‖ 


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 
Lost to Follow up – site personnel should check hospital records, the patients‘ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable CRF modules will be updated.) 
 
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable CRF modules 
will be updated.)    
7.3Withdrawal from the study 
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice 
to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further 
IP or further study observation, with the exception of follow-up for survival, which will continue 
until the end of the study unless the patient has expressly withdrawn their consent to survival 
follow-up. Note that the patient may be offered additional tests or tapering of treatment to 
withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
 
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.  
The Investigator will ensure that data are recorded on the electronic Case Report Forms. The 
Web Based Data Capture (WBDC) system will be used for data collection and query handling.  
The Investigator ensures the accuracy, completeness, for CRFs include: 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 paper/electronic Case Report Forms. 
A copy of the completed electronic Case Report Forms 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. 


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Adherence to the study design requirements, including those specified in the SoA, 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.  
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. 
The maximum amount of blood collected from each patient over the duration of the study for the 
biomarker analysis will not exceed 90 mL. Blood samples for patient safety will be collected 
according ususal clinical practice at each study site. 
Once the elegible participant has given the informed consent to be included at the program, the 
following demographyc and clinical variables will be collected: 
 Demographic characteristics: age, gender, race/ethnicity, smoking status, family history 
of cancer.  
 
 Clinical characteristics: SCLC stage, tumor site and histology, number and location of 
metastases including brain metastases, presence of other primary malignancy at diagnosis, 
performance status according to the ECOG scale. 
 
8.1Efficacy assessments  
This study will evaluate the efficacy of durvalumab + EP as secondary endpoints, in terms of OS, 
OS rates at 6, 12 and 18 months, as well as PFS, PFS rate at 6 and 12 months from inclusion, 
ORR, DoR, Time to Treatment Discontinuation and DCR, which will be derived (by 
AstraZeneca) using Investigator RECIST 1.1 assessments.  
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. 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 
0E), and 


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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 (0E) provide a method of assessment of change in tumor burden in 
response to treatment. Screening/Baseline imaging should be performed no more than 28 days 
before start of study treatment, and ideally should be performed as close as possible to and prior 
to the start of study treatment. The RECIST 1.1 assessments of baseline images identify Target 
Lesions (TLs) (defined as measurable) and Non-Target Lesions (NTLs). On-study images are 
evaluated for TLs and NTLs chosen at baseline, and for New Lesions (NLs) when they appear. 
This allows determination of follow-up TL response, NTL lesion response, the presence of 
unequivocal NLs, and overall timepoint responses (CR, PR, SD, PD, or Not Evaluable [NE]). 
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 0E. 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 0E. 
8.1.1Central reading of scans 
Not applicable.  
8.1.2Survival assessments 
Assessments for survival must be made every 2 months following treatment discontinuation. 
Survival information may be obtained via telephone contact with the patient or the patient‘s 
family, or by contact with the patient‘s current physician. The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cutoff for the primary analysis and all subsequent survival analyses to provide complete survival 
data. These contacts should generally occur within 7 days of the data cutoff. 
8.2Safety assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1Clinical safety laboratory assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the times indicated in the assessment schedules and as clinically indicated (see the 
SoAs).  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Pregnancy tests 


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may be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal 
clinically significant laboratory results should be repeated as soon as possible (preferably within 
24 to 48 hours). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will be 
recorded on the appropriate eCRF. 
The laboratory variables to be measured are presented in Table 8 (clinical chemistry), Table 9 
(hematology), and Table 10 (urinalysis). 
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies. 
The following laboratory variables will be measured: 
Table 8 
Clinical chemistry 
Albumin 
Lipaseb 
Alkaline phosphatase 
Magnesiumc 
ALTa 
Potassium 
Amylaseb 
Sodium 
ASTa 
Total bilirubina 
Bicarbonatec 
Total protein 
Calcium  
TSHe 
Chloridec 
T3 freef (reflex) 
Creatinined  
T4 freef (reflex) 
Gamma glutamyltransferasec 
Urea or blood urea nitrogen, depending on local practice 
Glucose 
 
Lactate dehydrogenase 
 
a 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If 
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert‘s syndrome), then fractionate into 
direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters 
is routinely measured, either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, magnesium, testing 
are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry assessments are 
performed within 3 days prior to Day 1), and if clinically indicated. 
d 
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body weight).  
e 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 
f 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system. 
ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid-stimulating hormone. 
 


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Table 9 
Hematology 
Absolute neutrophil counta 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
 
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. 
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. 
 
Table 10 
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 0 
for further instructions on cases of increases in liver biochemistry and evaluation of Hy‘s Law. 
These cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy‘s law 
case or if any of the individual liver test parameters fulfill any of the SAE criteria.  
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months 
(±1 week), and 3 months (±1 week) after permanent discontinuation of IP (see the SoAs). 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.7. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 or 
2, unless these values are not likely to improve because of the underlying disease. 
8.2.2Physical 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.  


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8.2.3Vital 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 durvalumab infusion, patients will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of IP as presented in the bulleted list below.  
BP and pulse will be collected from patients before, during, and after each infusion at the 
following times (based on a 60-minute infusion): 
 
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion]) 
 
Approximately 30 minutes during the infusion (halfway through infusion)  
 
At the end of the infusion (approximately 60 minutes ±5 minutes) 
If the infusion takes longer than 60 minutes, then BP and pulse 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 and EP.  
Subsequent infusions 
BP, 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 signs should be 
measured during and post infusion as per institution standard and as clinically indicated. Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
CRF page.  
Situations in which vital signs results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, the vital signs values should be entered into the CRF. 
8.2.4Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs). ECGs should be obtained after the patient has been in a supine position for 
5 minutes and recorded while the patient remains in that position. 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the 
finding.  
Situations in which ECG results should be reported as AEs are described in Section 8.3.7. 


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8.2.5Early patient review for safety 
Not applicable.  
8.2.6WHO/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. 
8.2.7Patient reported outcomes (PRO) 
 ―PRO‖ is an umbrella term referring to all outcomes and symptoms that are directly reported by 
the patient. PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical studies. The following PROs will be administered in this study: EORTC 
QLQ-C30 v3 (core questionnaire), EORTC QLQ-LC13 (lung cancer module), patient-reported 
outcomes version of the CTCAE (PRO-CTCAE). (see Appendix  H and, I). 
The PRO instruments will be completed by the patients using a paper format questionnaire on 
day 1 of every cycle. All assessments should be completed without assistance from anyone 
according to the assessment schedules. It takes approximately 30 minutes for patients to 
complete the questionnaires; therefore, the burden to the patient is moderate. 
8.2.7.1EORTC QLQ-C30 
The EORTC QLQ-C30 v3 questionnaire is included for the purpose of assessing HRQoL and is 
a well-established measure of HRQoL/health status and commonly used as an endpoint in cancer 
clinical studies. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales 
(physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea 
and vomiting), and a global health and quality-of-life (QoL) scale. Six single-item symptom 
measures are also included dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties (see Appendix H). For each of the 15 domains, final scores are transformed such that 
they range from 0 to 100, where higher scores indicate greater functioning, greater HRQoL, or 


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greater level of symptoms (Aaronson et al 1993). 
8.2.7.2 EORTC QLQ-LC13 
For patients with SCLC, a disease-specific 13-item self-administered questionnaire for lung 
cancer was developed (EORTC QLQ-LC13; Appendix I) to be used in conjunction with the 
EORTC QLQ-C30 (Bergman et al 1994). It comprises both multi-item and single-item measures 
of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side 
effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, 
and dysphagia). Similar to the EORTC QLQ-C30, all questions except one have a 4-point scale: 
―not at all‖, ―a little‖, ―quite a bit‖ and ―very much‖. One question (no. 43, ―Did you take any 
medicine for pain?‖) has a response option of ―yes‖ or ―no‖. The scoring approach for the 
EORTC QLQ-LC13 is similar to the EORTC QLQ-C30. 
8.2.7.3 PRO-CTCAE 
The PRO-CTCAE is included to address tolerability from the patients‘ perspective. It was 
developed by the National Cancer Institute (NCI). The PRO-CTCAE will only be administered 
in those countries where a linguistically validated version exists. It was developed in recognition 
that collecting symptom data directly from patients using PRO tools can improve the accuracy 
and efficiency of symptomatic AE data collection. This was based on findings from multiple 
studies demonstrating that physicians and nurses underestimate symptom onset, frequency, and 
severity in comparison with patient ratings (Antonia et al 2014, Litwin et al 1998, Sprangers and 
Aaronson 1992). These symptoms have been converted to patient terms (eg, the CTCAE term 
―myalgia‖ has been converted to ―aching muscles‖). For several symptoms, like fatigue and pain, 
additional questions are asked about symptom frequency, severity, and interference with usual 
activities. The items included in the PRO-CTCAE have undergone extensive qualitative review 
among experts and patients. These items have been extensively evaluated by cancer patients to 
be clear, comprehensible, and measure the symptom of interest. In this study, only items that are 
considered relevant for the study, site of cancer, and cancer treatment are selected. 
8.2.7.4Administration of the patient-reported outcome questionnaires 
Patients will complete the PRO assessments in paper format during clinic visits. Each center 
must allocate the responsibility for the administration of the PRO instruments to a specific 
individual (eg, a research nurse or study coordinator) and, if possible, assign a back-up person to 
cover if that individual is absent. The PRO questionnaires must be administered and completed 
at the clinic as per the schedule of assessments. The PRO questionnaires will be administered on 
the days specified in the schedules of assessments. The EORTC QLQ-C30 should always be 
completed prior to the EORTC QLQ-LC13 module. 
It is important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection. The following 
best practice guidelines should be followed when collecting PRO data: 
 
It is preferred that PRO questionnaires are completed prior to any other study procedures 
(following informed consent) and before discussion of disease progression to avoid biasing 
the patient‘s responses to the questions. 


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 
PRO questionnaires must be completed in private by the patient. 
 
Patients should be given sufficient time to complete the PRO questionnaires at their own 
speed. 
 
The research nurse or appointed site staff should stress that the information is confidential. 
Therefore, if the patient has any medical problems, he/she should discuss them with the 
doctor or research nurse separately from the ePRO assessment. 
 
The research nurse or appointed site staff must train the patient on how to complete the 
questionnaires. The research nurse or appointed site staff must remind patients that there 
are no right or wrong answers and avoid introducing bias by not clarifying items. The 
patient should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. 
8.2.8 Health care resource use 
The assessment of health care resource use will increase the understanding regarding the 
relationship between treatment and tumor-related cancer symptoms on resource use, such as the 
need for palliative procedures to address obstruction and bleeding. This will be captured and 
analyzed to inform submissions to payers. To investigate the impact of treatment and disease on 
health care resource use, the following variables will be captured: 
 
Number and length of hospitalizations. 
 
Number of visits to oncology service. 
 
Number of emergency visits. 
 
Number of outpatient visits. 
 
Number of imaging tests. 
 
Number of biopsy-related procedures. 
 
Treatment name, dose, duration, number of cycles. 
8.2.9Other safety assessments 
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 


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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: CRP, LDH 
(iv) 
Any test to rule out an active infectious disease and any other causes 
should be performed under investigator criteria. 
8.3Collection 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.  


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8.3.1Method 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.  
8.3.2Time period and frequency for collecting AE and SAE information  
AEs and SAEs will be collected from the time of the patient signing the informed consent form 
until the follow-up period is completed (90 days after the last dose of durvalumab). 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 AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient‘s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the Investigator should notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B. 
8.3.3Follow-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 SAE/non-serious AEs/AEs of special interest, 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 AE assessment in the study are followed up by 
the Investigator for as long as medically indicated (this may be beyond the 90 days after the last 
dose of durvalumab), but without further recording in the CRF. AstraZeneca retains the right to 
request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary. 
8.3.4Adverse 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) 


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 
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  
 
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). 
8.3.5Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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?‘ 


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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. 
8.3.6Adverse 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, 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. 
8.3.7Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs 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 investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
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 8.310. 
8.3.8Hy’s law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs. Please refer to 0 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy‘s Law 
8.3.9 
Disease-under study (DUS) 
Symptoms of DUS are those which might be expected to occur as a direct result of ES-SCLC or 
procedures to diagnose or treat ES-SCLC . Events which are unequivocally due to disease under 


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study should not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of the investigational product. 
8.3.10Disease progression 
Disease progression can be considered as a worsening of a patient‘s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of 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. 
8.3.11New cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after the 
patient‘s inclusion in this study. 
8.3.12Deaths 
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 
Death page. It should not be reported as an SAE. 
 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the 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 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 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. 
8.3.13Adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events 


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in order to characterize and understand them in association with the use of this investigational 
product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, myocarditis,myositis/polymyositis, pancreatitis and rare/less frequent imAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. 
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab IB. More specific guidelines for their evaluation and treatment are described 
in detail in the Dose Modification and Toxicity Management Guidelines (see Section 8.4.5). 
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting Investigator. 
8.3.14Safety data to be collected following the final DCO of the study 
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient‘s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5). All data 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. 


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All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure must 
be reported as detailed in Section 8.4.1. 
8.4Safety reporting and medical management 
8.4.1Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day (ie, immediately but no later than 24 hours of when he or she becomes aware 
of it). 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the Investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.For 
further guidance on the definition of a SAE, see Appendix B of the Clinical Study Protocol. 
8.4.2Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
 
If the pregnancy is discovered before the study patient has received any study drug 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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8.4.2.1Maternal exposure 
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day (ie, immediately but no later 
than 24 hours of when he or she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.4.2.2Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for  
90 days after the last dose of durvalumab + EP combination therapy or 90 days after receipt of 
the final dose of durvalumab maintenance therapy.  
Pregnancy of the patient‘s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
of durvalumab + EP combination therapy or 90 days after receipt of the final dose of durvalumab 
maintenance therapy should, if possible, be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient‘s partner. Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the Ethics 
Committees (ECs) prior to use. 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see the 
SoAs). 


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8.4.3Overdose 
8.4.3.1Durvalumab  
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. 
8.4.3.2EP treatment 
Use of etoposide or platinum 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. If any overdose is associated with an AE or SAE please record the AE/SAE diagnosis 
or symptoms in the relevant AE modules of the eCRF. 
8.4.4Medication error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but 
no later than 24 hours of when he or she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE associated 
with the medication error (see Section 8.3.2) and within 30 days for all other medication errors. 
The definition of a Medication Error can be found in Appendix B. 
8.4.5Management of IP-related toxicities  
The following general guidance should be followed for management of toxicities. 
 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required). 


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 
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of the assigned IP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted  
 
All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 
 
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, Version 5.0.  
8.4.5.1Specific toxicity management and dose modification information – 
Durvalumab  
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitor durvalumab [Medi4736] (PD-L1 inhibitor) Additionally, these 
guidelines are applicable when durvalumab is used alone or in combination and is administered 
concurrently or sequentially with other anti-cancer drugs (i.e. antineoplastic chemotherapy, 
targeted agents), as part of a protocol specific treatment regimen.   
The TMGs provide information for the management of immune-mediated reactions, infusion-
related reactions, and non-immune mediated reactions that may be observed with checkpoint 
inhibitor monotherapy or combination checkpoint inhibitor regimens, with specific instructions 
for dose modifications (including discontinuations) and treatment interventions.  Investigators 
are advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other cancer treatment (platinum and/or etoposide). The 
most current version of the TMGs entitled ―Dosing Modification and Toxicity Management 
Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune Mediated Reactions 
(MEDI4736) Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab 
Monotherapy‖ is provided to the investigative site as an Annex document and is maintained 
within the Site Master File. In addition, a version of the current Dosing Modification and 
Toxicity Management Guidelines is available through the following link: https://tmg.azirae.com. 
Please contact the clinical study associate for information on how to gain access to this website.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related.  In addition, there are certain circumstances in which durvalumab  should be 


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permanently discontinued (see Section 7.1 of this protocol and the Dosing Modification and 
Toxicity Management Guidelines).  Following the first dose of IP, subsequent administration of 
durvalumab can be modified based on toxicities observed as described in the Dosing 
Modification and Toxicity Management Guidelines. These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these 
types of toxicities. These guidelines apply to AEs considered causally related to durvalumab by 
the reporting Investigator. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician. 
8.4.5.2Specific toxicity management and dose modification information – EP 
treatment 
Chemotherapies are associated with a number of unwanted effects. Investigators should follow 
local standard clinical practice regarding dose modifications, including delays and reductions, for 
management of etoposide- and platinum-related toxicity. For specific information regarding the 
individual agent used in this study, please refer to 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).  
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 
Pharmacokinetics parameters are not evaluated in this study. 
8.6 Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 Genetics 
Genetic testing is not evaluated in this study. 
8.8 Biomarkers 
The patient may give specific consent for sample collection for the biomarker analyses . The use 
of donated biological samples will be as described here (also see Table 11).  
 
Archival tissue samples will be obtained from all screened patients, if available (see 
Appendix J).  


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 
Blood samples will be performed
 
 
 
Additional Blood samples will be performed 
 
 
Fresh tissue sample will be obtained 
 
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual. 
All samples collected for biomarker analyses will be stored at the study site or a reference 
laboratory, and may be used for subsequent research relevant to evaluating biological and/or 
clinical response to immunotherapy as described in the exploratory analyses section. 
The results may be pooled with biomarker data from other durvalumab studies to evaluate 
biological responses across indications and to compare results in monotherapy versus 
combination settings. 
8.8.1Exploratory biomarkers 
Blood and tumor samples for exploratory biomarker analyses will be obtained according to the 
schedules presented in the SoAs. Tissue samples will be collected from all screened patients in 
this study, if available, as specified in Section 8.8.1.1. 
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.  
The exploratory biomarker plan is described by sample type below. 
8.8.1.1Collection of tumor samples for exploratory tumor biomarkers 
Tumor sample requirements:  
• Provision of a tumor tissue
 Refer 
to the Laboratory Manual for details.  
At the screening visit, a tumor sample (formalin-fixed paraffin-embedded) will be obtained from 
all patients. The provision of tumor tissue sample is mandatory for the patients and requires a 
patient consent. If a tumor block exists and there is sufficient quantity to allow for biomarker 
analysis, then the tumor tissue block should be shipped to the central laboratory. If a tissue block 
is unavailable, unstained slides from the tissue block should be provided.  
See the Laboratory Manual for further details of requirements including sample quality control 
and shipping.  
 


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Tumor markers  
 
Tissue obtained as part of screening procedures may be analyzed for potential biomarkers 
 
  
Other tissue-based approaches may be pursued including 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, AstraZeneca facilities, or at an AstraZeneca-assigned Biobank and may be used for 
subsequent research relevant to evaluating biological and/or clinical response to immunotherapy. 
8.8.1.2Collection of samples 
 
Optional blood samples for exploratory biomarker analyses will be obtained according to the 
schedules presented in the SoAs (Table 1). Details for collection, volumes, storage, and shipment 
of biologic samples are presented in a separate Laboratory Manual.  
All samples collected for exploratory analyses will be stored at the site, a reference laboratory, or 
at AstraZeneca‘s facilities and may be used for subsequent research relevant to evaluating 
response to immunotherapy.  
The exploratory biomarker plan is described by sample type below. 
  
 
 


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Table 11: Biomarker analysis 
Sample 
Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
8.8.2Management of biomarker data 
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 


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employer, clinical study Investigator, general physician, or any other third party, unless required 
to do so by law. The patient‘s samples will not be used for any purpose other than those 
described in the study protocol and its appendices. 
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient‘s name nor any other personal identifiers will appear in any publication or 
report. 
8.8.3Storage, re-use and destruction of biomarker samples 
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the CSR in a separate report. The results of 
this biomarker research may be pooled with biomarker data from other studies involving 
durvalumab to generate hypotheses to be tested in future research. 
8.8.4Labeling and shipment of biological samples 
The Principal Investigator will ensure that samples are labeled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix C ―IATA 6.2 Guidance Document.‖ 
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved. 
8.8.5Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their life cycle. 
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of receipt of arrival. 
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival. 
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring 
of study sites, and auditing of external laboratory providers. 
8.8.6Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research. 


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The Principal Investigator will: 
 
Ensure that AstraZeneca is immediately notified of the patients‘ withdrawal of 
informed consent to the use of donated samples 
 
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed and the action documented 
 
Ensure that the organization(s) holding the samples is/are immediately informed about 
the withdrawn consent and that samples are disposed of or destroyed, the action is 
documented, and the signed document is returned to the study site 
 
Ensure that the patient and AstraZeneca are informed about the sample disposal 
8.9Medical Resource Utilization and Health Economics 
For the purposes of economic evaluation, it is necessary to capture health care resource use 
related to the treatment and the underlying disease. Within the study, the following will be 
captured: 
 
Number and length of hospitalizations. 
 
Number of visits to oncology service. 
 
Number of emergency visits. 
 
Number of outpatient visits. 
 
Number of imaging tests. 
 
Number of biopsy-related procedures. 
 
Treatment name, dose, duration, number of cycles. 
The above resource use data will mainly come from the patient‘s medical record and will be 
captured in the eCRF. 
The assessment of health economic resource use data will provide important information for 
payers and will be used within economic evaluations of durvalumab. 
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information. 


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9. STATISTICAL CONSIDERATIONS  
The primary aim of the study is to describe safety  profile of durvalumab in combination with 
platinum–etoposide as first-line treatment for patients with ES-SCLC and also as monotherapy 
maintenance treatment. 
9.1Statistical hypotheses 
There is no formal hypotheses in this study.  
9.2Sample size determination  
This is a safety study, and given the real-world setting, there is no formal predefined statistical 
hypothesis and no formal sample size calculation will be done. 
A convenience sample size of approximately 85 patients was estimated based on the expected 
accrual potential during 6 months in 30 sites, although the recruitment duration may be reduced 
or extended, until P&R approval of durvalumab in Spain for ES-SCLC based on CASPIAN 
results. Therefore the number of patients recruited could be higher than 85 patients. A maximum 
of 30% of recruited patients will have ECOG performance status of 2 at baseline.   
Assuming a sample size up to 85 and a 70% incidence of AE of CTCAE grade ≥3, the estimated 
precision will be no wider than 10% based on exact method (Clopper-Pearson).  In addition, 
assuming a 20% incidence of imAE, the estimated precision will be no wider than 9% using the 
same method. An illustration of the precision around the varying incidences of AE for the 
pateints enrolled is provided in Table 12. 
Table 11.  Precision around varying incidence of AE 
Precision of estimates of G3+ or imAE  for varying Sample Sizes using Exact Binomial 95% CI 
Sample size 
True rate of Grade 3+ AE or imAE (%) and 95% CI 
20% 
25% 
60% 
70% 
 
 
 
 
 
85 
+9.0% 
 
12.1-30.1 
+ 9.7% 
 
16-35.3 
10.9% 
 
48.8-70.5 
+ 10.0% 
 
59.7-80.0 
 
 


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9.3 
Populations for analyses 
Definitions of the analysis sets for each outcome variable are provided in Table 12. 
Table 12 
Summary of outcome variables and analysis populations 
Outcome variable 
Populations 
Efficacy Data 
 
PFS, 6mPFS, 12mPFS 
Safety analysis set  
OS, 6mOS, 12mOS, 18mOS, 
Safety analysis set 
ORR, PROs, and symptom endpoints 
Safety analysis set 
DoR  
Responders analysis set 
TTD 
Safety analysis set 
PRO 
Safety analysis set 
Hospital resources 
Safety analysis set 
Demography 
Safety analysis set 
Biomarkers 
Biomarkers Analysis Evaluable Set 
Safety Data 
 
Exposure 
Safety analysis set 
AEs 
Safety analysis set 
Laboratory measurements 
Safety analysis set 
Vital Signs 
Safety analysis set 
AE Adverse event; XmPFS Proportion of patients alive and progression free at X months from inclusion; XmOS 
Proportion of patients alive X months from inclusion; ITT Intent-to-treat population; ORR Objective response rate; 
OS Overall survival; PFS Progression-free survival; DoR Duration of Response; TTD Time to Treatment Duration; 
PRO Patient-reported outcome. 
 
9.3.1Safety analysis set 
The safety analysis set will include all included patients that received at least one dose of study 
treatment. Safety, efficacy, and PROs  data will be summarized using the safety analysis set. 
(Patients who were enrolled but did not subsequently go on to receive study treatment will not be 
included in the analysis.) 
Responders Analysis Set: The subset of patients, within the Safety Analysis Set who are 
evaluable for response analysis and who achieve an objective response. 
9.3.2Biomarker analysis evaluable population 
The Biomarker analysis set (BAS) will consist of all patients who received at least 1 dose of 
study treatment and for whom tumor and/or blood samples are available.  
9.4Outcome measures for analyses 
 


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AE: Number and proportion of patients with AEs in total and by causality and severity  
AE: Number and proportion of patients with Grade 3 and Grade 4 AEs in total and by causality  
SAE: Number and proportion of patients with SAEs in total and by causality and severity  
AEs leading to death: Number and proportion of patients with AEs leading to death  
AEs leading to treatment interruption or discontinuation: Number and proportion of patients 
with AEs leading to treatment interruption and/or discontinuation  
AESI: Defined as an AE of scientific and medical interest specific to understanding of the IP. 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:  
 
(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) Laboratory findings, vital signs, and other safety parameters associated with AESIs will 
be summarized as part of the AESI outcome measures.  
 
imAE: 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. 
 
 
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 IP 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.  


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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.  
 
ORR: Based on Investigator−assessed response to treatment of CR and PR, per RECIST1.1.  
 
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.  
 
Time to symptom deterioration (EORTC QLC-C30 and QLC-LC13): Defined as the time from 
start of study drug until the date of the first clinically meaningful symptom deterioration that is 
confirmed at the subsequent assessment or death (by any cause) in the absence of a clinically 
meaningful symptom deterioration, regardless of whether the patient withdraws from study drug or 
receives another anticancer therapy prior to symptom deterioration.  
Change from baseline (EORTC QLC-C30 and QLC-LC13, PRO-CTCAE): Defined as the post-
treatment value minus the value at baseline. The % change from baseline will be calculated as 
(postbaseline value - baseline value) / baseline value x 100.  
Treatment duration: Defined as Treatment end date - Treatment start date +1; will be summarized.  
 
In addition, demographics, medical history, comorbidities, extent of disease at diagnosis (eg, stage 
and histology) will be reported. Specific details of planned analyses will be described in the SAP. 
Use of resources: To describe health care resources use related to management of ES-SCLC 
patients treated with durvalumab in combination with platinum–etoposide as first-line treatment. 
Description will include: 
(a) Number of hospitalizations 
(b) Length of hospitalizations: time from date of admission to discharge date 
(c) Number of visits to oncology service 
(d) Number of emergency visits 
(e) Number of outpatient visits 
(f) Number of imaging tests 
(g) Number of biopsy-related procedures 
(h) Treatment dose, duration, number of cycles 
 


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9.5Statistical analyses 
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalized within 3 months of the first enrolled patient and 
will describe the patient populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data.   
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will be 
summarized by the number of observations (n), mean, standard deviation, 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 IP or events 
absent at baseline that emerge after administration of IP, for the period extending to 90 days after the 
last dose of IP. Baseline will be the last assessment of the variable under consideration prior to the 
first IP dose administration. 
9.5.1Analysis of the primary variables 
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 and Grade 4 PRAEs will be 
reported.All outputs will be summarized for the safety analysis test.  
A subgroup analysis may be conducted in the following subgroups, assuming sufficient sample 
size per subgroup: platinum therapy receiving (carboplatin or cisplatin), age, gender, 
performance status, smoking status and CNS metastasis at baseline (Y/N). 
9.5.2Analysis of the secondary variables 
9.5.2.1Safety 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 IP 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 IP 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 IP) will be 
flagged in the data listings. 
 
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 IP dose 
administration.  


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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. 
9.5.2.2Efficacy variables 
Efficacy data will be reported for patients overall.  Results of all statistical analysis will be 
presented using a 95% confidence interval (CI), unless otherwise stated. 
The following table (Table 13) details which endpoints are to be subjected to statistical analysis.  
Table 13 
Pre-planned statistical and sensitivity analyses to be conducted 
Endpoints analyzed 
Notes 
Progression-free survival 
Analysis by Kaplan Meier estimates using Investigator RECIST 1.1 
assessments 
Objective response rate 
Analysis using Investigator RECIST 1.1 assessments 
Duration of response 
Analysis by Kaplan Meier estimates using Investigator RECIST 1.1 
assessments, in patients with documented respnse  
PFS at 6 and 12 months  
Using the Kaplan Meier estimates of progression free survival at 6 
and 12 months 
Overall survival 
Analysis by Kaplan Meier estimates  
Overall survival at 6, 12 and 
18 months 
Using the Kaplan Meier estimates of OS at 6, 12 and 18 months  
Time to deterioration (EORTC 
QLQ-C30 
and 
QLQ-LC13 
endpoints) 
Analysis by Kaplan Meier estimates. Change from baseline values 
will be calculated. 
EORTC European Organisation for Research and Treatment of Cancer; QLQ-C30 v3 30-item Core Quality of Life 
Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality of Life Questionnaire; 


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RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1. 
Progression-free survival 
The PFS analysis will be based on the programmatically derived RECIST 1.1 using the 
Investigator tumor assessments. The analysis will be performed using Kaplan Meier plots. 
Summaries of the number and percentage of patients experiencing a PFS event will be provided 
along with median PFS and its 95% confidence interval. In addition, the proportion of patients 
who are progression-free at 6 and 12 months will be presented. 
A subgroup analysis may be conducted comparing PFS in the following subgroups, assuming 
sufficient sample size per subgroup: platinum therapy receiving (carboplatin or cisplatin), age, 
gender, performance status, smoking status and CNS metastasis at baseline (Y/N). 
Other baseline variables may also be assessed if there is clinical justification. The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across expected prognostic 
and/or predictive factors.  
For each subgroup, the HR and 95% CI will be calculated by Cox regression and a log-rank test 
will be provided.   
Objective response rate 
The ORR will be based on the programmatically derived RECIST 1.1 using the investigator 
tumor data. Summaries will be produced that present the number and percentage of patients with 
a tumor response (CR/PR). 95% CI will also be presented.  
Duration of response 
DoR will be analyzed using the investigator tumor data in responding patients. Descriptive data 
will be provided for the DoR in responding patients, including the associated Kaplan-Meier 
curves.  
Overall survival 
OS will be analyzed using a Kaplan-Meier plots. Summaries of the number and percentage of 
patients who have died, those still in survival follow-up, those lost to follow-up, and those who 
have withdrawn consent will be provided along with the median OS and corresponding 95% CI.  
In addition, the proportion of patients alive at 6, 12, and 18 months will be presented. 
A subgroup analysis may be conducted comparing OS in the following subgroups, assuming 
sufficient sample size per subgroup: platinum therapy receiving (carboplatin or cisplatin), age, 
gender, performance status, smoking status and CNS metastasis at baseline (Y/N). 
For each subgroup, the HR and 95% CI will be calculated by Cox regression and a log-rank test 
will be provided.   


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9.5.2.3Patient reported outcomes 
Summary measures of visit and overall compliance and completion rates will be derived for each 
PRO questionnaire.  Refer to the SAP for details. 
For PRO symptoms and health related quality of life endpoints, the main concepts of interest 
have been identified using a literature review, and detailed qualitative interviews SCLC patient 
and clinicians. The key symptoms were: cough, hemoptysis, dyspnea, chest pain, insomnia, 
fatigue and appetite loss. 
Therefore we would like to pre-specify that an effective treatment would reduce time to 
deterioration and effect mean change from baseline in these key SCLC symptoms. The 
prespecified symptomatic endpoints are as follows: time to deterioration from baseline of cough, 
hemoptysis, dyspnea and chest pain from EORTC QLQ- LC13; and insomnia, fatigue and 
appetite loss from EORTC QLQ -C30; as well as average mean change of the key symptoms.  
In addition, physical functioning and overall health status domains of the EORTC QLQ-C30 are 
furthermore pre-specified endpoints of interest. 
The detail how this data will be analysed and the effect we would like to see to determine a 
symptomatic treatment effect will further be detailed and pre-specified in the SAP. 
(a) EORTC QLQ-C30 
If possible, time to symptom deterioration will be summarized for each of the 3 symptom scales 
(fatigue, pain, nausea/vomiting) and the 5 individual symptom items (dyspnea, insomnia, appetite 
loss, constipation, diarrhea).Similarly, a summary of QoL/function deterioration will be 
summarized for each of the function scales (physical, role, emotional, cognitive, and social) and 
global health status/QoL.  This will be achieved by using Kaplan-Meier product limit methods to 
provide summaries of the number and percentage of patients experiencing a clinically meaningful 
deterioration or death, the median time to deterioration together with the corresponding 95% CIs, as 
well as the Kaplan-Meier plots.  
 
Summaries of original and change from baseline values of each symptom scale/item, the global 
HRQoL score, and each functional domain will be reported by visit. Details will provided in the 
SAP. 
Definition of clinically meaningful changes  
Changes in score compared with baseline will be evaluated. A minimum clinically meaningful 
change is defined as an absolute change in the score from baseline of ≥ 10 points for scales/items 
from the EORTC QLQ-C30 (Osoba et al 1998). For example, a clinically meaningful improvement 
in physical function (as assessed by EORTC QLQ-C30) is defined as an increase in the score from 
baseline of ≥ 10 points, whereas a clinically meaningful deterioration is defined as a decrease in the 
score from baseline of ≥ 10 points. At each post-baseline assessment, the change in 
symptoms/functioning from baseline will be categorised as improvement, no change, or deterioration 
as shown in Table 15. 
 
 


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Table 14. Mean change and visit response in health related quality of life 
Score 
Change from Baseline (points) 
Visit Response 
EORTC QLQ-C30 Global quality 
of life score  
 
≥ +10 
Improvement 
≤ −10 
Deterioration 
Otherwise 
No Change 
EORTC QLQ-C30 symptom 
scales/items  
 
≥ +10 
Improvement 
≤ −10 
Deterioration 
Otherwise 
No Change 
EORTC QLQ-C30 functional 
scales  
 
≥ +10 
Improvement 
≤ −10 
Deterioration 
Otherwise 
No Change 
EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire. 
 
For each subscale, if < 50% of the subscale items are missing, then the subscale score will be divided 
by the number of nonmissing items and multiplied by the total number of items on the subscales 
(Fairman et al 2014). If at least 50% of the items are missing, then that subscale will be treated as 
missing. Missing single items are treated as missing. The reason for any missing questionnaire will 
be identified and recorded. If there is evidence that the missing data are systematic, missing values 
will be handled to ensure that any possible bias is minimized.  
 
Time to symptom deterioration  
For each of the symptoms scales/items in the EORTC QLQ-C30 questionnaire, time to symptom 
deterioration will be defined as the time from start of study drug until the date of the first clinically 
meaningful symptom deterioration (an increase in the score from baseline of ≥ 10 points) that is 
confirmed at the subsequent assessment (at least 14 days apart) or death (by any cause) in the 
absence of a clinically meaningful symptom deterioration, regardless of whether the patient 
withdraws from study drug or receives another anticancer therapy prior to symptom deterioration. 
Death will be included as an event only if the death occurs within 2 visits of the last PRO assessment 
where the symptom change could be evaluated. 
Patients with a single deterioration and no further assessments will be treated as deteriorated in the 
analysis. Patients whose symptoms (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the time of 
their last PRO assessment where the symptom could be evaluated. Also, if symptoms deteriorate 
after 2 or more missed PRO assessment visits or the patient dies after 2 or more missed PRO 


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assessment visits, the patient will be censored at the time of the last PRO assessment where the 
symptom could be evaluated. If a patient has no evaluable visits or does not have baseline data, 
he/she will be censored at Day 1. 
The analysis of time to symptom deterioration will be done with a subset of patients who have 
baseline scores of ≤90. 
Time to quality of life/function deterioration  
For QoL, time to deterioration will be defined as the time from start of study drug until the date of 
the first clinically meaningful deterioration (a decrease in the function scales or the global health 
status/QoL from baseline of ≥ 10 points) that is confirmed at the subsequent assessment (at least 14 
days apart) or death (by any cause) in the absence of a clinically meaningful deterioration, regardless 
of whether the patient withdraws from study drug or receives another anticancer therapy prior to 
QoL/function deterioration. Death will be included as an event only if the death occurs within 2 visits 
of the last PRO assessment where the QoL/function change could be evaluated.  
 
Patients whose QoL (as measured by EORTC QLQ-C30) have not shown a clinically meaningful 
deterioration and who are alive at the time of the analysis will be censored at the time of their last 
PRO assessment where the QoL/function could be evaluated. Also, if QoL deteriorates after 2 or 
more missed PRO assessment visits or the patient dies after 2 or more missed PRO assessment visits, 
the patient will be censored at the time of the last PRO assessment where QoL/function could be 
evaluated. If a patient has no evaluable visits or does not have baseline data, he/she will be censored 
at Day 1. 
Symptom improvement rate  
The symptom improvement rate will be defined as the number (%) of patients with 2 consecutive 
assessments at least 14 days apart that show a clinically meaningful improvement (a decrease from 
baseline score ≥ 10 points for EORTC QLQ-C30 symptom scales/items) in that symptom from 
baseline.  
 
Quality of life/function improvement rate  
The QoL/function improvement rate will be defined as the number (%) of patients with 2 consecutive 
assessments at least 14 days apart that show a clinically meaningful improvement (an increase from 
baseline score ≥ 10 points for EORTC QLQ-C30 functional scales and global health status/QoL) in 
that scale from baseline. 
(b) EORTC QLQ-LC13 
Data will be summarized for each of the symptom items in EORTC QLQ-LC13 as outlined 
above for EORTC QLQ-C30. 
Summaries of original and change from baseline values of each symptom (dyspnea, cough, 
hemoptysis, chest pain, arm/shoulder pain, and other pain) and each treatment-related side effect 
(sore mouth, dysphagia, peripheral neuropathy, and alopecia) will be reported by visit. Details 
will be provided in the SAP. 


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(c) PRO-CTCAE 
PRO-CTCAE data will be presented using summaries and descriptive statistics. Further details 
will be provided in the SAP. 
9.5.2.4Healthcare resource use 
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalization, outpatient, or day case), reason, length of stay by ward type (including intensive 
care unit), procedures, and tests may be undertaken to examine the impact of disease and 
treatment on resource use to primarily support the economic evaluation of durvalumab + EP. 
This would include providing descriptive statistics as appropriate, including means, median, and 
ranges. Costs associated with HCRU use will be quantified by multiplying the natural units of 
use of each resource by the cost of each resource retrieved from Spanish databases. 
9.5.3Biomarker data 
The relationship of exploratory biomarkers to clinical outcomes (including but not restricted to) 
of PFS, ORR, and OS will be explored.  
Summaries and analyses for exploratory biomarkers will be documented in a separate analysis 
plan and will be reported outside the CSR in a separate report. 
9.6Interim analyses  
Not applicable  
 


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11. SIGNATURES  
ASTRAZENECA SIGNATURE(S) 
Study Title: A Phase IIIB, Single Arm Study, of Durvalumab in Combination 
with Platinum-Etoposide for Untreated Patients with Extensive-Stage Small 
Cell Lung Cancer reflecting Real World Clinical Practice in Spain 
(CANTABRICO). 
This Interventional Study Protocol has been subjected to an internal AstraZeneca review. 
I agree to the terms of this Study protocol. 
AstraZeneca representative 
 
Date 
(Day Month Year) 
AstraZeneca representative 
Date 
(Day Month Year) 
AstraZeneca representative 
Date 
(Day Month Year) 
AstraZeneca representative 
Date 
(Day Month Year) 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca.  Investigators are 
cautioned that the information in this protocol may be subject to change and revision. 
 


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COORDINATING INVESTIGATOR 
 
Study Title: A Phase IIIB, Single Arm Study, of Durvalumab in Combination with 
Platinum-Etoposide for Untreated Patients with Extensive-Stage Small Cell Lung 
Cancer reflecting Real World Clinical Practice in Spain (CANTABRICO). 
I agree to the terms of this Study protocol. 
I will carry out this study according to the procedures specified in this protocol and in 
accordance with the applicable local regulations. 
Signature: 
  
Date  
(Day Month Year) 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca.  Investigators are cautioned 
that the information in this protocol may be subject to change and revision. 
 
 


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Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
 
Applicable laws and regulations 
 
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. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the sponsor and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
Regulatory Reporting Requirements for SAEs 
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, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
For all studies except those utilizing medical devices investigator safety reports must be prepared 
for suspected unexpected serious adverse reactions (SUSAR) 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 [Investigator‘s Brochure or state other documents] and will notify the IRB/IEC, if 
appropriate according to local requirements. 


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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. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements local regulations and ICH guidelines, where applicable, and the IRB/IEC or study 
center.  
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study.  
A copy of the ICF(s) must be provided to the patient or the patient‘s legally authorized 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of the 
study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded 
from other aspects of the study. 
If a patient‘s partner becomes pregnant during or within 90 days after the last dose of 
durvalumab, the partner is asked to sign the "Adult Study Informed Consent Form for Pregnant 
Partners of Study Patients" and provide information about the pregnancy accordingly. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. The patient will give a separate agreement to allow any remaining specimens to be used 
for exploratory research. Patients who decline to participate in this optional research will indicate 
this in the ICF. If a patient withdraws consent to the use of donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples already have been 


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analyzed at the time of the request, AstraZeneca will not be obliged to destroy the results of this 
research. 
A 4 
Data protection 
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, their 
general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient‘s identity 
and might also have access to his or her genetic data. Also, regulatory authorities may require 
access to the relevant files. Even so, the patient‘s medical information and the genetic files 
would remain physically separate.  
Each Investigator will ensure that all site personnel involved will respect the confidentiality of 
any information about trial subjects. Management of personal data from subjects participating in 
the trial, particularly as regards consent, will comply with General Data Protection Regulation 
(EU) 679/2016 and the Spanish Organic Law 3/2018 of 05th December on the protection of 
personal data. 
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data sets 
transferred to the Sponsor will contain only the identifier; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Committees structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators. 
A 6 
Dissemination of clinical study data 
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 


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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 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
A 8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator‘s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study are defined as source documents. Source data are contained in source documents 
(original records or certified copies). 
A 9 
Publication policy 


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The results of this study may be published or presented at scientific meetings. This allows the 
Sponsor to protect proprietary information and to provide comments.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
A 10 
Trial Monitoring and serious breaches 
The clinical monitors are employees of APICES, and representatives of the sponsor. As such, 
they have the obligation to follow the trial closely so that all aspects of the trial are carefully 
monitored for compliance with applicable government regulations and with ICH E6(R2) 
guidelines.  
The clinical monitors will visit the study sites and Investigators at intervals as defined in the 
monitoring plan, in addition to maintaining necessary contact through telephone, e-mail, and 
letter. The clinical monitors will maintain current personal knowledge of the trial through 
observation, review of trial records and source documentation, and discussion of the conduct of 
the trial with the study site Investigators and staff. 
Serious breaches of the authorised protocol or of the Royal Decree 1090/2015 occurring in 
Spain must be reported by the sponsor without undue delay and no later than seven calendar 
days from becoming aware of the breach to the Spanish Agency of Medicines and Medical 
Devices (AEMPS) and the CEIm. 
To this end, a serious breach shall be defined as a breach that may significantly affect the safety 
and rights of the trial subjects or the reliability and robustness of the data generated in the 
clinical trial.  
Only serious breaches should be notified to the AEMPS and the CEIm, and the breaches that do 
not constitute a serious breach should not be notified. 
Each study site Investigator must document and explain in the subject‘s source documentation 
any breaches from the approved protocol and / or the Royal Decree 1090/2015. Investigators 
may implement a breach to eliminate an immediate hazard to trial subjects without prior IEC 
informed consent approval, but the breach must be reported to the monitor/CRA within 1 
working day. Such incidents will be evaluated for potential safety hazards of the ongoing study, 
and if deemed appropriate, a protocol amendment will be issued.  
The monitor/CRA will document breaches throughout the course of monitoring visits.  
 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability or incapacity.  
 
Is a congenital 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. 
 
Adverse Events (AEs) for malignant tumours reported during a study should generally 
be assessed as Serious AEs. If no other seriousness criteria apply, the ‗Important 
Medical Event‘ criterion should be used. In certain situations, however, medical 
bjudgement on an individual event basis should be applied to clarify that the malignant 
tumour event should be assessed and reported as a Non-Serious AE. For example, if 
the tumour is included as medical history and progression occurs during the study, but 
the progression does not change treatment and/or prognosis of the malignant tumour, 
the AE may not fulfill the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine 
treatment that does not require hospitalization, may be assessed as Non-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 (e.g., Richter's transformation of B cell chronic lymphocytic leukemia 
into diffuse large B cell lymphoma) should not be considered a new malignant tumour.  
B 3 
Life threatening 
‗Life-threatening‘ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient‘s 
death. ‗Life-threatening‘ does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure). 
B 4 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
B 5 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse 
B 6 
CTCAE grade 
The grading scales found in the revised National Cancer Institute CTCAE latest version will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the criteria recommended in the CTCAE manual that converts severity levels 


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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? 
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 


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‗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 participant or 
has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.  
 
occurred 
 
was identified and intercepted before the participant received the drug 
 
did not occur, but circumstances were recognize that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
 
Drug name confusion 
 
Dispensing error (eg, medication prepared incorrectly, even if it was not actually given 
to the participant) 
 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
 
Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as a 
solid tablet)  
 
Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature)  
 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 


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Examples of events that do not require reporting as medication errors in clinical studies: 
 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error  
 
Participant accidentally missed drug dose(s) (eg, forgot to take medication) 
 
Accidental overdose (will be captured as an overdose) 
 
Participant failed to return unused medication or empty packaging 
 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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


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AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site. 
C 3 
International Airline Transportation Association (IATA) 6.2 guidance 
document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). 
For transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus: 
 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name: 
 
UN 3373 – Biological Substance, Category B 
 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens: 
 
 
Clinical study samples will fall into Category B or exempt under IATA regulations 
 
Clinical study samples will routinely be packed and transported at ambient 
 
temperature 
in 
IATA 
650 
compliant 
packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 


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contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used. 


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Appendix D  Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
D1.  
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.  
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 TBL from a local 
laboratory.   
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy‘s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
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. 
 
D2.  
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  


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Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur. 
 
D3.  
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 ≥ 3xULN 
AST ≥ 3xULN 
TBL ≥ 2xULN 
 
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 2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
Promptly enter the laboratory data into the laboratory CRF 
 
D4.  
Follow-up 
1.1 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. 
 
1.2 Potential Hy’s Law Criteria met 
If the subject does meet PHL criteria the Investigator will: 


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Determine whether PHL criteria were met at any study visit prior to starting study treatment (See 
Appendix D, Section 6) 
 
 
D5.  
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. 
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 Potential 
Hy‘s Law SAE and AE CRFs accordingly with the new information (reassessing 
event term; causality and seriousness criteria) following the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the 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. 
 
 


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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. 
 
D6.  
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. 
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 
D, Section 3    
 
D7. 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: 


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Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g. 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 6 of this Appendix 
 
If No: follow the process described in Appendix D, Section 3 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 D, Section 3 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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D8  
Laboratory tests 
 
 
Hy’s Law lab kit for central laboratories  
Additional 
standard 
chemistry 
and 
coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgG anti-HCV 
HCV RNA*  
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-
transferrin)** 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive 
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend 
this list accordingly 
 
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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Appendix E 
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 15. 
Table 15 
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 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; Table 1]), 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 


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attempt should be made to perform the subsequent scan acquisitions at the next scheduled 
imaging visit. 
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 (table 1).  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 
 


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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 
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.   


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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.   
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 
                                                 
 
 
 
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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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. 
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.   


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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: 
o Bone lesions (see exception below for soft tissue component) 
o Leptomeningeal disease 
o Ascites, pleural effusion, or pericardial effusion 
o Inflammatory breast disease 
o 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  
                                                 
 
 
 
2 
The short axis is defined as the longest in-plane axis perpendicular to the long axis. 
3 
Lymph nodes with <10-mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs. 


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 Brain metastasis 
 
Special considerations regarding lesion measurability at baseline: 
 Bone lesions 
o 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. 
o 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.   
o 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. 
 
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. 
                                                                                                                                                             
 
 
 
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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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. 
 
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 


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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: 
o Target Lesion 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 Target lesion 
o If an Intervention on a Target Lesion 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.  
o If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that Target lesion.  
o 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.  
o No visit with a recorded Target Lesion Intervention can be used as the minimum 
(nadir) sum of diameters.  
 
Table 16 
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 (SD) 
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD. 


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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; SD  Stable disease; 
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 the basis of change in non-target disease in the face of stable disease (SD) or 
progressive disease (PR) of target disease will therefore be extremely rare. 
Table 17 
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. 


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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 18. 
Table 18 
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 
PR 
Non PD or NE or NA 
No 
PR 
SD  
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (non-CR/non-PD) 
NE 
Non PD or NE 
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. 


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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; SD  Stable disease; 
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 (SD), 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: NED (no evidence of disease; 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 
 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 et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 


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Appendix F Durvalumab weight-based dose calculation 
For durvalumab dosing done depending on patient weight. Weight-based dosing should be 
utilized for patients ≤30 kg: 
1. Dose: X mg/kg 
2. Patient weight: Y kg 
3. Dose for patient: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL).  
5. The number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
Example:  
1. Dose: 20 mg/kg 
2. Patient weight: 30 kg 
3. Dose for patient: 600 mg = 20 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5. The number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials 
 


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Appendix G 
Abbreviations 
 
Abbreviation 
or special term 
Explanation 
12mOS 
Overall survival at 12 months after inclusion 
18mOS 
Overall survival at 18 months after inclusion 
6mOS 
Overall survival at 6 months after inclusion 
12mPFS 
Progression-Free survival at 12 months after inclusion 
6mPFS 
Progression-Free survival at 6 months after inclusion 
ADA 
Anti-drug antibody 
AE 
adverse event 
AESI 
Adverse event of special inter 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma drug concentration-time curve 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BP  
Blood pressure 
C 
Cycle 
C/D 
Cycle/Day 
CCTG 
Canadian Cancer Trials Group 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form (electronic/paper) 
CRO 
Contract Research Organization 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen 4 
CXCL 
Chemokine (C-X-C motif) ligand 
DAE 
Discontinuation of investigational product due to adverse event 
DCR 
Disease control rate 


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Abbreviation 
or special term 
Explanation 
DL1 
Dose level 1 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid  
EC 
Ethics committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC) 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ES 
Extensive-stage  
EORTC 
European Organisation for Research and Treatment of Cancer 
EP 
Etoposide and platinum-based chemotherapy 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
Gx 
Genetic Research 
GMP 
Good Manufacturing Practice 
HbsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPV 
Human papilloma virus 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IB 
Investigator‘s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
Interferon gamma 
IgG 
Immunoglobulin G 
IL 
Interleukin 


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Abbreviation 
or special term 
Explanation 
imAE 
Immune-mediated adverse event 
IP 
Investigational product 
IRB 
Institutional Review Board, synonymous to Ethics Committee (EC) and 
IEC 
Independent Ethics Committee (IEC) 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent to treat 
IV 
Intravenous 
IWRS 
interactive web response system 
LD 
Limited-stage disease 
LIMS 
laboratory information management system 
LSLV 
last patient last visit 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labor, and Welfare 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non-small-cell lung cancer 
NTL 
Non-target lesion 
OAE 
other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PCI 
Prophylactic cranial irradiation 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PI 
Principal Investigator  
PK 
Pharmacokinetic(s) 


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Abbreviation 
or special term 
Explanation 
PNS 
Paraneoplastic syndrome 
PR 
Partial response 
PRO 
Patient-reported outcome 
PRO-CTCAE 
Patient-reported outcomes version of the CTCAE 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q12w 
Every 12 weeks 
QLQ-C30 v3 
30-item Core Quality of Life Questionnaire, version 3 
QLQ-LC13 
13-item Lung Cancer Quality of Life Questionnaire 
QoL 
Quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia‘s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SCLC 
Small Cell Lung Cancer 
SD 
Stable disease 
SoC 
Standard of care 
sPD-L1 
Soluble programmed cell death ligand 1 
STS 
Soft-tissue sarcoma 
TIL 
Tumor-infiltrating lymphocyte 
TL 
Target lesion 
ULN 
Upper limit of normal 
US 
United States 
VT 
Verbatim Term 
WBDC 
web based data capture 
 
 
 


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Appendix H 
EORTC QLQ-C30 questionnaire 
 


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Appendix I  EORTC QLQ-LC13 questionnaire 


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Appendix J  
Discovery of biomarkers to predict benefit from 
chemoimmunotherapy in SCLC using digital spatial 
profiling 
1. Background 
Small cell lung cancer (SCLC) represents about 10 to 15 % of all lung cancers. It is strongly 
associated with tobacco exposure and typically follows an aggressive clinical course, 
characterized by early metastatic spread and rapid tumor growth (Gazdar et al., 2017). Platinum-
based chemotherapy is the cornerstone of treatment of extensive stage SCLC. Despite initial 
objective responses in the majority of these patients, responses are not durable, and the median 
overall survival (OS) in this setting is about 11 months (Gazdar et al., 2017). The most notable 
recent clinical progress against SCLC has centered around immunotherapy with PD-1 checkpoint 
blockade. Atezolizumab and durvalumab added to first-line platinum-based chemotherapy have 
demonstrated a significant albeit modest 2-month increment in median OS in two randomized 
phase IIItrials (Horn et al., 2018; Paz-Ares et al., 2019). 
However, despite this improvement in OS, only a small minority of patients demonstrate durable 
benefit, and biomarkers to identify these patients are currently lacking. PD-L1 expression, 
assessed by conventional chromogenic immunohistochemistry, and tumor mutational burden 
(TMB), are the only biomarkers that have been studied as potential predictors of response to PD-
1 checkpoint blockade in SCLC. To date, none of them have shown consistent association with 
benefit from these drugs, and thus they are not approved for clinical use.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. Objectives 
Primary objective 
 
 
Secondary objectives 
 
3. Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix K  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 in combination with platinum 
and etoposide and their relation with the toxicity and efficacy. 
MATERIAL & METHODS 
Patients  
Patients with extensive disease SCLC included in the CANTABRICO trial and treated with first 
line treatment with durvalumab in combination with platinum and etoposide will be 
prospectively included in this study. Written informed consent will be obtained from each patient 
after the approval of the study by the Institutional Ethics Committee.  
Patients‘ data will be collected from the CRF of the trial.   
Patients will be included from 35 centers. 
 


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STATISTICAL ANALYSIS  
The Kolmogorov-Smirnov test will be used to analyze data with normal distribution. Normal 
distributed variables will be reported as mean ± standard error of mean (s.e.m.). To describe our 
population, numbers and percentages will be used for qualitative variables, while the median 
(interquartile ranges, IQR) will be calculated for ordinal and quantitative variables with an 
asymmetric distribution. Comparisons between groups will be tested with the Student‘s t or the 
Mann-Whitney test, according to a Gaussian distribution. ANOVA and Kruskal-Wallis tests will 
be used for comparisons between more than two groups. Fisher and Chi-square tests will be used 
for the comparison of frequencies. Correlation analyses will be carried out with Pearson‘s or 
Spearman correlations. All p values will be based on a 2-sided hypothesis, and those under 0.05 
will be considered statistically significant. All the analyses will be performed using Graph Pad 
Prism 7 software.  
 
 


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Appendix L   
Dosing Modification and Toxicity Management Guidelines 
(TMGs) for Durvalumab Monotherapy, Durvalumab in 
Combination with other Products, or Tremelimumab 
Monotherapy – 17 November 2020. 
 
See in a separate document.  

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Statistical analysis plan 
Study code 
D419QC00005 (CANTABRICO) 
Version 
0.2 
Date 
10 September 2021 
A Phase IIIB Study in Untreated Patients with Extensive-Stage 
Small Cell Lung Cancer 
A Phase IIIB, Single Arm Study, of Durvalumab in Combination 
with Platinum-Etoposide for Untreated Patients with Extensive-
Stage Small Cell Lung Cancer reflecting Real World Clinical 
Practice in Spain (CANTABRICO) 
 
 
 


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A Phase IIIB Study in Untreated Patients with Extensive-Stage 
Small Cell Lung Cancer 
A Phase IIIB, Single Arm Study, of Durvalumab in Combination 
with Platinum-Etoposide for Untreated Patients with Extensive-
Stage Small Cell Lung Cancer reflecting Real World Clinical 
Practice in Spain (CANTABRICO) 
Name 
Date 
 
 
 


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A Phase IIIB Study in Untreated Patients with Extensive-Stage 
Small Cell Lung Cancer 
A Phase IIIB, Single Arm Study, of Durvalumab in Combination 
with Platinum-Etoposide for Untreated Patients with Extensive-
Stage Small Cell Lung Cancer reflecting Real World Clinical 
Practice in Spain (CANTABRICO) 
Name 
Date 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE .............................................................................................................................1 
SIGNATURE OF STUDY STATISTICIAN ............................................................................2 
SIGNATURE OF EPIDEMIOLOGIST ....................................................................................3 
TABLE OF CONTENTS ...........................................................................................................4 
1. 
OBJECTIVES .........................................................................................................9 
1.1 
Primary objective ....................................................................................................9 
1.2 
Secondary objective ................................................................................................9 
2. 
STUDY DESIGN AND SAMPLE SIZE ................................................................9 
2.1 
Overall design .........................................................................................................9 
2.2 
Sample size ...........................................................................................................10 
3. 
ANALYSIS SETS.................................................................................................10 
3.1 
Intention to treat (ITT) population. .......................................................................10 
3.2 
Safety analysis set. ................................................................................................10 
3.3 
Responders analysis set. ........................................................................................10 
4. 
EXPOSURE(S) AND OUTCOMES ....................................................................11 
4.1 
Exposures ..............................................................................................................11 
4.1.1 
Definition of primary drug exposure ....................................................................11 
4.1.2 
Overall design .......................................................................................................11 
4.1.3 
Definition of comparison drug exposure ..............................................................11 
4.2 
Outcomes ..............................................................................................................12 
4.2.1 
Primary outcome ...................................................................................................12 
4.2.2 
Secondary outcome(s) ...........................................................................................12 
4.2.2.1 
Secondary outcome 1 ............................................................................................12 
4.2.2.2 
Secondary outcome 2 ............................................................................................14 
4.2.2.3 
Secondary outcome 3 ............................................................................................16 
4.3 
Other variables and covariates ..............................................................................16 
4.3.1 
Screening failure ...................................................................................................16 
4.3.2 
Demographic data and clinical characteristic .......................................................17 
4.3.3 
Cancer history & Performance status....................................................................18 
4.3.4 
Treatment description ...........................................................................................19 
4.3.4.1 
Chemotherapy phase (Cycle 1 to 4-6) ...................................................................19 
4.3.4.2 
Post-Chemotherapy phase (Cycle 5-7 to X): Durvalumab monotherapy .............20 
5. 
ANALYSIS METHODS.......................................................................................20 
5.1 
Primary outcome ...................................................................................................21 
5.2 
Secondary outcome(s) ...........................................................................................22 
5.2.1 
Secondary outcome 1 ............................................................................................22 
5.2.2 
Secondary outcome 2 ............................................................................................23 
5.2.3 
Secondary outcome 3 ............................................................................................24 
6. 
BIAS......................................................................................................................25 
6.1 
Methods to minimize bias .....................................................................................25 
6.1.1 
Patient enrolment ..................................................................................................25 


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6.1.2 
Procedures for handling incorrectly enrolled patients ..........................................25 
6.2 
Handling of missing data ......................................................................................26 
6.3 
Adjustment for multiple comparisons ...................................................................26 
7. 
INTERIM ANALYSES ........................................................................................26 
8. 
REFERENCES......................................................................................................26 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation or 
special term 
Explanation 
12 m OS  
Overall survival at 12 months after inclusion 
18 m OS 
Overall survival at 18 months after inclusion 
6 m OS 
Overall survival at 6 months after inclusion 
12 m PFS 
Progression-Free survival at 12 months after inclusion 
6 m PFS 
Progression-Free survival at 6 months after inclusion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CI 
Confidence interval 
CR 
Complete response 
eCRF 
Electronic Case report form 
CTCAE 
Common Terminology Criteria for Adverse Event 
DoR 
Duration of Response 
DoR 12 
Duration of Response at year 
ES 
Extensive-stage 
ES-SCLC 
Extensive-stage- Small Cell Lung Cancer 
EP 
Etoposide and platinum-based chemotherapy 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPV 
Human papilloma virus 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
imAE 
Immune-mediated adverse event 
IP 
Investigational product 
ITT 
Intent to treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
LSLV 
last patient last visit 
MOA 
Mechanism of Action 
NCI 
National Cancer Institute 


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Abbreviation or 
special term 
Explanation 
NSCLC 
Non-small-cell lung cancer 
NTL 
Non-target lesion 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PRO 
Patient-reported outcome 
PRO-CTCAE 
Patient-reported outcomes version of the CTCAE 
PT 
Preferred Term 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
QLQ-C30 v3 
30-item Core Quality of Life Questionnaire, version 3 
QLQ-LC13 
13-item Lung Cancer Quality of Life Questionnaire 
QoL 
Quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia‘s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
SAE 
Serious adverse event 
SCLC 
Small Cell Lung Cancer 
SD 
Stable disease 
SOC 
System Organ Class 
TL 
Target lesion 
TTD 
Time to Treatment Discontinuation 
 
 
 
 


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AMENDMENT HISTORY 
 
Date 
Brief description of change 
 
Not applicable 
 
 
 


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1. 
OBJECTIVES 
1.1 
Primary objective 
• To describe safety profile of durvalumab in combination with platinum–etoposide as 
first-line treatment for patients with ES-SCLC. 
1.2 
Secondary objective 
• To describe effectiveness of durvalumab in combination with platinum–etoposide as 
first-line treatment for patients with ES-SCLC. 
• To describe the impact of durvalumab in combination with platinum–etoposide as first-
line treatment for patients with ES-SCLC on patients‘ disease-related symptoms and 
Health Related Quality of Life (HRQoL) and (PROs). 
• To describe health care resources use related to management of ES-SCLC patients 
treated with durvalumab in combination with platinum–etoposide as first-line 
treatment. 
2. 
STUDY DESIGN AND SAMPLE SIZE 
2.1 
Overall design 
This is a Phase IIIb, interventional, single arm, multicentre study to evaluate safety, 
effectiveness, use of resources and patient reporting outcomes in patients with ES-SCLC 
treated with durvalumab in combination with platinum–etoposide as first-line treatment in 
Spain. 
 
This study will include approximately 85 eligible patients at participating Spanish sites. 
 
Durvalumab will be concurrently administered with first-line chemotherapy (EP) on every 3 
week (q3w) schedule for 4 to 6 cycles, and will continue to be administered as monotherapy 
post-chemotherapy on an every 4 week (q4w) schedule until confirmed progressive disease 
(PD) or unacceptable toxicity. 
 
Prophylactic cranial irradiation (PCI) is allowed in patients showing complete or partial 
responses after the durvalumab + EP combination cycles, at the discretion of the investigator 
according to their local clinical practice. 
 
 


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Figure 1. General study design 
 
 
2.2 
Sample size 
This is a safety study, and given the real-world setting, there is no formal predefined statistical 
hypothesis, and no formal sample size calculation will be done. 
A convenience sample size of approximately 85 patients was estimated based on the expected 
accrual potential during 6 months in 30 sites, although the recruitment duration may be reduced 
or extended, until P&R approval of durvalumab in Spain for ES-SCLC based on CASPIAN 
results, and the number of patients recruited could be higher. A maximum of 30% of recruited 
patients will have ECOG performance status of 2 at baseline. 
3. 
ANALYSIS SETS 
3.1 
Intention to treat (ITT) population 
Intention to treat (ITT) population consisted of all enrolled patients who had received at least 
1 dose of study drug (chemotherapy or Durvalumab).  
3.2 
Safety analysis set 
The safety analysis set will include all included patients that received at least one dose of study 
treatment. Patients who were enrolled but did not subsequently go on to receive study treatment 
will not be included in the analysis. Patients who were enrolled but did not subsequently go on 
to receive study treatment will not be included in the analysis. 
3.3 
Responders analysis set 
Responders analysis set will include the subset of patients, within the Safety Analysis Set who 
are evaluable for response analysis and who achieve an objective response. 


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4. 
EXPOSURE(S) AND OUTCOMES 
4.1 
Exposures 
Exposure of interest: Durvalumab (MEDI4736). It will be administered in combination with 
first-line chemotherapy (EP), which includes SoC agents’ platinum (carboplatin or cisplatin) + 
Etoposide, and as monotherapy after the chemotherapy phase. 
4.1.1 
Definition of primary drug exposure 
The exposure period started when the subject was administered the first cycle of study 
treatment (Chemotherapy plus Durvalumab). 
4.1.2 
Overall design 
Durvalumab will be concurrently administered with first-line chemotherapy (EP) on every 3-
week (q3w) schedule for 4 to 6 cycles, and will continue to be administered post-chemotherapy 
on an every 4 week (q4w) schedule until confirmed progressive disease (PD) or unacceptable 
toxicity. 
 
Durvalumab + chemotherapy combination: 
 
• Durvalumab 1500 mg via IV infusion q3w concurrently with chemotherapy, starting on 
Week 0, for 4-6 cycles. If a patient ‘s weight falls to 30 kg or below (≤30 kg), then the 
patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab after 
consultation between the Investigator and Study Physician, until the weight improves 
to above 30 kg (>30 kg), at which point the patient should start receiving the fixed 
dosing of durvalumab 1500 mg. 
 
• EP: the dose of etoposide + carboplatin or cisplatin investigated will not exceed the 
product label dose for the given indication dose (etoposide [80 to 100 mg/m2] via IV 
infusion with either carboplatin [area under the curve (AUC) 5-6] via IV infusion or 
cisplatin [75 to 80 mg/m2] via IV infusion), starting on Week 0, for 4-6 cycles. 
 
Durvalumab monotherapy: 
 
• Durvalumab 1500 mg via IV infusion q4w, starting 3 weeks after the last infusion of 
the combination, until confirmed progressive disease (PD) or unacceptable toxicity. If 
a patient ‘s weight falls to 30 kg or below (≤30 kg), then the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab q4w after consultation 
between Investigator and Study Physician, until the weight improves to above 30 kg 
(>30 kg), at which point the patient should start receiving the fixed dosing of 
durvalumab 1500 mg q4w. 
 
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
clinical progression or confirmed radiological progression. 
 
4.1.3 
Definition of comparison drug exposure 
Not applicable. 
 
 


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4.2 
Outcomes 
4.2.1 
Primary outcome 
Primary objective:  To describe safety profile of durvalumab in combination with platinum–
etoposide as first-line treatment for patients with ES-SCLC. 
 
Endpoints analyzed: 
 
• Incidence of grade ≥ 3 AEs 
• Incidence of imAE. 
 
This analysis will be performed for Safety analysis set. 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 IP or events absent at baseline 
that emerge after administration of IP, for the period extending to 90 days after the last dose of 
IP.  
 
The analysis will be performed with the information completed into the adverse event eCRF 
section. 
 
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 (SOC) and Preferred Term (PT), causality, and maximum 
NCI CTCAE Grade. Deaths from all causes will be also summarized.  
 
4.2.2 
Secondary outcome(s) 
 
4.2.2.1 
Secondary outcome 1 
To describe effectiveness of durvalumab in combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC: 
 
Endpoints analyzed: 
 
• Progression-free survival (PFS): This analysis will be performed for the Intention-to-
Treat population (ITT). PFS is 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 IP 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.  


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The PFS analysis will be based on the programmatically derived RECIST 1.1 using the 
Investigator tumor assessments. It will be analysed PFS, PFS at 6 months (6mPFS) and 
PFS at 12 months (12mPFS). 
 
• Objective response rate (ORR): This outcome will be analysed for the responder’s 
analysis set. The ORR will be based on the programmatically derived RECIST 1.1 using 
the investigator tumor data.  
 
• Duration of response (DoR): This outcome will be analysed for the responder’s analysis 
set. DoR is 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. It will be analysed 
DoR and DoR at 1 year (DoR12) 
 
• Overall survival (OS): This analysis will be performed for the Intention-to-Treat 
population (ITT). OS is 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. It will be analysed 
OS, OS at 6 months (6mOS) and OS at 12 months (12mOS) and OS at 18 months 
(18mOS). 
 
• Time to Treatment Discontinuation (TTD): This analysis will be performed for the 
Intention-to-Treat population (ITT). TTD is defined as the time from the first date of 
treatment until date of discontinuation of treatment. Date of discontinuation will be the 
date reported in end of study form. It will be performed just on the patients that report 
treatment discontinuation, determined if any of the following occurs: 
o Withdrawal of consent from further treatment with IP. 
o An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates 
further dosing. 
o Any AE that meets criteria for discontinuation as defined in the Dosing 
Modification and Toxicity Management Guidelines or as defined in the local 
prescribing information for the EP treatment. 
o Pregnancy or intent to become pregnant. 
o Non-compliance with the study protocol. 
o Initiation of alternative anticancer therapy including another investigational 
agent. 
o Clinical progression or confirmed radiological progression and Investigator 
determination that the patient is no longer benefiting from treatment with IP. 


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4.2.2.2 
Secondary outcome 2 
To describe the impact of durvalumab in combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC on patients‘disease-related symptoms and Health Related 
Quality of Life (HRQoL) and (PROs). 
Endpoints analyzed: 
 
• Change from baseline in European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30): 
 
This analysis will be performed for the Intention-to-Treat population (ITT). For the following 
endpoints, change from baseline is defined as the post-treatment value minus the value at 
baseline. The % change from baseline will be calculated as: 
 
(Postbaseline value - baseline value) / baseline value x 100. 
 
The EORTC QLQ-C30 v3 questionnaire is included for the purpose of assessing HRQoL 
and is a well-established measure of HRQoL/health status. It assesses HRQoL/health status 
through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and 
social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and 
quality-of-life (QoL) scale. Six single-item symptom measures are also included dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties. For each of the 15 
domains, final scores are transformed such that they range from 0 to 100, where higher scores 
indicate greater functioning, greater HRQoL, or greater level of symptoms (1). 
 
The principle for scoring these scales is the same in all cases: 
 
▪ Estimate the average of the items that contribute to the scale; this is the raw 
score. 
 
▪ Use a linear transformation to standardise the raw score, so that scores range 
from 0 to 100; a higher score represents a higher ("better") level of 
functioning, or a higher ("worse") level of symptoms. 
 
For all scales, the RawScore, RS, is the mean of the component items: 
 
𝑅𝑎𝑤𝑆𝑐𝑜𝑟𝑒= 𝑅𝑆= (𝐼1 +  𝐼2 + … + 𝐼𝑛)/𝑛 
 
Then for Functional scales:  
 
𝑆𝑐𝑜𝑟𝑒= {1 − (𝑅𝑆−1)
𝑟𝑎𝑛𝑔𝑒} 𝑥 100 
 
For Symptom scales/ items and Global health status/ QoL:  
 
𝑆𝑐𝑜𝑟𝑒= {(𝑅𝑆−1)
𝑟𝑎𝑛𝑔𝑒} 𝑥 100 
 


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The following outcomes will be analysed for this endpoint: 
 
- 
Time to symptom deterioration: defined as the time from start of study drug 
until the date of the first clinically meaningful symptom deterioration (a 
decrease in the score from baseline of ≥ 10 points) that is confirmed at the 
subsequent assessment (at least 14 days apart) or death (by any cause) in the 
absence of a clinically meaningful symptom deterioration, regardless of whether 
the patient withdraws from study drug or receives another anticancer therapy 
prior to symptom deterioration. Death will be included as an event only if the 
death occurs within 2 visits of the last PRO assessment where the symptom 
change could be evaluated.  
Patients whose QoL (as measured by EORTC QLQ-C30) have not shown a 
clinically meaningful deterioration and who are alive at the time of the analysis 
will be censored at the time of their last PRO assessment where the 
QoL/function could be evaluated. Also, if QoL deteriorates after 2 or more 
missed PRO assessment visits or the patient dies after 2 or more missed PRO 
assessment visits, the patient will be censored at the time of the last PRO 
assessment where QoL/function could be evaluated. If a patient has no 
evaluable visits or does not have baseline data, he/she will be censored at Day 
1. 
 
- 
Time to quality of life/ function deterioration: defined as the time from start of 
study drug until the date of the first clinically meaningful deterioration (a 
decrease in the function scales or the global health status/QoL from baseline of 
≥ 10 points) that is confirmed at the subsequent assessment (at least 14 days 
apart) or death (by any cause) in the absence of a clinically meaningful 
deterioration, regardless of whether the patient withdraws from study drug or 
receives another anticancer therapy prior to QoL/function deterioration. Death 
will be included as an event only if the death occurs within 2 visits of the last 
PRO assessment where the QoL/function change could be evaluated. 
 
- 
Symptom improvement rate: defined as the number (%) of patients with 2 
consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score ≥ 10 points for EORTC QLQ-
C30 symptom scales/items) in that symptom from baseline. 
 
- 
Quality of life/function improvement rate: defined as the number (%) of patients 
with 2 consecutive assessments at least 14 days apart that show a clinically 
meaningful improvement (an increase from baseline score ≥ 10 points for 
EORTC QLQ-C30 functional scales and global health status/QoL) in that scale 
from baseline. 
 
• Change from baseline in European Organisation for Research and Treatment of Cancer 
Quality of Life. Questionnaire-Lung Cancer 13 (EORTC QLQLC13): 
 
This analysis will be performed for the Intention-to-Treat population (ITT). For patients 
with SCLC, a disease-specific 13-item self-administered questionnaire for lung cancer 
was developed to be used in conjunction with the EORTC QLQ-C30. It comprises both 
multi-item and single-item measures of lung cancer-associated symptoms (i.e., 
coughing, haemoptysis, dyspnoea, and pain) and side effects from conventional 


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chemotherapy and radiotherapy (i.e., hair loss, neuropathy, sore mouth, and dysphagia). 
Similar to the EORTC QLQ-C30, all questions except one have a 4-point scale: (not at 
all, a little, quite a bit and very much). One question (no. 43, ―Did you take any 
medicine for pain?) has a response option (Yes; No). The scoring approach for the 
EORTC QLQ-LC13 is similar to the EORTC QLQ-C30. 
The following outcomes will be analysed for this endpoint: 
- 
Time to symptom deterioration 
- 
Symptom improvement rate 
 
• Changes from baseline in PRO-CTCAE: 
 
The PRO-CTCAE is included to address tolerability from the patients‘ perspective. It was 
developed in recognition that collecting symptom data directly from patients using PRO tools 
can improve the accuracy and efficiency of symptomatic AE data collection.  
In this study, only items that are considered relevant for the study, site of cancer, and cancer 
treatment are selected. 
 
4.2.2.3 
Secondary outcome 3 
To describe health care resources use related to management of ES-SCLC patients treated 
with durvalumab in combination with platinum– etoposide as first-line treatment. 
This analysis will be performed for the Intention-to-Treat population (ITT). To investigate the 
impact of treatment and disease on health care resource use, the following variables will be 
captured: 
• Number of hospitalizations (Categorical and continous) 
• Length of hospitalizations: time from date of admission to discharge date (Continuous) 
• Number of visits to oncology service (Categorical and continous) 
• Number of emergency visits (Categorical and continous) 
• Number of outpatients visits (Categorical and continous) 
• Number of imaging tests (Categorical and continous) 
• Number of biopsy-related procedures (Categorical and continous) 
• Listing of treatments administered, including: Treatment name, dose, duration and 
number of cycles (Categorical) 
• Assessment of health economic resource: Costs associated with HCRU use will be 
quantified by multiplying the natural units of use of each resource by the cost of each 
resource retrieved from Spanish databases.It will be described the overall costs and 
health care resources use as well as costs and health care resources use adjusted by time 
in years. 
4.3 
Other variables and covariates 
4.3.1 
Screening failure 
A detailed listing of screening failure patients will be provided, containing the following 
information: 
• Site 
• Patient ID 


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• Screening failure reason: If not compliance with any inclusion/exclusion criteria, 
criteria will be provided. If other reason, specific reason will be provided. 
• Re-screening (Yes; No). If affirmative: 
- 
 Date of re-screening. 
4.3.2 
Demographic data and clinical characteristic 
The demographic, baseline description and clinical characteristics will be performed for the 
Intent-to-treat (ITT) population. The following variables will be described: 
• Age (Categorical and continuous): Categorical data will be provided by defining two 
categories: <65 years and >65 years 
• Gender (Categorical) 
• Race (Categorical) 
• Ethnicity (Categorical) 
• Status of cigarette smoking (Categorical). If former or current smoker: 
o Number pack/year (Continuous) 
• Vital signs at baseline: 
o Height (Continuous) 
o Weight (Continuous) 
o SBP (Continuous) 
o DBP (Continuous) 
o Pulse (Continuous) 
o Respiratory rate (Continuous) 
o Temperature (Continuous) 
• Physical exam at baseline: 
o System (Categorical) 
o Finding (Categorical) 
• Medical history (Yes; No): If affirmative: 
o Illness/Surgery/Intercurrent illness (Categorical) 
• Serology: 
o Tuberculosis (Categorical) 
o HBsAg (Categorical) 
o HCV ab (Categorical): If positive: 
➢ HCV-RNA (Categorical) 
o VIH 
• ECG (Done; Not done): If done: 
o Overall evaluation (Categorical): If abnormal: 
▪ Listing of the abnormalities detected, including if clinically 
significant. 
• Charlson comorbidity index available (Yes; No): If affirmative: 
o Myocardial infarction (Yes; No) (Categorical) 
o Congestive heart failure (Yes; No) (Categorical) 
o Peripheral vascular disease (Yes; No) (Categorical) 
o Cerebrovascular disease (Yes; No) (Categorical) 


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o Dementia (Yes; No) (Categorical) 
o Chronic obstructive pulmonary disease (Yes; No) (Categorical) 
o Connective tissue disease (Yes; No) (Categorical) 
o Peptic ulcer disease (Yes; No) (Categorical) 
o Chronic liver disease mild (Yes; No) (Categorical) 
o Diabetes mellitus (mild) (Yes; No) (Categorical) 
o Hemiplegic (Yes; No) (Categorical) 
o Chronic Kidney disease moderate-severe (Yes; No) (Categorical) 
o Diabetes mellitus with lesion in target organ (moderate-severe) (Yes; 
No) (Categorical) 
o Tumor or solid neoplasia (Yes; No) (Categorical) 
o Leukemia (Yes; No) (Categorical) 
o Lymphoma (Yes; No) (Categorical) 
o Chronic liver disease moderate-severe (Yes; No) (Categorical) 
o Tumor or solid neoplasia with metastasis (Yes; No) (Categorical) 
o Acquired immunodeficiency syndrome (AISD) (Yes; No) (Categorical) 
o Total score (Continuous) 
o Presence of other comorbidities (Yes; No): If affirmative: 
▪ Other comorbidities (Categorical) 
4.3.3 
Cancer history & Performance status 
The following cancer history data will be described for the for the Intent-to-treat (ITT) 
population.  
• WHO/ECOG-PS (Categorical): It will be described at baseline, start of chemotherapy 
phase, start of post-chemotherapy phase and end of study.  
• Subject autonomy (Categorical): It will be described at baseline, start of chemotherapy 
phase, start of post-chemotherapy phase and end of study. 
• Time from initial diagnosis (Continuous): Defined as time, in months, from initial 
diagnosis date to informed consent date (enrolment in the study). 
• Histology (Categorical) 
• Initial stage (Categorical): 
• Initial TNM stage (Categorical) 
• Actual stage (Categorical) 
• Actual TNM stage (Categorical) 
• Primary tumor location (Categorical) 
• Metastatic location (Yes; No) (Categorical). If affirmative: 
o Number of metastatic locations (Continuous) 
o Metastatic location (Categorical): 
▪ It will be provided the frequency of brain or CNS metastases 
(Categorical) 
▪ It will be provided the frequency of liver metastases 
(Categorical) 
• Family history of cancer (Yes, No): If affirmative: 


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o Cancer type (Categorical) 
o Relative degree per cancer type (Categorical) 
4.3.4 
Treatment description 
4.3.4.1 
Chemotherapy phase (Cycle 1 to 4-6) 
This analysis will be performed for the Intention-to-Treat population (ITT). Treatment duration 
will be defined as time elapsed between treatment end date and treatment start date in 
chemotherapy phase. It will be described as continuous data for durvalumab, etoposide and 
platinum. 
It will be described the number of cycles administered as continuous data. It will be considered 
as cycle administered when the patient receives a complete pattern of durvalumab + EP. 
Additionally, the following data will be described: 
Durvalumab 
• Durvalumab total dose administered (mg) (Continuous) 
• Number of durvalumab doses (Categorical and continuous): 
o It will be provided the number and percentage of patients receiving 12 or more 
durvalumab doses (Categorical) 
• Duration of treatment with durvalumab in weeks (Continuous) 
• Treatment interruption (Yes, No): If affirmative: 
o Number and percentage of patients with at least one treatment interruption 
o Reason for interruption (Categorical) 
o Total number of cycles interrupted and percentage regarding total cycles 
EP 
• Platinum administered (Cisplatin; Carboplatin): The following data will be described 
for each category. 
• Total dose administered (mg) (Continuous) 
• Total dose programmed (mg/m2 for Cisplatin / AUC for Carboplatin) (Continuous) 
• Number and percentage of patients receiving 4 or more cycles of EP (Categorical) 
• Number and percentage of patients receiving 5 or more cycles of EP (Categorical) 
• Number and percentage of patients receiving 6 or more cycles of EP (Categorical) 
• Duration of EP treatment in weeks (Continuous) 
• Treatment interruption (Yes, No): If affirmative: 
o Number and percentage of patients with at least one treatment interruption 
o Reason for interruption (Categorical) 
o Total number of cycles interrupted and percentage regarding total cycles 
• Dose delay (Yes, No): If affirmative: 
o Number and percentage of patients with at least one dose delay 
o Reason for delay (Categorical) 
• Dose reduction (Yes, No): If affirmative: 


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o Number and percentage of patients with at least one dose reduction 
o Reason for reduction (Categorical) 
 
• Number and percentage of patients who received prophylactic cranial irradiation (PCI) 
in patients showing complete or partial responses after the durvalumab + EP 
combination cycles will be described. To calculate the number of patients receiving 
PCI, the information collected on concomitant study medication will be considered. 
 
4.3.4.2 
Post-Chemotherapy phase (Cycle 5-7 to X): Durvalumab monotherapy 
This analysis will be performed for the Intention-to-Treat population (ITT). Treatment duration 
will be defined as time elapsed between treatment end date and treatment start date in post-
chemotherapy phase. It will be described as continuous data.  
In will be considered as cycle administered when the patient receives at least one dose of 
durvalumab in post-chemotherapy phase. It will be described the number of cycles 
administered as continuous data. It will be described the number and percentage of patients 
with 12 cycles or more (Categorical). 
Additionally, the following data will be described: 
• Durvalumab total dose administered (mg) (Continuous) 
• Duration of post-chemotherapy treatment with durvalumab in weeks (Continuous)  
• Treatment interruption (Yes, No): If affirmative: 
o Number and percentage of patients with at least one treatment interruption 
o Reason for interruption (Categorical) 
o Total number of cycles interrupted and percentage regarding total cycles 
• Dose delay (Yes, No): If affirmative: 
o Number and percentage of patients with at least one dose delay 
o Reason for delay (Categorical) 
 
5. 
ANALYSIS METHODS 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will be 
summarized by the number of observations, mean, standard deviation, median, quartiles (Q1 
and Q3), minimum, and maximum. Categorical variables will be summarized by frequency 
counts and percentages for each category. The number of missing data will be provided for 
every analysed variable.  
Missing values will not be considered for calculating percentages or any other descriptive, 
meaning that only valid values will be presented. No use of any method for the handling of 
missing data is foreseen. 
For patients excluded from the statistical analyses, descriptive of the reasons for non- 
evaluability will be provided.  


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The software package SAS version 9.4 will be used for data analysis. 
5.1 
Primary outcome 
Primary objective:  To describe safety profile of durvalumab in combination with platinum–
etoposide as first-line treatment for patients with ES-SCLC. 
 
Endpoints analyzed: 
 
• Incidence of grade ≥ 3 AEs 
• Incidence of imAE. 
 
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 and Grade 
4 AEs will be reported. All outputs will be summarized for the Safety analysis set. 
 
A subgroup analysis may be conducted in the following subgroups, assuming sufficient sample 
size per subgroup: platinum therapy receiving (carboplatin or cisplatin), age, gender, 
performance status, smoking status and CNS metastasis at baseline (Yes/No). 
 
For this aims, the following summaries of AEs will be provided: 
• Number and percentage of patients with AEs in total and by causality and severity 
• Number and proportion of patients with Grade 3 and Grade 4 AEs in total and by 
casualty 
• Number and proportion of patients with SAEs in total and by causality  
• Number and proportion of patients with AEs leading to death 
• Number and proportion of patients with AEs leading to treatment interruption and/or 
discontinuation 
• Number and proportion of patients with AESI, by predefined type (or newly defined by 
this study) in total and by seriousness, severity and causality, including immune 
relatedness 
• Number and proportion of patients who received steroids, immunosuppressants, and/or 
hormone replacement therapy to manage AESIs 
• 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. 
• Duration of the intervention with steroids, immunosuppressants, and/or hormone 
replacement therapy until the resolution of AESI. 
• Number and proportion of patients with imAEs. 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. 
• Listing of SAEs per patient, including the following variables: 
o Patient ID 
o AE number 
o AE description 
o PT Term 
o Grade NCI-CTACAE v5.0 (1-5) 
o Onset date (DD-MMM-YYYY) 


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o End date (DD-MMM-YYYY) 
o Ongoing (Yes; No) 
o Outcome 
o Seriousness criteria 
o AESI (Yes; No) 
o Relationship 
o Action taken 
 
5.2 
Secondary outcome(s) 
5.2.1 
Secondary outcome 1 
To describe effectiveness of durvalumab in combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC: 
Endpoints analyzed: 
 
• Progression-free survival (PFS): The PFS analysis will be based on the 
programmatically derived RECIST 1.1 using the Investigator tumor assessments. The 
analysis will be performed using Kaplan Meier plots. Summaries of the number and 
percentage of patients experiencing a PFS event will be provided along with median 
PFS and its 95% confidence interval. In addition, the proportion of patients who are 
progression-free at 6 (PFS 6) and 12 (PFS 12) months will be presented. 
 
A subgroup analysis may be conducted comparing PFS in the following subgroups, 
assuming sufficient sample size per subgroup: platinum therapy receiving (carboplatin 
or cisplatin), age (≥65, <65), gender, performance status, smoking status, CNS 
metastasis at baseline (Yes/No) and number of chemotherapy cycles (5 or 6 cycles vs 
4 or less cycles)  
 
For each subgroup, the HR and 95% CI will be calculated by Cox regression and a log-
rank test will be provided. 
 
• Objective response rate (ORR): The ORR will be based on the programmatically 
derived RECIST 1.1 using the investigator tumor data. Summaries will be produced 
that present the number and percentage of patients with a tumor response (CR/PR). 95% 
CI will also be presented. 
 
A subgroup analysis may be conducted comparing ORR in the following subgroups, 
assuming sufficient sample size per subgroup: platinum therapy receiving (carboplatin 
or cisplatin), age (≥65, <65), gender, performance status, smoking status, CNS 
metastasis at baseline (Yes/No) and number of chemotherapy cycles (5 or 6 cycles vs 
4 or less cycles). Results will be compared using Chi-Squared test. 
 
• Duration of response (DoR): DoR will be analyzed using the investigator tumor data in 
responding patients. Descriptive data will be provided for the DoR in responding 
patients (continuous data), including the associated Kaplan-Meier curves. In addition, 
the DoR at 1 year (DoR 12) will be analyzed. 
A subgroup analysis may be conducted comparing DoR in the following subgroups, 
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or cisplatin), age (≥65, <65), gender, performance status, smoking status, CNS 
metastasis at baseline (Yes/No) and number of chemotherapy cycles (5 or 6 cycles vs 
4 or less cycles)  
 
For each subgroup, the HR and 95% CI will be calculated by Cox regression and a log-
rank test will be provided. 
 
• Overall survival (OS): OS will be analyzed using a Kaplan-Meier plots. Summaries of 
the number and percentage of patients who have died, those still in survival follow-up, 
those lost to follow-up, and those who have withdrawn consent will be provided along 
with the median OS and corresponding 95% CI. In addition, the survival rate at 6 (OS 
6), 12 (OS 12), and 18 (OS 18) months will be presented. 
 
A subgroup analysis may be conducted comparing OS in the following subgroups, 
assuming sufficient sample size per subgroup: platinum therapy receiving (carboplatin 
or cisplatin), age (≥65, <65), gender, performance status, smoking status, CNS 
metastasis at baseline (Yes/No) and number of chemotherapy cycles (5 or 6 cycles vs 
4 or less cycles)  
 
For each subgroup, the HR and 95% CI will be calculated by Cox regression and a log-
rank test will be provided. 
 
• Time to Treatment Discontinuation (TTD): Summaries for the TTD will be provided 
(continuous data). 
 
5.2.2 
Secondary outcome 2 
To describe the impact of durvalumab in combination with platinum–etoposide as first-line 
treatment for patients with ES-SCLC on patients‘disease-related symptoms and Health 
Related Quality of Life (HRQoL) and (PROs). 
Endpoints analyzed: 
 
• Change from baseline in European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) and Questionnaire-
Lung Cancer 13 (EORTC QLQLC13): 
 
 
Scores for the QLQ-C30 and QLQ-LC13 questionnaires will be calculated according to 
published scoring manuals or the developer’s guidelines. Raw scores from scales in both 
questionnaires will be standardized by linear transformation so that they range from 0 to 100. 
Higher scores for symptom items indicate greater symptom severity, while higher scores for 
function and global health status/QoL items indicate better function and health status/QoL. For 
both questionnaires, a clinically meaningful change will be prespecified as an absolute change 
in score from baseline of ≥10 points (either deterioration or improvement). For the five key 
disease-related symptoms (cough, dyspnea, and chest pain [QLQ-LC13], and fatigue and 
appetite loss [QLQ-C30]), changes at each visit from baseline to disease progression or end of 
follow-up (whichever came first) will be analyzed using a mixed model for repeated measures 
(MMRM) to derive an overall adjusted mean change from baseline, reflecting the average 
treatment effect over visits. The model assumes PROs will be collected at multiple visits per 


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patient. Visits with >75% missing data will be excluded from the analysis. The MMRM 
included treatment, age at baseline (<65 vs ≥65 years), sex, smoking history (smoker vs non-
smoker) and visit interaction as fixed factors, and baseline score as a covariate; the model 
further adjusted for baseline score-by-visit interaction.  
 
Summaries of original and change from baseline values of each symptom scale/item, the global 
HRQoL score, and each functional domain will be reported by visit. 
 
Time to symptom deterioration and time to quality of life / function deterioration (defined in 
4.2.2) will be analyzed by product limit methods to provide summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death, the median 
time to deterioration together with the corresponding 95% CIs, as well as the Kaplan-Meier 
plot. An stratified log-rank test adjusted for therapy will be used with HR s and 95% CIs 
calculated using a stratified Cox proportional hazards model. 
 
Symptom improvement rate and Quality of life / function improvement (defined in 4.2.2) will 
be summarized. 
 
 
• Changes from baseline in PRO-CTCAE: 
 
PRO-CTCAE data will be presented using summaries and descriptive statistics for categorical 
data for each question of the questionnaire. 
 
5.2.3 
Secondary outcome 3 
• To describe health care resources use related to management of ES-SCLC patients 
treated with durvalumab in combination with platinum– etoposide as first-line 
treatment. It will be described the overall costs and health care resources use as well as 
costs and health care resources use adjusted by time in years. 
 
The following data will be described as appropriate: 
• Number of hospitalizations (Categorical and continuous) 
• Length of hospitalizations: time from date of admission to discharge date (Continuous). 
• Number of visits to oncology service (Categorical and continuous) 
• Number of emergency visits (Categorical and continuous) 
• Number of outpatients visits (Categorical and continuous) 
• Number of imaging tests (Categorical and continuous) 
• Number of biopsy-related procedures (Categorical and continuous) 
• Listing of treatments administered, including: Treatment name, dose, duration and 
number of cycles 
• Assessment of health economic resource: Costs associated with HCRU use will be 
quantified by multiplying the natural units of use of each resource by the cost of each 
resource retrieved from Spanish databases 


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6. 
BIAS 
6.1 
Methods to minimize bias 
6.1.1 
Patient enrolment 
This is a single arm, open label study; no randomization or blinding will be performed. 
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 have been obtained within 28 days of 
inclusion. 
• Obtain a unique enrolment number (E-code), through the Interactive Web Response 
System (IWRS). This number is the patient’s unique identifier and is used to identify 
the patient on the electronic case report forms (eCRFs). 
• Determine patient eligibility based on inclusion/exclusion criteria. If the patient is 
ineligible and not included, the IWRS should be contacted to terminate the patient in 
the system. 
Patients will start treatment on Day 1. Treatment should start no more than 3 working days 
after being included. Patients must not be included and treated unless all eligibility criteria have 
been met. 
If a patient withdraws from participation in the study, then his or her enrolment code cannot be 
reused. 
 
6.1.2 
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 included in error, or incorrectly 
started on treatment, the Investigator should inform the Study Medical Monitor immediately, 
and a discussion should occur between the Study Medical Monitor and the Investigator 
regarding whether to continue or discontinue the patient from treatment. The Study Medical 
Monitor must ensure all decisions are appropriately documented and that the potential benefit: 
risk profile remains positive for the patient. 


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6.2 
Handling of missing data 
 
 
 
Missing values will not be considered for calculating percentages or any other descriptives, 
meaning that only valid values will be presented. The number of missing data will be provided 
for every analysed variable. No use of any method or imputation of data for the handling of 
missing data is foreseen.  
For the questionnaires EORTC QLQ-C30, EORTC QLQ-LC13 and PRO-CTCAE, for each 
subscale, if < 50% of the subscale items are missing, then the subscale score will be divided by 
the number of non missing items and multiplied by the total number of items on the subscales. 
If at least 50% of the items are missing, then that subscale will be treated as missing. Missing 
single items are treated as missing. The reason for any missing questionnaire will be identified 
and recorded. If there is evidence that the missing data are systematic, missing values will be 
handled to ensure that any possible bias is minimized. 
 
6.3 
Adjustment for multiple comparisons 
 
Not applicable. 
7. 
INTERIM ANALYSES  
Not applicable by study protocol. 
Following interim analysis will be performed: 
• Sept 2021: Demographic data & Cancer history: sections 4.3.2 and 4.3.3. 
• Oct 2021: Treatment administration: Section 4.3.4. and 5.1. (subgroup analysis will 
not be included). 
• Feb 2022: Progression free survival and QoL: Section 5.2.1 Progression free survival 
and 5.2.2. 
8. 
REFERENCES 
(1) Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 
1993;85(5):365-76.