Clinical trial NCT03830866
Conditions: Locally Advanced Cervical Cancer
Keywords: Durvalumab Chemoradiotherapy Locally Advanced Cervical Cancer
Sponsor: AstraZeneca
Start date: 2019-02-15; Completion date: 2023-07-03
Enrollment: 770 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multi-center, double-blind, placebo-controlled, global, Phase III study to determine the efficacy and safety of durvalumab + Chemoradiotherapy versus Chemoradiotherapy alone as treatment in Women With Locally Advanced Cervical Cancer

Detailed description:
Women will be randomized in a 1:1 ratio to receive treatment with concurrent durvalumab + standard of care (SoC) or Placebo + Soc, followed by durvalumab/placebo maintenance for 24 months.

Arms: arm 1: durvalumab + standard of care concurrent chemoradiation therapy(SoC CCRT) followed by durvalumab monotherapy up to 24 months or until PD from the date of randomization arm 2: placebo + standard of care concurrent chemoradiation therapy(SoC CCRT)
Interventions: intervention 1: Durvalumab intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: external beam radiation therapy (EBRT) + brachytherapy
Intervention descriptions: intervention 1: IV infusion every 4 weeks intervention 2: Platinum based Standard of Care Chemotherapy administered concurrent with radiation therapy intervention 3: For patients enrolled under CSP v2 and prior - platinum based Standard of Care Chemotherapy administered concurrent with radiation therapy intervention 4: Radiation therapy per standard of care

Protocol documents:
SAP_002.pdf: 
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Statistical Analysis Plan 
Study Code 
D9100C00001 
Edition Number 
3.0 
Date 
04 August 2021 
A Phase III, Randomized, Multi-Center, Double-Blind, Global 
Study to Determine the Efficacy and Safety of Durvalumab in 
Combination With and following Chemoradiotherapy Compared 
to Chemoradiotherapy Alone for Treatment in Women with 
Locally Advanced Cervical Cancer (CALLA) 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................... 6 
AMENDMENT HISTORY ..................................................................................................... 10 
1 
STUDY DETAILS ............................................................................................... 22 
1.1 
Study objectives .................................................................................................... 22 
1.1.1 
Primary objectives ................................................................................................ 22 
1.1.2 
Secondary objectives ............................................................................................ 23 
1.1.3 
Exploratory objectives .......................................................................................... 25 
1.2 
Study design ......................................................................................................... 26 
1.3 
Number of subjects ............................................................................................... 27 
2 
ANALYSIS SETS ................................................................................................ 28 
2.1 
Definition of analysis sets ..................................................................................... 28 
2.1.1 
Full analysis set (Intention to treat [ITT]) ............................................................ 29 
2.1.2 
Safety analysis set ................................................................................................. 29 
2.1.3 
Pharmacokinetics analysis set............................................................................... 29 
2.1.4 
PD-L1 analysis set ................................................................................................ 29 
2.2 
Violations and deviations ..................................................................................... 30 
3 
PRIMARY AND SECONDARY VARIABLES ................................................. 33 
3.1 
Derivation of visit responses ................................................................................ 33 
3.1.1 
RECIST 1.1 target lesions (TLs) .......................................................................... 34 
3.1.2 
RECIST 1.1 non-target lesions and new lesions .................................................. 39 
3.1.3 
Overall RECIST 1.1 visit response ....................................................................... 41 
3.1.4 
Independent review ............................................................................................... 42 
3.1.5 
Histopathologic confirmation of local progression .............................................. 43 
3.1.6 
Overall visit response ........................................................................................... 44 
3.2 
Efficacy variables ................................................................................................. 45 
3.2.1 
Progression-free survival (PFS) ............................................................................ 45 
3.2.1.1 
Time to first and second subsequent therapy or death .......................................... 47 
3.2.2 
Progression-free survival (3 years) ....................................................................... 48 
3.2.3 
Overall survival (OS) ............................................................................................ 48 
3.2.4 
Objective response rate (ORR) ............................................................................. 49 
3.2.5 
Complete response (CR) rate ................................................................................ 50 
3.2.6 
Duration of response (DoR) for complete responders .......................................... 50 
3.2.7 
Incidence of local progression, distant disease progression, and secondary 
malignancy ............................................................................................................ 50 
3.2.8 
Best objective response (BoR) ............................................................................. 52 
3.3 
Patient reported outcome (PRO) variables ........................................................... 52 
3.3.1 
EORTC-QLQ-C30 ................................................................................................ 53 
3.3.2 
EORTC QLQ-CX24 ............................................................................................. 54 


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3.3.3 
Patient-reported outcomes version of the common terminology criteria for 
adverse events (PRO-CTCAE) ............................................................................. 55 
3.3.4 
Patient global impression of change (PGIC) and patient global impression of 
severity (PGIS) ..................................................................................................... 55 
3.3.5 
Health state utility ................................................................................................. 56 
3.3.6 
Compliance ........................................................................................................... 56 
3.4 
Health care resource use variables ........................................................................ 57 
3.5 
Safety variables ..................................................................................................... 58 
3.5.1 
General considerations for safety assessments ..................................................... 58 
3.5.1.1 
Definition of baseline ........................................................................................... 58 
3.5.1.2 
Time windows for safety and PRO data ............................................................... 58 
3.5.1.3 
Handling of missing data ...................................................................................... 60 
3.5.1.4 
Safety Follow-up .................................................................................................. 61 
3.5.2 
Study treatments ................................................................................................... 62 
3.5.3 
Exposure and dose interruptions ........................................................................... 63 
3.5.3.1 
Treatment exposure for durvalumab or placebo ................................................... 63 
3.5.3.2 
Treatment exposure for SoCs and Radiotherapy .................................................. 64 
3.5.3.3 
Dose intensity ....................................................................................................... 66 
3.5.4 
Adverse events (AEs) ........................................................................................... 67 
3.5.5 
Other significant adverse events (OAE) ............................................................... 68 
3.5.6 
AEs of special interest (AESI) and AEs of possible interest (AEPI) ................... 68 
3.5.7 
Laboratory measurements ..................................................................................... 70 
3.5.8 
Vital signs ............................................................................................................. 71 
3.5.9 
Physical examinations .......................................................................................... 71 
3.5.10 
Electrocardiograms (ECGs) .................................................................................. 71 
3.5.11 
World Health Organisation (WHO)/Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) ......................................................................... 72 
3.6 
Pharmacokinetic (PK) variables ........................................................................... 72 
3.7 
Immunogenicity variables .................................................................................... 73 
3.8 
Biomarkers ............................................................................................................ 74 
3.9 
Prior and concomitant medications and therapies ................................................ 74 
4 
ANALYSIS METHODS ...................................................................................... 74 
4.1 
General principles ................................................................................................. 75 
4.2 
Multiplicity ........................................................................................................... 77 
4.3 
Analysis methods .................................................................................................. 78 
4.3.1 
Efficacy ................................................................................................................. 78 
4.3.2 
Primary efficacy endpoint..................................................................................... 81 
4.3.3 
Secondary efficacy endpoints ............................................................................... 90 
4.3.3.1 
Progression-free survival at 3 years (PFS (3 years)) ............................................ 90 
4.3.3.2 
Progression-free survival in PD-L1 positive high subjects .................................. 90 
4.3.3.3 
Overall survival (OS) ............................................................................................ 90 
4.3.3.4 
Overall survival in PD-L1 high subjects .............................................................. 91 


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4.3.3.5 
Objective response rate (ORR) ............................................................................. 91 
4.3.3.6 
Complete response (CR) rate ................................................................................ 92 
4.3.3.7 
Duration of response (DoR) for complete responders .......................................... 92 
4.3.3.8 
Incidence of local progression, distant disease progression, secondary 
malignancy ............................................................................................................ 92 
4.3.3.9 
Best objective response (BoR) ............................................................................. 93 
4.3.3.10 
Patient reported outcomes..................................................................................... 93 
4.3.4 
Exploratory endpoints ........................................................................................... 96 
4.3.4.1 
Health care resource use ....................................................................................... 96 
4.3.5 
Safety .................................................................................................................... 96 
4.3.5.1 
Adverse events ...................................................................................................... 97 
4.3.5.2 
Adverse events of special interest (AESI) and possible interest (AEPI) ............ 102 
4.3.5.3 
Summary of long-term tolerability ..................................................................... 103 
4.3.5.4 
Exposure ............................................................................................................. 104 
4.3.5.5 
Laboratory measurements ................................................................................... 104 
4.3.5.6 
Electrocardiograms ............................................................................................. 106 
4.3.5.7 
Vital signs ........................................................................................................... 107 
4.3.5.8 
Eastern Cooperative Oncology Group performance status ................................ 107 
4.3.6 
Pharmacokinetic data .......................................................................................... 107 
4.3.7 
Immunogenicity analysis .................................................................................... 107 
4.3.8 
Demographic, initial diagnosis and baseline characteristics data ....................... 108 
4.3.9 
Concomitant and other treatments ...................................................................... 109 
4.3.10 
Subsequent therapy ............................................................................................. 109 
4.3.11 
Biomarker data.................................................................................................... 109 
4.3.12 
Genetic data ........................................................................................................ 109 
4.3.13 
Radiotherapy Quality Control Assessment ......................................................... 110 
4.4 
COVID-19 .......................................................................................................... 110 
4.4.1 
Censoring Confirmed/Suspected COVID-19 Deaths for PFS Analysis ............. 111 
4.4.2 
Censoring Confirmed/Suspected COVID-19 Deaths for OS Analysis .............. 111 
5 
INTERIM ANALYSES ...................................................................................... 112 
5.1 
PFS and OS interim analyses .............................................................................. 112 
5.2 
Independent data monitoring committee ............................................................ 112 
6 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE) ....... 113 
7 
REFERENCES ................................................................................................... 113 
8 
APPENDIX (NOT APPLICABLE) ................................................................... 114 
 
LIST OF TABLES 
Table 1: Primary study objectives and corresponding endpoints/variables ............................ 22 
Table 2: Secondary study objectives and corresponding endpoints/variables ........................ 23 


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Table 3: Exploratory study objectives and corresponding endpoints/variables ...................... 25 
Table 4: Summary of outcome variables and analysis populations......................................... 28 
Table 5: TL Visit Responses (RECIST 1.1) ............................................................................ 35 
Table 6: Example of scaling .................................................................................................... 38 
Table 7: Non-target lesion visit responses ............................................................................... 40 
Table 8: Overall RECIST 1.1 visit responses .......................................................................... 41 
Table 9: Overall visit responses............................................................................................... 44 
Table 10: Visit responses for EORTC QLQ-C30 .................................................................... 54 
Table 11: Visit responses for EORTC QLQ-CX24 ................................................................. 55 
Table 12: Analysis visits and visit windows ........................................................................... 59 
Table 13: Study treatments ...................................................................................................... 62 
Table 14: Dose intensity scenarios for durvalumab administered 1500mg per cycle ............. 67 
Table 15: Formal statistical analyses to be conducted and pre-planned sensitivity analyses .. 79 
Table 16: Discontinuation example ......................................................................................... 94 
 
LIST OF FIGURES 
Figure 1: Overview of study design ........................................................................................ 27 
Figure 2: Multiple testing procedures for controlling the type I error rate.............................. 77 
 


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LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
ADA 
Antidrug antibody 
AE 
Adverse event 
AEPI 
Adverse event of possible interest 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AZ 
AstraZeneca 
BICR 
Blinded independent central review 
BoR 
Best objective response 
BP 
Blood pressure 
Brachy 
Brachytherapy 
CCRT 
Concurrent chemoradiation therapy 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CMH 
Cochran-Mantel Haenszel 
CR 
Complete response 
CrCl 
Creatine clearance 
CRO 
Contract research organization 
CRF 
Case report form 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse event 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CV 
Coefficient of variation 
DAE 
Discontinuation of investigational produce due to adverse event 
DBL 
Database lock 
DCO 
Data cut-off 
DoR 
Duration of response 
d.p. 
Decimal place 
EBRT 
External beam radiation therapy 


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Abbreviation or special 
term 
Explanation 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-5L 
EuroQol five-dimensional five-level questionnaire 
FAS 
Full analysis set 
FIGO 
International Federation of Gynecology and Obstetrics 
HR 
Hazard Ratio 
HRQol 
Health-related quality of life 
IA 
Interim analysis 
ICU 
Intensive care unit 
IDMC 
Independent data monitoring committee 
IHC 
Immunohistochemistry 
imAE 
Immune-mediated adverse event 
IP 
Investigational product 
IPD 
Important protocol deviation 
IRMC 
Independent review master charter 
ITT 
Intention to treat 
IUO 
Investigational use only 
KM  
Kaplan-Meier 
LD 
Longest diameter 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTp 
Multiple testing procedure 
nAb 
Neutralizing antibody 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NED 
No evidence of disease 
NTL 
Non-target lesion 
OAE 
Other significant adverse event 
OS 
Overall survival 
ORR 
Objective response rate 


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Abbreviation or special 
term 
Explanation 
PD 
Progressive disease 
PD-L1 
Programmed cell death protein 1 
PFS 
Progression-free survival 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetics 
PR 
Partial response 
PRO 
Patient reported outcome 
PRO-CTCAE 
Patient reported outcomes version of the common terminology criteria for adverse 
events 
PS 
Performance status 
q1w 
Every 1 week 
q4w 
Every 4 weeks 
q12w 
Every 12 weeks 
q24w 
Every 24 weeks 
QLQ-C30 
30 item core quality of life questionnaire 
QLQ-CX24 
Cervical cancer module 
QTcF 
Friderica’s correction 
RDI 
Relative dose intensity 
RECIST 
Response evaluation criteria in solid tumors 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SoC 
Standard of care 
TEAE 
Treatment emergent adverse event 
TFST 
Time to first subsequent therapy 
TL 
Target lesion 
TMB 
Tumor mutation burden 
TSH 
Thyroid stimulating hormone 
TSST 
Time to second subsequent anti-cancer therapy 
ULN 
Upper limit of normal 
WHO 
World Health Organisation 


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Abbreviation or special 
term 
Explanation 
WHO-DD 
World Health Organisation drug dictionary 
 


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AMENDMENT HISTORY 
Category: 
Change refers 
to 
Date 
Description of change 
In line with 
CSP? Y 
(version) / 
N / NA 
Rationale 
The primary 
or secondary 
endpoints 
09 Jan 2020 
Updated the list of secondary and 
exploratory objectives. Applies to 
Tables 2 and 3, Sections 4,3,4 and 
4.3.4 
Y (v2.0) 
To align with 
CSP 
 
09 Jan 2020 
Added text to the primary objective 
statement. Applies to Table 1 
Y (v2.0) 
To align with 
CSP 
 
04 Aug 2021 
Added text for DoR to the SAP and 
to the list of secondary objectives. 
Applies to Table 2 and new Sections 
3.2.8 and 4.3.3.7 
 
To align with 
CSP future 
edition? 
 
04 Aug 2021 
Added OS in PD-L1 positive 
subjects as a secondary objective and 
added a new section for the analysis 
set. Applies to Sections 1.1.2, 2.1, 
3.2.5, 4.3.3.4 and Tables 4 and 15 
Y (v3.0) 
To align with 
CSP 
 
04 Aug 2021 
Added sections to describe PFS in 
PD-L1 positive subjects and PFS (3 
Years). Applies to new Sections 
3.2.2 and 3.2.3 
Y (v3.0)  
To align with 
CSP 
 
04 Aug 2021 
Added text to explain what will be 
done for any OS analysis conducted 
prior to the final OS analysis where a 
survival call has not been made. 
Applies to Section 3.2.4 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added summaries related to subjects 
who have completed treatment/did 
not receive treatment when 
discussion treatment status at 
progression as well as time from last 
tumor assessment to DCO in 
NA 
To improve 
previous 
intent 


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censored subjects. Applies to Section 
4.3.2 
 
04 Aug 2021 
Removed reference to 20-week 
assessment for CR rate. Applies to 
Tables 2 and 15 and Sections 3.2.7 
and 4.3.3.6 
Y(v4.0) 
To align with 
CSP 
 
04 Aug 2021 
Ensured objectives in Section 3 
match the objectives in the CSP 
Y(v4.0) 
To align with 
CSP 
Derivation of 
primary or 
secondary 
endpoints 
09 Jan 2020 
Removed reference to 30/90 days 
after last dose and added text to 
indicate data will be mapped 
according to visit windowing rules. 
Applies to Sections 4.3.5.6, 4.3.5.7, 
4.3.5.8 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to clarify that subjects 
will have restaging physical exams at 
each visit. Applies to Section 3.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to indicate what happens 
if a subject with no measurable 
disease has been enrolled. Applies to 
Section 3.1.1, Table 8 and Table 9 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to indicate the TL visit 
response if all or more than 1 
measurements are missing and the 
rule when change in assessment 
method involved clinical 
examination. Applies to Section 
3.1.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated the text on analysis visits 
and visit windows and definition of 
baseline updated. Applies to Section 
3.5.10.2 and Table 14 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on rules for handling 
missing data. Applies to Section 
3.5.1.3 
NA 
To align with 
PHUSE 
Guidance and 
improve 


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previous 
intent 
 
09 Jan 2020 
Modified text on recording of new 
lesions and therefore also overall 
visit response. Applies to Section 
3.1.2 and Table 8 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on DoR for complete 
responders. Applies to Section 
4.3.3.4 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified the two-missed visits rule. 
Applies to Section 3.2.1 
NA 
To align with 
AZ standard 
oncology 
SAP 
guidance 
 
09 Jan 2020 
Updated text on local progression. 
Applies to Section 3.2.1 
Y (v2.0) 
To align with 
CSP 
 
 
Modified text to indicate which 
denominators are to be used for 
ORR. Applies to Section 3.2.3 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text for the 4-week window 
that will be applied for the analysis 
of CR rate. Applies to Section 3.2.4 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on exposure and dose 
interruptions. Applies to Section 
3.5.3 
NA  
To improve 
previous 
intent and 
align with 
TFLs 
 
04 Aug 2021 
Modified text on the derivation of 
overall visit response and removed 
Table 9. All references to Table 9 
updated and all subsequent table 
numbers and cross references 
updated. Applies to Section 3.2.1.1 
and throughout 
NA 
To improve 
previous 
intent 


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04 Aug 2021 
Modified text on DoR in complete 
responders to remove reference to 20 
weeks. Applies to Sections 3.2.9 and 
4.3.3.8 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Clarified the definition of a non-
evaluable assessment.  Applies to 
section 3.2.1 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Time from randomization to the date 
of first documented local 
progression, distant disease 
progression/secondary malignancy or 
death 
Y(v4.0) 
To align with 
CSP 
Sample size 
and multiple 
testing 
procedure 
09 Jan 2020 
Updated text on sample size, 
multiple testing procedure and 
interim analyses. Applies to Sections 
1.3, 4.2 and 5.0 
Y (v2.0) 
To align with 
CSP and aims 
to strengthen 
the analysis 
plan for the 
OS endpoint 
 
04 Aug 2021 
Added details of China cohort 
including number of subjects 
required and potential to recruit 
beyond global LSI. Applies to 
Section 1.2 
Y (v3.0) 
To align with 
CSP 
 
04 Aug 2021 
Updated text on sample size, 
multiple testing and interim analyses 
to align with CSP. Applies to 
Sections 1.3, 4.0, 4.2 and 5.0 
Y (v4.0) 
To align with 
CSP 
Statistical 
analyses 
09 Jan 2020 
Updated the list of statistical 
analyses and endpoints. Applies to 
Table 15 
Y (v2.0) 
To align with 
CSP 
 
09 Jan 2020 
Added extra sensitivity analyses for 
(a) suspected progression on physical 
exam and no confirmatory biopsy 
and (b) Max-Combo test. Also 
removed reference to stratified log-
Y (v2.0) 
To align with 
CSP 


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rank test for subgroup analysis of 
PD-L1. Applies to Section 4.3.2 
 
09 Jan 2020 
Modified text on competing risks 
methodology. Applies to Section 
4.3.3.7 
NA 
To improve 
previous 
intent 
 
 
Modified text on PRO summaries 
and removed text on Bonferroni-
Holm adjustment text. Applies to 
Section 4.3.3.9 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added text on new subgroup 
analyses for radiotherapy and lymph 
nodes. Modified the text to say eCRF 
or lab data will be used for all 
subgroup analyses. Applies to 
Section 4.3.2 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Modified the statistical analyses for 
PFS at 3 years to indicate no formal 
comparisons will be done and only 
summary information will be 
provided. Applies to Section 4.3.3 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added new sensitivity analysis for 
PFS where stratification factors are 
based on eCRF data. Also modified 
text to indicate imputation for day 
when month and year are presented 
for date of birth. Applied so Section 
4.3.2 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Modified the analyses of OS to make 
it clear that the analyses would 
follow that used for the primary PFS 
analyses 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added clarification related to 
COVID-19 censoring. Applies to 
Section 4.4 
NA 
To align with 
COVID-19 
related 
guidance 


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04 Aug 2021 
Added COVID-19 censoring analysis 
to Table 15 
NA 
To improve 
previous 
intent 
Editorial 
09 Jan 2020 
Replaced all occurrences of 
“patient(s)” with “subject(s)”. 
Applies throughout 
NA 
To align with 
ICH E6 
guidance 
 
09 Jan 2020 
Replaced all occurrences of “IVRS” 
with “IWRS”. Applies throughout 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated CSP version number from 
1.0 to 2.0. Applies to Section 
Y (v2.0) 
To align with 
CSP 
 
09 Jan 2020 
Updated text to indicate FIGO 
staging 2009 will be used. Applies to 
Section 1.0, 1.1, 2.2, 4.3.2, 4.3.3.7 
and Figure 1 
Y (v2.0) 
To improve 
previous 
intent 
 
09 Jan 2020 
Replaced “maintenance therapy” 
with “adjuvant therapy”. Applies to 
Section 1.2 
Y (v2.0) 
To align with 
CSP 
 
09 Jan 2020 
Removed redundant text when 
discussing PK analysis set. Applies 
to Section 2.1.3 
Y (v2.0) 
To improve 
previous 
intent 
 
09 Jan 2020 
Reference to Section 3.5.9 corrected 
to 3.5.10. Applies to Sections 3.5.6 
and 3.5.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Fixed typos and corrected the 
reference to Table 10 to Table 14. 
Applies to Section 3.5.10.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Reference to section 3.5.9.3 
corrected to Section 3.5.10.3. 
Applies to section 3.9.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Replaced “progression free” with 
“progression-free”. Applies to 
Sections 1.2, 2.2, 4.3.2 and 4.3.3.5 
NA 
To improve 
previous 
intent 


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09 Jan 2020 
Corrected typos of UK English and 
changed to US English. Applies to 
Section 3.1, 4.1, 4.3.2, 4.3.8 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added definition of ADA-evaluable 
set and modified text on ADA 
assessments. Applies to Section 
2.1.2, and 3.7  
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified definition of the SAF to 
include all study treatments. Applies 
to Section 2.1.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text that indicated what 
happens if subjects have no 
evaluable visits or baseline 
RECIST/physical assessment. 
Applies to Section 3.2.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to clarify data used for 
BoR and corrected timeframe for 
subjects who die with no evaluable 
assessments. Applies to Section 3.2.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on EORTC-QLQ-C30 
to clarify rules on missing data and 
correct date of Fayers reference. 
Applies to Section 3.3.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on treatment exposure 
for SoCs by removing repeated text. 
Applies to Section 3.5.2.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text on missed or forgotten 
doses when dealing with exposure. 
Applies to Section 3.5.2.2 
NA 
Updated to 
align with AZ 
standard 
oncology 
SAP 
guidance 
 
09 Jan 2020 
Moved general considerations for 
safety variables to the start of safety 
variables section and re-numbered all 
subsequent sections/subsections and 
NA 
To improve 
previous 
intent 


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cross references. Applies to Section 
3.5 
 
 
Modified text on definition of 
baseline to include dosing with any 
study treatment. Applies to Section 
3.5.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Moved the text on Safety Follow-up 
to a new section in general 
considerations. Applies to Section 
3.5.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on references ranges 
used for laboratory variables to 
indicate project ranges will be used 
throughout. Applies to Section 3.5.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to indicate the KM plot 
and landmark analyses will help 
understand treatment benefit. 
Applies to Section 4.3.2 
NA  
To improve 
previous 
intent 
 
09 Jan 2020 
Corrected SAP text on Deaths. 
Applies to Section 4.3.5.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Corrected the definition of prior 
therapies. Applies to Section 3.9 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified the text on 
inclusions/exclusions that count as 
violations and deviations. Applies to 
Section 2.2 
Y (v2.0) 
To align with 
CSP 
 
09 Jan 2020 
Added text to indicate summaries of 
ADA will be presented for each arm 
and modified the list of summaries. 
Applies to section 4.3.7 
Y (v2.0) 
To align with 
CSP and 
improve 
previous 
intent 


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09 Jan 2020 
Modified Deviation 4 to include 
physical exam and replace “assigned 
to treatment” with “randomized”. 
Applies to Section 2.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Replaced “distant disease 
recurrence” with “distant disease 
progression”. Applies to Sections 
3.2.1, 3.2.6  
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Changed the ordering of the PFS (3 
year), PFS in PD-L1 subjects and 
OS. Applies to Section 4.3.3 
NA 
To align with 
CSR ordering 
 
04 Aug 2021 
Modified the list of IPDs to 
incorporate two missing IPDs and 
remove reference to a PD. Applies to 
section 2.2 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Updated the version of the CSP from 
2.0 to 3.0. Applies to Section 1 
Y (v3.0) 
To align with 
CSP 
 
04 Aug 2021 
Modified text on AESIs to include 
AESI and AEPI as per AZ guidance. 
Applies to Section 3,5,6 and 4.3.5.2 
NA 
To improve 
previous 
intent and 
align with 
new guidance 
 
04 Aug 2021 
Changed type of chemotherapy to 
first dose of chemotherapy and 
appropriate to inappropriate. Applies 
to Section 4.3.2 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Modified definition of the safety 
analysis set to remove reference to 
chemotherapy and radiotherapy 
exposure. Applies to Section 2.1.2 
Y (v3.0) 
To align with 
CSP 
 
04 Aug 2021 
Aligned endpoints to match the CSP Y (v4.0) 
To align with 
CSP 
Data 
presentation 
09 Jan 2020 
Added text to indicate errors in 
stratifications will be summarized. 
Applies to Section 2.2 
NA 
To improve 
previous 
intent 


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09 Jan 2020 
Modified the list of safety data to be 
summarized by the SAF and ADA-
evaluable set. Applies to Table 4 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text on deriving change from 
baseline for vital signs. Applies to 
Section 3.5.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Language used for QTcF calculation 
modified and derivation of RR 
added, Applies to Section 3.5.10 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified list of summaries for ADA 
analyses. Applies to Section 3.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to confirm that strata will 
be checked and condensed prior to 
unblinding. Applies to Section 4.3.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text to indicate the primary 
source of strata and its comparison 
with source data. Applies to Section 
4.1 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Removed text stating the KM plots 
would be produced. Applies to 
Section 4.3.3.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text to clarify ECG 
summaries. Applies to Section 
4.3.5.6 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated the summaries of 
demographic, initial diagnosis and 
baseline characteristics. Applies to 
Section 4.3.8 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated list of AE summaries. 
Applies to Section 4.3.5.1, 4.3.5.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated list of exposure summaries. 
Applies to Section 4.3.5.4 
NA 
To improve 
previous 
intent 


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09 Jan 2020 
Updated the ECG summaries. 
Applies to Section 4.3.5.6 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Updated the vital signs summaries. 
Applies to Section 4.3.5.7 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text of heath care resource 
use. Applies to Section 4.3.4 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on concomitant 
medication and other treatment 
summaries. Applies to Section 4.3.9 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Modified text on PFS summaries and 
subgroup analyses of PFS in PD-L1 
subjects and Japan versus rest of the 
world. Applies to Section 4.3.2 
NA 
To improve 
previous 
intent 
 
09 Jan 2020 
Added text on PFS in PD-L1 positive 
subjects. Applies to Section 4.3.3.4 
Y (v2.0) 
To improve 
previous 
intent 
 
04 Aug 2021 
Added text for ECGs to indicate 
what would be presented when 
triplicate results are reported for a 
visit. Applies to Section 4.3.5.6 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Updated text on AEs and added extra 
summaries for AEs related to study 
drug by maximum CTCAE grade. 
Applies to Section 4.3.5.1 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Replaced ADA positive with ADA-
positive for consistency with other 
uses and TFLs. Applies throughout 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Modified the list of summaries for 
demographics and baseline 
characteristics to add summaries of 
agreement between IWRS and eCRF 
and time to start of subsequent 
NA 
To improve 
previous 
intent 


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therapy from treatment 
discontinuation. Removed previous 
disease related treatment modalities 
as this data is not collected. Applies 
to Section 4.3.7 
 
04 Aug 2021 
Removed references to R from 
discussions of local incidence and 
distant disease progression. Applies 
to Section 4.3.3.9 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Removed “or death from any cause” 
from the list of time from 
randomization summaries that will 
be produced when looking at 
incidence of local/distant disease 
progression. Applies to Section 
3.2.10 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added text to clarify the time frame 
of reporting ECGs and Vital signs. 
Applies to Sections 4.3.5.6 and 
4.3.5.7 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added text to indicate what 
summaries may be produced to show 
the impact of the COVID-19 
pandemic. Applies to Section 4.4 
NA 
To align with 
CSP 
 
04 Aug 2021 
Removed reference to hyper for 
Glucose summaries as this is not 
presented. Applies to Sections 3.5.7 
and 4.3.5.5 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Added text on time to second 
subsequent therapy or death as a 
supportive analysis of PFS. Applies 
to Sections 3.2.1.2 and 4.3.2 
NA 
To improve 
previous 
intent 
 
04 Aug 2021 
Infection AEs removed from 
AESI/AEPI section 
NA 
To improve 
previous 
intent 
 


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1 
STUDY DETAILS 
This statistical analysis plan (SAP) contains a more detailed description of the analyses in the 
clinical study protocol (CSP) and is based on version 4.0 of the CSP. 
This SAP will apply to the phase III study to determine the efficacy and safety of durvalumab 
in combination with and following chemoradiotherapy compared to chemoradiotherapy alone 
for locally advanced cervical cancer. 
The target population for this study is adult female subjects (age ≥18 years) with 
histologically confirmed cervical adenocarcinoma, cervical squamous carcinoma, or cervical 
adenosquamous carcinoma. Subjects must have International Federation of Gynaecology and 
Obstetrics (FIGO (2009)) Stages IB2 to IIB, node positive (N≥1) or FIGO (2009) Stages IIIA 
to IVA with any N state (N≥0). Nodal staging may be either surgical or by imaging (Response 
evaluation criteria in solid tumors [RECIST] v.1.1). Subjects should have no evidence of 
metastatic disease and no prior exposure to surgical, radiation, or systemic therapy for cervical 
cancer or immunotherapy. Subjects must also have a World Health Organization 
(WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at 
enrollment and randomization.  
1.1 
Study objectives 
1.1.1 
Primary objectives 
The primary objectives for this study and the corresponding endpoints/variables are shown in 
Table 1. 
Table 1: Primary study objectives and corresponding endpoints/variables 
Objective 
Endpoints/variables 
To assess the efficacy of durvalumab + 
SoC CCRT compared with placebo + 
SoC CCRT in terms of PFS 
Endpoints based on investigator assessment 
according to RECIST 1.1 or histopathologic 
confirmation of local tumor progression: 
• PFS: Time from date of randomization 
until tumor progression or death due to 
any cause 
CCRT Concurrent chemoradiation therapy; PFS Progression-free survival; RECIST Response evaluation 
criteria in solid tumors; SoC Standard of care 
 
 


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1.1.2 
Secondary objectives 
The secondary objectives for this study and the corresponding endpoints/variables are shown 
in Table 2. 
Table 2: Secondary study objectives and corresponding endpoints/variables 
Objective 
 
Endpoints/variables 
To further assess the efficacy of 
durvalumab + SoC CCRT compared 
with placebo + SoC CCRT in terms of 
PFS (3 year), PFS in PD-L1 positive 
patients, overall survival (OS) (key), 
OS in PD-L1 positive patients, ORR 
CR rate, and DoR in patients with a 
CR 
• OS: Time from date of randomization 
until the date of death by any cause 
• OS in PD-L1 positive subjects: Time 
from date of randomization until the 
date of death by any cause in subjects 
who are PD-L1 positive (>=1%) based 
on either tumor or immune cell staining 
Endpoints based on investigator assessment 
according to RECIST 1.1 or pathologic 
assessment of local disease progression: 
• PFS (3 years): Proportion of patients 
alive and progression-free at 3 years 
• PFS in PD-L1 positive subjects: Time 
from date of randomization until tumor 
progression or death due to any cause 
in patients who are PD-L1 positive 
(≥1%) based on either tumor or 
immune cell staining 
• ORR: The percentage of evaluable 
subjects with investigator-assessed visit 
response of CR or PR 
• CR rate: Disappearance of all target 
and non-target lesions 
• DoR in subjects with CR: Time from 
date of first detection of response of 
CR  until the date of disease 
progression 
 


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To assess the effect of durvalumab + 
SoC CCRT compared with placebo + 
SoC CCRT on the incidence of local 
progression, distant disease 
progression, and secondary 
malignancy as the first documented 
progression event 
Incidence of local progression, distant disease 
progression, and secondary malignancy: 
Number and percentage of subjects who 
develop local progression, distant disease 
progression, or secondary malignancy 
To assess disease-related symptoms 
and health-related quality of life 
(HRQoL) in subjects with cervical 
cancer treated with durvalumab + SoC 
CCRT compared with placebo + SoC 
CCRT using the core quality of life 
questionnaire (EORTC QLQ-C30) and 
core quality of life questionnaire 
cervical cancer module (CX24) 
Change from baseline in EORTC QLQ-C30 
and EORTC-CX24 
To assess the PK of durvalumab when 
in combination with SoC CCRT 
Blood concentration of durvalumab 
To investigate the immunogenicity of 
durvalumab in combination with SoC 
CCRT 
Presence of ADAs for durvalumab 
To assess the safety and tolerability 
profile of durvalumab + SoC CCRT 
compared to placebo + SoC CCRT 
AEs, laboratory findings, vital signs, physical 
examinations 
ADA Antidrug antibody; AE Adverse event; CCRT Concurrent chemoradiation therapy; CR Complete 
response; DoR Duration of response; EORTC European Organization for Research and Treatment of Cancer; 
HRQoL Health-related quality of life; ORR Objective response rate; OS Overall survival; PD-L1 Programmed 
cell death protein 1; PFS Progression-free survival; PK Pharmacokinetics; QLQ-C30 30 item core quality of 
life questionnaire; QLQ-CX24 Cervical cancer module; RECIST Response evaluation criteria in solid tumors; 
SoC Standard of care 


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1.1.3 
Exploratory objectives 
Table 3: Exploratory study objectives and corresponding endpoints/variables 
Exploratory objective: 
Endpoint/Variable: 
To collect blood and tissue samples for 
defining biological response to durvalumab 
+SoC CCRT compared to placebo +SoC 
CCRT for candidate markers that may 
correlate with likelihood of clinical benefit 
(All countries except China) 
Analysis of blood/tissue samples to assess 
exploratory biomarkers, which may include, 
but is not limited to ctDNA, mRNA 
signatures, CD8 by IHC, and tumor 
mutational burden (TMB) 
To assess treatment-related symptoms using 
the patient-reported outcomes version of the 
common terminology criteria for adverse 
events (PRO-CTCAE) 
Specific treatment related PRO-CTCAE 
symptoms  
To assess how a subject perceives her 
overall change in cancer symptoms since the 
start of study treatment using the PGIC and 
overall severity of cancer symptoms using 
the PGIS. 
PGIC and PGIS 
To explore the impact of treatment and 
disease state on health status assessed by 
EuroQol five-dimensional five-level 
questionnaire (EQ-5D-5L) to support health 
economic analysis and health technology 
assessment 
EQ-5D-5L 
To describe and evaluate resource use 
associated with durvalumab treatment and 
underlying disease 
Health resource utilization measures 
including hospitalization, outpatient visits, or 
emergency department visits  
CCRT Concurrent chemoradiation therapy; CD Cluster of differentiation; ctDNA Circulating tumor 
deoxyribonucleic acid; EQ-5D-5L EuroQol five-dimensional five-level questionnaire; IHC 
Immunohistochemistry; mRNA Messenger ribonucleic acid; PFS Progression-free survival; PGIC Patient global 
impression of change; PGIS Patient global impression of severity; PRO-CTCAE Patient-reported outcomes 
version of the Common Terminology Criteria for Adverse Events; RECIST Response Evaluation Criteria in 
Solid tumors; SoC Standard of care; TMB tumor mutation burden 


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1.2 
Study design 
This is a randomized, double-blind, placebo controlled, multi-center, global, Phase III study to 
determine the efficacy and safety of durvalumab when combined with standard of care (SoC) 
concurrent chemoradiation therapy (CCRT) and administered as adjuvant therapy following 
SoC CCRT compared to placebo with SoC CCRT as systemic treatment in subjects with 
FIGO (2009) Stages IB2 to IVA cervical cancer. 
Subjects will be randomized 1:1 to receive either durvalumab 1500 mg or placebo every 4 
weeks (q4w) for 24 doses. Subjects in both arms will receive SoC CCRT consisting of 
external beam radiation therapy (EBRT) plus brachytherapy, and concurrent cisplatin 
40 mg/m2 every 1 week (q1w) for 5 weeks or carboplatin area under the serum drug 
concentration curve 2 (AUC 2) q1w for 5 weeks (carboplatin only applies for subjects 
randomized prior to CSP version 3). A 6th week of platinum agent can be given per 
investigator discretion (CSP Section 6.1.2 for descriptions of the dosing regimens). 
Randomization will be stratified by disease stage status (FIGO (2009) Stage <III and node 
positive, FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node 
positive), and region (United States, Canada, European Union, South Korea, and Japan) versus 
rest of world.  
 
Subjects will receive their assigned treatment until completion of planned therapy, clinical 
progression or RECIST 1.1-defined radiological progression or histopathologic progression on 
biopsy unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met (CSP Section 7.1 for additional details on discontinuation of study treatment). 
Following completion of SoC CCRT, subjects will be evaluated by clinical and radiological 
assessment. During the first 164 weeks after randomization, this assessment will include an 
interval history for new signs or symptoms, targeted physical examination to evaluate for local 
progression, and imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) 
per RECIST 1.1 every 12 weeks (q12w). During years 4, and 5, imaging/histopathologic 
assessments will be performed every 24 weeks (q24w) and then annually until a progression-
free survival (PFS) endpoint has been met or closure of the study (CSP Section 8.1). 
An overview of the study design is shown in Figure 1.  


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Figure 1: Overview of study design 
 
Brachy brachytherapy; EBRT External beam radiation therapy; FIGO (2009) International Federation of 
Gynecology and Obstetrics; q4w Every 4 weeks; R Randomized  
1.3 
 Number of subjects 
Approximately 714 subjects (357 per treatment arm) will be randomized 1:1 to durvalumab 
plus SoC CCRT or placebo plus SoC CCRT to obtain approximately 227 PFS events in the 
intention to treat (ITT) population. The randomization will be stratified according to disease 
stage status (FIGO (2009) Stage <III and node positive, FIGO (2009) Stage ≥III and node 
negative, or FIGO (2009) Stage ≥III and node positive), and region (United States, Canada, 
European Union, South Korea, and Japan) versus rest of the world. 
In China, recruitment will continue until approximately 105 Chinese subjects have been 
randomized, irrespective of whether or not the overall study enrollment has been reached. It is 
anticipated that this target may not be met before the global recruitment of approximately 714 
subjects is achieved. Further details on the China cohort will be detailed in a China 
supplementary SAP 
The PFS analysis will occur when approximately 227 PFS events (approximately 32% 
maturity) have occurred across the durvalumab plus SoC CCRT and placebo plus SoC CCRT 
treatment arms. If the true hazard ratio (HR) is 0.65 [likely to correspond to a 11% increase in 
the proportion of subjects progression-free at 3 years from 65% to 76%] (Rose et al. 1999), 
this analysis will have 90% power to demonstrate a statistically significant difference for PFS, 
assuming a 2-sided 5% significance level. Assuming non-uniform recruitment, a 3-year PFS 
rate of 65% for placebo + SoC CCRT and an exponential distribution, recruitment of 714 
subjects in 18 months would be expected to yield 227 PFS events approximately 53 months 
following recruitment of the first subject. In addition, the sample size has been derived on the 
assumption that 5% of subjects will drop out at an exponential rate within 36 months 
following the randomization of the first subject. If the true OS HR is 0.65, the study is also 


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sized to provide 89% power for the OS endpoint in the comparison of durvalumab + SoC 
CCRT versus placebo + SoC CCRT, assuming a 2-sided 5% significance level allowing for 1 
interim analysis conducted at the same time as the PFS analysis, with an expected 86% of 
target OS events. The analysis of OS will only be undertaken if the PFS is statistically 
significant. The final OS analysis will occur at the earlier of 227 death events or 71 months 
following recruitment of the first subject. Assuming the same recruitment assumptions for 
PFS and a 3-year OS rate of 70% for placebo + SoC CCRT (Rose et al. 1999), 227 deaths 
would be expected to occur 61 months following the recruitment of the first subject. The 
boundaries of the treatment comparison will be derived based upon the actual number of OS 
events observed at that time.  
2 
 ANALYSIS SETS 
2.1 
Definition of analysis sets 
There are four analysis sets defined for this study. A summary of the analysis sets used for 
each outcome variable is provided in Table 4. 
Table 4: Summary of outcome variables and analysis populations 
Outcome variable 
Populations 
Demographics, baseline characteristics, medical/surgical 
history, concomitant medications/procedures 
Full analysis set 
Efficacy data: PFS, ORR, CR rate, DoR in subjects with 
CR, Incidence of local progression, distant progression and 
secondary malignancy, PFS (3 year), OS 
Full analysis set 
PROs 
Full analysis set 
PFS, OS 
PD-L1 analysis set 
Safety data: AEs (including SAEs), exposure, laboratory 
measurements, physical examinations, vital signs, 
WHO/ECOG PS 
Safety analysis set 
ADA data 
Safety analysis set 
PK data  
PK analysis set 


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Outcome variable 
Populations 
ADA Antidrug antibody; AE Adverse event; CR Complete response; DoR Duration of response; ECOG 
Eastern Cooperative Oncology Group; ORR Objective response rate; OS Overall survival; PFS Progression-
free survival; PRO Patient reported outcomes; PS performance status; WHO World health organization 
2.1.1 
Full analysis set (Intention to treat [ITT]) 
The full analysis set (FAS) will include all randomized subjects. The FAS will be used for all 
efficacy analyses (including patient reported outcomes [PROs]). Treatment arms will be 
compared on the basis of randomized study treatment, regardless of the treatment actually 
received. Subjects who were randomized but did not subsequently go on to receive study 
treatment are included in the analysis in the treatment arm to which they were randomized.  
2.1.2 
Safety analysis set 
The safety analysis set (SAF) includes all subjects who received at least 1 dose of study 
treatment (durvalumab or placebo). Safety data will not be formally analyzed but summarized 
using the SAF, according to the treatment received. Erroneously treated subjects (e.g., those 
randomized to durvalumab but actually given placebo) will be summarized according to the 
treatment they actually received. If a subject only receives therapy from the placebo arm, they 
will be summarized in the placebo treatment group. If a subject receives any amount of 
durvalumab, they will be summarized in the durvalumab treatment group. 
2.1.3 
Pharmacokinetics analysis set  
The pharmacokinetics (PK) analysis set includes all subjects who receive at least 1 dose of 
durvalumab per the protocol for whom any post-dose PK concentration data are available and 
who do not violate or deviate from the protocol in ways that would significantly affect the PK 
analyses. The population will be defined by the Study Physician, Pharmacokineticist, and 
Statistician prior to any analyses being performed. The PK analysis set will be summarized 
according to the treatment actually received. 
2.1.4 
PD-L1 analysis set 
The programmed cell death protein 1 (PD-L1) analysis set will include a subset of subjects in 
the FAS who have a baseline PD-L1 expression result as described in Section 3.2.2.  
The CSP uses the terms PD-L1 positive and PD-L1 negative. PD-L1 positive has the same 
meaning as PD-L1 high and PD-L1 negative has the same meaning as PD-L1 low. The SAP 
and CSR outputs will use PD-L1 high/low. 


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2.2 
Violations and deviations 
For this study, the following general categories will be considered important protocol 
deviations (IPDs) and will be programmatically derived from the electronic case report form 
(eCRF) data where possible to do so. These will be listed and summarized by randomized 
treatment group and discussed in the clinical study report (CSR) as appropriate: 
• 
Subjects who deviate from key inclusion criteria per the CSP:  
− 
Inclusion 5 (IPD 1.1): Histologically confirmed cervical adenocarcinoma, cervical 
squamous carcinoma, or cervical adenosquamous carcinoma and the following 
requirements:  
o 
FIGO (2009) Stages IB2 to IIB, node positive (N≥1) -OR- FIGO (2009) Stages 
IIIA to IVA with any N stage (N≥0) 
o 
Nodal staging may be either surgical or by imaging (CT or MRI) with 
pathological lymph node size defined by a short-axis diameter of ≥10mm (axial 
plane) 
o 
No evidence of metastatic disease  
− 
Inclusion 9 (IPD 1.2): Adequate organ and marrow function as defined below: 
o 
Hemoglobin ≥9.0 g/dL 
o 
Absolute neutrophil count ≥1.5 × 109 /L 
o 
Platelet count ≥75 × 109/L 
o 
Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to 
subjects with confirmed Gilbert’s syndrome, who will be allowed in consultation 
with their physician and AstraZeneca 
o 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 × ULN 
o 
Creatine clearance (CrCl) ≥60 mL/min calculated by Cockcroft-Gault equation 
(using actual body weight) or by measured 24-hour urine collection 
 
Females: 
Creatinine CL =  Weight (kg) × (140 - Age)   × 0.85 
(mL/min) 
72 × serum creatinine (mg/dL) 


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− 
Subjects who have not signed the informed consent form (IPD 1.3) 
• 
Subjects who deviate from key exclusion criteria per the CSP:  
− 
Exclusion 3 (IPD 2.1): Evidence of metastatic disease per RECIST 1.1 including 
lymph nodes ≥15 mm (short axis) above the L1 cephalad body or outside the planned 
radiation field 
− 
Exclusion 4 (IPD 2.2): Subjects who have undergone a previous hysterectomy, 
including a supracervical hysterectomy, or will have a hysterectomy as part of their 
initial cervical cancer therapy 
− 
Exclusion 6 (IPD 2.3): 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: 
o 
Subjects with vitiligo or alopecia 
o 
Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
o 
Subjects with any chronic skin condition that does not require systemic therapy 
o 
Subjects without active disease in the last 5 years may be included but only after 
consultation with the Study Physician 
o 
Subjects with celiac disease controlled by diet alone 
− 
Exclusion 14 (IPD 2.4): Prior history of vesicovaginal, colovaginal, or rectovaginal 
fistula 
− 
Exclusion 17 (IPD 2.5): Any concurrent chemotherapy, investigational product (IP), 
biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal 
therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is 
acceptable 
• 
Non-compliance with the study protocol that warrants withdrawal from treatment with IP 
(IPD 3.4) 


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• 
Subjects who were randomized who received treatment other than that to which they were 
randomized (IPD 5.1) 
• 
Subjects who were randomized but who did not receive at least one dose of study 
treatments  
− 
Subjects randomized but who did not receive durvalumab or matching placebo (IPD 
5.2/5.3) 
− 
Subjects randomized but who did not receive protocol defined CCRT (IPD 5.4) 
• 
Subjects who have known hypersensitivity to durvalumab or any of the excipients of the 
product prior to enrollment (IPD 5.6) 
• 
The subject received prohibited concomitant medications (including other anti-cancer 
agents). Please refer to the CSP Section 6.4 for those medications that are detailed as 
being ‘excluded’ from permitted use during the study. This will be used as a guiding 
principle for the physician review of all medications prior to the database lock (IPD 6.1) 
• 
Baseline assessments incorrectly completed/missed as defined below . 
− 
Baseline RECIST scan or physical exam > 42 days before date subject was 
randomized (based upon a 28-day screening period plus 2 weeks allowance, so that 
only serious violators are identified) (IPD 7.1) 
− 
No baseline RECIST 1.1 or physical exam assessment on or before date subject was 
assigned to treatment (IPD 7.2) 
Subjects who receive the wrong treatment at any time will be included in the SAF as 
described in Section 2.1. During the study, decisions on how to handle errors in treatment 
dispensing (with regard to continuation/discontinuation of study treatment or, if applicable, 
analytically) will be made on an individual basis with written instruction from the study team 
leader and/or statistician. 
The important protocol deviations will be listed and summarized by randomized treatment 
group. The summary will include a split of important protocol deviations that are and are not 
COVID-19 related. Deviation 1.1 (subjects randomized but who did not receive durvalumab 
or matching placebo) will lead to exclusion from the safety analysis set. None of the other 
deviations will lead to subjects being excluded from the analysis sets described in Section 2.1 
(with the exception of the PK analysis set, if the deviation is considered to impact upon PK). 


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A per-protocol analysis excluding subjects with specific important protocol deviations is not 
planned; however, a ‘deviation bias’ sensitivity analysis may be performed on the 
progression-free survival endpoint excluding subjects with deviations that may affect the 
efficacy of the trial therapy if >10% of subjects in either treatment group: 
• 
Did not have the intended disease or indication or 
• 
Did not receive any randomized therapy 
The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock (DBL) and will be documented prior to the primary analysis 
being conducted.  
In addition to the programmatic determination of the deviations above, other study deviations 
captured from the case report form (CRF) module for inclusion/exclusion criteria will be 
tabulated and listed. Any other deviations from monitoring notes or reports will be reported in 
an appendix to the CSR. 
Errors in stratifications (based upon stratification information recorded in the IxRS and eCRF 
source data) will also be summarized separately to the important deviations. 
3 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Derivation of visit responses 
For all subjects, the RECIST version 1.1 (Appendix F of the CSP) tumor response data will be 
combined with physical examination and biopsy data to determine each subject’s visit 
response. It will also be used to determine if and when a subject has progressed and also their 
best objective response (BoR).  
For all subjects, a physical examination including a pelvic examination and (if indicated) 
biopsy for histopathological determination of tumor progression will be assessed on the same 
schedule as the tumor assessments. If progression is suspected by the investigator during the 
pelvic exam, a biopsy must be performed for the purpose of confirming histopathological 
tumor progression. Some subjects may have a pap smear as part of the physical exam. If 
progression is suspected from the results of the pap smear, a biopsy must be performed for the 
purpose of confirming histopathologic tumor progression. The physical examination, pap 
smear, and biopsy data will be used to determine if and when a subject has histopathologic 
tumor progression. Throughout this document, the term “physical exam data” includes results 
from a pap smear where those results are available. 


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Baseline radiological tumor assessments and the baseline physical exam are to be performed 
no more than 28 days before the start of randomized treatment and ideally as close as possible 
to the start of study treatment. Post-baseline tumor assessments and physical exams by the 
investigator start 20 weeks (± 1 week) after randomization and continue every 12 weeks (±1 
week) through 164 weeks (relative to date of randomization). Post 164 weeks, these occur 
every 24 weeks (±2 weeks) thereafter (relative to date of randomization) until RECIST 1.1 
defined- disease progression or histopathologic confirmation of local disease progression plus 
an additional follow-up assessment consisting only of a RECIST 1.1 tumor assessment that is 
performed at the next (and no later than the next) scheduled imaging visit following either 
RECIST 1.1 defined progression or histopathologic confirmation of local disease progression 
and performed no less than 4 weeks after the prior assessment of PD.  
If an unscheduled assessment is performed, and the subject has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 
is to be followed in order to minimize any unintentional bias caused by some subjects being 
assessed at a different frequency than other subjects.  
From the investigator’s review of the imaging scans, the RECIST tumor response data will be 
used to determine each subject’s visit response according to RECIST version 1.1. At each 
visit, subjects will be programmatically assigned a RECIST 1.1 visit response of complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), using 
the information from target lesions (TLs), non-target lesions (NTLs) and new lesions and 
depending on the status of their disease compared with baseline and previous assessments. If a 
subject has had a tumor assessment that cannot be evaluated then the subject will be assigned 
a RECIST 1.1 visit response of not evaluable (NE), (unless there is evidence of progression in 
which case the response will be assigned as PD). At each visit, subjects will also have a 
restaging physical examination including a pelvic examination and (if indicated) biopsy for 
histopathological determination of tumor progression.  
Please refer to Section 3.1.1 for the definitions of CR, PR, SD and PD. The determination of 
overall visit response using the RECIST 1.1 tumor data, physical exam data, and biopsy data 
is discussed in Section 3.2.16. 
3.1.1 
RECIST 1.1 target lesions (TLs) 
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥10mm in the longest diameter (LD), (except lymph nodes that must have 
a short axis ≥15mm) with CT or MRI and which is suitable for accurate repeated 
measurements. A subject can have a maximum of five measurable lesions recorded at baseline 
with a maximum of two lesions per organ (representative of all lesions involved and suitable 


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for accurate repeated measurement) and these are referred to as target lesions (TLs). If more 
than one baseline scan is recorded, then measurements from the one that is closest and prior to 
randomization will be used to define the baseline sum of TLs. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement. In which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected. 
All other lesions (or sites of disease) not recorded as TL should be identified as non-target 
lesions (NTLs) at baseline. Measurements are not required for these lesions, but their status 
should be followed at subsequent visits. 
Measurable disease (i.e., at least one TL) is one of the entry criteria for the study. However, if 
a subject who does not have measurable disease is enrolled into the study (i.e., no TLs), 
evaluation of the overall visit responses will be based on the overall NTL assessment and the 
absence/presence of new lesions (see Section 3.1.3 for further details). If a subject does not 
have measurable disease at baseline, then the TL visit response will be not applicable (NA). 
Table 5: TL Visit Responses (RECIST 1.1) 
Visit Responses 
Description 
Complete response (CR) 
Disappearance of all TLs. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis to 
<10mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of TLs, 
taking as reference the baseline sum of diameters as long 
as criteria for PD are not met. 
Progressive disease (PD) 
A ≥20% increase in the sum of diameters of TLs and an 
absolute increase of ≥5mm, taking as reference the 
smallest sum of diameters since treatment started 
including the baseline sum of diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. 
Not evaluable (NE) 
Only relevant in certain situations (i.e. if any of the TLs 
were not assessed or not evaluable or had a lesion 
intervention at this visit; and scaling up could not be 
performed for lesions with interventions). Note: If the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL 
response. 
Not applicable (NA) 
No TLs are recorded at baseline. 


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Rounding of TL data 
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to one decimal place (d.p.) before assigning a TL response. For 
example, 19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  
Missing TL data  
For a visit to be evaluable then all TL measurements should be recorded. However, a visit 
response of PD should still be assigned if any of the following occurred: 
• 
A new lesion is recorded 
• 
A NTL visit response of PD is recorded 
• 
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5mm, from nadir even assuming the non-recorded TLs have disappeared 
Note: the nadir can only be taken from assessments where all the TLs had a LD recorded. If 
all TL measurements are missing, then the TL visit response is NE. If there is at least one TL 
measurement missing and a TL visit response of PD cannot be assigned, the TL visit response 
is NE. 
Lymph nodes 
For lymph nodes if the size reduces to < 10mm then these are considered non-pathological. 
However, a size will still be given, and this size should still be used to determine the TL visit 
response as normal. In the special case where all lymph nodes are <10mm and all other TLs 
are 0mm then although the sum may be >0mm the calculation of TL response should be over-
written as a CR.  
TL visit responses subsequent to CR 
Only CR, PD or NE can follow a CR. If a CR has occurred, then the following rules at the 
subsequent visits must be applied: 
• 
Step 1: If all lesions meet the CR criteria (i.e. 0mm or <10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met i.e. 
if a lymph node LD increases by 20% but remains <10mm  
• 
Step 2: If some lesion measurements are missing but all other lesions meet the CR criteria 
(i.e. 0mm or <10mm for lymph nodes) then response will be set to NE irrespective of 
whether, when referencing the sum of TL diameters, the criteria for PD are also met 


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• 
Step 3: If not all lesions meet the CR criteria (i.e. a pathological lymph node selected as 
TL has short axis >10mm or the reappearance of previously disappeared lesion) or a new 
lesion appears, then response will be set to PD 
Step 4: If after steps 1 – 3 a response can still not be determined the response will be set to 
remain as CR  
TL too big to measure 
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded. If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment. It is expected that a 
visit response of PD will remain in the vast majority of cases.  
TL too small to measure 
If a TL becomes too small to measure, then this will be indicated as such on the case report 
form and a value of 5mm will be entered into the database and used in TL calculations. 
However, a smaller value may be used if the radiologist has not indicated ‘too small to 
measure’ on the case report form and has entered a smaller value that can be reliably 
measured. If a TL response of PD results (at a subsequent visit) then this will be reviewed by 
the study team blinded to treatment assignment. 
Irradiated lesions/lesion intervention 
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment. 
 
Any TL (including lymph nodes), which has had intervention during the study (surgery / 
embolization), should be handled in the following way. The current study includes 
radiotherapy as study treatment, and this will not be considered as a TL intervention in the 
eCRF. Once a lesion has had intervention then it should be treated as having intervention for 
the remainder of the study noting that an intervention will most likely shrink the size of 
tumors: 
• 
Step 1: The diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD, this will remain as a valid response category  
• 
Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing and if 1/3 of the TLs have missing 


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measurements then scale up as described in the ‘Scaling’ section below. If the scaling 
results in a visit response of PD then the subject would be assigned a TL response of PD 
• 
Step 3: If, after both steps, PD has not been assigned, then, if appropriate (i.e., if 1/3 of 
the TLs have missing measurements), the scaled sum of diameters calculated in step 2 
should be used, and PR or SD then assigned as the visit response. Subjects with 
intervention are evaluable for CR as long as all non-intervened lesions are 0 (or <10mm 
for lymph nodes) and the lesions that have been subject to intervention have a value of 0 
(or <10mm for lymph nodes) recorded. If scaling up is not appropriate due to too few 
non-missing measurements, then the visit response will be set as NE 
At subsequent visits, the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up (as per step 2 above). 
 
Scaling (applicable only for irradiated lesions/lesion intervention) 
If >1/3 of TL measurements are missing (because of intervention) then the TL response will 
be NE, unless the sum of diameters of non-missing TL would result in PD (i.e., if using a 
value of 0 for missing lesions, the sum of diameters has still increased by 20% or more 
compared to nadir and the sum of TLs has increased by ≥5mm from nadir).  
If ≤1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters) and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements. 
Table 6: Example of scaling 
Lesion Longest diameter 
(mm) at nadir visit 
Longest diameter 
(mm) at follow-up 
visit 
1 
16 
18 
2 
14 
16 
3 
14 
16 
4 
18 
18 
5 
12 
Intervention 


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Sum 
74 
68 
 
Lesion 5 has had an intervention at the follow-up visit. It had a baseline measure of 74mm. 
The sum of lesions 1 – 4 at the follow-up is 68mm. The sum of the corresponding lesions at 
nadir visit is 62mm. Scale up as follows to give an estimated follow-up visit TL sum of 
81mm: 
68
62 × 74 = 81𝑚𝑚 
CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases. However, for visits 
with 1/3 lesion assessments not recorded, the scaled-up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression. 
Lesions that split in two or more parts 
If a TL splits in two or more parts, then the longest diameters of the split lesions should be 
summed and reported as the longest diameter for the lesion that split. 
Lesions that merge 
If two or more TLs merge, then the longest diameter of the merged lesion should be recorded 
for one of the TL sizes and the other TL sizes should be recorded as 0mm. 
Change in method of assessment of TLs 
CT and MRI are the only methods of assessment that can be used within a trial to assess target 
lesions. A clinical exam to assess for cervical cancer should be done following the tumor 
schedule however it cannot be used to assess target lesions. If a change in method of 
assessment occurs between CT and MRI, this will be considered acceptable and no adjustment 
within the programming is needed. 
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing. 
3.1.2 
RECIST 1.1 non-target lesions and new lesions 
At each visit, the investigator should record an overall assessment of the NTL response. This 
section provides the definitions of the criteria used to determine and record overall response 
for NTL at the investigational site at each visit. 


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NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows:  
Table 7: Non-target lesion visit responses 
Visit responses 
Description 
Complete response (CR) 
Disappearance of all NTLs present at baseline with 
all lymph nodes non-pathological in size (<10 mm 
short axis) 
Progressive disease (PD) 
Unequivocal progression of existing NTLs. 
Unequivocal progression may be due to an important 
progression in one lesion only or in several lesions. 
In all cases, the progression MUST be clinically 
significant for the physician to consider changing (or 
stopping) therapy 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence of 
progression 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were 
not assessed and, in the investigator's opinion, they 
are not able to provide an evaluable overall NTL 
assessment at this visit 
Note: For subjects without TLs at baseline, this is 
relevant if any of the NTLs were not assessed at this 
visit and the progression criteria have not been met. 
Not applicable (NA) 
Only relevant if there are no NTLs at baseline 
NTL Non-target lesion; TL Target lesion 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumor burden has increased sufficiently to merit a determination of disease 
progression. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status. 
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. 


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A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor. 
New lesions will be identified via a Yes/No tick box. The presence of new lesions at each visit 
should be listed alongside the TL and NTL visit responses. 
A new lesion indicates progression, so the overall visit response will be PD irrespective of the 
TL and NTL response. 
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs. 
Subjects with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed. 
3.1.3 
Overall RECIST 1.1 visit response 
Table 8 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response. 
Table 8: Overall RECIST 1.1 visit responses 
Target 
Non-target 
New lesions 
Overall visit response 
CR 
CR or NA 
Not recorded 
CR 
CR 
Non-CR/Non-PD or NE 
Not recorded 
PR 
PR 
Non-PD or NE or NA 
Not recorded 
PR 
SD 
Non-PD or NE or NA 
Not recorded 
SD 
PD 
Any 
Any (i.e., Yes/Not 
recorded) 
PD 
Any 
PD 
Any (i.e., Yes/Not 
recorded) 
PD 


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Any 
Any 
Yes 
PD 
NE 
Non-PD or NE or NA 
Not recorded 
NE 
NA 
CR 
Not recorded 
CR 
NA 
Non-CR/Non-PD 
Not recorded 
SD 
NA 
NE 
Not recorded 
NE 
CR Complete response; NA Not Applicable; NE Not evaluable; PD Progressive disease; PR Partial 
response; SD Stable disease 
3.1.4 
Independent review 
A planned blinded independent central review (BICR) of all radiological imaging data will be 
carried out using RECIST version 1.1. All radiological scans for all subjects (including those 
at unscheduled visits, or outside visit windows) will be collected on an ongoing basis and sent 
to an AstraZeneca appointed Contract Research Organisation (CRO) for central analysis. The 
imaging scans will be reviewed by two independent radiologists using RECIST 1.1 and will 
be adjudicated, if required (i.e., two reviewers review the scans, and adjudication is performed 
by a separate reviewer in case of a disagreement). For each subject, the BICR will define the 
overall visit response (i.e., the response obtained overall at each visit by assessing TLs, NTLs 
and new lesions) data and no programmatic derivation of visit response is necessary. (For 
subjects with TLs at baseline: CR, PR, SD, PD, NE; for subjects with NTLs only: CR, SD, 
PD, NE). If a subject has had a tumor assessment that cannot be evaluated, then the subject 
will be assigned a visit response of NE (unless there is evidence of progression in which case 
the response will be assigned as PD). Tumor assessments/scans contributing towards a 
particular visit may be performed on different dates and for the central review the date of 
progression for each reviewer will be provided based on the earliest of the scan dates of the 
component that triggered the progression.  
If adjudication is performed, the reviewer that the adjudicator agreed with will be selected as a 
single reviewer (note in the case of more than one review period, the latest adjudicator 
decision will be used). In the absence of adjudication, the records for all visits for a single 
reviewer will be used. The reviewer selected in the absence of adjudication will be the 
reviewer who read the baseline scan first. The records from the single selected reviewer will 
be used to report all BICR RECIST information including dates of progression, visit response, 
censoring and changes in target lesion dimensions. Endpoints (of objective response rate 
(ORR), PFS and duration of response [DoR]) will be derived programmatically from this 
information.  


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Results of this independent review will not be communicated to investigators and the 
management of subjects will be based solely upon the results of the RECIST 1.1 assessment 
and physical examination conducted by the investigator. 
A BICR of all subjects will be performed for the database lock for PFS, which will cover all 
scans up to the data cut-off (DCO). 
Further details of the BICR will be documented in the independent review master charter 
(IRMC) Charter. 
3.1.5 
Histopathologic confirmation of local progression 
At response assessment physical exams, subjects will be evaluated for local progression. A 
physical exam can include a pelvic examination with or without speculum, bimanual 
examination, rectovaginal examination, abdominal examination and optional pap smear. 
Physical examinations should be performed following the same schedule as tumor 
assessments by imaging. Any lesion detected on physical exam that is not evaluable through 
RECIST 1.1 and is within the radiation field and suspected to be progressive disease will be 
biopsied. Lesions identified as progressive disease by RECIST 1.1 on CT or MRI do not 
require a biopsy. At the discretion of the investigator, pap smears are an optional component 
of the response assessment physical exam. If a subject has a pap smear result indicating 
potential progression, a biopsy should be performed. Lesions with histopathologic 
confirmation of disease will be reported as a response of PD.  
Note that pap smear is a component of the restaging physical exam. For the restaging physical 
exam, no suspected progression on the restaging physical exam indicates that there were no 
findings on the physical exam that were concerning for progressive disease. Suspected 
progression on the restaging physical exam indicates that either there were findings on the 
physical exam, the pap smear was performed and the results were indicative of progression, or 
both. Any positive biopsy result, without a linked pap smear, RECIST or CERCAPE result 
will be queried. 
Radiological assessments should be obtained on all subjects within 28 days of progression if 
confirmed by histopathology. If the physical examination and biopsy are performed as 
unscheduled assessments and there is no evidence of active cervical cancer on histopathology, 
the subject will not be reported as PD, and will continue with all study procedures according 
to the Schedule of Assessments in the protocol. 


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3.1.6 
Overall visit response 
The overall visit responses will be determined using RECIST 1.1 criteria and the findings of 
response assessment physical exams and required confirmatory biopsies following suspected 
progression at a physical exam.  
A subject’s overall visit response will be classified as follows: 
• 
If evidence of progression = yes from the CERCAPE eCRF and confirmation of previous 
equivocal progression from scan or PE = yes from the PATHROM eCRF then the overall visit 
response is PD regardless of the other categories. This applies to physical examination and 
biopsy assessments that are performed as scheduled and unscheduled assessments. 
• 
If the above criteria are not met, then the overall visit response will be determined using 
RECIST 1.1 as shown in Table 8. 
Table 9: Overall visit responses 
Overall RECIST response 
Physical exam 
Biopsy result  Overall 
CR   
No suspected progression NA       
CR 
PR   
No suspected progression NA       
PR 
SD   
No suspected progression NA       
SD 
NE   
No suspected progression NA       
NE 
PD   
No suspected progression NA       
PD 
Any 
Suspected progression 
PD        
PD  
Any 
Suspected progression 
not PD  
overall RECIST 
response 
Missing 
No suspected progression NA 
Evaluable 
Missing 
Suspected progression 
not PD 
Evaluable 
Missing 
Suspected progression 
PD 
PD 
Missing 
Suspected progression 
missing 
Non evaluable 


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Any 
Suspected progression 
missing 
overall RECIST 
response 
CR Complete response; Evaluable Assessment was performed in the absence of a RECIST scan; NA Not 
Applicable; NE Not evaluable; PD Progressive disease; PR Partial response; SD Stable disease 
                              
3.2 
Efficacy variables 
3.2.1 
Progression-free survival (PFS) 
The primary endpoint of the trial is PFS. PFS (per RECIST 1.1 as assessed by investigator 
tumor assessments or histopathologic confirmation of local tumor progression) is defined as 
the time from randomization until the date of objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the subject withdraws from 
randomized therapy or receives another anti-cancer therapy prior to progression (i.e., date of 
PFS event or censoring – date of randomization + 1). Objective disease progression is further 
detailed as one of the following: 
• 
Local progression 
• 
Distant disease progression 
• 
Secondary malignancy 
If two progression events are reported but more than 2 months has elapsed between the events 
than the events will be regarded as two separate progression events and the earlier event and 
corresponding date of event will be used in the derivation of PFS.  
Subjects who have not progressed or died at the time of analysis will be censored at the time 
of the latest date of assessment at which the RECIST 1.1 assessment and/or response 
evaluation physical exam were evaluable. However, if the subject progresses or dies 
immediately after two or more consecutive missed visits, the subject will be censored at the 
time of the latest assessment at which the RECIST 1.1 assessment and/or response assessment 
physical exam were evaluable prior to the two missed visits (Note: NE visit is not considered 
as missed visit).  
A physical exam will be considered non evaluable if a physical exam is performed and 
progression is suspected and a biopsy is not reported. Similarly, in the absence of 
histopathologic confirmation of local tumor progression, an assessment will be considered 
non-evaluable if the RECIST visit assessment is not performed. 


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A missed visit will only occur if no scan and no physical exam are performed. 
In the absence of histopathologic confirmation of disease progression, given the scheduled 
visit assessment scheme (i.e., at 20 weeks following randomization then every 12 weeks until 
week 164 then every 24 weeks thereafter), the definition of two missed RECIST 1.1 
assessment visits will be as follows:  
• 
If the previous evaluable assessment is <= day 133 (i.e., week 19) then two missed visits 
will equate to 33 weeks (i.e., 20 weeks + 12 weeks + 1 week allowing for a late visit at 
the end of the period) 
• 
If the previous evaluable assessment is > day 133 and <= day 1,057 (i.e., week 151) then 
two missed visits will equate to 26 weeks (i.e., 2 x 12 weeks + 1 week allowing for an 
early assessment at the start of the period + 1 week allowing for a late assessment at the 
end of the period). 
• 
If the two missed visits occur over the period where the visit schedule switches from 12-
weekly to 24-weekly this will equate to 39 weeks (i.e., take the average of 12 and 24 to 
get 18 weeks and apply the same rationale, hence 2 x 18 weeks + 1 week allowing for an 
early visit at the start of the period + 2 weeks allowing for a late visit at the end of the 
period). The time period for the previous evaluable exam will be from days 1,058 to 
1,141 (i.e., weeks 151 to 163). 
• 
From day 1,142 (week 163) onwards (when the scheduling changes to 24-weekly 
assessments) two missing visits will equate to 52 weeks (i.e., 2 x 24 weeks + 2 weeks 
allowing for an early visit at the start of the period + 2 weeks allowing for a late visit at 
the end of the period).  
If the subject has no evaluable visits or does not have a baseline RECIST scan, they will be 
censored at Day 1 unless they die within two visits of baseline (32 weeks plus 1 week 
allowing for a late assessment within the visit window); then they will be treated as an event 
with date of death as the event date. 
The PFS time will always be derived based on scan/assessment dates, not visit dates. 
Tumor assessments and physical exams contributing towards a particular visit may be 
performed on different dates within a 4-week window for the specific timepoint assessment. 
The following rules will be applied: 


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• 
For progression by histopathologic evidence of disease, date of progression will be 
determined based on the date of the physical exam which showed progression (including 
pap smear findings for which the date of pap smear would be used for progression).  
• 
For on-study tumor assessments, the date of progression will be determined based on the 
earliest date of the scan for RECIST 1.1 defined radiological progression or progression 
seen on physical exam  
• 
For BICR sensitivity analysis, date of progression will be determined based on the earliest 
of the dates of the component that triggered the progression on the first set of scans that 
indicates progression for the adjudicated reviewer selecting PD, or of either reviewer 
where both reviewers select PD as a timepoint response, and there is no adjudication for 
central review (BICR) data  
• 
For both on-study tumor assessments and the BICR sensitivity analysis, when censoring a 
subject for PFS the subject will be censored at the latest of the dates contributing to a 
particular overall visit assessment 
Note: for TLs only, the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of all 
scans performed at that assessment for the NTLs. 
3.2.1.1 
Time to first and second subsequent therapy or death 
As a supportive summary to PFS, time to first subsequent therapy or death (TFST) is defined 
as the time from the date of randomization to the earlier of start date of the first subsequent 
anti-cancer therapy after discontinuation of randomized treatment, or death (i.e. date of first 
subsequent cancer therapy/death or censoring – date of randomization + 1). Any subject not 
known to have had a first subsequent anti-cancer therapy will be censored at the last date that 
the subject was known not to have received a first subsequent anti-cancer therapy (obtained 
from the TTSCAPRX form). If a subject terminated the study for reason other than death 
before first subsequent therapy, these subjects will be censored at the earliest of their last 
known to be alive and termination dates. Subjects not receiving randomized treatment would 
have TFST calculated in the same way (i.e., time from date of randomization to the 
subsequent therapy or death). 
Time to second subsequent therapy or death (TSST) is defined as the time from the date of 
randomization to the earlier of start date of the second subsequent anti-cancer therapy after 
discontinuation of first subsequent treatment, or death (i.e. date of second subsequent cancer 
therapy/death or censoring – date of randomization + 1).  Any subject not known to have had 
a second anti-cancer subsequent therapy will be censored at the last date that the subject was 


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known not to have received a second subsequent anti-cancer therapy (obtained from the 
TTSCAPRX form).  If a subject terminated the study for reason other than death before 
second subsequent therapy, these subjects will be censored at the earliest of their last known 
to be alive and termination dates.  Subjects not receiving randomized treatment would have 
TSST calculated in the same way, i.e. time from date of randomization to the subsequent 
therapy or death. 
3.2.2 
Progression-free survival (3 years) 
Progression-free survival (3 years) will be defined as the Kaplan-Meier estimate of PFS at 3 
years. 
3.2.3 
Overall survival (OS) 
Overall survival is defined as the time from the date of randomization until death due to any 
cause regardless of whether the subject withdraws from randomized therapy or receives 
another anti-cancer therapy (i.e. date of death or censoring – date of randomization + 1). Any 
subject not known to have died at the time of analysis will be censored based on the last 
recorded date on which the subject was known to be alive (SUR_DAT, recorded within the 
SURVIVE module of the eCRF). Note: Survival calls will be made in the week following the 
date of DCO for each analysis, and if subjects are confirmed to be alive or if the death date is 
post the DCO date these subjects will be censored at the date of DCO. The status of ongoing, 
withdrawn (from the study) and “lost to follow-up” subjects at the time of the final OS 
analysis should be obtained by the site personnel by checking the subject’s notes, hospital 
records, contacting the subject’s general practitioner and checking publicly-available death 
registries. In the event that the subject has actively withdrawn consent to the processing of 
their personal data, the vital status of the subject can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws. 
Note: For any OS analysis performed prior to the final OS analysis, in the absence of survival 
calls being made, it may be necessary to use all relevant CRF fields to determine the last 
recorded date on which the subject was known to be alive for those subjects still on treatment 
(since the SURVIVE module is only completed for subjects off treatment if a survival sweep 
is not performed). The last date for each individual subject is defined as the latest among the 
following dates recorded on the case report forms (CRFs): 
• 
AE start and stop dates 
• 
Admission and discharge dates of hospitalization 
• 
Study treatment date 


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• 
End of treatment date 
• 
Laboratory test dates 
• 
Date of vital signs 
• 
Disease assessment dates on RECIST CRF 
• 
Start and stop dates of alternative anti-cancer treatment 
• 
Date last known alive on survival status CRF 
• 
End of study date 
If a subject is known to have died where only a partial death date is available, then the date of 
death will be imputed as the latest of the last date known to be alive + 1 from the database and 
the death date using the available information provided: 
a. For Missing day only – using the 1st of the month  
b. For Missing day and Month – using the 1st of January 
If there is evidence of death but the date is entirely missing, it will be treated as missing, i.e. 
censored at the last known alive date. 
3.2.4 
Objective response rate (ORR) 
To fulfil the analysis of the secondary endpoint of ORR, ORR (per RECIST 1.1 using 
investigator assessments or pathologic assessment of local disease progression) is defined as 
the percentage of subjects with at least one investigator-assessed overall visit response of CR 
or PR (Table 9) and will be based on a subset of all randomized subjects with measurable 
disease at baseline per the site investigator. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Subjects who discontinue randomized treatment 
without progression, receive a subsequent anti-cancer therapy (note that for this analysis 
radiotherapy is not considered a subsequent anti-cancer therapy) and then respond will not be 
included as responders in the ORR.  
In addition to ORR, an analysis of confirmed ORR (per RECIST 1.1 using investigator 
assessments or pathologic assessment of local disease progression) will also be performed. 
Confirmed ORR is defined as the percentage of subjects with at least one confirmed visit 


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response of CR or PR. Confirmed ORR is intended as a supplementary analysis to ORR but 
will not be used for the interpretation of the secondary endpoint of ORR.  
ORR will also be analyzed for all randomized subjects, but this will not be used for the 
interpretation of the secondary endpoint of ORR. 
The number of subjects who received surgery at the site of the cervical cancer will be 
produced. 
If applicable, an additional analysis of ORR will be performed in which subjects who have 
surgery that results in the absence of any tumor after surgery are treated as a CR in the 
derivation. It is reasonable to assume in this setting that the intervention of therapy has 
contributed to the ability to perform the surgery and thus the disappearance of the tumor.  
3.2.5 
Complete response (CR) rate 
CR rate (per RECIST 1.1 using investigator assessments or pathologic assessment of local 
disease progression) is defined as the percentage of subjects with an overall visit response of 
CR (as defined in Table 9).   
3.2.6 
Duration of response (DoR) for complete responders 
DoR in complete responders (per RECIST 1.1 using Investigator assessments, physical 
examination, and histopathological confirmation of local disease) will be defined as the time 
from the date of first documented complete response prior to starting subsequent anti-cancer 
therapy, until date of documented progression or death in the absence of disease progression 
(i.e. 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. The 
time of the initial response will be defined as the latest of the dates contributing towards the 
first visit response of CR. 
If a subject does not progress following a response, then their DoR will use the PFS censoring 
time. 
Similarly, the duration of response for subjects with CR or PR will also be defined as per the 
duration of response for CR responders only. 
3.2.7 
Incidence of local progression, distant disease progression, and 
secondary malignancy 
The incidence of local progression, distant disease progression, and secondary malignancy 
will each be considered separately and defined as the number and percentage of subjects with 


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documented evidence of local progression, distant disease progression, and secondary 
malignancy.  
The time from randomization to the date of first documented local progression, distant disease 
progression/secondary malignancy or death from any cause will also be summarized.  
For the summaries, if two progression events (local progression and distant disease 
progression) occur within 2 months of each other, then this is referred to as a simultaneous 
event and will be considered a single event. In this situation the worst case will be taken as the 
event ‘type’, but the date of recurrence will be the earliest of the two events. For example, if 
local progression and distant progression are reported within a 2 month period then for the 
analysis and reporting of incidence of local progression, distant disease, and secondary 
malignancy and time to date of first local progression, distant disease progression, secondary 
malignancy or death from any cause, the event will be counted as distant disease progression, 
but the date will be the earliest date of the two events. 
Distant disease progression, secondary malignancy, and deaths are considered to be competing 
risks for local progression. Local progression and death are considered to be competing risks 
for distant disease progression/secondary malignancy. For the time to event endpoint, distant 
disease progressions and secondary malignancies will be summarized together.  
Local progressions will be determined by RECIST 1.1 or histopathologic confirmation of 
disease. Local progressions will be classified as any enlargement of the target or non-target 
lesions with no new lesions outside the radiation field. Distant disease progression should be 
diagnosed by RECIST 1.1 or histopathological confirmation of disease when metastatic lesion 
is easily accessible for biopsy. Distant disease progression will be classified as any new 
lesions outside the radiation field. 
Secondary malignancies must be confirmed by biopsy. If a biopsy is not able to be performed, 
then the suspected secondary malignancy will be counted as a distant disease progression for 
the summary. Secondary malignancies are SAEs coded to the MedDRA system organ class 
neoplasms benign, malignant and unspecified (including cysts and polyps). All terms recorded 
in this system organ class at data cut-off are reviewed by AZ clinical and all terms considered 
secondary malignancies are flagged. 
New cancers are those that are not the primary reason for the administration of the study 
treatment and have been identified after the subjects’ inclusion in this study. They do not 
include metastases of the original cancer. 


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3.2.8 
Best objective response (BoR) 
Best objective response (BoR) is calculated based on the overall visit responses of CR, PR, 
SD, PD and NE as described in section 3.1.6. It is the best response a subject has had 
following randomization, but prior to starting any subsequent cancer therapy and up to and 
including RECIST progression or histopathologic confirmation of progression or the last 
evaluable assessment in the absence of RECIST progression or histopathologic confirmation 
of progression.  
For determination of a best response of SD, the earliest of the dates contributing towards a 
particular overall visit assessment will be used. SD should be recorded at least 20 weeks 
minus 1 week, i.e. at least 134 days (to allow for an early assessment within the assessment 
window), after randomization. For CR/PR, the initial overall visit assessment that showed a 
response will use the latest of the dates contributing towards a particular overall visit 
assessment. 
BoR will be determined programmatically based on RECIST, physical exam data, and 
confirmatory biopsy data from the overall visit response using all site investigator RECIST 
1.1, physical exam data, and biopsy data up until the first progression event or start of 
subsequent anti-cancer therapy. The denominators for each case will be consistent with those 
used in the ORR analysis. 
For subjects whose progression event is death, BoR will be calculated based upon all 
evaluable tumor assessments prior to death. 
For subjects who die with no evaluable tumor assessments or confirmed histopathological 
local progression, if the death occurs ≤21 weeks (i.e., 20 weeks + 1 week to allow for a late 
assessment within the assessment window) after randomization, then BoR will be assigned to 
the progression (PD) category. For subjects who die with no evaluable tumor assessments or 
confirmed histopathological local progression, if the death occurs >21 weeks after 
randomization then BoR will be assigned to the NE category. 
A subject will be classified as a responder if the criteria for an overall visit of CR or PR, are 
satisfied at any time following randomization, prior to progression and prior to starting any 
subsequent cancer therapy. 
3.3 
Patient reported outcome (PRO) variables 
The following PRO questionnaires will be used to assess the subject experience, including 
global health status/health-related quality of life (HRQoL), functioning and symptoms: 
EORTC-QLQ-C30 with the EORTC-QLQ-CX24 cervical cancer module, PGIC, PGIS, PRO-
CTCAE and EQ-5D-5L. All items/questionnaires will be scored according to published 


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guidelines or the developer’s guidelines, if published guidelines are not available. All PRO 
analyses will be based on the FAS, unless stated otherwise.  
3.3.1 
EORTC-QLQ-C30 
The EORTC-QLQ-C30 consists of 30 questions which can be combined to produce 5 
functional scales (physical, role, cognitive, emotional, social), 3 multi-item symptom scales 
(fatigue, pain, nausea/vomiting), 5 individual symptom items (dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea) and a global measure of health status/QoL. The EORTC-QLQ-
C30 will be scored according to the EORTC scoring manual (Fayers et al. 2001). An outcome 
variable consisting of a score of 0 to 100 will be derived for each of the symptom scales/items, 
the functional scales and the global health status/QoL scale of the EORTC-QLQ-C30 
according to the EORTC-QLQ-C30 Scoring Manual. Higher scores on the global health 
status/QoL and functioning scales indicate better health status/function but higher scores on 
symptom scales/items represent greater symptom severity. 
For each subscale, if ≤50% of the subscale items are missing, then the equation provided in 
the scoring manual can be applied excluding the missing items. If more than 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. 
HRQoL will be assessed using the EORTC-QLQ-C30 global health status/QoL scale which 
includes 2 items from the QLQ-C30: “How would you rate your overall health during the past 
week?” (Item 29) and “How would you rate your overall quality of life during the past week?” 
(Item 30). 
At each post-baseline assessment, the change from baseline in symptom and functional scale 
scores will be calculated.  
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorized as improved, stable, or worsened using the clinically meaningful cut-offs. 
Definition of clinically meaningful changes  
Changes in score compared with baseline will be evaluated. Changes in symptoms, 
functioning and global health status/QoL from baseline will be categorized as improved, 
stable or worsened as shown in Table 10. A clinically meaningful change is defined as a 
change of at least 10 points (Osoba et al. 1998). Specifically, a clinically meaningful 
improvement in a symptom scale/item score is defined as a decrease in the score from baseline 
of ≥10, whereas a clinically meaningful deterioration is defined as an increase in the score 
from baseline of ≥10. In contrast, a clinically meaningful improvement in a functional scale or 
global health status/QoL is defined as an increase in the score from baseline of ≥10, while a 


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clinically meaningful deterioration in a functional scale or global health status/QoL is defined 
as a decrease in the score from baseline of ≥10. At each post-baseline assessment, the change 
in symptoms, functioning, and global health status/QoL from baseline will be categorized as 
worsened, improved or stable as shown in Table 10.  
Table 10: Visit responses for EORTC QLQ-C30 
Score 
Change from baseline 
Visit response 
Symptom scales/items 
≥+10 
Worsened 
≤-10 
Improved 
Otherwise 
Stable 
 
 
 
Functional scales and global 
health status/QoL 
≥+10 
Improved 
≤-10 
Worsened 
Otherwise 
Stable 
QoL Quality of life 
 
3.3.2 
EORTC QLQ-CX24 
The QLQ-CX24 consists of 24 questions that can be combined to produce three multi-item 
scales (symptom experience, body image, and sexual/vaginal functioning) and six single-item 
scales (lymphedema, peripheral neuropathy, menopausal symptoms, sexual activity, sexual 
worry, and sexual enjoyment). The scales and single item measures are also scored from 0 to 
100. In sexual activity and sexual enjoyment, higher scores indicate better functioning, 
however, in the other scales and single-items, higher scores reflect more problematic 
functioning or status.  
At each post-baseline assessment, the change from baseline in symptom and functional scale 
scores will be calculated.  
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorized as improved, stable, or worsened using the clinically meaningful cut-offs. 
Definition of clinically meaningful changes  
Changes in score compared with baseline will be evaluated. Changes in multi-item scales and 
single item scales from baseline will be categorized as improved, stable or worsened as shown 
in Table 11. A minimum clinically meaningful change is defined as a change of 10 points. 
Specifically, a clinically meaningful improvement in a symptom scale/item score is defined as 
a decrease in the score from baseline of ≥10, whereas a clinically meaningful deterioration is 


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defined as an increase in the score from baseline of ≥10. In contrast, a clinically meaningful 
improvement in a functional item is defined as an increase in the score from baseline of ≥10, 
while a clinically meaningful deterioration in a functional scale or global health status is 
defined as a decrease in the score from baseline of ≥10.  
Table 11: Visit responses for EORTC QLQ-CX24 
Score 
Change from baseline 
Visit response 
Symptom scales/items 
≥+10 
Worsened 
≤-10 
Improved 
Otherwise 
Stable 
 
 
 
Functional items: Sexual 
activity/Sexual enjoyment 
≥+10 
Improved 
 
≤-10 
Worsened 
 
Otherwise 
Stable 
 
3.3.3 
Patient-reported outcomes version of the common terminology criteria 
for adverse events (PRO-CTCAE) 
The patient reported outcomes version of the common criteria for adverse events (PRO-
CTCAE), a PRO version of the CTCAE system developed by the NCI, is included to assess 
tolerability from the subject’s perspective. It was developed in recognition that collecting 
symptom data directly from subjects can improve the accuracy and efficiency of symptomatic 
AE data collection. Symptoms have been converted to subject terms (e.g., CTCAE term 
“myalgia” converted to “aching muscles”). Items capture the presence, frequency, severity 
and/or interference with usual activities, depending on the AE. Six items that are considered 
relevant for the trial were selected (CSP Appendix H). For each question, subjects select the 
value that best describes their experience over the past week. 
The PRO-CTCAE items are not currently scored. The data will be descriptively summarized.  
3.3.4 
Patient global impression of change (PGIC) and patient global 
impression of severity (PGIS) 
The response options of the PGIC are scored as follows: Much Better (+3), Moderately Better 
(+2), A Little Better (+1), No Change (0), A Little Worse (-1), Moderately Worse (-2) and 
Much Worse (-3). 
The response options of the PGIS are scored using a 6-point scale: 1 = None; 2 = Very Mild; 3 
= Mild; 4 = Moderate; 5 = Severe; 6 = Very Severe. 


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3.3.5 
Health state utility 
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility.  
The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal. The EQ-5D-5L questionnaire comprises six questions that cover five dimensions of 
health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). For each 
dimension, respondents select which statement best describes their health on that day from a 
possible five options of increasing levels of severity (no problems, slight problems, moderate 
problems, severe problems and unable to/extreme problems). A unique EQ-5D health state, 
termed the EQ-5D-5L profile, is reported as a five-digit code with a possible 3,125 health 
states. For example, state 11111 indicates no problems on any of the five dimensions. 
Respondents also assess their health today using the EQ-VAS, which ranges from 0 (worst 
imaginable health) to 100 (best imaginable health). 
The EQ-5D profile will be converted into a weighted health state utility value, termed the EQ-
5D index, by applying a country-specific equation to the EQ-5D-5L profile that represents the 
comparative value of health states. This equation is based on national valuation sets elicited 
from the general population and the base case will be the UK perspective. Where a valuation 
set has not been published, the EQ-5D-5L profile will be converted to the EQ-5D index using 
a crosswalk algorithm (van Hout et al. 2012). The EQ-VAS is reported separately. Further 
details regarding the evaluation of EQ-5D-5L will be presented in the payer analyses plan.  
The evaluable population will comprise a subset of the FAS who have a baseline EQ-5D-5L 
assessment. 
3.3.6 
Compliance 
Summary measures of overall compliance and compliance over time will be derived for 
EORTC-QLQ-C30, EORTC QLQ-CX24 and EQ-5D-5L respectively. These will be based 
upon: 
• 
Received questionnaire: A questionnaire that has been received and has a completion date 
and at least one individual item completed 
• 
Expected questionnaire: A questionnaire that is expected to be completed at a scheduled 
assessment time e.g., a questionnaire from a subject who has not withdrawn from the 
study at the scheduled assessment time but excluding subjects in countries with no 
available translation. For subjects that have progressed, the latest of progression and last 
dose of IP follow-up (6 months following progression and 6 months following last dose 


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of IP) will be used to assess whether the subject is still under PRO follow-up at the 
specified assessment time. Date of study discontinuation will be mapped to the nearest 
visit date to define the number of expected forms 
• 
Evaluable questionnaire: A questionnaire with a completion date and at least one subscale 
that is non-missing 
• 
Overall PRO compliance rate is defined as: Total number of evaluable questionnaires 
across all time points, divided by total number of questionnaires expected to be received 
across all time points multiplied by 100 
• 
Overall subject compliance rate is defined for each randomized treatment group as: Total 
number of subjects with an evaluable baseline and at least one evaluable follow-up 
questionnaire (as defined above), divided by the total number of subjects expected to have 
completed at least a baseline questionnaire multiplied by 100 
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of subjects with an evaluable questionnaire at the time point (as defined above), 
divided by number of subjects still expected to complete questionnaires. Similarly, the 
evaluability rate over time will be calculated separately for each visit, including baseline, as 
the number of evaluable questionnaires (per definition above), divided by the number of 
received questionnaires. 
3.4 
Health care resource use variables 
To investigate the impact of treatment and disease on health care resource, the following 
variables will be captured: 
• 
Planned and unplanned hospital attendances beyond trial protocol mandated visits 
(including physician visits, emergency room visits, day cases and admissions)  
• 
Primary sign or symptom the subject presents with 
• 
Length of hospital stay 
• 
Length of any time spent in an intensive care unit (ICU) 
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalization or 
start of study drug if the start of study drug is after start date of hospitalization (length of 
hospital stay = end date of hospitalization – start date of hospitalization + 1). Subjects with 


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missing discharge dates will be calculated as the difference between the last day with 
available data and the start date of hospitalization. The length of ICU stay will be calculated 
using the same method. 
3.5 
Safety variables 
Safety is a secondary outcome for this study. Safety and tolerability will be assessed in terms 
of adverse events (AEs) [including serious adverse events (SAEs)], deaths, physical 
examinations, laboratory findings, vital signs, electrocardiograms (ECGs) and exposure, 
which will be collected for all subjects. 
Data from all cycles of treatment will be combined in the presentation of safety. The SAF will 
be used for reporting of safety data. 
3.5.1 
General considerations for safety assessments 
3.5.1.1 
Definition of baseline 
Baseline will be defined as the last assessment of the variable under consideration prior to the 
intake of the first dose of study treatment (durvalumab, placebo, chemotherapy, radiotherapy). 
That is, the latest result prior to the start of study treatment. If two visits are equally eligible to 
assess subject status at baseline (e.g., screening and baseline assessments both on the same 
date prior to the first dose with no washout or other intervention in the screening period), the 
average will be used as the baseline value. For non-numeric laboratory tests where taking the 
average is not possible, the best value would be taken as baseline as this is most conservative. 
In the scenario where there are two assessment recorded on the day, one with time recorded 
and the other without time recorded, the one with the time recorded would be selected as 
baseline. Where safety data are summarized over time, time on study will be calculated in 
relation to date of first study treatment. 
3.5.1.2 
Time windows for safety and PRO data 
Time windows will be defined for all presentations of safety and PRO data that summarize 
values by visit according to the following conventions.  
• 
The time windows should be exhaustive so that data recorded at any time point 
(scheduled or unscheduled) has the potential to be summarized. Inclusion within the time 
window should be based on the actual data and not the intended date of the visit 
• 
The window for visits following baseline will be constructed in such a way that the upper 
limit of the interval falls halfway between the two visits (the lower limit of the first post 
baseline visit will be Day 2). If an even number of days exist between two consecutive 
visits, then the upper limit will be taken as the midpoint value minus 1 day. For 


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demonstration purposes, Table 12 shows the visit windows for vital signs to week 40. 
Note that assessments will continue until study end. 
Table 12: Analysis visits and visit windows 
Cycle 
 
Scheduled day 
Analysis window (day) 
1  
Day 1 
See Section 3.5.1.1 for 
baseline definition 
2  
Day 29 
2 to 43 
3  
Day 57 
44 to 71 
4  
Day 85 
72 to 99 
5  
Day 113 
100 to 127 
6  
Day 141 
128 to 155 
7  
Day 169 
156 to 183 
8  
Day197 
184 to 211 
9  
Day 225 
212 to 239 
10  
Day 253 
240 to 267 
11  
Day 281 
268 to 295 
 
• 
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment (as defined in Section 4.3.5.5) will be used (regardless of where it 
falls in an interval) 
• 
Listings will display all values contributing to a time point for a subject 
• 
For visit-based summaries, if there is more than one value per subject within a time 
window then the closest value to the scheduled visit date will be summarized. If the 
values are equidistant from the nominal visit date, then the earlier value will be used. Data 
listings will highlight the values used in the summary table, wherever feasible. Note: In 
summaries of extreme values, all post-baseline values collected are used including those 


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collected at unscheduled visits regardless of which value is closest to the scheduled visit 
date 
• 
For summaries at subject level, all values will be included when deriving a subject level 
statistic such as a maximum regardless of whether they appear in the corresponding visit-
based summary 
3.5.1.3 
Handling of missing data 
Missing safety data will generally not be imputed. 
Safety assessments of the form of “<x” (i.e., below the lower limit of quantification) or “>x” 
(i.e., above the upper limit of quantification) will be imputed as “x” in the calculation of 
summary statistics but will be displayed as “<x” or “>x” in the listings. 
For missing diagnostic dates, if day and/or month are missing use 01 and/or Jan. If year is 
missing, put the complete date to missing. 
Adverse events that have missing causality (after data querying) will be assumed to be related 
to study drug. 
For missing start dates for AEs and concomitant medications/procedures, the following will be 
applied: 
• 
Missing day: Impute the 1st of the month unless month is the same as month of the first 
dose of study drug then impute first dose date 
• 
Missing day and month: Impute 1st January unless year is the same as first dose date then 
impute first dose date 
• 
Completely missing date: Impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end date 
When imputing a start date, ensure that the new imputed date is sensible e.g., prior to the end 
date of the AE. 
For missing stop dates of AEs or concomitant medications/procedures, the following will be 
applied: 
• 
Missing day: Impute the last day of the month unless month is the same as month of last 
dose of study drug then impute last dose date 


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• 
Missing day and month: Impute 31st December unless year is the same as last dose date 
then impute last dose date 
For completely missing stop dates for a medication, the following will be applied: 
• 
Check whether the medication is still ongoing and when it started in relation to study drug 
before imputing a date. If the ongoing flag is missing, then assume that the medication is 
still being taken (i.e. do not impute a date). If the medication has stopped and its start date 
is prior to first dose date then impute the first dose date; if it started on or after first dose 
date then impute to the day after the last dose date (first dose date/last dose date of 
maintenance will take the priority).  
Flags will be retained in the database indicating where any programmatic imputation has been 
applied, and in such cases, any durations would not be calculated. 
If a subject is known to have died where only a partial death date is available, then the date of 
death will be imputed as the latest of the last date known to be alive + 1 from the database and 
the death date using the available information provided: 
• 
Missing day only: Using the 1st of the month 
• 
Missing day and month: Using the 1st January 
Subjects with a partial date of birth (i.e., for those countries where year of birth only is given) 
will have 1st of the month imputed if the day is missing, and 1st Jan imputed if the day and 
month is missing. 
For partial subsequent anti-cancer therapy dates, the following will be applied: 
• Missing day: If the month is the same as treatment end date then impute to the day 
after treatment, otherwise first day of the month 
• Missing day and month: If year is the same as treatment end date then impute to the 
day after treatment, otherwise 1st January of the same year as anti-cancer therapy date 
3.5.1.4 
Safety Follow-up 
Total Safety Follow-up = min (last dose date +90, date of withdrawal of consent, date of 
death, date of DCO) – first dose date +1 


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3.5.2 
Study treatments 
Study treatment in this study refers to chemotherapy and radiation (CCRT), durvalumab, and 
placebo. See Table 12 for further details on the IPs. Exposure will be defined for durvalumab 
or placebo and the SoC CCRTs outlined in Table 13.  
Table 13: Study treatments 
 
Durvalumab 
Placebo 
Chemoradiotherapy 
EBRT + 
brachytherapy 
Chemotherapyf 
Study 
treatment 
name: 
Durvalumab 
(MEDI4736)a 
Saline 
solution 
External beam 
radiotherapy and 
brachytherapy 
 
Cisplatin 
Carboplatin 
Dosage 
formulation: 
500-mg vial 
solution for 
infusion after 
dilution, 
50 mg/mL 
Sterile 
solution of 
0.9% (w/v) 
sodium 
chloride for 
injection 
 
As sourced locally 
As sourced 
locally 
As sourced 
locally 
Route of 
administration  
IV 
IV 
Whole pelvic or 
pelvic and para-
aortic radiation and 
brachytherapyb 
IV 
IV 
Dosing 
instructions: 
1500 mg IV 
q4w 
Dosing to 
match 
durvalumab 
As described in 
Appendix G of the 
CSP 
40 mg/m2 
q1w × 5 
weeksc,d  
 
AUC 2 q1w 
× 5 weeksd 
Provider 
AstraZeneca 
Sourced 
locally by site 
Sourced locally by 
sitee 
Sourced 
locally by 
sitee 
Sourced 
locally by 
sitee 
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 
b 
Pelvic and paraaortic radiotherapy is added based on extent of disease at baseline 
c 
Standard antiemetic regimens consist of a steroid and 5HT-antagonist, with or without a substance P 
antagonist such as aprepitant 
d 
An additional 6th week of platinum agent will be administered per investigator discretion 
e 
Under certain circumstances when local sourcing is not feasible, an SoC treatment may be supplied 
centrally through AstraZeneca 
f 
For subjects who were treated with carboplatin prior to CSP version 3 see the explanatory paragraph below 


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EBRT External beam radiotherapy; Gy Grey unit; IV Intravenous; n/a Not applicable; qxw Every x weeks; SoC 
Standard of care; w/v Weight/volume 
In versions of the protocol prior to version 3 carboplatin AUC2 was given for initial treatment 
or if cisplatin was intolerable. Subjects recruited to the study under this regimen may continue 
unchanged, as clinically indicated. Carboplatin is to be given AUC 2 q1w × 5 weeks, and an 
additional 6th week will be administered per investigator discretion. Antiemetics are 
recommended. Standard antiemetic regimens consist of a steroid and 5HT-antagonist, with or 
without a substance Pantagonist such as aprepitant. 
3.5.3 Exposure and dose interruptions 
Exposure variables comprise the measure of treatment durations, number of infusions/cycles 
received, counts of dose delays and dose interruptions, and dose intakes.  
3.5.3.1 
Treatment exposure for durvalumab or placebo  
Since durvalumab or placebo is dosed every 4 weeks for 24 doses, calculation of exposure 
(otherwise known as treatment duration) will be defined as follows: 
Total (or intended) treatment duration of durvalumab/placebo: 
• 
Total (or intended) treatment duration (days) = min (last dose date where dose > 0mg + 
27 days, date of death, date of DCO) – first dose date +1  
Actual treatment duration of durvalumab/placebo: 
Actual treatment duration (days) = intended treatment duration (days) – total duration of dose 
delays (days), where intended treatment duration will be calculated as above. 
Dose interruptions - infusion 
For durvalumab/placebo, a dose interruption is an infusion interruption that occurs during the 
infusion. The total dose received is >0. The drug can be restarted after the interruption and so 
it is possible for an infusion interruption to occur and the whole dose to still be administered. 
If the same infusion was interrupted multiple times, then this would just be captured as one 
infusion interruption. 
Dose delays 
A treatment cycle is started when >0 dose of durvalumab/placebo is administered. As such, a 
dose delay for durvalumab/placebo occurs when the start of a cycle is started at a later date 
than planned. If durvalumab/placebo is delayed, leading to other drugs that were scheduled to 
be administered on the same day being administered at a later date (but still the same day that 
durvalumab/placebo is eventually administered), then in this instance only 


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durvalumab/placebo is classed as being delayed. This is because the other drugs would have 
been administered on the correct day relative to durvalumab/placebo. 
Dose reductions 
Doses that are intentionally permanently reduced are not permitted per CSP for 
durvalumab/placebo. 
Calculation of duration of dose delays (for actual treatment duration) 
• 
Since subjects will receive durvalumab/placebo 1500 mg via IV infusion q4w (for 24 
doses), the duration of dose delays will be calculated as follows:  
o For all dosing dates: Total duration of dose delays (days) = Sum of (Date of the 
dose – Date of previous dose – 28 days) 
Thus, if no delays were encountered, the duration would sum up to 0, since infusions were 
done every 4 weeks (28 days). 
Number of infusions 
Number of infusions of durvalumab/placebo: 
Exposure will also be summarized by the number of infusions received. Cycles of treatment 
with durvalumab/placebo are of 28 days duration with a single dose on day 1 of each cycle. If 
a cycle is prolonged due to toxicity, this should be counted as one cycle. A cycle will be 
counted if treatment is started even if the full dose is not delivered. 
Received planned starting dose 
A subject is considered to have received their planned starting dose of durvalumab or placebo 
if the infusion volume before administration is non-zero and the infusion volume after 
administration = 0. 
3.5.3.2 
Treatment exposure for SoCs and Radiotherapy 
Carboplatin and cisplatin 
SoC platinum-based chemotherapy agents, carboplatin and cisplatin, are dosed weekly for 5 
weeks, based on Investigator discretion, in addition to radiation therapy. A sixth cycle of 
chemotherapy is allowed per protocol at investigator discretion. Exposure to carboplatin and 
cisplatin (otherwise known as treatment duration) will be defined as follows: 
Total (or intended) exposure of carboplatin and cisplatin will be summarized separately for 
subjects who receive 5 or 6 cycles of chemotherapy. 


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Total (or intended) treatment duration (days) of carboplatin and cisplatin: 
• 
Minimum of (infusion date of the last cycle + 6 days, date of death, date of DCO) – first 
infusion date of first cycle + 1 
Number of doses of carboplatin/cisplatin: 
• 
Exposure will be measured by the number of doses received. A cycle of 
carboplatin/cisplatin corresponds to a period of one week with a single dose administered. 
If a cycle is prolonged due to toxicity, this should still be counted as one cycle. A cycle 
will be counted if treatment is started even if the full dose is not delivered 
The number of subjects who are initially treated with carboplatin and switch to cisplatin and 
who are initially treated with cisplatin and switch to carboplatin during the course of the trial 
will be summarized.  
Received planned starting dose 
A subject is considered to have received their planned starting dose of carboplatin or cisplatin 
if the infusion volume before administration is non-zero and the infusion volume after 
administration = 0. 
Dose reductions 
Dose reductions, doses that are intentionally permanently reduced, are permitted as per CSP. 
This term is not used for interruptions or invalidly administered doses. A dose reduction is 
counted once for each time the dose is reduced. 
Dose delays 
A dose delay for carboplatin or cisplatin occurs when the first administration of that drug (> 0 
dose) in a cycle is administered at a later date relative to the durvalumab/placebo dose. Note 
that if the drug is completely skipped then this is not classed as a delay (it is classed as a dose 
interruption). 
 
Dose interruptions - infusion 
An infusion interruption of carboplatin or cisplatin is defined the same as for 
durvalumab/placebo. 
 
Dose interruptions - skipped doses 
Since carboplatin and cisplatin are administered multiple times per cycle, a skipped dose is a 
temporary interruption during a cycle. That is, during the cycle a dose is completely skipped 
or is taken at a later date than scheduled. Note that this is only applicable to drugs with 
multiple doses in a cycle (if the first dose is later than planned it would be a delay). 
 


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Radiation 
Total Dose of Radiotherapy in Grays administered for EBRT will be calculated Fraction Dose 
multiplied by Number of Fraction doses. This will be for the pelvis only (i.e., of the 45 grays). 
The Total Biological Equivalent Dose or EQD2 dose to the target area administered for 
brachytherapy will be determined from the QS module of the CRF according to whether the 
subject is receiving Point A directed brachytherapy or volumetric brachytherapy (QSTEST = 
Point A EQD2 for Point A directed brachytherapy or QSTEST = CTV_HR 90 EQD2 for 
volumetric brachytherapy).  
 
Total (or intended) exposure  
• 
Minimum of (radiotherapy stop date, date of death, date of DCO) – radiotherapy 
start date + 1 
Actual exposure: 
• 
Actual exposure = intended exposure – total duration of dose delays, where intended 
exposure will be calculated as above, and a dose interruption is defined as any length of 
time where the subject has not taken any of the planned dose (taking into account the 
scheduled off treatment period) 
 
Subjects who permanently discontinue during a dose interruption 
If a subject permanently discontinues study treatment in-between cycles or during a dose 
delay, then the date of last administration of study medication recorded on DOSDISC will be 
used in the programming. 
3.5.3.3 Dose intensity  
Dose intensity will be derived for study treatment durvalumab/placebo. Relative dose intensity 
(RDI) is the percentage of the actual dose intensity delivered relative to the intended dose 
intensity through to last day of dosing. RDI will be defined as follows: 
• 
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual last 
day of dosing for that drug and D is the intended cumulative dose up to the actual last day 
of dosing. D is the total dose that would be delivered, if there were no modification to 
dose or schedule.  


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When deriving actual dose administered the volume before and after infusion will also be 
considered.  
For durvalumab/placebo, where the last dose is on the cycle 24 visit and if there are no scans 
post cycle 24, the censoring of progression should occur at cycle 24 for the purposes of RDI. 
An example of dose intensity for durvalumab can be found in Table 14. In this example, RDI 
of durvalumab: d = 5200mg, D= 7500mg. RDI= 100%*(5200/7500) = 69.3%. 
Table 14: Dose intensity scenarios for durvalumab administered 1500mg per cycle 
Cycle 
Date 
Duration 
(days) 
Delay 
(days) 
No. 
cycles, 
based on 
duration 
+ delays 
(A) 
No. 
actual 
cycles 
received 
(B) 
Planned 
total dose D 
= 
Max(int(A), 
B)*1500mg 
Actual 
dose 
intake d 
1 
01-Jan-19 
28 
+ 14 
 
 
 
1500 
2 
12-Feb-19 
28 
+ 14 
 
 
 
1000 
3 
26-Mar-19 
28 
+ 0 
 
 
 
1500 
4 
23-Apr-19 
28 
+ 0 
 
 
 
1200 
Total 
 
4*28 + 2*14 = 
140 
140/28 = 
5 
4 
5*1500 = 
7500mg 
5200mg 
 
3.5.4 
Adverse events (AEs) 
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a subject or clinical study subject 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 (e.g., 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. 
AEs and SAEs will be collected throughout this study. For this study, on treatment will be 
defined between date of first dose of study treatment (durvalumab, matching placebo, 
chemotherapy, radiotherapy) and 90 days following the last dose of study treatment. If an 
event starts outside of this period and it is considered possible that it is due to late onset 
toxicity to study treatment, then it should be reported as an AE or SAE. 


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On treatment AEs (or treatment emergent AEs [TEAEs]) will be defined as any AEs that 
started after dosing or that started prior to dosing and worsened (by investigator report of a 
change in intensity) following exposure to treatment. If an AE is not worse than the baseline 
(pre-dose) severity, then it will not be classified at a TEAE. 
The medical dictionary for regulatory activities (MedDRA) [using the latest or current 
MedDRA version] will be used to code AEs. AEs will be graded according to the National 
Cancer Institute (NCI) common terminology criteria for adverse event (CTCAE) version 5.0. 
The CTCAE grade will be assigned by the investigator as follows: 
• 
Grade 1: Mild AE 
• 
Grade 2: Moderate AE 
• 
Grade 3: Severe AE 
• 
Grade 4: Life-threatening or disabling AE 
• 
Grade 5: Death related to AE 
Missing start and stop dates for AEs will be handled using the rules described in Section 3.5.1.  
3.5.5 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and ‘Discontinuation of Investigational Product 
due to Adverse Events’ (DAEs). Based on the expert’s judgement, significant adverse events 
of particular clinical importance may, after consultation with the Global Patient Safety 
Physician, be considered other significant adverse events (OAEs) and reported as such in the 
CSR. A similar review of laboratory/vital signs/ECG data will be performed for identification 
of OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment. 
3.5.6 
AEs of special interest (AESI) and AEs of possible interest (AEPI) 
Some clinical concepts (including some selected individual preferred terms and higher level 
terms) have been considered “AEs of special interest” (AESI) and “AEs of possible interest” 
(AEPI) to the durvalumab program. All AESIs are being closely monitored in clinical studies 
using durvalumab alone, and durvalumab in combination with other anti-cancer agents. 


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AESIs are defined as AEs with a likely inflammatory or immune-mediated pathophysiological 
basis resulting from the mechanism of action of durvalumab and requiring more frequent 
monitoring and/or interventions such as corticosteroids, immunosuppressants, and/or 
endocrine therapy. Endocrine therapies include standard endocrine supplementation, as well 
as treatment of symptoms resulting from endocrine disorders (for example, therapies for 
hyperthyroidism include beta blockers [e.g., propranolol], calcium channel blockers [e.g., 
verapamil, diltiazem], methimazole, propylthiouracil, and sodium perchlorate). In addition, 
infusion-related reactions and hypersensitivity/anaphylactic reactions are also considered 
AESIs. 
AEPIs are defined as AEs that could have a potential inflammatory or immune-mediated 
pathophysiological basis resulting from the mechanism of action of durvalumab but are more 
likely to have occurred due to other pathophysiological mechanisms, thus, the likelihood of 
the event being inflammatory or immune-mediated in nature is not high and/or is most often 
or usually explained by the other causes. These AEs not routinely arising from an 
inflammatory or immune-mediated mechanism of action – typically quite general clinical 
terms that usually present from a multitude of other causes –are classified as AEPIs. 
These AESIs and AEPIs have been identified as Pneumonitis, Hepatic events, 
Diarrhea/Colitis, Intestinal perforations, Adrenal Insufficiency, Type 1 diabetes mellitus, 
Hyperthyroid events, Hypophysitis, Hypothyroid events, Thyroiditis, Renal events, 
Dermatitis/Rash, Pancreatic events, Myocarditis, Myasthenia gravis, Guillain-Barre 
syndrome, Myositis, Infusion/hypersensitivity reactions and Other rare/miscellaneous. Other 
categories may be added, or existing terms may be merged as necessary. An AstraZeneca 
medically qualified expert after consultation with the Global Patient Safety Physician has 
reviewed the AEs of interest and identified which MedDRA preferred terms contribute to each 
AESI/AEPI. A further review will take place prior to Database lock (DBL) to ensure any new 
terms not already included in the older MedDRA version are captured within the categories 
for the new higher MedDRA version. The list will be provided by AZ prior to database lock. 
Immune-mediated adverse events 
Durvalumab belongs to a class of drugs called immune checkpoint inhibitors. Because the 
mechanism of action of this class of drugs is to block the inhibitory signals that prevent T-cell 
activation, this drug may potentially cause immune-mediated adverse events (imAEs). imAEs 
will be identified from both AESIs and AEPIs based on programmatic rules that consider 
interventions involving systemic steroid therapy, immunosuppressant use, and/or endocrine 
therapy (which, in the case of AEPIs, occurs after first considering an Investigator’s causality 
assessment and/or an Investigator’s designation of an event as immune-mediated). Endocrine 
therapies include standard endocrine supplementation, as well as treatment of symptoms 


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resulting from endocrine disorders (for example, therapies for hyperthyroidism include beta 
blockers [e.g., propranolol], calcium channel blockers [e.g., verapamil, diltiazem], 
methimazole, propylthiouracil, and sodium perchlorate). Infusion-related reactions and 
hypersensitivity/anaphylactic reactions are exceptions because they are common to 
monoclonal antibody drugs in general and occur due to a mechanism of action different than 
that for imAEs, thus, these events are not considered imAEs as defined in the Durvalumab 
imAE charter. Identification of imAEs will be performed by the Sponsor and further details 
are provided in the Sponsor Durvalumab imAE charter.  
In addition, the Sponsor may perform medical review of those AESIs and classify them as 
imAEs or not imAEs via an independent manual adjudication process.  
3.5.7 
Laboratory measurements 
Laboratory data will be collected throughout the study as described in Tables 1 and 2 of the 
CSP. Blood and urine samples for determination of clinical chemistry, hematology, and 
urinalysis will be collected as described in Section 8.2.4 of the CSP. 
For the derivation of baseline and post baseline visit values, the rules described in Section 
3.5.1 of this document considering definition of baseline, visit windows and how to handle 
multiple records will be used. 
Change from baseline in hematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. CTCAE grades will be defined at each visit according to the 
CTCAE grade criteria using local or project ranges as required, after conversion of lab result 
to corresponding AZ preferred units. The following parameters have CTCAE grades defined 
for both high and low values: Potassium, sodium, magnesium, and corrected calcium so high 
and low CTCAE grades will be calculated. Glucose has CTCAE grades defined only for low 
values and will be calculated as such. 
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)] x 0.02) 
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or limits of range) and high (above range). 
The maximum or minimum on treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value at any time. 


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Project reference ranges will be used throughout for reporting purposes. If the project range is 
unavailable for a test, local ranges will be used. The denominator used in laboratory 
summaries of CTCAE grades will only include evaluable subjects (i.e., those who had 
sufficient data to have the possibility of an abnormality). For example,  
• 
If a CTCAE criterion involves a change from baseline, evaluable subjects would have 
both a pre-dose and at least 1 post-dose value recorded 
• 
If a CTCAE criterion does not consider changes from baseline, to be evaluable the subject 
needs only to have 1 post dose-value recorded 
3.5.8 
Vital signs 
The following vital signs will be measured as described in Section 8.2.2 of the CSP: Systolic 
and diastolic blood pressure (BP), pulse rate, temperature, and respiratory rate. Body weight 
will also be recorded along with vital signs. 
Vital signs will be collected at multiple times at same visit for the first infusion (pre-dose, 
during infusion, and at the end of infusion). At subsequent visits they may be taken at each of 
these timepoints as per institution and as clinically indicated. 
Change from baseline in vital signs variables will be calculated for each post-baseline visit on 
treatment, for each timepoint as data are available (pre-dose, during infusion, end of infusion). 
Timepoints are reported by visit for each treatment arm, provided at least one treatment arm 
has >= 20 subjects with data at a given visit. For derivation of post-baseline visit values 
considering visit window and how to handle multiple records, derivation rules as described in 
Section 3.5 will be used.  
3.5.9 
Physical examinations 
Physical examinations will be performed as described in Section 8.2.1 of the CSP. 
Abnormalities recorded prior to the first dose of study treatment will be recorded as part of the 
subject’s baseline signs and symptoms. Abnormalities first recorded after first dose of study 
treatment will be recorded as AEs unless unequivocally related to the disease under study. 
3.5.10 
Electrocardiograms (ECGs) 
Resting 12-lead ECGs will be recoded at screening and as clinically indicated throughout the 
study as described in Section 8.2.3 of the CSP. 
The following ECG variables will be collected: ECG heart rate, PR duration, QRS duration, 
QT duration, RR duration and overall ECG evaluation. 


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The overall evaluation of an ECG will either be “normal” or “abnormal” with abnormalities 
categorized as either “clinically significant” or “not clinically significant”. In case of clinically 
significant ECG abnormalities, 2 additional ECGs will be obtained over a brief period (e.g., 
30 minutes) to confirm the finding. 
Where QTcF (Friderica) is not reported, it will be calculated programmatically using the ECG 
values (RR and QT) as follows (where RR are in seconds): 
𝑄𝑇𝑐𝐹= 𝑄𝑇
√𝑅𝑅
3
 
Alternatively, RR (or QT) can be programmatically derived if not reported but QTcF and QT 
(or RR, respectively) is reported. RR can be calculated as follows: 
𝑅𝑅= ( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
 
3.5.11 
World Health Organisation (WHO)/Eastern Cooperative Oncology 
Group (ECOG) performance status (PS) 
WHO/ECOG PS will be assessed as described in Section 8.2.5 of the CSP as 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 (e.g., light housework or office work) 
2. Ambulatory and capable of self-care, but unable to carry out any activities; up and about 
more than 50% of waking hours 
3. Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4. Completely disabled; unable to carry out any self-care and totally confined to bed or chair 
5. Dead 
Any significant changes from baseline or screening will be reported as AE. 
3.6 
Pharmacokinetic (PK) variables 
PK concentration data will be collected as described in Section 8.5 of the CSP.  


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The actual sampling times will be used in the PK calculations. PK parameters, such as peak 
and trough concentration will be obtained from raw PK data measurements as data allow. 
3.7 
Immunogenicity variables 
Serum samples for ADA assessments will be conducted utilizing a tiered approach (screen, 
confirm, titer), and ADA data will be collected at scheduled visits shown in the CSP (Section 
8.5.1.1). ADA result from each sample will be reported as either positive or negative. If the 
sample is positive, the ADA titer will be reported as well. In addition, the presence of 
neutralizing antibody (nAb) may be tested for all ADA-positive samples using a ligand-
binding assay. The nAb results will be reported as positive or negative.  
The number of subjects in the ADA-evaluable set who fulfil the following the criteria will be 
determined. The percentage of ADA-positive subjects in each of the category will be 
calculated, using the number of subjects in the ADA-evaluable set (defined in Section 2.1.2) 
of the treatment group as the denominator. A subject is defined as being ADA-positive if a 
positive ADA result is available at any time, including baseline and all post-baseline 
measurements; otherwise ADA negative.  
• 
ADA-positive at any visit; the percentage of ADA-positive subjects in the ADA-
evaluable set is known as ADA prevalence 
• 
Treatment-emergent ADA, which is defined as either treatment-induced or treatment-
boosted ADA; the percentage of subjects fulfilling this criterion in the ADA-evaluable set 
is known as ADA incidence  
• 
ADA-positive post-baseline and positive at baseline 
• 
ADA-positive post-baseline and not detected at baseline (treatment-induced ADA)  
• 
ADA not detected post-baseline and positive at baseline 
• 
Treatment-boosted ADA, defined as a baseline positive ADA titer that was boosted to a 
4-fold or higher level (greater than the analytical variance of the assay) following drug 
administration  
• 
Persistently positive ADA, defined as having at least 2 post-baseline ADA-positive 
measurements with at least 16 weeks (112days) between the first and last positive 
measurement. or an ADA-positive result at the last available assessment. The category 
may include subjects meeting these criteria who are ADA-positive at baseline 


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• 
Transiently positive ADA, defined as having at least one post-baseline ADA-positive 
measurement and not fulfilling the conditions for persistently positive. The category may 
include subjects meeting these criteria who are ADA-positive at baseline 
• 
nAb positive at any visit 
3.8 
Biomarkers 
Blood samples for exploratory biomarker analyses will be obtained according to the schedules 
presented in Section 1.1 of the CSP. 
Results of the exploratory biomarker data will be reported separately. 
3.9 
Prior and concomitant medications and therapies 
All therapies (drug and non-drug), including herbal preparations, whether prescribed or over-
the-counter, that are used within the four weeks prior to initiation of study treatment up until 
90 days following last dose of study treatment will be recorded on the eCRF. Details include 
generic and/or brand names of the medications, World Health Organization Drug Dictionary 
(WHO-DD) encoding (using the latest or current WHO-DD version), reason for use, route, 
dose, dosing frequency, and start and stop times. 
Prior therapies are defined as those taken prior to study treatment with a stop date prior to the 
first dose of study medication (durvalumab, matching placebo, chemotherapy or 
radiotherapy). 
Concomitant therapies are defined as those with at least one dose/treatment taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of study drug. 
Missing start and stop dates for medications will be handled using the rules in Section 3.5.1. 
Missing coding terms should be listed and summarized as "Not coded". 
4 
ANALYSIS METHODS 
There will be 1 treatment comparison of interest: 
• 
Durvalumab 1500 mg plus SoC CCRT vs placebo plus SoC CCRT 
 
The primary endpoint is PFS using RECIST 1.1 and histopathologic confirmation of tumor 
progression. The study has been sized to characterize the PFS and OS benefit of durvalumab 
1500 mg plus SoC CCRT relative to placebo plus SoC CCRT.  


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Results of all statistical analysis will be presented using a 95% confidence interval (CI) and 2-
sided p-value, unless otherwise stated.  
The formal statistical analysis will be performed to test the main hypotheses: 
• 
H0: No difference between durvalumab plus SoC CCRT and placebo plus SoC CCRT 
• 
H1: Difference between durvalumab plus SoC CCRT and placebo plus SoC CCRT 
There will be up to 2 data cut-offs applied for this study: 
1. The DCO for the PFS analysis and first OS interim (DCO 1):  The DCO for the PFS 
analysis will be when approximately 227 (32% maturity) PFS events have occurred.  The 
OS interim will occur at the time of the PFS analysis, if PFS is statistically significant. It 
is anticipated that approximately 86% of the OS events will be available for this OS IA 
(approximately 195 of 227 OS events). 
2. If the criteria for statistical significance is met for PFS but not OS at the time of 
the analysis for PFS, follow-up will continue until the earlier of 227 OS events or 71 
months following randomization of the first subject, at which point OS will be retested. 
4.1 
General principles 
Efficacy and PRO data will be summarized and analyzed on the FAS. Safety and treatment 
exposure data will be summarized based upon the SAF. Study population and demography 
data will be summarized based upon the FAS. PK data will be analyzed using the PK analysis 
set. 
Physical exam data will include pap smear data where it is available. 
A month is operationally defined to be 30.4375 days. Six months is operationally defined to 
be 183 days. 
The below mentioned general principles will be followed throughout the study: 
• 
All analyses and reporting will be by treatment arm 
• 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables 
will be summarized by the number of observations, mean, standard deviation, median, 
upper and lower quartiles minimum, and maximum. For log-transformed data it is more 
appropriate to present geometric mean, coefficient of variation (CV), median, minimum 


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and maximum. Categorical variables will be summarized by frequency counts and 
percentages for each category  
• 
Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding treatment group. Overall totals will be calculated for baseline summaries 
only 
• 
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data 
• 
For categorical data, percentages will be rounded to 1 decimal place 
• 
The primary source for the stratification factors will be those captured in the IWRS 
during randomization. However, source data will be used to check concordance against 
data entered into IWRS. 
• 
The covariates in the statistical modelling will be based on the values entered into the 
IWRS at randomization, even if it is subsequently discovered that these values were 
incorrect 
• 
SAS® version 9.1 (or higher) will be used for all analyses 
In general, for efficacy the last observed measurement prior to randomization will be 
considered the baseline measurement. However, if an evaluable assessment is only available 
after randomization but before the first dose of randomized treatment then this assessment will 
be used as baseline. For safety endpoints the last observation before the first dose of study 
treatment will be considered the baseline measurement unless otherwise specified. For 
assessments on the day of first dose where time is not captured, a nominal pre-dose indicator, 
if available, will serve as sufficient evidence that the assessment occurred prior to first dose. 
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose. 
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as (post-
baseline value - baseline value) / baseline value x 100.  


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4.2 
Multiplicity  
The multiple testing procedure (Figure 2) will define which significance levels should be 
applied to the interpretation of the raw p-values.  
In order to strongly control the Type I error at 5% (2-sided), a multiple testing procedure 
(MTP) will be applied to the primary endpoint of PFS and the key secondary endpoint of OS. 
The overall 5% type I error rate will first be allocated to test the primary endpoint of PFS for 
durvalumab plus SoC CCRT versus placebo plus SoC CCRT. If the primary endpoint of PFS 
is significant, 5% alpha will be recycled to the lower level of the hierarchy, where the 5% 
alpha will be used for the test of OS for durvalumab plus SoC CCRT versus placebo plus SoC 
CCRT.  
Hypotheses will be tested using a multiple testing procedure with an alpha-exhaustive 
recycling strategy (Burman et al. 2009). With this approach, hypotheses will be tested in a 
pre-defined order with the hypothesis for PFS tested before the hypothesis for OS. According 
to alpha (test mass) splitting and alpha recycling, the test mass that becomes available after 
each rejected hypothesis is recycled to secondary hypotheses not yet rejected.  
 
Figure 2: Multiple testing procedures for controlling the type I error rate 
 
 
The primary endpoint of PFS will be tested once. The key secondary endpoint of OS will be 
tested up to 2 timepoints: 1 interim analysis and 1 final analysis. The tests including the 
interim and final analysis that are for the comparison of durvalumab plus SoC CCRT versus 
placebo plus SoC CCRT for the analyses of OS will be considered as one test family. As long 
as 1 test in the family can be rejected, the family is rejected. Thus, the assigned total alpha to 
the family will be recycled to the next MTP level. 


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This testing procedure stops when the entire mass is allocated to non-rejected hypotheses. 
Implementation of this pre-defined ordered testing procedure, including recycling, will 
strongly control type I error at 5% (2-sided), among the primary hypothesis of PFS and key 
secondary hypothesis of OS. 
For the OS endpoint, there is 1 IA planned, and the alpha level will be controlled at the 
interim and primary analysis timepoints by using the Lan-DeMets (Lan and DeMets 1983) 
spending function that approximates an O’Brien Fleming approach, with the boundaries for 
the treatment comparison derived based upon the actual number of OS events observed at the 
time of analysis. It is anticipated that approximately 86% of the OS events will be available 
for this OS IA (approximately 195 of 227 OS events). If exactly 86% of the target events are 
available at the time of the interim analysis, with overall 2-sided alpha level of 5.0%, the 2-
sided alpha to be applied at the interim analysis and final analysis would be 3.1% and 4.1%, 
respectively. 
 
4.3 
Analysis methods 
4.3.1 
Efficacy 
Table 15 details which endpoints are to be subjected to formal statistical analysis, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as primary 
for that endpoint. 
 
Prior to unblinding, the number of subjects across both treatment groups in each level of each 
strata will be reviewed, and the planned stratification factors may be removed or have levels 
combined if too few subjects are represented in any cell. 
 


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Table 15: Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses 
Endpoints analyzed 
Notes 
Progression-free survival 
Stratified log-rank analysis for: 
Primary analysis using Investigator RECIST 1.1 assessments 
or histopathologic confirmation of local tumor progression 
 
Sensitivity analyses using BICR assessments (RECIST 1.1) 
or histopathologic confirmation of local tumor progression 
 
Sensitivity analysis to assess possible evaluation-time bias 
using Investigator RECIST 1.1 assessments or 
histopathologic confirmation of local tumor progression 
 
Sensitivity to assess attrition bias using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of 
local tumor progression 
 
Sensitivity analysis to assess bias introduced by subjects with 
suspected progression on physical exam and no confirmatory 
biopsy 
 
Sensitivity analysis to assess impact of non-proportional 
hazards using the max-combo test 
 
Sensitivity analysis to assess impact of COVID-19 deaths 
(see Section 4.4.1 for further details) 
 
Sensitivity analysis to assess bias introduced by mis-
stratification  
 
PFS (3 year) 
Kaplan Meier estimate of PFS at 3 years 
 
 


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Endpoints analyzed 
Notes 
PFS in PD-L1 high subjects 
Stratified log-rank analysis for: 
PFS in PD-L1 high subjects 
 
 
Overall survival 
Stratified log-rank analysis for: 
Overall survival 
Sensitivity analysis to assess impact of COVID-19 deaths 
(see Section 4.4.2 for further details) 
 
Overall survival in PD-L1 
high subjects 
Stratified log-rank analysis for: 
Overall survival in PD-L1 high subjects 
  
 
Objective response rate 
  
Secondary analysis for the ITT population  
Logistic regression for: 
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of 
local tumor progression 
 
Complete response rate 
Logistic regression for: 
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of 
local tumor progression  
 
 
Duration of response in 
subjects with a complete 
response 
Summary statistics and KM plot by treatment arm for: 
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of 
local tumor progression in subjects who have achieved a best 
objective response of complete response 
 
 


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Endpoints analyzed 
Notes 
Incidence of local 
progression, distant disease 
progression, and secondary 
malignancy 
Summary statistics and cumulative incidence plot by 
treatment arm for: 
Secondary analysis for the ITT population 
 
 
Change from baseline 
(EORTC QLQ-C30 and 
EORTC QLQ-CX24)  
Average change from baseline using a Mixed Model 
Repeated Measurements (MMRM) analysis 
EQ-5D-5L (health state 
utility values and Visual 
Analog Scale) 
Summary statistics for health state utilities and visual 
analogue scale, including change from baseline. 
Healthcare resource use 
Descriptive statistics (as appropriate, including means, 
median, ranges or frequencies and percentages) 
 
Prior to unblinding, the number of subjects across both treatment groups in each level of each 
strata will be reviewed, and the planned stratification factors may be removed or have levels 
combined if too few subjects are represented in any cell. 
 
4.3.2 
Primary efficacy endpoint  
Progression-free Survival (PFS) 
Analysis of the primary endpoint, PFS, will occur when 227 PFS events have occurred (32% 
maturity). PFS based on the investigator RECIST 1.1 and histopathologic confirmation of 
progression will be analyzed using a stratified log-rank test adjusting for disease stage status 
(FIGO (2009) Stage <III and node positive, FIGO (2009) Stage ≥III and node negative, or 
FIGO (2009) Stage ≥III and node positive), and region ([United States, Canada, European 
Union, South Korea, and Japan] versus rest of the world) for generation of the p-value and 
using a method that corresponds to the Breslow approach for handling ties (Breslow, 1974). 
The HR and its CI will be estimated from a stratified Cox proportional hazards model (Cox, 
1972) with ties = Efron and the stratification variables included in the strata statement) and the 
CI calculated using the profile likelihood approach.  


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The effect of treatment will be estimated by the hazard ratio (HR) together with its 
corresponding 95% CI and p-value for the FAS (a HR < 1 will favor durvalumab + SoC 
CCRT). 
KM plots of PFS will be presented by treatment arm and by treatment arm and PD-L1 tumor 
status. Summaries of the number and percentage of subjects experiencing a PFS event and 
type of event (RECIST 1.1, histopathologic confirmation of progression, or death) will be 
provided along with the median PFS and 95% CI for each treatment arm. 
Assumptions of proportionality 
The assumption of proportionality will be assessed. Proportional hazards will be tested firstly 
by examining plots of complementary log-log (event times) versus log (time) and, if these 
raise concerns, by fitting a time dependent covariate (adding a treatment-by-time or treatment-
by-ln(time) interaction term) to assess the extent to which this represents random variation. If 
a lack of proportionality is evident, the variation in treatment effect can be described by 
presenting piecewise HR calculated over distinct time-periods for example 0-6m, 6-12m etc. 
In such circumstances, the HR from the primary analysis can still be meaningfully interpreted 
as an average HR over time unless there is extensive crossing of the survival curves. If lack of 
proportionality is found this may be a result of a treatment-by-covariate interaction, which 
will be investigated. In addition, the KM curve along with landmark analyses (e.g., 1-year PFS 
rate) will also help in understanding the treatment benefit.  
PFS Sensitivity Analyses 
The following sensitivity analyses will be performed:  
1. Evaluation-time bias 
A sensitivity analysis will be performed to assess possible evaluation-time bias that may be 
introduced if scans and physical exams are not performed at the protocol-scheduled time 
points. The midpoint between the time of progression and the previous evaluable assessment 
(using the final date of the assessment) will be analyzed using a stratified log-rank test, as 
described for the primary analysis of PFS. Note that midpoint values resulting in non-integer 
values should be rounded down. For subjects whose death was treated as a PFS event, the date 
of death will be used to derive the PFS time used in the analysis. This approach has been 
shown to be robust to even highly asymmetric assessment schedules (Sun and Chen 2010). To 
support this analysis, the mean of subject-level average inter-assessment times will be 
tabulated for each treatment. This approach will use the site investigator tumor assessments as 
well as physical examinations, and confirmatory biopsy results.  
2. Attrition bias 
 


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Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of subjects who progressed or died in the absence of 
progression immediately following two, or more, non-evaluable tumor assessments will be 
included. In addition, and within the same sensitivity analysis, subjects who take subsequent 
therapy (note that for this analysis radiotherapy is not considered a subsequent anti-cancer 
therapy) prior to their last evaluable assessment or progression or death will be censored at 
their last evaluable assessment prior to taking the subsequent therapy. This analysis will be 
supported by a Kaplan-Meier (KM) plot of the time to censoring using the PFS data from the 
primary analysis and where the censoring indicator of the PFS analysis is reversed. 
3. Ascertainment bias 
Ascertainment bias will be assessed by analyzing the BICR data. The stratified log-rank test 
will be repeated on PFS using the BICR data based upon RECIST as well as the physical 
exam and confirmatory biopsy data. The HR and CI will be presented. 
For RECIST progressions, if there is an important discrepancy between the primary analysis 
using the site investigator data and this sensitivity analysis using BICR data then the 
proportion of subjects with site but no central confirmation of progression will be 
summarized; such subjects have the potential to induce bias in the central review due to 
informative censoring. An approach of imputing an event at the next visit in the central review 
analysis may help inform the most likely HR value (Fleischer et al. 2011), but only if an 
important discrepancy exists. 
Disagreements between investigator and central reviews of RECIST progression will be 
presented for each treatment group. 
4. Randomization bias 
Cox proportional hazards modeling will be employed to assess the effect of the pre-specified 
covariates on the HR estimate. A model will be constructed, containing treatment and the 
stratification factor(s) alone, to ensure that any output from the Cox modeling is likely to be 
consistent with the results of the primary analysis using the stratified log-rank test. The result 
from the initial model and the model containing additional covariates (in the MODEL 
statement) will be presented.  
Additional covariates for this model will be age at randomization, PD-L1 expression, race 
(Asian vs non-Asian), type of CCRT (IMRT vs other), first dose of chemotherapy (cisplatin vs 
carboplatin).  


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The model will include the effect regardless of whether the inclusion of effect significantly 
improves the fit of the model provided there is enough data to make them meaningful. 
Missing covariate data will be imputed using the mean (for continuous variables) or the most 
common category (for categorical factors). 
This analysis evaluates the treatment effect adjusting for any potential imbalances in baseline 
prognostic factors that are not balanced by stratification. 
A forest plot illustrating the hazard ratio and 95% confidence interval will be provided to 
compare the primary and sensitivity analyses of progression-free survival. 
5. Suspected progression on physical exam and no confirmatory biopsy  
For this analysis, subjects who do not progress by RECIST but have suspected progression by 
physical exam at an assessment and do not have a confirmatory biopsy will be imputed as 
progressions with the date of progression based on the date of the physical exam.  
The stratified log-rank test will be repeated on PFS using the Investigator data based upon 
RECIST, physical exam and confirmatory biopsy data, with subjects who have no progression 
by RECIST and suspected progression by physical exam without confirmatory biopsy data 
imputed as progressions as described. The HR and CI will be presented. 
6. Max-combo test 
The max-combo test will be conducted as a sensitivity analysis on the PFS data in the full 
analysis set to test for treatment differences in the case of non-proportional hazards. The 
analysis will be based on adaptive procedure involving selection of best test statistics with 
log-rank (G0,0) and the Fleming-Harrington (FH) test (G0,1, G1,0, and G1,1) with alpha 
correction (Duke-Margolis, 2018). 
7. 
Stratification factors based on eCRF data 
This sensitivity analysis will repeat the PFS analysis using the stratified log-rank test, as 
described for the primary analysis of PFS where the stratification factors will be based on the 
values recorded on the eCRF instead of the IWRS. This analysis will only be performed if 
more than 5% of subjects were mis-stratified. 
Additional supportive summaries/figures 
The treatment status at progression of subjects at the time of analysis will be summarized for 
the FAS. This will include the number (%) of subjects who were on treatment at the time of 
progression, the number (%) of subjects who have progressed before receiving treatment, the 


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number (%) of subjects who completed treatment prior to progression, the number (%) of 
subjects who discontinued study treatment prior to progression, the number (%) of subjects 
who have not progressed and were on treatment, did not receive treatment, completed 
treatment or discontinued treatment. This will also provide distribution of number of days 
prior to progression for the subjects who have discontinued treatment. 
In addition, the number of subjects prematurely censored will be summarized by treatment 
arm together with baseline prognostic factors of the prematurely censored subjects. A subject 
would be defined as prematurely censored if they had not progressed (or died in the absence 
of progression) and the latest date of assessment at which the RECIST 1.1 assessment and 
response evaluation physical exam were evaluable prior to DCO was more than one scheduled 
assessment interval plus 2 weeks prior to the DCO date. 
Additionally, summary statistics will be given for the number of days from censoring to DCO 
for all censored subjects. 
A summary of the number of days between progression assessments (RECIST and physical 
exam) will be presented for each visit schedule for each treatment arm. A summary of the 
number of days between RECIST and physical exam assessments over time will also be 
presented for each treatment arm in the FAS. Furthermore, a summary of the time from last 
tumor assessment to DCO in censored subjects will be presented for each treatment arm in the 
FAS. 
A summary of the duration of follow-up will be summarized using median time from 
randomization to date of censoring (date last known to have not progressed) in censored (not 
progressed) subjects only, presented by treatment group. 
Additionally, summary statistics for the number of weeks between the time of progression and 
the last evaluable tumor assessment prior to progression will be presented for each treatment 
group. 
Summaries of the number and percentage of subjects who miss two or more consecutive 
tumor assessments will be presented for each treatment group. 
All of the collected RECIST 1.1, physical exam, confirmatory biopsy data will be listed for all 
randomized subjects. In addition, a summary of new lesions (i.e. sites of new lesions) will be 
produced. 
Subgroup analysis 
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using Investigator 
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durvalumab plus SoC CCRT and placebo plus SoC CCRT in the following subgroups of the 
FAS (but not limited to):  
• 
Age at randomization  
o < 65 versus ≥ 65 years of age 
o This will be determined from the date of birth (BIRTHDAT in the DEM module) 
and date of randomization (RND_DAT in the CRIT1 module) on the eCRF at 
screening. Subjects with a partial date of birth (i.e. for those countries where year 
of birth only is given) will have an assumed date of birth of 1st Jan [given year]). 
Subjects with a date of birth where day is missing will have an assumed day of 
1st of the month. Subjects with a missing age value will be included using the 
mean age (overall FAS) and categorized accordingly 
 
The primary interpretation of the secondary endpoint of PFS in PD-L1 subjects will be from 
the stratified log-rank test but a subgroup analysis of PD-L1 expression will also be 
performed. 
• 
PD-L1 expression 
o ≥1% vs < 1% in either the tumor or immune component and ≥5% vs < 5% in 
either the tumor or immune component (determined from an investigational use 
only (IUO) immunohistochemistry (IHC) test result obtained retrospectively after 
enrolment using a validated VENTANA PD-L1 (SP263) Assay) 
o PD-L1 status expression will be assigned based on the following algorithm: 
▪ Only sample with sample date on or before first dose will be used 
▪ Most recent sample “sampled date” should be used, unless this sample is 
unevaluable, in which case most recent evaluable sample is used 
▪ For multiple evaluable samples with the same sampled date, the sample 
with the highest PD-L1 % staining result should be used  
• 
Disease stage status  
o FIGO (2009) <III and node positive, FIGO (2009) Stage ≥ III and node negative, 
or FIGO (2009) Stage ≥ III and node positive 
• PET/CT or PET/MRI at staging vs. no PET/CT at staging 
• 
First dose of cisplatin or carboplatin 


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o Subjects will be assigned based on whether they have received carboplatin or 
cisplatin as the first chemotherapy agent 
• 
Radiotherapy 
o Incomplete EBRT and brachytherapy vs. completed EBRT and brachytherapy 
o Did not receive brachytherapy 
o Unacceptable variations vs. no unacceptable variations 
o IMRT/VMAT vs. non-IMRT/VMAT 
o EBRT + brachytherapy administered ≤59 days vs >59 days 
o Midline block administered vs. no midline block administered 
o LN boost administered vs. no LN boost administered 
o Brachytherapy HDR administered vs. other 
o Brachytherapy given vs. no brachytherapy given 
• Lymph nodes 
o Paraaortic lymph node vs. no paraaortic lymph node 
o Pelvic lymph node vs. no pelvic lymph node 
o Stage III, IV pelvic or paraaortic lymph node positive vs. stage III, IV pelvic or 
paraaortic lymph node negative 
• 
Race  
o Asian versus non-Asian 
▪ This will be determined from the response to “Race” (DEM module) on 
the eCRF at screening  
• 
Region  
o [United States, Canada, European Union, South Korea, and Japan] versus rest of 
the world 


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▪ This will be determined from the center number (CENTRE) 
• Japan 
o Japan versus rest of the world 
 
• 
HPV status  
o HPV 16, HVP 18 versus other 
▪ This will be determined from the response to “Abnormal Result” (HPV 
module) on the eCRF at screening. For these subgroup analyses any 
subject with missing values will be excluded from that particular 
subgroup.  
The subgroup analyses for the stratification factors will be based on the values entered into the 
IVRS, all other factors will be based on values recorded on the eCRF (or laboratory) data.  
Other baseline variables may also be assessed if there is clinical or biological justification, or 
an imbalance is observed between the treatment arms. The purpose of the subgroup analyses is 
to assess the consistency of treatment effect across expected prognostic factors. If a baseline 
imbalance is observed between treatment arms, ad-hoc subgroup analysis may be used to 
investigate any potential for impact on the main results. 
No adjustment to the significance level for testing will be made since all these subgroup 
analyses will be considered exploratory and may only be supportive of the primary analysis of 
PFS. For each subgroup level of a factor, the HR (for the treatment comparisons of interest) 
and 95% CI will be calculated from a Cox proportional hazards model that only contains a 
term for treatment. The Cox models will be fit using a SAS PROC PHREG with the Efron 
method to control for ties, using the by statement to obtain HR and 95% CI for each subgroup 
level separately. These will be presented on a forest plot including the HR and 95% profile 
likelihood CI, along with the results of the overall primary analysis.  
If there are too few events for a meaningful analysis of a particular subgroup (it is considered 
inappropriate to present analyses where there are less than 20 events), the relationship 
between that subgroup and PFS will not be formally analyzed. In this case, only descriptive 
summaries will be provided.  
Unless there is a marked difference between the results of the statistical analyses of the PFS 
from the site Investigator tumor data and the BICR tumor data, the subgroup analyses will 
only be performed upon the PFS endpoint using the site investigator data.  


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Consistency of treatment effect between subgroups 
The presence of quantitative interactions between treatment and stratification factors will be 
assessed by means of an overall global interaction test for plausible subgroups. 
This is performed by comparing the fit of a Cox proportional hazards model including 
treatment, all covariates, and all covariate-by treatment interaction terms, with one that 
excludes the interaction terms, and will be assessed at the 2-sided 10% significance level. If 
there are not more than 10 events per stratum for any covariate (i.e., within each stratum of a 
treatment*covariate interaction [2 treatments * 2 levels of the covariate = 4 stratum]) a pre-
defined pooling strategy should be applied to the covariate. If the pooling strategy does not 
meet the event criteria, then the covariate-by-treatment interaction term should be omitted 
from the model. Moreover, if the covariate does not have more than 10 events per level of 
covariate then the main effect of the covariate will also be excluded. If the fit of the model is 
not significantly improved, then it will be concluded that overall the treatment effect is 
consistent across the subgroups. 
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant, and all excluded 
interactions are non-significant. Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present. This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985. 
Time to first and second subsequent therapy or death  
The time to the start of first and second subsequent therapy will be analyzed using the same 
methodology and model as that used for the primary analysis of PFS. The HR for the 
treatment effect together with its 95% CI will be presented. In addition, medians and a 
Kaplan-Meier plot of the time to the start of subsequent therapy will be presented by treatment 
arm and the time between progression and starting subsequent therapy will be assessed based 
upon the date of objective disease progression (per primary definition of progression). This 
will be summarized per treatment arm, but no formal comparisons will be made. No 
multiplicity adjustment will be applied as this is viewed as a supportive endpoint.  


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In subjects who received a subsequent cancer therapy, a summary table of first subsequent 
cancer therapies by treatment arm will be provided.  
A summary of the number of subjects prematurely censored will also be produced. 
4.3.3 
Secondary efficacy endpoints 
4.3.3.1 
Progression-free survival at 3 years (PFS (3 years)) 
PFS (3 years) will be summarized (using the Kaplan-Meier curve) and presented by treatment 
arm together with its corresponding 95% CI with no formal comparison or p-value attached. 
4.3.3.2 
 Progression-free survival in PD-L1 positive high subjects 
PFS in PD-L1 high subjects will be analyzed using a stratified log-rank test, using the same 
methodology as for the primary PFS endpoint. The effect of durvalumab + SoC CCRT versus 
placebo + SoC CCRT will be estimated by the HR together with its corresponding CI and p-
value using the same methodology as described for PFS in the subset of subjects with PD-L1 
expression of ≥1%. Kaplan-Meier plots will be presented by treatment arm. Summaries of the 
number and percentage of subjects experiencing a PFS event and type of event (local 
progression, distant progression, or death) will be provided along with median PFS for each 
treatment. 
PFS in PD-L1 low subjects will be summarized and analyzed in a similar manner to PFS in 
PD-L1 high subjects. 
4.3.3.3 
Overall survival (OS) 
OS will be analyzed using the same methodology and model as that used for the primary 
analysis of PFS. The effect of treatment will be estimated by the HR together with its 
corresponding 95% CI. Kaplan-Meier plots of OS will be presented by treatment arm.  
Summaries of the number and percentage of subjects who have died, those still in survival 
follow-up, those lost to follow-up, and those who have withdrawn consent will be provided 
along with the median OS for each treatment.  
Sensitivity analyses 
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias with 
regard to the treatment comparisons, achieved by a Kaplan-Meier plot of time to censoring 
where the censoring indicator of OS is reversed. 
The number of subjects prematurely censored will be summarized by treatment arm. A subject 
would be defined as prematurely censored if their survival status was not defined at the DCO. 


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In addition, duration of follow-up will be summarized using medians: 
• 
In all subjects: Time from randomization to the date of death (i.e. overall survival) or to 
the date of censoring (date last known to be alive) for censored subjects regardless of 
treatment arm 
• 
In censored subjects who are alive at DCO only: Time from randomization to date of 
censoring (date last known to be alive) for each arm 
4.3.3.4 
Overall survival in PD-L1 high subjects 
Overall survival in PD-L1 high subjects will be analyzed using a stratified log-rank test, using 
the same methodology as described by the primary PFS endpoint. The effect of durvalumab + 
SoC CCRT versus placebo + SoC CCRT will be estimated by the HR together with its 
corresponding CI and p-value using the same methodology as described for the PFS. Kaplan-
Meier plots will be presented by treatment arm. Summaries of the number of percentage of 
subjects 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 overall survival for each 
treatment. 
Overall survival in PD-L1 low subjects will be summarized and analyzed in a similar manner 
to overall survival in PD-L1 high subjects. 
These analyses will be performed at the same time as the final analysis of OS. 
4.3.3.5 
Objective response rate (ORR)  
The ORR will be based on the site investigator RECIST 1.1 data as well as physical exam and 
confirmatory biopsy data and using all scans and physical exams regardless of whether they 
were scheduled or not. The ORR will be compared between durvalumab plus SoC CCRT 
versus placebo plus SoC CCRT using logistic regression models, adjusting for the same 
stratification factors as the primary endpoint as covariates in the model. The results of the 
analysis will be presented in terms of an odds ratio (an odds ratio greater than 1 will favor 
durvalumab) together with its associated profile likelihood 95% CI (e.g., using the option 
‘LRCI’ in SAS procedure GENMOD) and p-value (based on twice the change in log-
likelihood resulting from the addition of a treatment factor to the model). The logistic 
regression analysis will be repeated for confirmed ORR based on investigator RECIST 1.1 
data as well as physical exam and confirmatory biopsy data, but this will not be considered the 
primary interpretation of the secondary endpoint of ORR.  
If there are not enough responses for a meaningful analysis using logistic regression, then a 
Cochran-Mantel Haenszel (CMH) test will be presented. The CMH test will be stratified using 


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the same stratification factors as the primary endpoint. The results of the analysis will be 
presented in terms of an odds ratio together with the 95% CI and p-value. The odds ratio, 95% 
CI and p-value will be obtained using SAS PROC FREQ and the CMH test option. The 
STRATUM variable used in the TABLE statement will be based on region and disease stage 
status. 
Summaries will be produced that present the number and percentage of subjects with a tumor 
response (CR/PR) based upon the number of subjects with measurable disease at baseline per 
the site investigator.  
Overall response data will be listed for all subjects (i.e., the FAS).  
4.3.3.6 
Complete response (CR) rate 
The CR Rate will be based on the site investigator RECIST 1.1 data as well as physical exam 
and confirmatory biopsy data. The CR rate will be compared between durvalumab plus SoC 
CCRT versus placebo plus SoC CCRT using logistic regression models, using the same 
methodology as described for the ORR endpoint in Section 4.3.3.4. If there are not enough 
responses for a meaningful analysis using logistic regression, then a Cochran-Mantel Haenszel 
(CMH) test will be presented using the same methodology described for the ORR endpoint.  
Summaries will be produced that present the number and percentage of subjects with a tumor 
response of CR.  
4.3.3.7 
Duration of response (DoR) for complete responders 
Descriptive statistics will be provided for the duration of response in subjects with a complete 
response (CR) observed including the associated Kaplan-Meier curves (without any formal 
comparison or p-value attached).  
 
The summaries described above will also be produced for duration of response for subjects 
with a CR or PR. 
4.3.3.8 
Incidence of local progression, distant disease progression, secondary 
malignancy  
The actual number and percentage of subjects with a progression-free survival event will be 
presented by treatment arm for the FAS according to whether the first progression-free 
survival event was a local progression, distant progression, secondary malignancy, or death.  
As mentioned in Section 3.2.77, distant disease progressions and secondary malignancies will 
be summarized together for time to event endpoints. 


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The cumulative incidence of local progressions and distant disease progressions/secondary 
malignancies will be compared between treatment groups using competing risk analysis (Gray 
test, Fine and Gray 1999). Death will be considered a competing risk for local progression and 
distant disease progression or secondary malignancy. In addition, distant disease progression 
and secondary malignancy will be considered to be competing risks for local progression and 
local progression will be considered to be a competing risk for distant disease progression and 
secondary malignancy. Hazard ratios and 95% confidence intervals from competing risks 
regression analyses (Fine and Gray, 1999) adjusted for randomized treatment group and the 
stratification factors will also be presented.  
The Gray test and Fine and Gray models can be implemented in SAS version 9.4 by 
specifying the event code option in PROC PHREG. 
• 
The data derivation requirements are similar to those of a traditional survival analysis, 
with “survival time” calculated as the time from randomization to the occurrence of an 
event (or, here one or more possible events) or censored at the time of analysis if the 
event has not yet occurred. The key difference is a status variable which labels distinct 
codes for different causes of failure and a distinct code for censored observations 
• 
Cumulative incidence estimates will be plotted by treatment arm, for both the cause of 
interest and the competing risk(s). Because of the limitations of available computational 
tools, the effect of treatment arm will be assessed by a Wald Test  
• 
Proportional hazards model for the sub distribution of the competing risk, Fine and Gray 
models, will include the treatment arm and stratification factors  
• 
As with the proportional hazards model, tests will be performed to assess whether the 
Fine and Gray model is actually a reasonable fit to the data  
4.3.3.9 
Best objective response (BoR) 
For each treatment arm, best objective response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD and NE). No formal statistical analyses are planned for BoR. 
4.3.3.10 
Patient reported outcomes 
All patient reported outcomes will be presented using the FAS, unless otherwise stated. 
The PRO endpoints identified as primary are symptom experience as assessed by the EORTC 
-QLQ-CX24 and global health status/QoL, physical functioning, and role functioning as 
assessed by the EORTC-QLQ-C30.  


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The analysis will be performed using a linear mixed model for repeated measures (MMRM) 
analysis of change from baseline in the scores for each assessment timepoint (see next section 
for further details)  
Compliance rates summarizing questionnaire completion at each visit will be tabulated. 
Mixed models repeated measures (MMRM analysis) 
Change from baseline in the PRO symptom scores of symptom experience as assessed by the 
EORTC-QLQ-CX24 and global health status/QoL, physical functioning, and role functioning 
as assessed by the EORTC-QLQ-C30 will be analyzed using a mixed model for repeated 
measures (MMRM) analysis of all post-baseline scores for each visit . Adjusted mean change 
from baseline estimates per treatment group and corresponding 95% CIs will be presented 
along with an overall estimate of the treatment difference, 95% CI, and p-value. The analysis 
will be to compare the average treatment effect from the point of randomization until 24 
months or where 20 or more subjects on each treatment arm have a score. Note that the default 
method will be used to weight the coefficients in the least square means calculations. 
It is acknowledged that subjects will discontinue treatment at different timepoints during the 
study and that this is an important time with regards to symptoms and HRQoL data collection. 
To account for this, and to include the discontinuation and follow up visits, a generic visit 
variable will be derived for each subject in order that the average treatment effect can be 
analyzed using the above method. Each visit will be assigned a sequential number. The time 
from randomization to each of these will be derived to select only those visits occurring within 
the first X months of randomization. 
As an example, say a subject X attends the first 4 scheduled visits of a 2-weekly schedule and 
then discontinues treatment, whilst subject Y discontinues treatment after the first scheduled 
visit, the first 6 generic visits would be as follows:  
Table 16: Discontinuation example 
Generic Visit 
Study Day 
 
Subject X 
Subject Y 
Baseline 
Baseline 
Baseline 
1 
29 
28 
2 
57 
50 (discontinuation) 


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3 
85 
85 
4 
113 
113 
5 
130 (discontinuation) 
141 
6 
169 
169 
The MMRM model will include the fixed, categorical effects of treatment, visit, and 
treatment-by-visit interaction, disease stage status (FIGO (2009) Stage <III and node positive, 
FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node positive) and 
region ([United States, Canada, European Union, South Korea, and Japan] versus rest of 
world) as well as the continuous fixed covariate of baseline score and the baseline score-by-
visit interaction. Restricted maximum likelihood (REML) estimation will be used. An overall 
adjusted mean estimate will be derived that will estimate the average treatment effect over 
visits giving each equal weight. For this overall treatment comparison, adjusted mean 
estimates per treatment group and corresponding 95% CIs will be presented along with an 
estimate of the treatment difference, 95% CI (for the 4 key symptoms only) and p-value. 
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. If the fit of 
the unstructured covariance structure fails to converge, the following covariance structures 
will be tried in order until convergence is reached: Toeplitz with heterogeneity, autoregressive 
with heterogeneity, Toeplitz, autoregressive and compound symmetry.  
Multiple imputation techniques for missing values may be considered to explore the 
robustness of any treatment effect.  
Change from baseline  
For both the EORTC-QLQ-CX24 and EORTC-QLQ-C30, summaries of absolute and 
unadjusted change from baseline values for each scale/item will be reported for each treatment 
arm. Summaries of the number and percentage of subjects in each response category at each 
assessment time period for each ordinal item (in terms of the proportion of subjects in the 
categories of improvement, stable, and deterioration as defined in Tables 10 and 11) will also 
be produced for each treatment arm.  
PRO-CTCAE 
Data from the PRO-CTCAE will be summarized using the FAS. The number and percentage 
of subjects with each level of response for each CTCAE item at baseline and over time may be 
summarized. A bar chart of the incidence by visit will be presented for each CTCAE. Further 


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summaries to explore the data (i.e., the severity of symptoms) may be produced if needed. 
Visits will be presented provided at least one treatment arm has >=20 subjects with data at a 
given visit. 
EQ-5D-5L 
The evaluable population will comprise a subset of the FAS who have a baseline EQ-5D-5L 
assessment. 
Descriptive statistics will be calculated for each scheduled visit/time point in the study, for 
each trial arm. These will report the number of subjects, the number of EQ-5D questionnaires 
completed at each visit, the number and proportion responding to each dimension of the EQ-
5D-5L. Additionally summary statistics (e.g. n, mean, median, SD, min, max) may be reported 
for the EQ-5D index score and the EQ-VAS score, and the change from baseline for the EQ-
5D index score and the EQ-VAS score. 
Summary statistics will be supported by plots of mean and mean change from baseline in EQ-
5D index score and VAS score, and associated 95% CIs, by time/scheduled visit and treatment 
arm. To support submissions to payers, additional analyses may be undertaken, and these will 
be outlined in a separate Payer Analysis Plan, which will be reported outside of the CSR. 
PGIS and PGIC 
PGIC and PGIS summaries will include the number and percentage of subjects with each 
response at each visit. 
4.3.4 
Exploratory endpoints 
4.3.4.1 
Health care resource use 
The potential impact the disease and treatment have on health care resource use will be 
analyzed for the purposes of submissions to payers. Descriptive statistics (as appropriate, 
including means, median, ranges or frequencies and percentages) will be provided for each 
arm on the different types of hospital admissions, the length of stay of people admitted in to 
hospital for at least one overnight stay and length of stay of people admitted to intensive care / 
high dependency units, as well as the primary sign or symptom the subject presents with. To 
support submissions to payers, additional analyses may be undertaken, and these will be 
outlined in a separate Payer Analysis Plan. 
4.3.5 
Safety 
Safety and tolerability data from all cycles will be summarized. No formal statistical analyses 
are planned for safety data. All safety data will be presented using the SAF.  
The following sections describe the planned safety summaries for AEs, laboratory 
measurements, vital signs, physical examinations, ECG and WHO/ECOG performance status. 


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Note that additional safety tables (not specified in this SAP) may need to be produced to aid 
interpretation of safety data. 
4.3.5.1 
Adverse events 
All AEs, both in terms of MedDRA preferred term and CTCAE grade, will be listed and 
summarized descriptively by count (n) and percentage (%). Any AE occurring before 
treatment with IP (as defined in Table 13) and which did not worsen during the course of the 
study will be included in all AE listings but will not be included in the summary tables (unless 
otherwise stated). These shall be referred to as ‘pre-treatment’. However, any AE occurring 
before the administration of IP that worsens after Study Day 1 will be regarded as treatment 
emergent and this will be included in the summary tables. Note: If an AE is not worse than 
baseline (pre-dose) severity then it will not be classified as TEAE. 
AEs observed up until 90 days following last dose of study treatment or until the initiation of 
the first subsequent anti-cancer therapy following discontinuation of study treatment 
(whichever occurs first) will be used for the reporting of the AE summary tables. This will 
more accurately depict AEs attributable to study treatment only as opposed to presenting all 
AEs reported up to 90 days following discontinuation of IP. This is due to the fact that a 
number of AEs up to 90 days following discontinuation are likely to be attributable to 
subsequent anti-cancer therapy. However, to assess the longer-term toxicity profile, limited 
AE summaries will also be produced containing AEs observed up until 90 days following 
discontinuation of durvalumab plus SoC CCRT or placebo plus SoC CCRT (i.e., without 
taking subsequent anti-cancer therapy into account). Any events in this period that occur after 
a subject has received further therapy for cancer (following discontinuation of study 
treatment) will be flagged in the data listings.  
A separate listing of AEs occurring more than 90 days after discontinuation of study treatment 
will be produced. These events will not be included in AE summaries. 
All reported AEs will be listed along with the date of onset (including study day), date of 
resolution (if AE is resolved), investigator’s assessment of CTCAE grade and relationship to 
study drug. Frequencies and percentages of subjects reporting each preferred term will be 
presented (i.e., multiple events per subject will not be accounted for apart from any episode 
level summaries which may be produced). 
Summary information (the number and percentage of subjects by treatment arm) by system 
organ class and preferred term will be tabulated for: 
• 
All AEs 


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• 
All AEs possibly related to durvalumab/placebo only (as determined by the reporting 
investigator) 
• 
All AEs possibly related to SoC CCRT only (as determined by the reporting investigator) 
• 
All AEs possibly related to durvalumab/placebo or SoC CCRT (as determined by the 
reporting investigator) 
• 
All AEs possibly related to durvalumab/placebo only (as determined by the reporting 
investigator) by system organ class, preferred term and maximum CTCAE grade 
• 
All AEs possibly related to SoC CCRT only (as determined by the reporting investigator) 
by system organ class, preferred term and maximum CTCAE grade 
• 
All AEs possibly related to durvalumab/placebo or SoC CCRT (as determined by the 
reporting investigator) by system organ class, preferred term and maximum CTCAE 
grade 
• 
Most common AEs (frequency of ≥ 5%)  
• 
AEs with CTCAE grade 3 or 4 
• 
AEs with CTCAE grade 3 or 4, possibly related to durvalumab/placebo only (as 
determined by the reporting investigator) 
• 
AEs with CTCAE grade 3 or 4, possibly related to SoC CCRT only (as determined by the 
reporting investigator) 
• 
AEs with CTCAE grade 3 or 4, possibly related to durvalumab/placebo or SoC CCRT (as 
determined by the reporting investigator) 
• 
Most common AEs with CTCAE grade 3 or 4 (frequency of ≥ 1%) 
• 
AEs with outcome of death 
• 
AEs with outcome of death possibly related to durvalumab/placebo only (as determined 
by the reporting investigator) 
• 
AEs with outcome of death possibly related to SoC CCRT only (as determined by the 
reporting investigator) 


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• 
AEs with outcome of death possibly related to durvalumab/placebo or SoC CCRT (as 
determined by the reporting investigator) 
• 
All SAEs 
• 
All SAEs possibly related to durvalumab/placebo only (as determined by the reporting 
investigator) 
• 
All SAEs possibly related to SoC CCRT only (as determined by the reporting 
investigator) 
• 
All SAEs possibly related to durvalumab/placebo or SoC CCRT (as determined by the 
reporting investigator) 
• 
AEs leading to study drug dose delays of durvalumab/placebo only 
• 
AEs leading to study drug dose delays of SoC CCRT only 
• 
AEs leading to study drug dose delays of durvalumab/placebo or SoC CCRT 
• 
AEs leading to discontinuation of durvalumab/placebo only 
• 
AEs leading to discontinuation of SoC CCRT only 
• 
AEs leading to discontinuation of durvalumab/placebo or SoC CCRT 
• 
AEs leading to discontinuation of durvalumab/placebo only, possibly related to 
durvalumab/placebo only (as determined by the reporting investigator) 
• 
AEs leading to discontinuation of SoC CCRT only, possibly related to SoC CCRT only 
(as determined by the reporting investigator) 
• 
AEs leading to discontinuation of durvalumab/placebo or SoC CCRT, possibly related to 
durvalumab/placebo or SoC CCRT (as determined by the reporting investigator) 
• 
AEs leading to dose interruption of durvalumab/placebo only 
• 
AEs leading to dose interruption of SoC CCRT only 
• 
AEs leading to dose interruption of durvalumab/placebo or SoC CCRT 
• 
SAEs leading to discontinuation of durvalumab/placebo only 


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• 
SAEs leading to discontinuation of durvalumab/placebo, possibly related to 
durvalumab/placebo only (as determined by the reporting investigator) 
• 
SAEs leading to discontinuation of SoC CCRT 
• 
SAEs leading to discontinuation of durvalumab/placebo or SoC CCRT 
• 
SAEs leading to dose interruption of durvalumab/placebo only 
• 
SAEs leading to dose interruption of durvalumab/placebo only, possibly related to 
durvalumab/placebo only (as determined by the reporting investigator) 
• 
SAEs leading to dose interruption of SoC CCRT only 
• 
SAEs leading to dose interruptions of durvalumab/placebo or SoC CCRT 
• 
Other significant AEs 
• 
Other significant AEs, possibly related to durvalumab/placebo only (as determined by the 
reporting investigator) 
• 
Other significant AEs, possibly related to SoC CCRT only (as determined by the 
reporting investigator) 
• 
Other significant AEs, possibly related to durvalumab/placebo or SoC CCRT (as 
determined by the reporting investigator) 
• 
Immune mediated AEs (as determined by the reporting investigator) 
• 
 Infusion reaction AEs (as determined by the reporting investigator) 
An overall summary of the number and percentage of subjects in each category will be 
presented. For the truncated AE tables of most common AEs, all events that occur in at least 
5% of subjects overall will be summarized by preferred term, by decreasing frequency. This 
cut-off may be modified after review of the data. When applying a cut-off (e.g., 5%), the raw 
percentage should be compared to the cut-off, no rounding should be applied first (i.e., an AE 
with frequency 4.9% will not appear if the cut-off is 5%). 
Each AE event rate (per 100 subject years) will also be summarized by preferred term within 
each system order class for the output summarizing all AEs. For each preferred term, the event 
rate is defined as the number of subjects with that AE divided by [the total treatment duration 
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discontinuation of study treatment or up until the start of subsequent therapy, whichever 
comes first] summed over subjects and then multiplied by 365.25 x 100 to present in terms of 
per 100 subject years. 
AEs will be assigned CTCAE grades and summaries of the number and percentage of subjects 
will be provided by maximum reported CTCAE grade, system organ class and preferred term. 
For each treatment arm, time to first adverse event (days) will be tabulated by system organ 
class and preferred term. For each AE, time to first onset of the AE from date of first dose will 
be presented in the listing. 
Deaths 
Two summaries of all deaths will be provided with number and percentage of subjects by 
treatment group categorized as: 
• 
Total number of deaths (regardless of date of death) 
• 
Death related to disease under investigation only as determined by investigator 
• 
Death related to disease under investigation and an AE with an outcome of death 
a. AE onset prior to subsequent therapy. Which includes AEs with onset date (or 
pre-treatment AEs that increase in severity) on or after the date of first dose and 
up to and including 90 days following the last dose of study medication 
(durvalumab/placebo) or AE start date ≤ the date of initiation of the first 
subsequent therapy (whichever occurs first) 
b. AE onset after start of subsequent therapy. Which includes AEs with start date 
>90 days following the last dose of study medication (durvalumab/placebo) 
and/or AE start date > the date of initiation of the first subsequent therapy 
(whichever occurs first) 
• 
AE with outcome of death only 
a. AE onset prior to subsequent therapy. Which includes AEs with an onset date (or 
pre-treatment AEs that increase in severity) on or after the date of first dose and 
up to and including 90 days following the last dose of study medication 
(durvalumab/placebo), or AE start date ≤ the date of initiation of the first 
subsequent therapy (whichever occurs first) 


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b. AE onset after the start of subsequent therapy. Which includes AEs with a start 
date >90 days following the last dose of study medication (durvalumab/placebo) 
and/or AE start date > date of initiation of the first subsequent therapy (whichever 
occurs first) 
• 
Death after end of safety follow-up period (last dose of study medication 
(durvalumab/placebo + 90 days) and not due to disease under investigation 
• 
Unknown reason for death 
• 
Other deaths 
This summary will be repeated for all deaths on treatment or within 90 days of the last dose of 
durvalumab/placebo. 
4.3.5.2 
Adverse events of special interest (AESI) and possible interest (AEPI) 
Preferred terms used to identify AESIs/AEPIs will be listed before DBL and documented in 
the Trial Master File. Grouped summary tables for certain MedDRA preferred terms will be 
produced and may also show the individual preferred terms which constitute each AESI/AEPI 
grouping. For each ‘grouped’ term, the number (%) of subjects experiencing any of the 
specified terms will be presented.  
Groupings will be based on preferred terms provided by the medical team prior to DBL, and a 
listing of the preferred terms in each grouping will be provided. 
Summaries of the above-mentioned grouped AE categories will include number (%) of 
subjects who have: 
• 
Any AESI/AEPI 
• 
Any AESI/AEPI by grouped term, PT by outcome 
• 
Any AESI/AEPI by grouped term, PT and maximum CTCAE grade 
• 
Any AESI/AEPI possibly related to durvalumab/placebo only 
• 
Any AESI/AEPI possibly related to SoC CCRT only 
• 
Any AESI/AEPI possibly related to durvalumab/placebo or SoC CCRT 
• 
Any AESI/AEPI leading to concomitant medication use (steroids) 


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• 
Any AESI/AEPI leading to concomitant medication use (high dose steroids) 
• 
Any AESI/AEPI leading to concomitant medication use (endocrine therapy) 
• 
Any AESI/AEPI leading to concomitant medication use (other 
immunosuppressants) 
• 
At least one AESI/AEPI leading to discontinuation of durvalumab/placebo only 
• 
At least one AESI/AEPI leading to discontinuation of SoC CCRT only 
• 
At least one AESI/AEPI leading to discontinuation of durvalumab/placebo or 
SoC CCRT 
An overall AESI/AEPI summary will be presented, including number and percentage of 
subjects in each of these categories.  
Immune-mediated Adverse events (imAEs) 
The imAEs (as classified by the Sponsor) will be summarized in the similar manner as for the 
summaries for AESI/AEPI described above.  
4.3.5.3 
Summary of long-term tolerability 
To assess the long-term tolerability, if there are sufficient subjects with events to warrant it, 
prevalence plots, life plots and cumulative incidence plots may be presented for each of the 
AESI grouped terms and any other events considered important after review of the safety data, 
provided there are ≥10 events, that is 10 events per treatment group. 
A prevalence plot provides information on the extent to which the events may be an ongoing 
burden to subjects. The prevalence at time t after the first dose of study treatment is calculated 
as the number of subjects experiencing the event divided by the number of subjects receiving 
study treatment or in the safety follow-up at time t: generally, t is categorized by each day 
after dosing. The prevalence over time may be plotted and presented. Multiple occurrences of 
the same event are considered for each subject, but a subject is only counted in the numerator 
whilst they are experiencing one of the occurrences of the event. These plots may only be 
produced for AESIs that have ≥10 events, that is 10 events per treatment group. 
A life table can be used to describe the time to onset (date of onset – start date of treatment + 
1) of the event and specifically when subjects are most at risk of first experiencing the event. 
The hazard, or in other words the probability of having and AE in a specific time-period (e.g., 
0 – 1 months, 1 – 3 months, 3 – 6 months, etc.) given that the subject reaches the time-period 


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without having an event is plotted for each time-period. These plots may only be produced for 
AESIs that have ≥10 events, that is 10 events per treatment group. 
A cumulative incidence plot is a plot of the raw cumulative incidence and cumulative 
incidence function over time, these may be presented on separate plots. The raw cumulative 
incidence is the actual probability that a subject will have experienced their first occurrence of 
the event at a given time-point. These plots may only be produced for AESIs that have ≥10 
events, that is 10 events per treatment group. 
4.3.5.4 
Exposure 
Exposure will be summarized for the SAF. Note all summaries related to carboplatin exposure 
apply only to subjects initially treated with carboplatin prior to CSP version 3.0. The 
following summaries will be produced: 
• 
Duration of exposure to durvalumab/placebo (number of infusions, number of infusions 
group [1, 2 - <6, 6 – <12, 12 - <18, 18 - <24, >=24), total treatment duration (days), 
actual treatment duration (days), RDI) 
• 
Duration of exposure to radiotherapy (total treatment duration for EBRT (days), actual 
treatment duration for EBRT (days), total treatment duration for EBRT + brachytherapy 
(days), actual treatment duration for EBRT + brachytherapy (days), total dose of 
radiotherapy to the pelvis, biologically equivalent dose, Subjects with boost [lymph node, 
parametrial and paraaortic], Subjects with any unacceptable variations, Subjects with any 
unacceptable variations requiring intervention) 
• 
Number of doses received (carboplatin or cisplatin only) 
• 
Summary of dose delays and infusion interruptions for durvalumab/placebo 
• 
Summary of dose delays, reductions and interruptions (infusion interruptions and skipped 
doses) of chemotherapy (cisplatin or carboplatin) 
• 
Summary of dose interruptions for radiotherapy (EBRT and/or brachytherapy) 
• 
Exposure over time to any protocol mandated study treatment 
4.3.5.5 
Laboratory measurements 
Laboratory data obtained until 90 days after the last dose of study treatment or until the 
initiation of the first subsequent anti-cancer therapy following discontinuation of study 
treatment (whichever occurs first) will be used for reporting. This will more accurately depict 
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days following discontinuation of study treatment are likely to be attributable to subsequent 
anti-cancer therapy. 
Data summaries and listings will be provided by AZ preferred units. 
All laboratory data will be listed. Flags will be applied to values falling outside – reference 
ranges (which will be explicitly noted on these listings where applicable), and to values for 
which CTCAE grading applies. 
Scatter plots (shift plots) of baseline to maximum/minimum values (as appropriate) on 
treatment (i.e., on treatment is defined as data collected between the start of treatment and the 
relevant follow-up period following the last dose of study treatment) may be produced for 
certain parameters if warranted after data review.  
Boxplots of absolute values by week, and boxplots of change from baseline by week, may be 
presented for certain parameters if warranted after data review. 
Shift tables of laboratory values by worse common toxicity criteria (CTCAE) grade will be 
produced, and for specific parameters separate shift tables indicating hyper- and hypo- 
directionality of change will be produced. The laboratory parameters for which CTCAE grade 
shift outputs will be produced are: 
• 
Hematology: Hemoglobin, Leukocytes, Lymphocytes (absolute count), Neutrophils 
(absolute count), Platelets 
• 
Clinical Chemistry: ALT, AST, Albumin, Alkaline Phosphatase, Total bilirubin, 
Magnesium (hypo- and hyper-), Sodium (hypo- and hyper-), Potassium (hypo- and hyper-
), Corrected Calcium (hypo- and hyper-), Glucose (hypo-), Gamma-glutamyl transferase, 
Creatinine 
For parameters with no CTCAE grading that are listed in the CSP, shift tables from baseline to 
worse value on treatment will be provided. Additional summaries will include a shift table of 
urinalysis (Bilirubin, Blood, Glucose, Ketones, Protein) comparing baseline value to 
maximum on treatment value. 
The denominator used in laboratory summaries of CTCAE grades will only include evaluable 
subjects. If a CTCAE criterion involved a change from baseline, evaluable subjects are those 
who have both a pre-dose and at least 1 post-dose value recorded. If a CTCAE criterion does 
not consider changes from baseline, evaluable subjects are those who have at least 1 post-dose 
value recorded. 


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Hy’s law 
The following summaries will include the number (%) of subjects who have 
Elevated ALT, AST, and Total bilirubin during the study: 
• 
ALT ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x ULN during the study 
• 
AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x ULN during the study 
• 
Total bilirubin ≥2x – ≤3x, >3x – ≤5x, >5x ULN during the study 
• 
ALT or AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, >20x ULN during the study 
• 
ALT or AST ≥3x ULN and total bilirubin ≥2x ULN during the study (potential Hy’s law): 
the onset date of ALT or AST elevation should be prior to or on the date of total bilirubin 
elevation 
• Narratives will be provided in the CSR for subjects who have ALT ≥ 3x ULN plus total 
bilirubin ≥ 2x ULN or AST ≥ 3x ULN plus total bilirubin ≥ 2x ULN at any visit. 
Liver biochemistry test results over time for subjects with elevated ALT (i.e. ≥ 3x ULN) or AST 
(i.e. ≥ 3x ULN), and elevated total bilirubin (i.e. ≥ 2x ULN) (at any time) will be plotted. 
Individual subject data where ALT or AST plus total bilirubin are elevated at any time will be 
listed also. 
Plots of maximum post-baseline ALT and AST vs. maximum post-baseline total bilirubin, 
expressed as multiples of ULN, will also be produced with reference lines at 3×ULN for ALT 
and AST, and 2×ULN for Total bilirubin. In each plot, total bilirubin will be in the vertical axis. 
Abnormal Thyroid function 
Elevated thyroid stimulating hormone (TSH) will be summarized per treatment group in terms 
of number (%) of subjects with elevated TSH (higher than the upper normal range), low TSH 
(lower than lower normal range), elevated TSH post-dose and within normal range at baseline, 
low TSH post-dose and within normal range at baseline. Shift tables showing baseline to 
maximum and baseline to minimum will be produced. 
4.3.5.6 
Electrocardiograms 
Summaries of ECG data will include all data obtained up until 30 days after the last dose of 
study treatment. These data will be mapped in accordance with Section 3.5.1.2. Absolute 
values and change from baseline for ECG heart rate, PR duration, QRS duration, QT duration, 
and RR duration will be presented. 
The number and percentage of subjects with normal and abnormal (not clinically significant 
and clinically significant) ECG results will be presented as a shift table from baseline to worst 
evaluation during the study.  


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A summary of QTcF intervals at any observation on treatment in each of the treatment arms 
will be presented. 
Where ECGs are recorded in triplicate at a visit, an average of each measurement will be taken 
in order to obtain a single value to be used in the analysis/summaries. Where an average cannot 
be taken for the categorical variable of overall evaluation, the worst evaluation will be reported 
for a visit. 
4.3.5.7 
Vital signs 
Summaries for vital signs data will include all data obtained up until 30 days after the last 
dose of study treatment. These data will be data mapped in accordance with Section 3.5.1.2. 
Absolute values and change from baseline for diastolic and systolic BP, pulse, respiratory rate 
and temperature will be summarized at each scheduled measurement. The denominator in vital 
sign data should include only those subjects with recorded data. 
Boxplots will be produced to show the absolute values and change from baseline at each 
scheduled measurement. 
4.3.5.8 
Eastern Cooperative Oncology Group performance status 
Summaries of ECOG data will include all data mapped in accordance with Section 3.5.1.2. 
Absolute values and change from baseline for ECOG PS will be summarized at each visit. 
4.3.6 
Pharmacokinetic data 
PK concentration data for durvalumab will be summarized for all subjects in the PK analysis 
set. 
Serum concentrations of durvalumab will be summarized by nominal sample time using 
standard summary statistics for PK concentrations (geometric mean, geometric coefficient of 
variation, geometric mean ± standard deviation, arithmetic mean, standard deviation, 
minimum, maximum and n). All serum concentrations will be listed. 
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modelling approach.  
4.3.7 
Immunogenicity analysis 
Immunogenicity results will be listed for all subjects regardless of ADA-evaluable status. The 
number and percentage of subjects who develop detectable ADA to durvalumab within each 
ADA response category listed in Section 3.7 will be summarized based on the SAF with a 
non-missing baseline anti-drug antibody (ADA) result and at least one non-missing post-
baseline ADA result. ADA titer and neutralizing ADA data will be listed for samples 
confirmed positive for the presence of anti-durvalumab antibodies. AEs in ADA-positive 


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subjects by ADA-positive category will be listed. Details for the presentation and derivation 
of ADA data is provided in Section 3.7.  
The effect of immunogenicity on PK, efficacy and safety will be evaluated if data allow.  
4.3.8 
Demographic, initial diagnosis and baseline characteristics data 
The following will be summarized for all subjects in the FAS (unless otherwise specified) by 
treatment group: 
• 
Subject disposition  
• 
Important protocol deviations 
• 
Inclusion in analysis sets 
• 
Demographics (age, age group [<50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 75 years], race 
(White, Black or African American, Asian, Native Hawaiian or other Pacific Islander, 
American Indian or Alaska Native, Other) and ethnicity (Hispanic or Latino, Not 
Hispanic or Latino), Country) 
• 
Subject characteristics at baseline (height, weight, weight group [<70kg, >=70kg - 
<=90kg, >90kg], body mass index, body mass index group [<18.5, >=18.5 - <25.0, 
>=25.0 - <30, >=30]) 
• 
Subject recruitment by region, country and center 
• 
Stratification factors recorded (at randomization by IWRS, on eCRF and agreement 
between IWRS versus eCRF) 
• 
Medical history 
• 
Disease characteristics at baseline (WHO/ECOG performance status, primary tumor 
location, histology type, regional lymph nodes, tumor grade, FIGO (2009) stage and 
overall disease classification) 
• 
Extent of disease at study entry 
• 
Primary tumor location at initial diagnosis (locally advanced – primary tumor [by FIGO 
2009 stage], locally advanced – regional lymph nodes [N0, N1], nodal involvement 
[pelvic or paraaortic lymph nodes], pelvic lymph node involvement [by FIGO 2009 
stage], paraaortic lymph node involvement [by FIGO 2009 stage]) 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 1 0 0 C 0 0 0 0 1  - 3. 0  
0 4 A u g ust 2 0 2 1  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 0 9  of 1 1 4  
 
•  
Me dical hist or y ( past a n d c urre nt)  
•  
S ur gical hist or y  
•  
Disall o we d c o nc o mita nt me dicati o ns  
•  
All o we d c o nc o mita nt me dicati o ns  
•  
P ost -disc o nti n uati o n ca ncer t hera p y  
•  
Nic oti ne use, cat e g orize d ( ne ver, c urre nt, f or mer)  
T he me dicati o ns will be c o de d f oll o wi n g Astra Z e neca sta n d ar d dr u g dicti o nar y/ W H O dr u g 
dicti o nar y as a p plica ble.  
4. 3. 9  
C o nc o mit a nt a n d ot h er tre at m e nts  
All c o nc o mita nt a n d ot her treat me nt data will be liste d f or all s u bjects i n t he F A S.  
Me dicati o ns recei ve d pri or t o, c o nc o mita ntl y, or p ost treat me nt will be c o d e d usi n g t he 
Astra Ze neca Dr u g Dicti o nar y A nat o mical T h era p e utic C he mical ( A T C) classificati o n c o des. 
C o nc o mita nt me dicati o ns will be s u m marize d f or t he F A S b y A T C classifi cati o n c o des. 
S u bjects wit h t he sa me c o nc o mita nt me dicati o n/ pr oce d ure m ulti ple ti mes will be c o u nte d o nce 
per me dicati o n/ pr o ce d ure. A me dicati o n/ pr oce d ure t hat ca n b e classifie d i n t o m ore t ha n o ne 
c he mical a n d/ or t h era p e utic s u b gr o u p will be pres e nte d i n eac h s u b gr o u p.  
4. 3. 1 0  
S u bse q ue nt t he r a p y  
S u bse q ue nt t hera pies recei ve d after disc o nti n uati o n of st u d y treat me nt will be s u m marize d b y 
treat me nt gr o u p, t o get her wit h t he n u m ber of re gi me ns recei ve d. 
4. 3. 1 1  
Bi o m ar ker d at a  
S u m maries a n d a nal yses f or e x pl orat or y bi o mar kers will be d oc u me nte d i n a se parate a n al ysis 
pla n a n d will be re p orte d o utsi de t he C S R se paratel y.  
4. 3. 1 2  
Ge netic d at a  
C CI


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4.3.13 
Radiotherapy Quality Control Assessment 
Radiotherapy quality is monitored through an external vendor with deviations to the protocol 
specified radiotherapy marked as variations unacceptable if the dose or contour is incorrect or 
missing or total treatment duration exceeds 59 days. Radiotherapy doses outside of the range 
set by the protocol are listed as deviation unacceptable. Listings and summary tables of 
unacceptable variations and deviations unacceptable will be developed. Clinical significance 
will be assigned following a review from the CALLA radiotherapy steering committee of all 
applicable cases and will be summarized in the CSR. Clinical significance is defined on 
whether a dosing deviation results in substantial risk in toxicity and suboptimal efficacy. 
4.4 
COVID-19 
Depending on the extent of any impact, summaries of data relating to subjects diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued study treatment, and other protocol deviations) may be generated, including: 
• Disposition (discontinued study treatment due to COVID-19 and withdrew study due 
to COVID-19) 
• Deviations (overall deviations plus if due to COVID-19 and not due to COVID-19) 
• Summary of COVID-19 disruptions (visit impact, drug impacted) 
• Listing for subjects affected by the COVID-19 pandemic 
• Listing for subjects with reported issues in the Clinical Trial Management System due 
to the COVID-19 pandemic 
If there are sufficient number of subjects with confirmed or suspected COVID-19 infections, 
the following tables will also be produced: 
• Number of subjects with adverse events in any category - subject level, patients with 
confirmed / suspected COVID-19 infection 
• Number of subjects with adverse events in any category - subject level, patients 
without confirmed / suspected COVID-19 infection 
• Number of subjects with adverse events by system organ class, preferred term and 
maximum reported CTCAE grade, patients with confirmed / suspected COVID-19 
infection  


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• Number of subjects with adverse events by system organ class, preferred term and 
maximum reported CTCAE grade, patients without confirmed / suspected COVID-19 
infection  
• Number of subjects with adverse events, associated with COVID-19 by system organ 
class and preferred term  
• Number of subjects with adverse events, excluding AEs associated with COVID-19 by 
system organ class and preferred term 
• Number of subjects with confirmed / suspected COVID-19 adverse events, by system 
organ class and preferred term 
• Number of subjects with adverse events, excluding confirmed / suspected COVID-19 
AEs by system organ class and preferred term 
• Number of subjects with adverse events associated with COVID-19 with outcome of 
death, by system organ class and preferred term  
• Number of subjects with adverse events with outcome of death, excluding AEs 
associated with COVID-19) by system organ class and preferred term  
• Number of subjects with adverse events associated with COVID-19 leading to 
discontinuation of investigational product, by system organ class and preferred term 
• Number of subjects with adverse events leading to discontinuation of investigational 
product, excluding AEs associated with COVID-19, by system organ class and 
preferred term 
4.4.1 
Censoring Confirmed/Suspected COVID-19 Deaths for PFS Analysis 
A sensitivity analysis will be conducted to assess for the potential impact of COVID deaths on 
PFS. This will be assessed by repeating the PFS analysis except that any subject who had 
a PFS event due to death where primary/secondary cause of death was due to COVID-19 
Infection, or a COVID-19 infection reported as a fatal AE, will be censored at their last 
evaluable assessment prior to their COVID infection death date. 
4.4.2 
Censoring Confirmed/Suspected COVID-19 Deaths for OS Analysis 
A sensitivity analysis will be conducted to assess for the potential impact of COVID deaths on 
OS. This will be assessed by repeating the OS analysis except that any subject who had a 


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death with primary/secondary cause as COVID-19 Infection, or a COVID-19 infection 
reported as a fatal AE will be censored at their COVID infection death date. 
5 
INTERIM ANALYSES 
5.1 
PFS and OS interim analyses 
No PFS interim analyses are planned in this study.  
There will be an interim analysis performed for OS. The first interim analysis for OS will 
occur at the time of the PFS analysis, if PFS is statistically significant. It is anticipated that 
approximately 86% of the OS events will be available for this OS IA (~195 of 227 OS 
events). If exactly 86% of the target events are available at the time of the interim analysis, 
with overall 2-sided alpha level of 5%, the 2-sided alpha to be applied to the interim and final 
analysis would be 3.1% and 4.1%, respectively.  
If the criteria for statistical significance is met for PFS but not OS at the time of the PFS 
analysis, follow-up will continue until the earlier of 227 OS events or 71 months following 
randomization of the first subject, at which point OS will be retested. If the criteria for 
statistical significance for OS is met at the interim analysis, OS will not be retested, but 
follow-up will continue until the earlier of 227 OS events or 71 months following 
randomization of the first subject. 
5.2 
Independent data monitoring committee 
This study will use an external independent data monitoring committee (IDMC) to assess 
ongoing safety analyses as well as the interim efficacy analysis. The committee will first meet 
when the first 25 subjects across both treatment arms have completed SoC CCRT and have 
had at least 28 days of follow-up. The second safety review will take place when the first 60 
subjects across both treatment arms have completed SoC CCRT and have had at least 28 days 
of follow-up. An additional safety review for Japanese subjects will take place when the first 9 
subjects in Japan have completed SoC CCRT and had 28 days of follow-up. Safety reviews 
will be carried out by the IDMC in an unblinded manner. The IDMC will meet at least every 6 
months thereafter. Following each meeting, the IDMC will report to the sponsor and may 
recommend changes in the conduct of the study. 
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca and are free from conflict of interest. 
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way. Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca. The report will include the 


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recommendation and any potential protocol amendments and will not contain any unblinding 
information. 
The final decision to modify or stop the study will sit with the sponsor. The sponsor or IDMC 
may call additional meetings if at any time there is concern about the safety of the study. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter. The 
safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department. Issues identified will be addressed; this could involve, for instance, amendments 
to the Clinical Study Protocol and letters to investigators. 
6 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE) 
7 
REFERENCES 
Duke-Margolis Public Workshop 2018 
Public Workshop: Oncology Clinical Trials in the Presence of Non‐Proportional Hazards, The 
Duke‐Margolis Center for Health Policy Feb. 2018. 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 
70:659-63 
Breslow, 1974 
Breslow, NE. Covariance Analysis of Censored Survival Data. Biometrics 1974; 30:89-99 
Burman et al 2009 
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Statistics in Medicine 2009; 28:739-61 
Fayers et al 1999 
Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality 
of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. Available on 
request 
Fine, J. P., and Gray, R. J. 1999  
A Proportional Hazards Model for the Subdistribution of a Competing Risk.” Journal of the 
American Statistical Association 94:496–509. 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 


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1983; 70:659-63 
Osoba et al 1998 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44 
Rose et al 1999 
Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent 
cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J 
Med 1999;340(15):1144-53 
Lin et al 2020 
Lin RS, Lin J, Roychoudhury S, Anderson KM, Hu T, Huang B, et al. Alternative Analysis 
Methods for Time to Event Endpoints Under Nonproportional Hazards: A Comparative 
Analysis. Statistics in Biopharmaceutical Research 2020;12(2):187-98 
8 
APPENDIX (NOT APPLICABLE) 
 
 

Prot_000.pdf: 
Clinical Study Protocol - 4.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
1
Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D9100C00001
Version
4.0
Date
11 March 2021
A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to 
Determine the Efficacy and Safety of Durvalumab in Combination With and 
following Chemoradiotherapy Compared to Chemoradiotherapy Alone for 
Treatment in Women With Locally Advanced Cervical Cancer (CALLA)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): 2018-002872-42




Clinical Study Protocol - 4.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
3
Removal of Carboplatin. To ensure appropriate balance between patients treated with 
cisplatin and carboplatin as the radiosensitizer across regions in the ongoing study, no 
further use of carboplatin as the radiosensitizer will be allowed in this study.
Section 1.1 Schedule of activities, Section 5.2 Exclusion Criteria
Clarified requirement to perform ECG once during screening unless clinical abnormalities 
are present. 
Section 6.1.1.2 Standard of care
Separated sections for cisplatin and carboplatin as carboplatin is not a treatment option in 
this version 
Section 1.2 Synopsis, Section 3 Objectives and Endpoints, Section 6.1.1 Investigational 
products, Section 6.1.2 Dose and treatment regimens, Section 6.4 Concomitant 
therapy, Section 9.3 Populations for analyses, 9.3.3 PK analysis set; Section 9.4.1.6 
Overall survival in PD-L1 positive patients, Section 9.5.1 Efficacy analyses
Added OS PD-L1 positive patients to secondary objective and analysis to determine 
consistency of effect between PFS and OS in this cohort
Section 1.2 Synopsis, Section 1.1 Schedule of activities, Section 4.1 Overall design, 9.7 
China cohort
Added details of China cohort, including number of patients required and potential to 
recruit beyond global LSI
Section 8.4.5.1 Specific toxicity management and dose modification information –
durvalumab
Added information that 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.
Section 9.2 Sample size determination 
Change of the expression of the statistical power to be consistent with the rest of the 
protocol.
Section 1.1. Schedule of activities, Appendix A7 Study and Site start and closure, 
Appendix B2 Definitions of serious adverse event, Appendix E Actions Required in 
Cases of Increases in Liver Biochemistry and Evaluation of Hy’s law, Appendix G12.1 
General Principals
Administrative changes based on updated information.




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Word “maintenance” changed to “adjuvant” in these sections, as this is a more accurate 
description of the intent of the Durvalumab/Placebo treatment post CCRT for this patient 
population.
Section 2.2.4 Treatment of cervical cancer
Rationale for the completion of CCRT within 56 days has been added
Section 2.2.4 Treatment of cervical cancer
Background information for the treatment of cervical cancer has been updated
Table 1 Schedule of assessments for durvalumab/placebo ± chemoradiation therapy 
screening and treatment and retreatment periods (up to total of 24 doses), Section 4.1 
Overall Design, Section 7.1.1 Procedures for discontinuation of study treatment, 
Section 8.1 Efficacy assessments
Clarified the role of pelvic examination in the assessment of progressive disease. 
Table 1 Schedule of assessments for durvalumab/placebo ± chemoradiation therapy 
screening and treatment and retreatment periods (up to total of 24 doses), Table 6 
Treatment regimen 
Clarified SoC platinum chemotherapy dosing window.
Section 4.2.4 Rationale of administering durvalumab concurrent with CCRT
Duplicate information that was already covered in section 2.1.1 Rationale for combining 
checkpoint inhibitor therapy with chemoradiotherapy, has been removed from this section
Section 4.2.5 Rationale for treatment duration
Duration of treatment clarified to include histopathologic confirmation of local tumor 
progression in addition to PD by RECIST 1.1
Section 4.2.6 Rationale for stratification factors
New section added to provide rationale for stratification factors.
Section 5.1 Inclusion criteria 5.0 & multiple sections
Multiple sections of CSP updated to emphasise that FIGO (2009) is used for this protocol. 


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Section 5.2 Exclusion criteria
Added mucinous adenocarcinoma into exclusion criteria 1.0. 
Section 6.1.1.1 Durvalumab (MEDI4736), Section 6.1.1.3 Placebo
Durvalumab blinding procedure updated to include the use of coloured infusion sleeves.
Section 6.1.1.1 Durvalumab (MEDI4736) - Order of Adminsitration

Clarified SOC chemotherapy administration timing post durvalumab/placebo 
administration from 24 hour to 1 calendar day 

Removed “Cisplatin or carboplatin should commence within the first 3 radiation 
treatments” as inconsistent with other sections.”
Section 6.1.3 Duration of treatment and criteria for treatment through progression
This section updated to provide clarity on criteria for treatment through progression 
Table 7 Prohibited concomitant medications
Added immunosuppressive, EGFR & TKI as additional prohibited medications
Section 8.1.3.6 Administration of patient reported outcome questionnaires
This section updated to allow

ePRO assessment can be performed post blood sample collection, 

ePRO can be performed prior to C1D1 as long as first of dose of Durvalumab and 
CCRT is given within 3 days of ePRO completion 

Added that illiterate patients will not be required to complete the PRO assessments.
Section 8.1.4.1 Administration of health care resource assessment
Clarified that HOSPAD eCRF will be completed when there are hospitalization/hospital 
visits only.
Section 8.8.1.1 Tumor sample collection

Clarification provided on the screening tumor sample age requirement


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
Additional sentence added requesting to refer specific instructions and guidelines 
refer to lab manual for tumor sample collection.
Section 8.8.2 Exploratory biomarkers

Previous section 8.8.1.3 deleted and exploratory tumor markers moved to this 
section.

ctDNA sample collection section updated to provide more clarity.

Added the information about Microsatellite instability and tumor mutation burden 
and tumor markers.
Section 8.8.4 Storage, re-use, and destruction of biomarker samples
Sample storage requirement for China is updated.
Section 1.2 Synopsis, Section 9.2 Sample size determination, 9.5.7 Methods for 
Multiplicity Control, Section 9.6 Interim analyses
Updated this section to strengthen the analysis plan for the OS endpoint. OS will be 
analysed at the time of each PFS analysis, in the event that PFS is positive at the same 
timepoint.
Section 9.4.1.1 RECIST 1.1-based endpoints, Section 9.4.1.2 Primary endpoint -
progression-free survival
This section updated to clarify criteria and relationship between date of progression & 
physical exam
Section 9.4.1.3 Progression Free Survival (3 years), Section 9.4.1.4 Progression free 
survival in PD-L1 positive patients, Section 9.5.1.2 Progression Free Survival (3 year), 
Section 9.5.1.2 Progression free survival in PD-L1 positive patients, Table 14 Pre-
planned statistical and sensitivity analyses to be conducted
These sections are re-aligned and updated in line with changes made to study objectives
Section 9.4.3.2 EORTC QLQ CX24
Language for threshold value for clinically meaningful change and analysis plan for this 
PRO has been updated




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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 9
1.
PROTOCOL SUMMARY................................................................................ 16
1.1
Schedule of activities ........................................................................................ 16
1.2
Synopsis ........................................................................................................... 25
1.3
Schema............................................................................................................. 33
2.
INTRODUCTION............................................................................................ 34
2.1
Study rationale.................................................................................................. 34
2.1.1
Rationale for combining checkpoint inhibitor therapy with chemoradiotherapy. 34
2.2
Background ...................................................................................................... 36
2.2.1
Human papilloma virus infection in cervical cancer.......................................... 36
2.2.2
Staging of cervical cancer ................................................................................. 37
2.2.3
Lymph node status in cervical cancer................................................................ 37
2.2.4
Treatment of cervical cancer ............................................................................. 38
2.2.5
Cervical cancer establishes an immunosuppressive environment....................... 40
2.2.6
Previous checkpoint inhibitor therapy in cervical cancer................................... 41
2.2.7
Immunotherapies .............................................................................................. 41
2.2.8
Durvalumab...................................................................................................... 42
2.3
Benefit/risk assessment..................................................................................... 43
2.3.1
Potential benefits .............................................................................................. 43
2.3.1.1
Durvalumab as monotherapy in cervical cancer ................................................ 43
2.3.1.2
Concurrent immunotherapy and chemoradiotherapy in cervical cancer ............. 44
2.3.2
Overall risks ..................................................................................................... 45
2.3.2.1
Durvalumab...................................................................................................... 46
2.3.3
Overall benefit/risk ........................................................................................... 46
3.
OBJECTIVES AND ENDPOINTS................................................................... 47
4.
STUDY DESIGN ............................................................................................. 49
4.1
Overall design................................................................................................... 49
4.2
Scientific rationale for study design .................................................................. 51
4.2.1
Rationale for study endpoints (efficacy)............................................................ 51
4.2.2
Rationale for study endpoints (other exploratory endpoints).............................. 52
4.2.3
Choice of standard of care regimen................................................................... 52
4.2.4
Rationale of administering durvalumab concurrent with CCRT......................... 53
4.2.5
Rationale for treatment duration........................................................................ 53
4.2.6
Rationale for stratification factors..................................................................... 54
4.3
Justification for dose......................................................................................... 54
4.3.1
Durvalumab monotherapy dose rationale .......................................................... 54
4.3.2
Rationale for fixed dosing................................................................................. 55


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4.4
End of study definition...................................................................................... 56
5.
STUDY POPULATION ................................................................................... 56
5.1
Inclusion criteria............................................................................................... 57
5.2
Exclusion criteria.............................................................................................. 58
5.3
Lifestyle restrictions ......................................................................................... 62
5.4
Screen failures .................................................................................................. 63
6.
STUDY TREATMENTS.................................................................................. 64
6.1
Treatments administered................................................................................... 64
6.1.1
Investigational products.................................................................................... 64
6.1.1.1
Durvalumab (MEDI4736)................................................................................. 67
6.1.1.2
Standard of care................................................................................................ 68
6.1.1.3
Placebo............................................................................................................. 69
6.1.2
Dose and treatment regimens ............................................................................ 69
6.1.2.1
Durvalumab (MEDI4736) monotherapy............................................................ 70
6.1.2.2
Standard of care................................................................................................ 70
6.1.3
Duration of treatment and criteria for treatment through progression................. 71
6.1.4
Storage ............................................................................................................. 72
6.2
Measures to minimize bias: randomization and blinding ................................... 73
6.2.1
Subject enrollment and randomization .............................................................. 73
6.2.2
Procedures for handling incorrectly enrolled or randomized subjects ................ 74
6.2.3
Methods for assigning treatment arms............................................................... 74
6.2.4
Methods for ensuring blinding .......................................................................... 75
6.3
Treatment compliance....................................................................................... 75
6.4
Concomitant therapy......................................................................................... 75
6.4.1
Other concomitant treatment............................................................................. 79
6.4.2
Durvalumab drug-drug interactions................................................................... 79
6.4.3
Rescue medication............................................................................................ 79
6.5
Dose modification............................................................................................. 79
6.6
Treatment after the end of the study.................................................................. 80
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 80
7.1
Discontinuation of study treatment.................................................................... 80
7.1.1
Procedures for discontinuation of study treatment............................................. 81
7.2
Lost to follow-up .............................................................................................. 81
7.3
Withdrawal from the study................................................................................ 82
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................. 82
8.1
Efficacy assessments......................................................................................... 83
8.1.1
Central reading of scans.................................................................................... 84
8.1.2
Survival assessments......................................................................................... 85
8.1.3
Patient-reported Outcomes (PROs) ................................................................... 85
8.1.3.1
EORTC QLQ-C30 and QLQ-CX24 .................................................................. 85
8.1.3.2
PRO-CTCAE.................................................................................................... 86


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8.1.3.3
PGIC ................................................................................................................ 86
8.1.3.4
PGIS................................................................................................................. 86
8.1.3.5
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) and visual 
analogue scale (VAS) ....................................................................................... 86
8.1.3.6
Administration of patient reported outcome questionnaires ............................... 87
8.1.4
Health care resource use ................................................................................... 88
8.1.4.1
Administration of health care resource assessment............................................ 88
8.2
Safety assessments............................................................................................ 88
8.2.1
Physical examinations....................................................................................... 88
8.2.2
Vital signs......................................................................................................... 89
8.2.3
Electrocardiograms........................................................................................... 90
8.2.4
Clinical safety laboratory assessments............................................................... 90
8.2.5
WHO/ECOG performance status ...................................................................... 92
8.2.6
Early subject review for safety.......................................................................... 93
8.2.7
Other safety assessments................................................................................... 93
8.3
Collection of adverse events ............................................................................. 94
8.3.1
Method of detecting Adverse Events and Serious Adverse Events..................... 94
8.3.2
Time period and frequency for collecting adverse event and serious adverse 
event information.............................................................................................. 94
8.3.3
Follow-up of adverse events and serious adverse events.................................... 95
8.3.4
Adverse event data collection............................................................................ 95
8.3.5
Causality collection........................................................................................... 96
8.3.6
Adverse events based on signs and symptoms................................................... 97
8.3.7
Adverse events based on examinations and tests ............................................... 97
8.3.8
Hy’s law ........................................................................................................... 97
8.3.9
Disease progression .......................................................................................... 97
8.3.10
New cancers ..................................................................................................... 98
8.3.11
Deaths .............................................................................................................. 98
8.3.12
Adverse events of special interest ..................................................................... 98
8.3.13
Safety data to be collected following the final Data Cutoff of the study........... 100
8.4
Safety reporting and medical management...................................................... 100
8.4.1
Reporting of serious adverse events ................................................................ 100
8.4.2
Pregnancy....................................................................................................... 101
8.4.2.1
Maternal exposure .......................................................................................... 101
8.4.3
Overdose ........................................................................................................ 102
8.4.3.1
Durvalumab.................................................................................................... 102
8.4.3.2
Standard of Care ............................................................................................. 102
8.4.4
Medication error ............................................................................................. 102
8.4.5
Management of durvalumab-related toxicities................................................. 103
8.4.5.1
Specific toxicity management and dose modification information - durvalumab103
8.4.5.2
Specific toxicity management and dose modification information -
chemoradiotherapy ......................................................................................... 104
8.5
Pharmacokinetics............................................................................................ 104
8.5.1
Collection of samples...................................................................................... 104
8.5.1.1
Collection of samples to measure for the presence of antidrug antibodies........ 104


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8.5.2
Storage and destruction of pharmacokinetic/antidrug antibody samples .......... 105
8.6
Pharmacodynamics......................................................................................... 105
8.7
Genetics.......................................................................................................... 105
8.7.1
Optional exploratory genetic sample ............................................................... 105
8.7.2
Storage and destruction of genetic samples ..................................................... 106
8.8
Biomarkers ..................................................................................................... 106
8.8.1
Tumour samples: ............................................................................................ 106
8.8.1.1
Tumor sample collection:................................................................................ 106
8.8.1.2
PD-L1 expression assessment ......................................................................... 106
8.8.2
Exploratory biomarkers................................................................................... 107
8.8.2.1
Microsatellite instability and tumor mutation burden....................................... 107
8.8.2.2
Tumor biomarkers .......................................................................................... 108
8.8.2.3
Whole blood gene expression (PAXgene RNA).............................................. 108
8.8.2.4
Plasma - ctDNA mutations.............................................................................. 108
8.8.3
Management of biomarker data....................................................................... 109
8.8.4
Storage, re-use, and destruction of biomarker samples .................................... 109
8.8.5
Labeling and shipment of biological samples .................................................. 109
8.8.6
Chain of custody of biological samples........................................................... 110
9.
STATISTICAL CONSIDERATIONS............................................................. 110
9.1
Statistical hypotheses...................................................................................... 111
9.2
Sample size determination .............................................................................. 111
9.3
Populations for analyses.................................................................................. 112
9.3.1
Full analysis set .............................................................................................. 112
9.3.2
Safety analysis set........................................................................................... 112
9.3.3
PK analysis set................................................................................................ 113
9.3.4
PD-L1 positive analysis set............................................................................. 113
9.4
Outcome measures for analyses ...................................................................... 113
9.4.1
Calculation or derivation of efficacy variables ................................................ 113
9.4.1.1
RECIST 1.1-based endpoints .......................................................................... 113
9.4.1.2
Primary endpoint - progression-free survival................................................... 114
9.4.1.3
Progression Free Survival (3 years)................................................................. 115
9.4.1.4
Progression free survival in PD-L1 positive patients ....................................... 115
9.4.1.5
Overall survival .............................................................................................. 116
9.4.1.6
Overall survival in PD-L1 postive patients...................................................... 116
9.4.1.7
Objective response rate................................................................................... 116
9.4.1.8
Complete response rate................................................................................... 116
9.4.1.9
Incidence of Local Progression, Distant Disease Progression, Secondary 
Malignancy..................................................................................................... 116
9.4.1.10
Duration of response for Complete Responders............................................... 117
9.4.2
Calculation or derivation of safety variables.................................................... 117
9.4.2.1
Adverse events................................................................................................ 117
9.4.2.2
Safety assessments.......................................................................................... 118
9.4.3
Calculation or derivation of patient-reported outcome variables...................... 119
9.4.3.1
EORTC-QLQ-C30.......................................................................................... 119


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9.4.3.2
EORTC QLQ-CX24 ....................................................................................... 120
9.4.4
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events............................................................................................... 120
9.4.5
Patient Global Impression of Change and Patient Global Impression of 
Severity .......................................................................................................... 121
9.4.6
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) ..................... 121
9.4.7
Definition of compliance and evaluability rates............................................... 121
9.4.8
Calculation or derivation of health care resource use....................................... 122
9.4.9
Calculation or derivation of pharmacokinetic variables................................... 122
9.4.9.1
Population pharmacokinetics and exposure-response/safety analysis............... 122
9.4.9.2
Pharmacokinetic analysis................................................................................ 122
9.4.9.3
Immunogenicity analysis ................................................................................ 123
9.4.10
Calculation or derivation of biomarker variables............................................. 123
9.4.11
Calculation or derivation of pharmacogenetic variables .................................. 123
9.5
Statistical analyses.......................................................................................... 123
9.5.1
Efficacy analyses ............................................................................................ 123
9.5.1.1
Primary endpoint: Progression-free survival.................................................... 126
9.5.1.2
Progression Free Survival (3 year) .................................................................. 128
9.5.1.3
Progression-free survival in PD-L1 positive patients....................................... 128
9.5.1.4
Overall survival .............................................................................................. 128
9.5.1.5
Overall survival in PD-L1 positive patients..................................................... 129
9.5.1.6
Objective response rate................................................................................... 129
9.5.1.7
Complete response rate................................................................................... 129
9.5.1.8
Incidence of Local Progression, Distant Disease Progression, and Secondary 
Malignancy..................................................................................................... 129
9.5.1.9
Duration of complete response........................................................................ 130
9.5.1.10
Patient-reported outcomes............................................................................... 130
9.5.1.11
Health care resource use ................................................................................. 131
9.5.2
Safety analyses ............................................................................................... 132
9.5.3
Pharmacokinetic data...................................................................................... 132
9.5.4
Immunogenicity data ...................................................................................... 132
9.5.5
Pharmacokinetic/pharmacodynamic relationships ........................................... 132
9.5.6
Biomarker data ............................................................................................... 133
9.5.7
Methods for multiplicity control ..................................................................... 133
9.6
Interim analyses.............................................................................................. 133
9.6.1
Data monitoring committee............................................................................. 134
9.7
China Cohort .................................................................................................. 134
10.
REFERENCES............................................................................................... 136
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 149


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LIST OF TABLES
Table 1
Schedule of assessments for durvalumab/placebo ± chemoradiation 
therapy screening and treatment and retreatment periods (up to total of
24 doses) ................................................................................................. 17
Table 2
Schedule of assessments for patients who have completed or 
discontinued treatment............................................................................. 22
Table 3
Study objectives....................................................................................... 47
Table 4
Highly effective methods of contraception (<1% failure rate) .................. 63
Table 5
Study treatments ...................................................................................... 65
Table 6
Treatment regimen................................................................................... 69
Table 7
Prohibited concomitant medications......................................................... 77
Table 8
Supportive medications............................................................................ 78
Table 9
Clinical chemistry.................................................................................... 91
Table 10
Hematology............................................................................................. 91
Table 11
Urinalysis ................................................................................................ 92
Table 12
Summary of outcome variables and analysis populations ....................... 112
Table 13
Visit responses for EORTC QLQ-C30................................................... 120
Table 14
Pre-planned statistical and sensitivity analyses to be conducted ............. 124
Table 15
Summary of imaging modalities for tumor assessment........................... 172
Table 16
Evaluation of target lesions.................................................................... 180
Table 17
Evaluation of non-target lesions............................................................. 181
Table 18
Overall visit response algorithm............................................................. 181
Table 19
Target Volume Definition and Nomenclature......................................... 188
Table 20
Critical Structure and Avoidance Structure Nomenclature...................... 190
Table 21
Dose Prescription................................................................................... 192
Table 22
Target Criteria and Normal Structure Constraints for IMRT................... 193
Table 23
Detailed Specifications .......................................................................... 196
Table 24
HDR-Point A determined implant or volume directed approach............. 197
Table 25
PDR and LDR-Point A determined implant ........................................... 198
Table 26
Target and Normal Tissue Compliance Criteria...................................... 198
Table 27
Target and Normal Tissue Compliance Criteria...................................... 199
Table 28
Cisplatin Toxicity Management ............................................................. 216
Table 29
Cisplatin Hematologic Toxicity Management ........................................ 217


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Table 30
Carboplatin Toxicity Management......................................................... 219
Table 31
Carboplatin Hematologic Toxicity Management .................................... 219
Table 32
Radiation Therapy Toxicity Management .............................................. 222
Table 33
Cervical Cancer FIGO 2009 Staging Guidelines .................................... 224
LIST OF FIGURES
Figure 1
Study design............................................................................................ 33
Figure 2
Durvalumab dosing schedule ................................................................... 70
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 150
Appendix B
Adverse Event Definitions and Additional Safety Information............... 156
Appendix C
Handling of human biological samples .................................................. 161
Appendix D
Genetics................................................................................................. 164
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s law .......................................................................... 168
Appendix F
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors)........................ 172
Appendix G
Standard of Care Radiation Therapy Guidelines..................................... 184
Appendix H
Patient Reported Outcomes Instruments................................................. 202
Appendix I
Abbreviations ........................................................................................ 211
Appendix J
Standard of care treatment management................................................. 216
Appendix K
FIGO (2009) guidelines for Cervical Cancer Staging ............................. 224
Appendix L
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including 
COVID-19 Outbreak.............................................................................. 225


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1.
PROTOCOL SUMMARY
1.1
Schedule of activities
The procedures for the screening and treatment periods in this study are presented in Table 1, 
and the procedures for the follow-up period are presented in Table 2. Patients who continue on 
the trial beyond Cycle 24 will continue with assessments until termination of the study 
(Table 2).
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws. The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, 
Pharmacokinetics [PK] blood sample) to occur at the timepoints indicated in the schedule of 
assessments (SoAs). Whenever electrocardiograms (ECGs), vital signs, and blood draws are 
scheduled for the same nominal time, the assessments should occur in the following order: 
ECG, vital signs, and then blood draws. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the timepoints indicated in the 
SoAs.
For durvalumab/placebo + standard of care chemoradiation therapy combination arms

Patients may delay dosing under certain circumstances.

Dosing may be delayed per the Dosing Modification and Toxicity 
Management Guidelines, due to either an immune or a non-immune-
related adverse events (AE).

If dosing must be delayed for reasons other than treatment-related 
toxicity, dosing will resume as soon as feasible.

Dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of 
tumor efficacy (Response Evaluation Criteria in Solid Tumors version 1.1 
[RECIST 1.1]) and patient-reported outcome (PRO) assessments. 
Subsequent time between 2 consecutive doses cannot be less than 21 
days, based on the half-life of durvalumab (see current Investigator’s 
Brochure [IB] for durvalumab).


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Table 1
Schedule of assessments for durvalumab/placebo ± chemoradiation therapy screening and treatment and 
retreatment periods (up to total of 24 doses) 
Screening
C1a
C2a
C3a
C4a
C5 to 
PD/C24a
For details, see 
Section
Week
-4 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for toxicity reasons
Informed consent
Informed consent: study proceduresb
X
5.1
Consent: genetic sample and analysis 
(optional)
X
5.1
Study procedures
Physical exam (full)
X
8.2.1
Targeted physical exam c 
X
X
X
X
X
8.2.1
Vital signsd
X
X
X
X
X
X
8.2.2
ECGe
Xf
As clinically indicated
8.2.3
Concomitant medications
<----------------------------------------------------------------------------------------------------------------------->
6.4
Demography, including baseline 
characteristics and tobacco use
X
5.1
Eligibility criteria
X
5.1, 5.2
Radiation plan collection
X
Appendix G
Laboratory assessments
Clinical chemistryg
X
Xh
X
X
X
X
Table 9
Hematologyh
X
Xh
X
X
X
X
Table 10
TSHi (reflex free T3 or free T4)j
X
X
X
X
X
X
Table 9
Urinalysis
X
As clinically indicated
Table 11
Hepatitis B and C and HIV
X
8.2.4
Pregnancy testk
X
X
X
X
X
X
8.2.4
HPV genotype, if available
X
8.2.4


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Screening
C1a
C2a
C3a
C4a
C5 to 
PD/C24a
For details, see 
Section
Week
-4 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for toxicity reasons
Pharmacokinetics 
PK sample (serum)
Xl
Xm
Xm
8.5
Monitoring
WHO/ECOG performance statusn
X
X
X
X
X
X
8.2.5
AE/SAE assessmento
<------------------------------------------------------------------------------------------------------------>
8.3
Patient follow-up contact/Patient review for 
safety
Days 14 (±24 hours) of C1, C2, and C3
8.2.6
IP administration
Durvalumab/placebop,q
Xp
X
X
X
X
6.1.1.1, 6.1.2.1
SoC cisplatin chemotherapy 
Weekly for 5 weeksr (± 1 day 
except cycle 1)
6.1.1.2, 6.1.2.2
SoC radiation therapy 
Refer to Appendix G
6.1.1.2, 6.1.2.2, 
Appendix G
Other assessments and assays
Immunogenicity assessment (ADA sampling 
to identify ADA responses in patient 
circulation)
Xm
Xm
Xm
8.5.1.1
Whole blood for gene expression (PAXgene 
RNA tubes)
X
X
8.8.2
ctDNA (plasma)
X 
X s
X
X
(at 6 months 
and PD)
8.8.2
EORTC QLQ-C30 and CX24, PGIS, EQ-
5Dt
0 (C1D1), 2 (mid-cycle 1), 4 (C2D1), 8 (C3D1), 12 (C4D1), 16 (C5D1), 20 (C6D1) 
weeks from C1D1, then q12 weeks ±1w through 164 weeks (relative to C1D1), and 
then q24w ±2w thereafter (relative to C1D1) through 260 weeks, then q52w ±2w 
(relative to C1D1) up to PD and at IP pre-mature discontinuation and PD; if IP 
discontinuation due to PD, then also at month 2 and month 3 post discontinuation; if 
PD but continue on treatment, follow treatment period schedule.
8.1.3


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Screening
C1a
C2a
C3a
C4a
C5 to 
PD/C24a
For details, see 
Section
Week
-4 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for toxicity reasons
PRO-CTCAE
Same as other PROs, but will end at week 104 or first follow-up post IP 
discontinuation (if no PD), or at month 2 post IP discontinuation (if PD)
8.1.3
PGICt
Same as PRO-CTCAE but starting 4 weeks (C2D1) from C1D1
8.1.3
Healthcare resource use (HOSPAD)u
To be completed at each hospitalization
8.1.3
FFPE tumor sample (mandatory; a newly 
acquired sample is preferred if available per 
site’s routine clinical practice; otherwise, 
archival sample ≤3 months old can be 
provided)v
X
8.8
Optional newly acquired tumor biopsy 
collected upon progressionv
X (at PD only, strongly encouraged)
Genetics research sample (optional DNA 
element for long-term storage/future use) w
X
8.7
Efficacy evaluations 
Tumor radiological assessments 
(RECIST 1.1) y
-AND-
Physical exam including a pelvic 
examination 
Xx
On-study tumor assessments occur 20w ±1w after randomization and continue q12w 
±1w through 164 weeks (relative to the date of randomization) and then q24w ±2w 
thereafter (relative to the date of randomization) until RECIST 1.1-defined 
radiological progression plus an additional follow-up scan. If progressive disease is 
determined through histopathologic progression on biopsy, a scan is required within 
28 days of biopsy. This on-study imaging schedule MUST be followed regardless of 
any delays in dosing.
-AND-
Physical examination including a pelvic examination and (if indicated) biopsy for 
histopathological determination of tumor progression will be assessed on the same 
schedule as the imaging assessments.z,aa
8.1
a
These cycles refer to the 28-day cycles of administration of durvalumab/placebo.
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 or newly acquired biopsy) for entry into this 
study. This consent is included in the main patient ICF. Informed consent of study procedures may be obtained prior to the 28-day screening window, if necessary. The 
collection of additional biopsies upon progression is OPTIONAL but strongly encouraged. If laboratory or imaging procedures were performed for alternate reasons prior 


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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 randomization.
c
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical observations and symptomatology and can include assessments of the head, 
eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine 
systems
d
Body weight is recorded at each visit along with vital signs.
e
Any clinically significant abnormalities detected require triplicate ECG results. 
f
A single ECG at screening should be done. Any clinically significant abnormalities detected require triplicate ECG results.
g
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated or based on the local clinical 
practice.
h
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. 
i
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
j
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
k
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 treatment and then q4w. Results must be available and reviewed by the treating physician or Investigator prior to commencing an 
infusion. 
l
Post infusion within 1 hour of the end of infusion.
m
Pre-dose same day as infusion (may not exceed 6 hours prior to start of infusion).
m
ECOG performance status (PS) of 0 or 1 at enrolment and randomization.
o
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed
p
During the combination portion of treatment, durvalumab or placebo will be administered first. If there is not enough time to administer cisplatin afterward on that day, it 
should be given the following day and must be administered within 1 calendar day of the durvalumab infusion. Treatment should start no more than 3 working days after 
being randomized. The day patients begin treatment will be designated C1D1.
q
Results for LFTs, electrolytes, full blood count (while on chemotherapy), and creatinine must be available before commencing an infusion (within 3 days) and reviewed 
by the treating physician or Investigator prior to dosing.
r
A 6th week of platinum agent is optional per investigator discretion. 
s
Sample will be taken at last dose of platinum administration (C2D8 if a 6th week of platinum agent is needed or C2D1 if platinum agent is administered only for 5 weeks)
t
Will be administered using a site-based, ePRO device. The PRO questionnaires must be administered and completed at the clinic prior to treatment administration
performed at the site and ideally before any discussions of health status to avoid biasing the participant’s responses to the questions. As feasible, site staff should also 
ensure PRO questionnaires are completed prior to other study procedures, such as collection of laboratory samples and before discussion of disease progression to avoid 
biasing the patient’s responses to the questions.PRO-CTCAE will only be administered in those countries where a linguistically validated version exists. It is permitted 
for the baseline ePROs to be completed prior to C1D1 as long as treatment is given within 3 days of ePRO completion.
u
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital. A reminder will be provided at each clinic visit. 
Any routine visits for protocol-related requirements do not need to be captured. If the patient discontinues study treatment for reasons other than RECIST progression, the 
HOSPAD form should continue to be administered during the non-study protocol required hospital visits until progression has been confirmed
v
Blocks are preferred to slides (except China). Refer to the Laboratory Manual for further details on tissue requirements.
w
The sample for genetic research will be obtained at Day 1 pre-dose (at or after randomization). If, for any reason, the sample is not drawn at Day 1, it may be taken at any 
visit until the last study visit. Only 1 sample should be collected per patient for genetics during the study.
x
Patients will have baseline scans collected no more than 28 days before the date of randomization and, ideally, should be performed as close as possible to the date of
randomization.
y
RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen, and pelvis. Additional 
anatomy should be imaged based on the signs and symptoms of individual patients at baseline and follow-up. The follow-up scan collected after a RECIST 1.1-defined 
PD should be performed no less than 4 weeks after and no later than 12 weeks after the prior assessment of PD, and this follow-up scan is evaluated using the criteria 


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outlined in Appendix F. 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 resume the subsequent assessments following the original imaging visit schedule (relative to the date of randomization). See Section 6.1.3,
Section 8.1 and Appendix F for additional details relevant to imaging assessments.
z
Pap smear should be done per investigator discretion. If results are concerning for progression, progression must be confirmed by biopsy
aa
A radiological tumor assessment should be obtained within 28 days of confirmed histopathological progression unless no further radiological tumour assessments are 
indicated for the patient due to RECIST PD already being recorded and the follow up scan for the RECIST PD being completed
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
Abbreviations: ADA Antidrug antibody; AE Adverse event; C Cycle; CR Complete response; CRT Chemoradiation therapy; CT Computerized tomography; ctDNA 
Circulating tumor deoxyribonucleic acid; DNA Deoxyribonucleic acid; ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation 
for Research and Treatment of Cancer; EQ-5D-5L EuroQol five-dimensional five-level questionnaire; Gy Grey unit; HIV Human immunodeficiency virus; HOSPAD Hospital 
Admission; HPV Human papillomavirus; ICF Informed consent form; IP Investigational product; IV Intravenous; LFT Liver function tests; MRI Magnetic resonance imaging; 
PD Progression of disease; PGIC Patient Global Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; PR Partial response; PRO Patient-
reported outcomes; PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; qxw Every x weeks; q28d Every 28 days; 
QLQ-C30 30 item core quality of life questionnaire; QLQ-CX24 Cervical cancer module; RECIST Response Evaluation Criteria in Solid Tumors version 1.1; 
RNA Ribonucleic acid; SAE Serious adverse event; SD Stable disease; SoC Standard of care; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid stimulating hormone; WHO 
World Health Organization.
.


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Table 2
Schedule of assessments for patients who have completed or discontinued treatment 
Time since last dose of IP
Evaluation
Day (±3)
Months (±2 week)
21 months and 
every 6 months 
(±2 weeks)
For details, see 
Section
30
2
3
6
9
12
15
Physical examination (full)
X
8.2.1
Vital signs (temperature, respiratory 
rate, blood pressure, and pulse)
X
8.2.2
Weight
X
X
X
8.2.2
Pregnancy testa
X
As clinically indicated
8.2.4
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
8.2.5
Subsequent anticancer therapyc,d
<------------------------------------------------------------------------------------------------------------------------------------
>
8.1
Survival statuse
X
X
X
X
X
X 
8.1
Hematology
X
X
X
Table 10
Clinical chemistry
X
X
X
Table 9
Urinalysis
As clinically indicated
Table 11
TSH (reflex free T3 or free T4f)
X
X
X
Table 9
PK assessmentg
X
8.5
Immunogenicity assessment (ADA 
sampling) to identify ADA responsesg
X
Xh
8.5.1.1
Whole blood for gene expression 
(PaxGene-RNA tubes)
X
X
8.8.2
ctDNA (plasma)
X
X
X
8.8, 8.8.2


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Time since last dose of IP
Evaluation
Day (±3)
Months (±2 week)
21 months and 
every 6 months 
(±2 weeks)
For details, see 
Section
30
2
3
6
9
12
15
EORTC QLQ-C30 and CX24, PGIS, 
EQ-5Di
0 (C1D1), 2 (mid-cycle 1), 4 (C2D1), 8 (C3D1), 12 (C4D1), 16 (C5D1), 20 (C6D1) weeks 
from C1D1, then q12 weeks ±1w through 164 weeks (relative to C1D1), and then q24w 
±2w thereafter (relative to C1D1) through 260 weeks, then q52w ±2w (relative to C1D1) 
up to PD and at IP pre-mature discontinuation and PD; if IP discontinuation due to PD, 
then also at month 2 and month 3 post discontinuation; if PD but continue on treatment, 
follow treatment period schedule.
8.1.3
PRO-CTCAE
Same as other PROs, but will end at week 104 or first follow-up post IP discontinuation (if no PD), or at month 
2 post IP discontinuation (if PD)
8.1.3
PGICi
Same as PRO-CTCAE but starting 4 weeks (C2D1) from C1D1 
8.1.3
Healthcare resource use (HOSPAD) j
To be completed at each hospitalization.
8.1.3
Tumor radiological assessment 
(RECIST 1.1)k 
-AND-
Physical exam including a pelvic 
examination
On-study tumor assessments occur 20w ±1w after randomization and continue q12w ±1w through 164 weeks 
(relative to the date of randomization) and then q24w ±2w thereafter (relative to the date of randomization) 
until RECIST 1.1-defined radiological progression plus an additional follow-up scan. If progressive disease is 
determined through histopathologic progression on biopsy, a scan is required within 28 days of biopsy. This on-
study imaging schedule MUST be followed regardless of any delays in dosing.
-AND-
Physical examination including a pelvic examination and (if indicated) biopsy for histopathological 
determination of tumor progression will be assessed on the same schedule as the imaging assessments.l, m
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 cervical cancer (including surgery) after the last dose of IP must be recorded in the eCRF. At minimum, collect the start date and description 
of the subsequent anticancer therapy. 
d
For patients who discontinue their assigned IP following confirmed progression, available readings of CT/MRI from local practice will be collected from patients’ 
medical charts while information on subsequent anticancer treatment is collected.
e
Patients may be contacted in the week following data cutoffs to confirm survival status. Details of any treatment for cervical cancer (including surgery) after the last dose 
of IP must be recorded in the eCRF.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g
PK and immunogenicity samples are collected 90 days (3 months) (±7 days) after study treatment ends. In addition, a final immunogenicity sample is taken 6 months 
(±7 days) after study treatment ends.
h 
Immunogenicity sample and ctDNA sample should be obtained at a scheduled study tumor assessments visit
i
Will be administered using a site-based, ePRO device. The PRO questionnaires must be administered and completed at the clinic prior to treatment administration 
performed at the site and ideally before any discussions of health status to avoid biasing the participant’s responses to the questions. As feasible, site staff should also 


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ensure PRO questionnaires are completed prior to other study procedures, such as collection of laboratory samples and before discussion of disease progression to avoid 
biasing the patient’s responses to the questions. PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.
j
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital. A reminder will be provided at each clinic visit. 
Any routine visits for protocol-related requirements do not need to be captured. If the patient discontinues study treatment for reasons other than RECIST progression, the 
HOSPAD form should continue to be administered during the non-study protocol required hospital visits until progression has been confirmed. 
k
Only for patients yet to progress, RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast, of the chest, 
abdomen, and pelvis. Additional anatomy should be imaged based on signs and symptoms of individual patients. The follow-up scan collected after a RECIST 1.1-
defined PD should be performed no less than 4 weeks after and no later than 12 weeks after the prior assessment of PD, and this follow-up scan is evaluated also using 
the criteria outlined in Appendix F. If an unscheduled assessment was performed (eg, to investigate clinical signs/symptoms of progression) and the patient has not 
progressed, every attempt should be made to resume the subsequent assessments following the original imaging visit schedule (relative to the date of randomization). See 
Section 6.1.3, Section 8.1, and Appendix F for additional details relevant to imaging assessments.
l
Pap smear should be done per investigator discretion. If results are concerning for progression, progression must be confirmed by biopsy 
m
Radiological tumor assessments should be obtained on all patients within 28 days of progression confirmed by histopathology
Abbreviations: ADA Antidrug antibody; AE Adverse event; CT Computerized tomography; ctDNA Circulating tumor deoxyribonucleic acid; ECOG Eastern Cooperative 
Oncology Group; eCRF Electronic case report form; EORTC European Organization for Research and Treatment of Cancer; EQ-5D-5L EuroQol five-dimensional five-level 
questionnaire; IP Investigational product; IV Intravenous; MRI Magnetic resonance imaging; PD Progression of disease; PFS Progression-free survival; PGIC Patient Global 
Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; PRO Patient-reported outcome; PRO-CTCAE Patient-reported outcomes version of 
the Common Terminology Criteria for Adverse Events; qxw Every x weeks; QLQ-C30 30 item core quality of life questionnaire; QLQ-CX24 Cervical cancer module; RECIST 
Response Evaluation Criteria in Solid Tumors; RNA Ribonucleic acid; SAE Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid stimulating hormone; 
WHO World Health Organization.


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1.2
Synopsis
International Co-ordinating Investigator
Phoenix, AZ 85016
Phone: 
Fax: 
Protocol Title: A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to 
Determine the Efficacy and Safety of Durvalumab in Combination With and following 
Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women With 
Locally Advanced Cervical Cancer (CALLA)
Rationale:
Cervical cancer is the 4th most common cancer in women worldwide despite the introduction 
of the Papanicolaou test (Pap smear) for early screening and prevention of cervical cancer in 
the 1950s, and more recently, human papillomavirus (HPV) vaccination. Most women 
globally do not have access to screening and, thus, the global incidence of cervical cancer at 
all stages continues to rise throughout the world as the population rises and ages. The use of 
combination chemoradiotherapy is a mainstay of oncology therapy in multiple tumor types. 
The goal of combination chemotherapy is to utilize agents that affect cancer cells by different 
mechanisms, thus improving clinical responses and reducing the risk of developing resistance. 
Non-clinical and clinical studies have indicated that blockade of immune checkpoints 
(programmed cell death protein 1 [PD-1]/programmed death-ligand 1 [PD-L1] and cytotoxic 
T-lymphocyte-associated protein 4 [CTLA-4]) can have a positive effect on anti-tumor 
immunity. Chemotherapy is thought to synergize with PD-1/PD-L1 blockade by making the 
tumor “immunogenic” by initiating cell death, promoting phagocytosis of tumor cells, and 
ultimately leading to reactivation of immune-mediated tumor surveillance. The PACIFIC trial 
evaluated the efficacy of durvalumab after definitive chemoradiotherapy in Stage III non-
small cell lung cancer (NSCLC) compared to placebo after chemoradiotherapy and found a 
significant improvement with durvalumab with a median progression-free survival (PFS) of 
16.8 months (95% confidence interval [CI] 13.0 to 18.1) compared to 5.6 months (95%CI, 4.6 
to 7.8) in the placebo controlled group. The study’s hypothesis is that durvalumab, when 
administered concurrently with chemotherapy and radiotherapy (CCRT) and as adjuvant 
therapy following CCRT will also improve PFS when compared to standard of care 
concurrent chemoradiation therapy (SoC CCRT) with placebo in patients with International 
Federation of Gynaecology and Obstetrics (FIGO 2009) Stage IB2 to IVA cervical cancer.
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol - 4.0
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Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
CCRT compared with placebo + SoC CCRT in 
terms of PFS
Endpoints based on the investigator assessment 
according to RECIST 1.1 or histopathologic 
confirmation of local tumor progression:

PFS: Time from date of randomization until 
tumor progression or death due to any cause
Secondary objectives:
Endpoints/variables:
To further assess the efficacy of durvalumab + 
SoC CCRT compared with placebo + SoC 
CCRT in terms of PFS (3 year), PFS in PD-L1 
positive patients, overall survival (OS) (key), OS 
in PD-L1 positive patients, ORR, CR rate, and 
DoR in Patients with a CR

OS: Time from date of randomization until the 
date of death by any cause 
Endpoints based on the investigator assessment 
according to RECIST 1.1 or pathologic assessment 
of local disease progression

PFS (3 year): Proportion of patients alive and 
progression-free at 3 years

PFS in PD-L1 positive patients: Time from date 
of randomization until tumor progression or 
death due to any cause in patients who are PD-
L1 positive (>=1%) based on either tumor or 
immune cell staining

OS in PD-L1 positive patients: Time from date 
of randomization until the date of death by any 
cause in patients who are PD-L1 positive 
(>=1%) based on either tumor or immune cell 
staining

ORR: The percentage of evaluable patients with 
an Investigator-assessed visit response of CR or 
PR 

CR rate: Disappearance of all target and non-
target lesions DoR in Patients with a CR: Time 
from date of first detection of CR until the date 
of objective disease progression according to 
RECIST 1.1
To assess the effect of durvalumab + SoC CCRT 
compared with placebo + SoC CCRT on the 
incidence of local progression, distant disease 
progression, and secondary malignancy as the 
first documented progression event

Incidence of Local Progression, Distant Disease 
Progression, and Secondary Malignancy: 
Number and percentage of patients who 
develop local progression, distant disease 
recurrence, or secondary malignancy 


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Objectives and Endpoints
To assess disease-related symptoms and health 
related quality of life (HRQoL) in patients with 
cervical cancer treated with durvalumab + SoC 
CCRT compared with placebo + SoC CCRT 
using the core quality of life questionnaire 
(EORTC QLQ-C30) and core quality of life 
questionnaire cervical cancer module (CX24) 

Change from baseline in EORTC QLQ-C30 
and EORTC CX24
To assess the PK of durvalumab when in 
combination with CCRT 
Blood concentration of durvalumab 
To investigate the immunogenicity of 
durvalumab in both arms in combination with 
CCRT 
Presence of ADAs 
Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab + SoC CCRT compared to placebo 
+ SoC CCRT
AEs, laboratory findings, vital signs, and physical 
examinations,
Exploratory objective:
Endpoint/variable:
To collect blood and tissue samples for defining 
biological response to durvalumab +SoC CCRT 
compared to placebo +SoC CCRT for candidate 
markers that may correlate with likelihood of 
clinical benefit. (All countries except China)

Analysis of blood/tissue samples to assess 
exploratory biomarkers, which may include, but 
is not limited to ctDNA, mRNA signatures, 
CD8 by IHC, and Tumor Mutational Burden 
(TMB)
To assess treatment-related symptoms using the 
patient-reported outcomes version of the 
Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)

Specific treatment-related PRO-CTCAE 
symptoms 
To assess how a patient perceives her overall 
change in cancer symptoms since the start of 
study treatment using the PGIC and overall 
severity of cancer symptoms using PGIS.

PGIC and PGIS
To explore the impact of treatment and disease 
state on health status assessed by EuroQol five-
dimensional five-level questionnaire (EQ-5D-
5L) to support health economic analysis and 
health technology assessment

EQ-5D-5L
To describe and evaluate resource use associated 
with durvalumab treatment and underlying 
disease

Health resource utilization measures 
including hospitalization, outpatient visits, 
or emergency department visits 
Abbreviations: ADA Antidrug antibody; AE Adverse event; BICR Blinded independent central review; CCRT 
Concurrent chemoradiation therapy; CR Complete response; EORTC European Organization for Research and 
Treatment of Cancer; EQ-5D-5L EuroQol five-dimensional five-level questionnaire; HOSPAD Hospital 


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Admission; HRQoL Health-related quality-of-life; IHC Immunohistochemistry; ORR Objective response rate; 
OS Overall survival; PFS Progression-free survival; PFS (3yr) Progression-free survival at 3 years; PGIC Patient 
Global Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; PR Partial 
response; PRO-CTCAE Patient-reported oucomes version of the Common Terminology Criteria for Adverse 
Events; QLQ-C30 30item core quality of life questionnaire; QLQ-CX24 Cervical cancer module; RECIST 
Response Evaluation Criteria in Solid tumors; SoC CCRT Standard of care concurrent chemoradiation therapy.
Overall design:
This is a randomized, double-blind, placebo controlled, multi-center, global, Phase III study to 
determine the efficacy and safety of durvalumab when combined with SoC CCRT and 
administered as adjuvant therapy following SoC CCRT compared to placebo with SoC CCRT 
as systemic treatment in patients with FIGO (2009) Stage IB2 to IVA cervical cancer.
In order to be eligible for this study, patients must be ≥18 years of age with FIGO (2009) 
Stage IB2 to IIB N+ and IIIA to IVA with any N. Patients must not have previously received 
any definitive surgical, radiation, or systemic therapy for cervical cancer and must be 
immunotherapy-naïve. 
Approximately 714 patients from multiple sites will be randomized 1:1 to receive either 
durvalumab 1500 mg or placebo every 4 weeks (q4w) for 24 doses. In China, recruitment will 
continue until approximately 105 Chinese patients have been randomised, irrespective of 
whether or not the overall study enrolment has been reached. It is anticipated that this target 
may not be met before the global recruitment of approximately 714 is achieved. Patients in 
both arms will receive SoC CCRT consisting of external beam radiotherapy (EBRT) and 
brachytherapy (See Appendix G) , and concurrent cisplatin 40 mg/m2 every 1 week (q1w) × 5 
weeks with an optional 6th week  (See Section 6.1.2 for descriptions of the dosing regimen.) 
Randomization will be stratified by disease stage status (FIGO (2009) Stage <III and node 
positive, FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node 
positive), and region [United States, Canada, European Union, South Korea, and Japan] versus 
rest of the world. Patients will receive their assigned treatment until completion of planned 
therapy, clinical progression or RECIST 1.1-defined or histopathologic confirmation of local 
disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation 
criteria is met. (See Section 7.1 for additional details on discontinuation of study treatment.) 
Following completion of SoC CCRT, patients will be evaluated by clinical and radiological 
assessment. During the first 3 years (164 weeks) after randomization, this assessment will 
include an interval history for new signs or symptoms, physical examination including a 
pelvic examination to evaluate for local cervical cancer progression, and imaging (computed 
tomography [CT] scan or magnetic resonance imaging [MRI]) per RECIST 1.1 or 
histopathologic assessment every 12 weeks (q12w). During Years 4, and 5, 
imaging/histopathologic assessments will be performed every 6 months (24 weeks) and then 
annually until a PFS endpoint has been met or closure of the study.


Clinical Study Protocol - 4.0
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Study Period:
Estimated date of first patient enrolled Q1 2019
Estimated date of last patient completed Q2 2024
Number of patients:
Approximately 714 patients from multiple sites will be randomized 1:1 to receive either 
durvalumab + SoC CCRT or placebo + SoC CCRT. In China, recruitment will continue until 
approximately 105 Chinese patients have been randomised, irrespective of whether or not the 
overall study enrolment has been reached. It is anticipated that this target may not be met 
before the global recruitment of approximately 714 is achieved.
Treatments and treatment duration:
Durvalumab 1500 mg via intravenous (IV) infusion q4w, starting C1D1, until completion of 
planned treatment or progression of disease (PD). (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).
Placebo: Sterile solution of 0.9% (weight/volume [w/v]) sodium chloride for injection via IV 
infusion q4w, starting on C1D1, until completion of planned treatment or PD. 
Chemoradiotherapy:

Cisplatin 40 mg/m2 IV q1w × 5 weeks. Per investigator discretion, patients can 
continue with an optional 6th week of platinum agent. 

See Appendix G for details regarding the radiotherapy regimen.
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
completion of planned therapy or clinical progression or RECIST 1.1-defined or 
histopathologic confirmation of local disease progression. 
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 


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patient. A follow-up scan is to be collected after the initial RECIST 1.1-defined PD, no later 
than the next scheduled imaging visit, and no less than 4 weeks after the prior assessment of 
PD; this scan is evaluated using the criteria outlined in Appendix F. If the subsequent scan 
does not demonstrate radiological PD, then patient should continue IP. Scanning should 
continue until the next RECIST 1.1-defined PD which in turn will require a subsequent scan 
(must be evaluated using the criteria outlined in Appendix F). 
Alternatively, patients may continue treatment until histopathological determination of tumor 
progression on biopsy. Patients may not continue on durvalumab/placebo if there is 
histopathological determination of progression. 
Follow-up of patients post-discontinuation of study treatment
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 PD (based on RECIST 1.1) plus an additional follow-up scan 
or until death (whichever comes first) and followed for survival. 
Survival
All patients randomized in the study should be followed for survival.
Independent Data Monitoring Committee:
An independent data monitoring committee (IDMC) composed of independent experts will be 
convened to confirm the safety and tolerability of the proposed dose and schedule of 
durvalumab + SoC CCRT. The first safety review will take place when the first 25 patients 
across both treatment arms have completed SoC CCRT and have had at least 28 days of 
follow-up. The second safety review will take place when the first 60 patients across both 
treatment arms have completed SoC CCRT and have had at least 28 days of follow-up. Safety 
reviews will be carried out by the IDMC in an unblinded manner. After review of the 
unblinded data, the IDMC will make a recommendation on whether the study should continue 
recruitment as planned or hold recruitment.
An additional safety review for Japanese patients will take place when the first 9 patients in 
Japan have completed SoC CCRT and had 28 days of follow-up. This review will be carried 
out by the IDMC in an unblinded manner. After review of the unblinded data, the IDMC will 
make a recommendation on whether the study should continue recruitment as planned or hold 
recruitment in Japan.
In addition, the IDMC will meet approximately every 6 months thereafter to continue safety 
monitoring. 


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Full details of the IDMC procedures and processes can be found in the IDMC Charter.
Statistical methods
The primary objective of this study is to assess the efficacy of durvalumab + SoC CCRT 
compared with placebo + SoC CCRT in terms of PFS as assessed by investigator tumor 
assessments and histopathologic confirmation of local tumor progression. PFS (per RECIST 
1.1 as assessed by investigator tumor assessments or histopathologic confirmation of local 
tumor progression) will be defined as the time from the date of randomization until the date of 
objective disease progression or death (by any cause in the absence of progression) regardless 
of whether the patient withdraws from therapy or receives another anticancer therapy prior to 
progression (ie, date of event or censoring – date of randomization + 1). A key secondary 
objective is to assess the efficacy of durvalumab + SoC CCRT compared with placebo + SoC 
CCRT in terms of OS. In order to provide strong control of the type I error rate α=5% (2-
sided), the testing procedure for the primary endpoint and key secondary endpoint is 
hierarchical.
The analysis of the secondary endpoints of PFS (3 year), PFS and OS in PD-L1 positive 
patients, ORR, and CR rate will be based on investigator assessments using RECIST 1.1 or 
histopathologic confirmation of local progression. In addition, the key secondary endpoint 
(OS) and other secondary endpoints (Incidence of Local Progression, Distant Disease 
Recurrence, and Secondary Malignancy) will also be analyzed.
Efficacy data will be summarized and analyzed on an intent-to-treat (ITT) basis, and the
treatment arms will be compared on the basis of randomized treatment, regardless of the 
treatment actually received. Patients who were randomized but did not subsequently go on to 
receive study treatment are included in the full analysis set (FAS) population.
Approximately 714 patients will be randomized 1:1 to durvalumab + SoC CCRT or placebo + 
SoC CCRT to obtain approximately 227 PFS events in the ITT population. The randomization 
will be stratified according to disease stage status (FIGO (2009) Stage <III and node positive, 
FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node positive) and 
region [United States, Canada, European Union, South Korea, and Japan] versus rest of world.
The primary endpoint of PFS will be tested once. The secondary endpoint of OS will be tested 
at an interim and at a final timepoint. The alpha level allocated to OS will be controlled at the 
interim and final timepoints using the Lan DeMets (Lan and DeMets 1983) spending function 
separately for PFS and OS that approximates the O’Brien-Fleming approach, where the alpha 
allocated at the interim depends upon the proportion of information available. 


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The analysis of PFS and the interim analysis of OS will occur when approximately 227 PFS 
events have occurred across the durvalumab + SoC CCRT and placebo + SoC CCRT 
treatment arms. If the true hazard ratio (HR) for PFS is 0.65 (likely to correspond to an 11% 
increase in the proportion of patients event-free at 3 years from 65% to 76%), this analysis 
will have 90% power to demonstrate a statistically significant difference for PFS, assuming a 
2-sided 5% significance level. Given the recruitment assumptions for PFS outlined above, the 
analysis for PFS is anticipated to occur approximately 53 months following the randomization 
of the first patient. It is anticipated that 86% of the target number of OS events (ie, 
approximately 195 of 227 OS events) will be available for the OS interim analysis.
The final OS analysis will occur at the earlier of 227 death events or 71 months following 
recruitment of the first patient. Assuming the same recruitment assumptions for PFS and a 3-
year OS rate of 70% for placebo + SoC CCRT (Rose et al 1999), 227 deaths would be 
expected to occur 61 months following the randomization of the first patient. If the true hazard 
ratio (HR) is 0.65 (likely to correspond to an 9% increase in the proportion of patients alive at 
3 years from 70% to 79%), this analysis will have 89% power to demonstrate a statistically 
significant difference for OS, assuming a 2-sided 5% significance level.
The primary PFS analysis will be based on the programmatically derived RECIST 1.1 using 
the investigator tumor assessments or histopathologic confirmation of local tumor progression. 
The effect of durvalumab + SoC CCRT versus placebo + SoC CCRT will be analyzed using a 
log-rank test stratified by disease stage status (FIGO (2009) Stage <III and node positive, 
FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node positive) and 
region [United States, Canada, European Union, South Korea, and Japan] versus rest of the 
world. The HR together with its 95% CI and p-value will be presented (an HR less than 1 will 
favor durvalumab + SoC CCRT). The HR and CI will be estimated from a stratified Cox 
proportional hazards model using the same strata as for the primary analysis by stratified log 
rank test and using the Efron model for ties. The point estimate of the treatment effect, i.e. HR 
will be obtained by maximizing the Cox partial likelihood functions, which is the product of 
the likelihood of each stratum (an HR less than 1 will favor durvalumab + SoC CCRT). The 
95% CI will be estimated using the profile likelihood approach. The 95% CI and HR from the 
stratified Cox proportional hazards model will be in support of the p-value from the stratified 
log rank test, no p-value will be reported from the stratified Cox proportional hazards model.
Safety is a secondary endpoint in this study. All safety analyses will be performed on the 
safety population. Safety and tolerability data will be presented by treatment arm using the 
safety population. Safety data will be summarized descriptively and will not be formally 
analyzed.


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1.3
Schema
The general study design is summarized in Figure 1. 
Figure 1
Study design
Abbreviations: brachy Brachytherapy; EBRT External Beam Radiotherapy; FIGO (2009) International 
Federation of Gynaecology and Obstetrics; q4w Every 4 weeks.


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2.
INTRODUCTION
2.1
Study rationale
Cervical cancer is the 4th most common cancer in women worldwide despite the introduction 
of the Pap smear for early screening and prevention of cervical cancer in the 1950s, and more 
recently, HPV vaccination. Many women continue to be diagnosed with and die from this 
disease, with an estimated 528000 new cases diagnosed in 2012 and 266000 deaths (Ferlay et 
al 2013). North America has the third lowest rate of cervical cancer; however, in the US there 
were 12109 women diagnosed with cervical cancer and 4092 deaths in 2011 (Benard et al 
2014). In contrast, in China 98900 women were diagnosed with cervical cancer and 30500 
women died of the disease in 2015 (Chen et al 2016). Overall, the 5-year OS in this patient 
population remains poor with survival at Stage IIB 58%, IIIA 35%, and IVA 16% (Ferlay et al 
2013).
Rates of cervical cancer vary greatly between the developing world and developed countries 
due to disparities in access to care and preventive screening. The Pap smear was introduced in 
the 1950s as a screening method to diagnose atypical, premalignant lesions and early stage 
cervical cancer. United States Preventive Services Task Force (USPSTF) guidelines 
recommend screening for cervical cancer in all women aged 21 to 65 years and screening for 
HPV every 5 years in women aged 30 to 65 years (USPSTF 2016). Where implemented, this 
preventive care measure has reduced the incidence of advanced stage cervical cancer 
dramatically. However, most women globally do not have access to screening, and thus the 
global incidence of cervical cancer at all stages continues to rise throughout the world as the 
population rises and ages. Additionally, there are barriers to cervical cancer screening. Only 
25% of women in Japan are screened for cervical cancer, and the rates of screening in China 
and India are similarly low with less than 20% of women in China screened and less than 10% 
in India (De Sanjose 2012). In contrast, the rate of women screened in the US is 88.6% 
(Benard et al 2014).
2.1.1
Rationale for combining checkpoint inhibitor therapy with 
chemoradiotherapy
Concurrent chemoradiation therapy (CCRT) have been shown to induce immunogenic cell 
death. Cell death, from radiation or CCRT, enhances the ability of the immune system to 
recognize and respond to the tumor through enhanced antigen release and presentation (tumor 
specific T cell activation; Formenti and Demaria 2013, Weichselbaum et al 2017). In addition, 
ionizing radiation causes upregulation of various pro-inflammatory signals and cytokines, 
which play a key role in immune regulatory pathway, leading to improved anti-tumor 


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immunity. Victor et al also showed that radiation enhanced the diversity of the T cell receptor 
repertoire of intra-tumoral T cells (Twyman-Saint Victor et al 2015).
Radiotherapy induces double-stranded deoxyribonucleic acid (DNA) breaks that are 
catastrophic for the rapidly dividing tumor cells, promoting a cascade of cytokine release and 
mitochondrial disruption and results in apoptosis and activation of both the innate and 
adaptive immune system. This mechanism promotes neoantigen production, resulting in 
antigen presentation to dendritic cells, natural killer (NK) cell activation, and cluster of 
differentiation 8 (CD8) + T cell recruitment to the area of damage (Salama et al 2016).
The PACIFIC trial evaluated the efficacy of durvalumab after definitive chemoradiotherapy in 
Stage III NSCLC compared to placebo after chemoradiotherapy and found a significant 
improvement with durvalumab with a median PFS of 16.8 months (95%CI 13.0 to 18.1) 
compared to 5.6 months (95%CI, 4.6 to 7.8) in the placebo controlled group (Antonia et al 
2017). This improvement in PFS in this patient population was thought to be due to multiple 
variables, with the highly immunogenic tumor microenvironment associated with 
chemoradiotherapy likely an important contributor. 
Concomitant administration of radiotherapy with anti-PD-L1 monoclonal antibodies (mAb) 
resulted in substantially improved survival benefit in a mouse model. Here, low dose 
fractionated radiotherapy resulted in an increase in interferon gamma (IFN-y) producing 
CD8+ T cells and PD-L1 tumor expression during radiotherapy, peaking at 72 hours after the 
last dose and significantly declining at 7 days after radiotherapy (Dovedi et al 2014). 
Radiation therapy can additionally induce an abscopal effect, where tumors not directly in the 
field of radiation therapy also become more immunogenic due to the release of neoantigens 
from the tumor site, when given sequentially (Postow et al 2012) and also concurrently 
(Stamell et al 2013).
The use of concurrent durvalumab therapy with chemotherapy and/or radiotherapy is currently 
being studied in NSCLC 
 (
), colorectal cancer 
(
), urothelial bladder cancer 
, and hepatocellular carcinoma 
(NCT02821754). 
The use of combination chemoradiotherapy is a mainstay of oncology therapy in multiple 
tumor types. The goal of combination chemotherapy is to utilize agents that affect cancer cells 
by different mechanisms, thus improving clinical responses and reducing the risk of 
developing resistance. Non-clinical and clinical studies have indicated that blockade of 
immune checkpoints (PD-1/PD-L1 and CTLA-4) can have a positive effect on anti-tumor 
immunity. Chemotherapy is thought to synergize with PD-1/PD-L1 blockade by making the 
tumor “immunogenic” by initiating cell death, promoting phagocytosis of tumor cells, and 
ultimately leading to reactivation of immune-mediated tumor surveillance (Menderes et al 
CCI
CCI
CCI
CCI


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2016). Current studies are now adding immunotherapeutics to chemoradiotherapy to broaden 
anti-tumor responses through recruitment of the immune system.
The study’s hypothesis is that durvalumab, when administered with SoC CCRT and as 
adjuvant therapy following SoC CCRT, will improve PFS when compared to SoC CCRT 
combined with placebo.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the current IB.
2.2.1
Human papilloma virus infection in cervical cancer
Persistent infection with HPV is central to the onset of cervical cancer. There are more than 
120 HPV types that have been identified, with 40 types infecting the genital tract and 
15 potentially oncogenic. About 50% and 20% of cervical cancer has been linked to HPV 16 
and HPV 18 infections, respectively. HPV infection occurs through microtrauma to the 
suprabasal epidermal cells, allowing the virus access to the basal layer. Viral oncoproteins E6 
and E7 promote tumor suppressor p53 degradation and Rb inactivation, respectively, 
promoting carcinogenesis (Lowy and Schiller 2006). Cell cycle deregulation mediated by 
deactivation of tumor suppressors and integration of HPV into host genome are key precursors 
to the invasive disease (Crosbie et al 2013). The most common screening methods for cervical 
cancer include conventional Papanicolaou (Pap) smear and HPV DNA testing, depending on 
the geographical region. The Pap smear can identify cellular abnormalities whereas the HPV 
test can detect suspicious viruses (Jin 2014). For many years, the Pap smear has been the 
standard method for cervical cancer screening, reducing the incidence by 60% to (Marth et al 
2017) and has been shown to provide 60% to 70% greater protection against invasive cancer 
compared with cytology-based screening (Ronco et al 2014).
To prevent a primary infection with HPV, the quadrivalent vaccine Gardasil was approved by 
the FDA in 2006 for children and adults between the ages of 11 to 25 years. Currently, there 
are 3 vaccines in use: the Cervarix bivalent vaccine, which targets HPV 16 and 18, the 
Gardasil quadrivalet vaccine (HPV 6, 11, 16, and 18) and the Gardasil-9, a 9 valent HPV 
vaccine (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58). HPV vaccination is part of the National 
Immunization Programs (NIP) or pilot demonstration programs in 83 countries (Markowitz et 
al 2012); however, there are instances where the vaccination program is not being optimally 
utilized. In Japan, for example, the proactive recommendations for the HPV vaccine were
suspended 2 months after its inclusion into the NIP in 2013 after unconfirmed reports of AEs 
following vaccination (Hanley et al 2015). As a result, current low uptake of the HPV vaccine 
in Japan (3.5% in 7th to 11th grades in 2013) may potentially lead to a high incidence of 
cervical cancer in the future (Sekine et al 2016). As of October 2014, about 59.2 million 


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women have received at least 1 dose of the vaccine, with the majority of women from high-
income and upper-middle income countries. With increasing vaccine utilization, it is expected 
that by 2080 that approximately 440000 cervical cancer cases will be prevented; yet, because 
many countries have not implemented widespread vaccination or because the cost of vaccine 
precludes its widespread implementation, an additional 510000 women will develop cervical 
cancer during this interval (Bruni et al 2016).
2.2.2
Staging of cervical cancer
Cervical tumors are staged using FIGO (2009) classification, which is the most widely used 
classification (Haie-Meder et al 2010) and is one of the most important prognostic factors 
(Marth et al 2017). Cervical cancer is the only gynecological cancer that is clinically staged 
based on tumor size, vaginal or parametrial involvement, bladder/rectum extension, and
distant metastases. It requires examination under anaesthesia, radiological imaging such as 
chest X-ray and IV pyelogram, or other diagnostic tools. CT can detect pathological lymph 
nodes, MRI can determine tumor size, degree of stromal penetrations, parametrial 
involvement, vaginal extension, and corpus extension with high accuracy (Wagenaar et al 
2001).
2.2.3
Lymph node status in cervical cancer
Lymph node status is not part of the FIGO (2009) staging system for cervical cancer, but 
provides important information for prognosis and treatment (Gien and Covens 2009). As the 
FIGO stage increases, the risk of lymph node metastasis and parametrial involvement also 
increases. In patients who have had a surgical resection, the incidence of pelvic lymph node 
metastasis in Stage IB cervical cancer ranges from 11.5% to 21.7% (Lee et al 2006). For Stage 
IIA and IIB cervical cancers, the incidence ranges from 10% to 26.7% and 28.6% to 43.4%, 
respectively (Benedetti-Panici et al 1996, Havrilesky et al 2004, Inoue et al 1990, Lai et al 
1993, Lee et al 2006, Morice et al 1999, Sakuragi et al 1999). In patients with Stage IB 
cervical cancer, the incidence of para-aortic node involvement is low at 2% to 4%. In the more 
advanced stages, the incidence increases to 7% to 17% (Benedetti-Panici et al 1996, Berman 
et al 1984, Morice et al 1999, Sakuragi et al 1999).
Lymph node status is a prognostic predictor of survival (Macdonald et al 2009). The 3 year 
OS in FIGO (2009) Stage IB to II node-positive patients is lower (55%) compared to 
node-negative (94%) (Morice et al 1999). Based on data from over 2200 patients in Stage IA1 
to IIB, higher number of positive lymph nodes is associated with adverse survival outcomes 
(Zhou et al 2017), and the extra-pelvic recurrence is higher in patients with ≥3 involved lymph 
nodes compared to patients with 0 to 2 lymph nodes (data from 141 patients, Stage IB to IIB) 
(Kasuya et al 2013). Typically, the adjacent obturator nodes will be the first site of lymph 
node metastasis, and then it will spread in a step-wise fashion to the ipsilateral common iliac 
lymph nodes and para-aortic lymph nodes (PALN). Patients with PALN metastasis have lower 


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survival rates and need extended field radiation (EFRT). In a retrospective study looking at 90 
patients with Stage IB to IVA cervical cancer and PALN metastasis between 1987 and 2012, 
it was shown that EFRT was an efficient treatment for uterine cervical cancer with involved 
PALN, with a 5-year OS of 62.6% and PFS of 43.9% (Yoon et al 2015).
2.2.4
Treatment of cervical cancer
Stage IA1 cervical cancer is typically managed conservatively to preserve fertility, with 
conization without lymphadenectomy because the risk of nodal metastasis is <1%. Stage IA2 
with no lymphovascular space involvement can be treated by conization (if fertility is to be 
preserved) or extrafascial hysterectomy. In patients with surgical contraindication, 
brachytherapy may represent an alternative option. Stages IB and IIA cervical carcinoma can 
be cured by radical surgery including pelvic lymphadenectomy or radiotherapy (Haie-Meder 
et al 2010). In women with locally advanced cervical cancer (Stages 1B2 to IVA), cisplatin 
with concurrent radiotherapy has remained the SoC (Colombo et al 2012) and is unchanged 
since 1999 (Rose et al 1999, Koh et al 2013).
For women who develop locally advanced cervical cancer, the SoC has evolved from EBRT 
alone, to EBRT plus brachytherapy, to combined EBRT plus brachytherapy with concurrent 
chemotherapy (Green et al 2001). Brachytherapy involves the application of a radioactive 
source in close proximity to the tumor, allowing a very high dose of radiation being delivered 
to the tumor with relative sparing of the surrounding normal structures (Banerjee and 
Kamrava 2014). Brachytherapy treatments are either interdigitated with EBRT (generally, 
starting no earlier than Week 3 of treatment) or are given after EBRT is completed. Starting 
brachytherapy later in the treatment course allows for maximal tumor shrinkage, thus allowing 
for smaller brachytherapy treatment volumes. Ultimately, the most critical part of deciding 
when to start brachytherapy is the monitoring of treatment response, through regular pelvic 
examinations during the course of EBRT (Banerjee and Kamrava 2014). Brachytherapy can 
be performed using an intracavitary, interstitial, or combination approach. Intracavitary 
brachytherapy involves placing the radioactive source using an applicator, through the vaginal 
cavity, and can treat the upper vagina, cervix, and uterus. In interstitial brachytherapy, 
catheters (small tubes) are placed in and around residual disease, using a transperineal/vaginal 
approach. The choice of technique depends primarily on disease extent and anatomy (Banerjee 
and Kamrava 2014).


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In the pivotal study, Rose et al 1999 randomized 526 women with Stage IIB, III, or IVA 
cervical cancer to receive radiation therapy with either cisplatin, cisplatin with 5-fluorouracil 
(5FU) with hydroxyurea or hydroxyurea alone. For the cisplatin monotherapy cohort when 
compared to hydroxyurea monotherapy, the PFS risk ratio (RR) of 0.57 (95% CI 0.42 to 0.78) 
and OS RR of 0.61 (95%CI 0.44 to 0.85) were observed and was similar to- the cisplatin with 
5FU group (PFS RR=0.55). Toxicities included cytopenias-, gastrointestinal (GI) effects, renal
toxicity, and neurotoxicity (Rose et al 1999). Additionally, the duration for CCRT 
administration is critical to patient outcome. Completion of CCRT in 56 days compared to 
more than 56 days was associated with benefits in reduced pelvic failure rate and improved 
OS, compared to prolonged CCRT administration (Song et al. 2013, Petereit et al. 1995). In 
certain clinical scenarios, carboplatin has been substituted for cisplatin as a radiosensitizer,. 
The potential difference between carboplatin and cisplatin was retrospectively evaluated in 
247 women receiving definitive chemoradiotherapy for locally advanced cervical cancer. In 
this evaluation, cisplatin was superior, with a CR rate of 88.3% compared to 73.9% (p=0.004) 
(Valdivieso et al 2017). However, in women that are unable to receive cisplatin due to specific 
pre-existing conditions such as renal insufficiency or peripheral neuropathy, carboplatin is an 
acceptable alternative. Another study evaluated 51 women who received concurrent 
carboplatin with radiotherapy in comparison to a historical control of cisplatin with 
radiotherapy, and there was no appreciable difference in OS and PFS between the 2 groups; 
there was an increase in the number of cycles administered and a reduction in AEs in the 
carboplatin group (Nam et al 2013). An additional retrospective study of 148 women treated 
with carboplatin and concurrent radiotherapy showed that 142 (95.9%) women had a CR and 
only 6 (4.1%) had persistent disease. The 2-year PFS and OS rates were 75.1% and 81.9%, 
respectively (Katanyoo et al 2011). In patients that are able to receive cisplatin, both the 
NCCN guidelines (NCCN 2020) and ESMO guidelines (Marth et al 2017
) for cervical cancer recommend cisplatin to be given with EBRT.  To ensure appropriate 
balance between patients treated with cisplatin and carboplatin as the radiosensitizer across 
regions in the ongoing study, no further use of carboplatin as the radiosensitizer will be 
allowed in this study. 
Although data are limited, available evidence suggests that concurrent chemoradiotherapy is 
superior to sequential treatment. An analysis of the trials evaluating systemic chemotherapy 
after chemoradiotherapy showed that there is limited benefit and instead there may be an 
increased toxicity in this patient population (Tangjitgamol et al 2014). Currently, the 
Gynecologic Oncologic Group (GOG) is performing a Phase III randomized multicenter study 
in 900 women with cervical cancer to evaluate the efficacy of carboplatin with paclitaxel 
given adjuvantly following definitive chemotherapy/radiotherapy with a primary endpoint of 
OS (OUTBACK Trial, NCT01414608). 
Surgery is not typically indicated in patients with locally advanced cervical cancer. . In a 
single-center Phase 3 randomized controlled clinical trial, 633 women with locally advanced 


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cervical cancer were randomly assigned to receive neoadjuvant chemotherapy followed by 
radical hysterectomy or chemoradiotherapy without surgery; those who received surgery had 
decreased 5-year disease-free survival (DFS) (69.3% versus 76.7%, p=0.038) (Gupta et al 
2018) In a retrospective analysis of 211 patients undergoing definitive chemoradiation and 
brachytherapy, completion hysterectomy after definitive chemoradiation and brachytherapy 
was associated with increased morbidity with no change in OS or DFS. Cumulative incidence 
of severe late morbidity was observed in 22.5% of patients in in the group that received a 
hysterectomy compared to 6.5% in the non-hysterectomy group (p=0.016) (Mazeron et al 
2016). 
The relapse rate of cervical cancer ranges between 28 and 64% in FIGO (2009) Stages IIB to 
IVA (Quinn et al 2006). Although the majority of the recurrences develop in the first 2 to 3 
years after treatment, in some patients, cervical cancer recurs after 3 years (Elit et al 2009, 
Fuglsang et al 2015, Wiebe et al 2012). 
2.2.5
Cervical cancer establishes an immunosuppressive environment
HPV is the primary causative agent for the majority of cervical cancer cases, with more than 
90% of squamous cervical cancers containing HPV DNA. In the presence of a chronic HPV 
infection, a natural immune response develops with activation of the adaptive immune system. 
HPV proteins E6 and E7 also promote neoantigen generation, further stimulating the immune 
response (Qin et al 2017). However, the viral oncoproteins E5, E6, and E7 play a role in 
immune evasion, with E5 inhibiting expression of human leukocyte antigens-A (HLA-A) and 
HLA-B. This results in evasion of CTL and NK cell killing (Menderes et al 2016). HPV16 
positive tumors have a unique immune suppressive environment with increasing numbers of 
tumor-associated macrophages observed, contributing to chronic infection (Lepique et al 
2009). From retrospective tissue evaluation of pre-malignant cervical tissue, there is 
increasing PD-1 expression seen on cervical T cells with increasing levels seen at higher 
grades of cervical intraepithelial neoplasia (Yang et al 2017). On evaluation of tumor tissue 
from 115 patients with cervical cancer, PD-L1 was expressed in 19% of samples, and 
programmed death-ligand 2 (PD-L2) expressed in 29% of tumors (Karim et al 2009).
Histologically, cervical cancer is predominantly squamous cell carcinoma (80% to 90%) with 
a high tumor mutational burden (TMB). Chronic HPV infection is thought to contribute to 
continued somatic mutations and therefore the high TMB in cervical cancer. This high 
mutational load in cervical cancer additionally correlated with increased expression of PD-L1, 
transforming growth factor beta (TGF-β), and interleukin 10 (IL-10), which supports the role 
for immunotherapy (Qin et al 2017). Cervical cancer additionally evades the immune response 
through mutations in the IFN-γ signaling pathway and Janus Kinase 2 (JAK2) (Ojesina et al 
2014). The TMB is thought to be directly correlated to response of immune checkpoint 
inhibitor therapy, which appears to be true for cervical cancer as well (Yarchoan et al 2017).


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These nonclinical studies demonstrate that immune suppression is an important factor for PD 
in cervical cancer. By promoting an immunogenic environment through chemoradiotherapy, 
there is an opportunity to change the balance in cancer progression through checkpoint 
inhibitor therapy.
2.2.6
Previous checkpoint inhibitor therapy in cervical cancer
Based on the strong rationale for immunotherapy in this patient population, multiple studies 
have been done in patients with cervical cancer that were previously treated. In Study CD-
ON-MEDI4736-1108 (hereafter referred to as Study 1108), 10 women with cervical cancer 
were treated with durvalumab monotherapy; an ORR of 20% (2/10) was observed. This is 
broadly consistent with results seen with other checkpoint inhibitors in previously treated 
cervical cancer. The KN-158 trial treated 98 women with cervical squamous cell cancer with 
pembrolizumab. This study demonstrated an ORR of 12% (12/98) with 3 patients with a CR 
(Schellens et al 2017). The  FDA granted accelerated approval to pembrolizumab for the 
treatment of patients with advanced, PD-L1-positive cervical cancer with disease progression 
on or after chemotherapy in June 2018. CheckMate 358 treated 19 women with recurrent 
cervical cancer with nivolumab and found an ORR of 26.3% and median PFS of 5.5 months 
(Hollebecque et al 2017). These checkpoint inhibitors were well tolerated and had a 
reasonable toxicity profile. PD-L1 and PD-1 expression positively correlates with HPV-
positivity, increase in cervical intraepithelial neoplasia (CIN) grade, and tumor metastasis. In 
fact, low expression (score 0 or 1) of PD-L1 was found to be a prognostic factor of tumor 
relapse, highlighting the need for patients with low or negative expression of PD-L1 to use 
more aggressive treatment other than conventional CRT (Yang et al 2017).
2.2.7
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells 
(Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; 
CD273) (Okazaki et al 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.


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PD-L1 is constitutively expressed by -B cells-, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly overexpressed on tumor cells or on nontransformed 
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 anti-tumor 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 anti-tumor 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 anti-tumor immune responses in patients
with cancer. Results of pre-clinical and clinical studies of mAbs targeting the PD-L1/PD-1 
pathway have shown evidence of clinical activity and a manageable safety profile, supporting 
the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance anti-
tumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Iwai et al 
2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) with responses that tend to 
be more pronounced in patients with tumors that express PD-L1 (Powles et al 2014, Rizvi et al 
2015, Segal et al 2015). In addition, high mutational burden (eg, in bladder carcinoma; 
Alexandrov et al 2013) may contribute to the responses seen with immune therapy.
Pre-clinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as 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, squamous cell carcinoma of the head and neck, and urothelial 
carcinoma. In addition there are data from agents in the anti-PD-1/PD-L1 class showing 
clinical activity in a wide range of tumor types.
2.2.8
Durvalumab
Durvalumab (MEDI4736, Imfinzi™) is a human monoclonal antibody (mAb) of the 
immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) 


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with PD-1 on T cells and CD80 (B7.1) on immune cells. It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-
1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those 
that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes 
the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation 
of IFN-γ (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor 
growth in xenograft models via a T cell-dependent mechanism (Stewart et al 2015). Based on 
these data, durvalumab is expected to stimulate the patient’s anti-tumor immune response by 
binding to PD-L1 and shifting the balance toward an anti-tumor response. Durvalumab has 
been engineered to reduce antibody-dependent cellular cytotoxicity and complement-
dependent cytotoxicity. 
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12. Refer 
to the current durvalumab IB for a complete summary of pre-clinical and clinical information 
including safety, efficacy, and PK.
2.3
Benefit/risk assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab may be found in the IB.
See Section 9.6.1 and Appendix A for information regarding the IDMC.
2.3.1
Potential benefits
2.3.1.1
Durvalumab as monotherapy in cervical cancer
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single-agent study, Study 1108, in patients with advanced solid tumors, the 
study of durvalumab monotherapy in NSCLC (Study D4191C00003 [ATLANTIC]), and the 
study of durvalumab monotherapy in NSCLC following completion of platinum-based 
chemotherapy concurrent with radiation therapy (the PACIFIC study). Data from these studies 
have demonstrated clinical activity of durvalumab therapy in patients with NSCLC. Study 
1108 included a 10-patient cohort with cervical cancer that showed 14.3% ORR following 
durvalumab monotherapy (10 mg/kg every 2 weeks [q2w]). Details pertaining to Study 1108 
and ATLANTIC are provided in the durvalumab IB. In a combination study of durvalumab 
with AXELimogene (HPV vaccine) in recurrent/persistent or metastatic cervical cancer, the 
durvalumab monotherapy arm showed 8% ORR, and ORR+ stable disease (SD) was 40%.


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PACIFIC has shown significant improvements in median PFS with durvalumab treatment 
compared with placebo for patients with NSCLC (16.8 months [95% CI: 13.0, 18.1] versus 
5.6 months [95% CI: 4.6, 7.8]; stratified HR for disease progression or death, 0.52; 95% CI: 
0.42, 0.65; p<0.001). Similar findings in favor of durvalumab compared with placebo were 
found for duration of response (72.8% versus 46.8% of patients had ongoing response at 
18 months, respectively) and median time to death or distant metastasis (23.2 months versus 
14.6 months, respectively; p<0.001). In addition, CCRT followed by durvalumab 
monotherapy (10 mg/kg q2w) was well tolerated and had a manageable safety profile relative 
to the SoC.
2.3.1.2
Concurrent immunotherapy and chemoradiotherapy in cervical cancer
Concurrent immunotherapy and chemotherapy
The efficacy of immunotherapy administered concurrently with chemotherapy agents is 
supported by recent results from the KEYNOTE021 study (pembrolizumab; PD-1 inhibitor), 
the CheckMate 012 study (nivolumab; PD-1 inhibitor), and preliminary results from 
The anti-tumor activity of pembrolizumab administration concurrent with various 
chemotherapy regimens versus chemotherapy (carboplatin-pemetrexed) alone as first-line 
treatment for NSCLC (the KEYNOTE-021 study) demonstrated ORRs of 55% (95% CI: 42, 
68) versus 29% (95% CI: 18, 41), respectively (p=0.0016), with durations of response of at 
least 6 months in 92% (95% CI: 73, 98) and 81% (95% CI: 51, 93), respectively (Langer et al 
2016).
The anti-tumor activity of nivolumab administered concurrently with platinum-based doublet 
chemotherapy as firstline treatment for advanced NSCLC (the CheckMate 012 study) 
demonstrated ORRs for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg 
plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 
5 mg/kg plus paclitaxel-carboplatin of 33%, 47%, 47%, and 43%, respectively, and 24-week 
PFS rates of 51%, 71%, 38%, and 51%, respectively (Rizvi et al 2016).
The efficacy of durvalumab ± tremelimumab with standard platinum-based chemotherapy in 
advanced cancers is being generated from 2 ongoing Phase I studies: internal 
Study
 and a 
 run by the Canadian Cancer 
Trials Group (CCTG). Study 
 is evaluating the safety and 
tolerability of durvalumab + tremelimumab in combination with first line chemotherapy 
regimens in patients with locally advanced or metastatic solid tumors: 
ovarian/peritoneal/fallopian tube cancer, squamous cell carcinoma of the head and neck 
(SCCHN), triple negative breast cancer (TNBC), small cell lung carcinoma (SCLC), and 
gastric/gastro-esophageal junction (GEJ) cancer, pancreatic ductal adenocarcinoma (PDAC) 
CCI
CCI
CCI
CCI


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and esophageal squamous cell carcinoma (ESCC). Results from this study are expected in 
2019. Patients in the CCTG study were treated with durvalumab ± tremelimumab at 1 of 4 
dose levels concomitantly with either pemetrexed + carboplatin/cisplatin followed by 
pemetrexed consolidation for non-squamous histology (45 patients) or gemcitabine + 
carboplatin/cisplatin for squamous histology (9 patients). Preliminary results from this study 
indicated that a total of 45 patients (44% male; median age=62 years [range 36 to 78]; 100% 
Eastern Cooperative Oncology Group [ECOG] PS ≤1) in the pemetrexed-platinum cohort 
received a total of 346 treatment cycles whereas 9 patients (78% male; median age=64 years 
[range 57 to 80]; 100% ECOG PS ≤1) in the gemcitabine-platinum group received a total of 
55 treatment cycles. The ORR was 57.1% (95% CI: 39.4, 73.7) in 35 evaluable patients 
receiving pemetrexed-platinum and 37.5% (95% CI: 8.5, 75.5) in 8 evaluable patients 
receiving gemcitibine-platinum (Juergens et al 2017). 
Concurrent immunotherapy and radiation therapy
Currently, over a dozen clinical studies are evaluating anti-PD-1 and anti-PD-L1 antibodies in 
administration concurrently with (as opposed to after completion of) radiation for cancer 
treatment, but robust efficacy results are not yet available (Weichselbaum et al 2017). Several 
non-clinical studies, as described below, suggest that inhibition of the PD-1/PD-L1 checkpoint 
combined with radiotherapy liberates T cells from immunosuppression, which in turn 
positively alters the tumor microenvironment owing to killing of suppressive cells via 
cytokine secretion. Mouse tumor models have been used to demonstrate the synergistic effect 
of radiotherapy and immunotherapy via checkpoint inhibition in solid tumors (Weichselbaum 
et al 2017). A preliminary non-clinical report from the Drake laboratory indicates that 
radiotherapy combined with anti-PD-1 antibody treatment can result in primary tumor control 
and an abscopal effect (Sharabi et al 2014). More recent data from the same group indicate 
that this therapy combination results in the induction of endogenous antigen-specific immune 
responses, leading to improved local control in single tumor models of melanoma or breast 
carcinoma (Sharabi et al 2015); however, no experiments on the abscopal effect were 
reported. Dovedi and Illidge (Dovedi and Illidge 2015) subsequently noted that the timing of 
anti-PD-L1 blockade is crucial; concurrent radiation and anti-PD-L1 treatment, but not 
sequential treatment, resulted in long-term tumor control, suggesting that concurrent 
administration of durvalumab and SoC radiotherapy may have improved clinical benefit over 
sequential therapy.
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against tumor cells. By stimulating the immune system, however, there is the potential for 
adverse effects on normal tissues.


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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 GI AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypo- and hyper-
thyroidism. 
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypo-thyroidism, type I diabetes mellitus and diabetes inspidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/dermatitis (including pemphigoid), myocarditis, myositis/polymyositis, immune 
thrombocytopenia, infusion-related reactions, hypersensitivity reactions, pancreatitis, serious 
infections, and other rare or less frequent inflammatory events including neuromuscular 
toxicities (eg, Guillain-Barré 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% includes events such as 
fatigue anddecreased appetite. Approximately 10% of patients discontinued the drug due to an 
AE. Please see the current version of the IB for a detailed summary of the monotherapy data 
including AEs, serious adverse events (SAEs), and common terminology criteria (CTC) 
Grades 3 to 5 events reported across the durvalumab program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
2.3.3
Overall benefit/risk
The clinical activity associated with potentiating the proinflammatory effects of CCRT 
suggests that giving durvalumab in combination with CCRT may have clinical benefits, 
including increasing the response rate to CCRT, improving the CR rate, and decreasing the 
number of patients who progress on CCRT. 


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Safety observations to date have demonstrated that concurrent administration of CCRT and 
immunotherapy has generally been well tolerated, with toxicities comparable to administration 
of either agent alone. The safety of concurrent administration of durvalumab and CCRT is 
further supported by results from the PACIFIC study, which showed that durvalumab 
administered within 42 days of completion of CCRT had a well tolerated and manageable 
safety profile that was consistent with the established safety profile to date.
Therefore, the overall benefit-risk assessment supports the proposed study to evaluate the 
efficacy and safety of concurrent administration of durvalumab + SoC CCRT.
3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/Variable:
To assess the efficacy of durvalumab + SoC 
CCRT compared with placebo + SoC CCRT in 
terms of PFS
Endpoints based on the investigator assessment 
according to RECIST 1.1 or histopathologic 
confirmation of local tumor progression:

PFS: Time from date of randomization until 
tumor progression or death due to any cause
Secondary objectives:
Endpoint/Variables:
To further assess the efficacy of durvalumab + 
SoC CCRT compared with placebo + SoC 
CCRT in terms of PFS (3 year), PFS in PD-L1 
positive patients, overall survival (OS) (key), OS 
in PD-L1 positive patients, ORR CR rate, and 
DoR in Patients with a CR

OS: Time from date of randomization until 
the date of death by any cause 
Endpoints based on the investigator assessment 
according to RECIST 1.1 or pathologic 
assessment of local disease progression

PFS (3 year): Proportion of patients alive 
and progression-free at 3 years

PFS in PD-L1 positive patients: Time from 
date of randomization until tumor 
progression or death due to any cause in 
patients who are PD-L1 positive (>=1%) 
based on either tumor or immune cell 
staining

OS in PD-L1 positive patients: Time from 
date of randomization until date of death by 
any cause in patients who are PD-L1 positive 
(>=1%) based on either tumor or immune 
cell staining


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
ORR: The percentage of evaluable patients 
with an Investigator-assessed visit response 
of CR or PR 

CR rate: Disappearance of all target and non-
target lesions DoR in Patients with a CR: 
Time from date of first detection of CR until 
the date of objective disease progression 
according to RECIST 1.1
To assess the effect of durvalumab + SoC CCRT 
compared with placebo + SoC CCRT on the 
incidence of local progression, distant disease 
progression, and secondary malignancy as the 
first documented progression event

Incidence of Local Progression, Distant 
Disease Progression, and Secondary 
Malignancy: Number and percentage of 
patients who develop local progression, 
distant disease recurrence, or secondary 
malignancy 
To assess disease-related symptoms and 
health-related quality of life (HRQoL) in 
patients with cervical cancer treated with 
durvalumab + SoC CCRT compared with 
placebo + SoC CCRT using the core quality of 
life questionnaire (EORTC QLQ-C30) and core 
quality of life questionnaire cervical cancer 
module (CX24) 

Change from baseline in EORTC QLQ-C30 
and EORTC CX24
To assess the PK of durvalumab when in 
combination with CCRT 

Blood concentration of durvalumab 
To investigate the immunogenicity of 
durvalumab in both arms in combination with 
CCRT 

Presence of ADAs 
Safety objective:
Endpoint/Variable:
To assess the safety and tolerability profile of 
durvalumab + SoC CCRT compared to placebo 
+ SoC CCRT

AEs, laboratory findings, vital signs, and 
physical examinations
Exploratory objective:
Endpoint/Variable:
To collect blood and tissue samples for defining 
biological response to durvalumab +SoC CCRT 
compared to placebo +SoC CCRT for candidate 
markers that may correlate with likelihood of 
clinical benefit. (All countries except China)

Analysis of blood/tissue samples to assess 
exploratory biomarkers, which may include, 
but is not limited to ctDNA, mRNA 
signatures, CD8 by IHC, and tumor 
mutational burden (TMB)
To assess treatment-related symptoms using the 
Patient-reported outcomes version of the 
Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)

Specific treatment-related PRO-CTCAE 
symptoms 


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To assess how a patient perceives her overall 
change in cancer symptoms since the start of 
study treatment using the PGIC and overall 
severity of cancer symptoms using the PGIS.

PGIC and PGIS
To explore the impact of treatment and disease 
state on health status assessed by EuroQol five-
dimensional five-level questionnaire (EQ-5D-
5L) to support health economic analysis and 
health technology assessment

EQ-5D-5L
To describe and evaluate resource use associated 
with durvalumab treatment and underlying 
disease

Health resource utilisation measures 
including hospitalization, outpatient visits, or 
emergency department visits 
Abbreviations: ADA Antidrug antibody; AE Adverse event; CR Complete response; ECG Electrocardiogram; 
EORTC European Organisation for Research and Treatment of Cancer; EQ-5D-5L EuroQol five-dimensional 
five-level questionnaire; HOSPAD Hospital Admission; HRQoL Health-related quality-of-life; IHC 
Immunohistochemistry; ORR Objective response rate; OS Overall survival; PFS Progression-free survival; PGIC 
Patient Global Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; PR 
Partial response; PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events; QLQ-C30 30-item core quality-of-life questionnaire; QLQ-CX24 Cervical cancer module; 
RECIST Response Evaluation Criteria in Solid tumors .
4.
STUDY DESIGN
4.1
Overall design
This is a randomized, double-blind, placebo controlled, multi-center, global, Phase III study to 
determine the efficacy and safety of durvalumab when combined with SoC CCRT and 
administered as adjuvant therapy following SoC CCRT compared to placebo with SoC CCRT 
as systemic treatment in patients with FIGO (2009) Stages IB2 to IVA cervical cancer.
In order to be eligible for this study, patients must be ≥18 years of age with FIGO (2009) 
Stages IB2 to IIB N+ and IIIA to IVA with any N. Patients must not have previously received 
any definitive surgical, radiation, or systemic therapy for cervical cancer and must be 
immunotherapy-naïve. (Additional details are provided in Sections 5.1 and 5.2.)
Approximately 714 patients from multiple sites will be randomized 1:1 to receive either 
durvalumab 1500 mg or placebo q4w for 24 doses. In China, recruitment will continue until 
approximately 105 Chinese patients have been randomised, irrespective of whether or not the 
overall study enrolment has been reached. It is anticipated that this target may not be met 
before the global recruitment of approximately 714 is achieved. Patients in both arms will 
receive SoC CCRT consisting of EBRT + brachytherapy , and concurrent cisplatin 40 mg/m2
q1w × 5 weeks. A 6th week of platinum agent can be given per investigator discretion (See 
Section 6.1.2 for descriptions of the dosing regimens.) Randomization will be stratified by 


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disease stage status (FIGO (2009) Stage <III and node positive, FIGO (2009) Stage ≥III and 
node negative, or FIGO (2009) Stage ≥III and node positive), and region [United States, 
Canada, European Union, South Korea, and Japan] versus rest of world. Patients will receive 
their assigned treatment until completion of planned therapy, clinical progression or 
RECIST 1.1-defined radiological progression or histopathologic progression on biopsy unless 
there is unacceptable toxicity, withdrawal of consent, or another discontinuation criteria is 
met. (See Section 7.1 for additional details on discontinuation of study treatment.) Following 
completion of SoC CCRT, patients will be evaluated by clinical and radiological assessment. 
During the first 3 years (164 weeks) after randomization, this assessment will include an 
interval history for new signs or symptoms, physical examination including a pelvic 
examination, and imaging (CT or MRI) per RECIST 1.1 or histopathologic assessment q12w. 
During Years 4, and 5, imaging/histopathologic assessments will be performed q24w and then 
annually until a PFS endpoint has been met or closure of the study (Section 9.2).
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered. 
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints. 
4.1.1.
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions and 
considerations if site personnel or study participants become infected with severe acute 
respiratory syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which 
would prevent the conduct of study-related activities at study sites, thereby compromising the 
study site staff or the participant’s ability to conduct the study. The investigator or designee 
should contact the study sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity. Where allowable by local health 
authorities, ethics committees, health care provider guidelines (eg, hospital policies) or local 
government, these changes may include the following options: 
Obtaining [reconsent] for the mitigation procedures (note, in the case of verbal [reconsent], 
the informed consent form [ICF] should be signed at the participant’s next contact with the 
study site).


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For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix L. 
4.2
Scientific rationale for study design
The primary aim of this study is to assess the efficacy of durvalumab + SoC CCRT compared 
with placebo + SoC CCRT in terms of PFS, with a key secondary objective to assess the 
efficacy of durvalumab + SoC CCRT compared with placebo + SoC CCRT in terms of OS.
4.2.1
Rationale for study endpoints (efficacy)
PFS may serve as a surrogate endpoint for OS when differences between treatment arms are of 
sufficient magnitude and clinically important (FDA Guidance 2015, Mauguen et al 2013, 
Pazdur 2008). In particular, a close association of PFS and OS has been observed in Stage III 
NSCLC.
ORR can be a useful endpoint because it is a direct measure of the drug’s anti-tumor activity 
(Pazdur 2008). The use of ORR in the setting of locally advanced cervical cancer, especially 
when the responses are sustained and durable (a key feature of immunotherapy), is justified 
because it is anticipated that it will serve as an early measure of clinical benefit that may be 
confirmed by the survival endpoints employed in a randomized confirmatory study. Assessing 
ORR (and CR rate) will help ascertain the benefit of adding durvalumab on top of SoC CCRT 
versus SoC CCRT alone. Additionally, for patients treated with immunotherapies, including 
durvalumab, responses appear to be durable, reinforcing the importance of ORR as a likely 
surrogate for clinical benefit.
The key secondary efficacy endpoints (ie, those included in the multiple testing procedure) of 
OS, and other secondary endpoints including rate of CR, will be examined to further evaluate 
the anti-tumor effect of durvalumab + SoC CCRT versus placebo + SoC CCRT.
The patterns of disease relapse of durvalumab + SoC CCRT compared with placebo + SoC 
CCRT will be described in terms of incidence of local progression, distant disease 
progression, and secondary malignancy as the first documented progression event.
The secondary symptoms and overall health-related quality of life (HRQoL) endpoints will be 
assessed using the European Organisation for Research and Treatment of Cancer (EORTC) 
core cancer instrument (EORTC QLQ-C30) and supplemental cervical cancer module 
(EORTC CX24). The EuroQol five-dimensional five-level questionnaire (EQ-5D-5L), Patient 
Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS) and 
Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events 


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(PRO-CTCAE) questionnaires will be administered as exploratory endpoints. Health resource 
utilisation measures including hospitalization, outpatient visits, or emergency department 
visits will be recorded in eCRF. These will show the overall influence of the benefits and 
toxicity of the treatment from a patient’s perspective and will aid in understanding of the 
benefit/risk evaluation. These PRO questionnaires are well established instruments that have 
been previously included in clinical cancer studies.
Anti-tumor activity will be assessed according to RECIST 1.1 guidelines in addition to 
progression seen on physical exam and identified from histopathology. The analysis of PFS 
and OS will be based on programmatically derived PFS and OS based on investigator 
assessments; PFS can also be assessed according to histopathologic confirmation of local 
tumor progression. Sensitivity analyses will also be performed using data from BICR tumor 
assessments based on RECIST 1.1 and histopathologic confirmation of local tumor 
progression.
Biological samples will be taken from all patients to allow for research into PK and 
immunogenicity of durvalumab, and the relationship between durvalumab PK exposure and 
clinical outcomes, efficacy, AEs, and/or safety parameters.
4.2.2
Rationale for study endpoints (other exploratory endpoints)
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or 
serum, which may influence the progression of cancer (and associated clinical characteristics) 
and/or response. 
4.2.3
Choice of standard of care regimen
The study will randomize approximately 714 patients in a 1:1 ratio to the following treatment 
arms: durvalumab concurrent with and following chemotherapy and radiotherapy and placebo 
concurrent with or following chemotherapy and radiotherapy. In China, recruitment will 
continue until approximately 105 Chinese patients have been randomised, irrespective of 
whether or not the overall study enrolment has been reached. It is anticipated that this target 
may not be met before the global recruitment of approximately 714 is achieved.  Patients will 
receive SoC CCRT consisting of EBRT and brachytherapy. Pelvic and paraaortic radiation 
therapy (RT) can be added based on extent of disease at baseline. This regimen will be 
administered concurrently with cisplatin 40 mg/m2 q1w for 5 weeks. Both chemotherapy and 
radiotherapy should be completed within 59 days. Only cisplatin is permitted, and an 
additional 6th week of therapy can be given per investigator discretion. Following completion 
of SoC CCRT, patients will be evaluated by clinical and radiological assessment.
In certain clinical scenarios, carboplatin has been substituted for cisplatin as a radiosensitizer. 
The data directly comparing potential differences between carboplatin and cisplatin in cervical 


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cancer are limited and inconsistent in findings. Cisplatin and carboplatin were retrospectively 
evaluated in 247 women receiving definitive CRT for locally advanced cervical cancer. In this 
evaluation, cisplatin was superior, with a CR rate of 88.3% compared to 73.9% (p=0.004) 
(Valdivieso et al 2017). However, another study evaluated 51 women who received 
concurrent carboplatin with radiotherapy in comparison to a historical control of cisplatin with 
radiotherapy, and there was no appreciable difference in OS and PFS between the 2 groups; 
there was an increase in the number of cycles administered and a reduction in adverse events 
in the carboplatin group (Nam et al 2013). An additional retrospective study of 148 women 
treated with carboplatin and concurrent radiotherapy showed that 142 (95.9%) women had a 
CR and only 6 (4.1%) had persistent disease. The 2-year PFS and OS rates were 75.1% and 
81.9%, respectively (Katanyoo et al 2011).  To ensure appropriate balance between patients 
treated with cisplatin and carboplatin as the radiosensitizer across regions in the ongoing 
study, no further use of carboplatin as the radiosensitizer will be allowed in this study.
4.2.4
Rationale of administering durvalumab concurrent with CCRT
The use of concurrent durvalumab therapy with chemotherapy and/or radiotherapy is currently 
being studied in NSCLC 
 colorectal cancer 
, urothelial bladder cancer 
, and hepatocellular carcinoma 
(NCT02821754). As reviewed in Section 2.1.1, there is a strong scientific rationale for 
combining CCRT with immunotherapy. 
The key aspects of the rationale are as follows: Emerging datasets in other solid tumors, most 
notably NSCLC, suggest that concurrent administration of PD1 or PD-L1 antagonists with 
chemotherapy substantively improves OS compared to chemotherapy alone, and this benefit 
extends to patients with low or negative PD-L1 expression. Next, preclinical evidence 
suggests that concurrent administration of PD-L1 with radiotherapy could have synergistic 
immunomodulatory effects. Additionally, the PD1 or PD-L1 antibodies have been combined 
with CCRT in several disease settings with acceptable safety profile. Finally, because 
brachytherapy is administered after concurrent platinum and EBRT, if a sequential approach 
was utilized, there could be a long delay between completion of platinum + EBRT and 
initiation of PD-L1 which could attenuate the potential therapeutic benefit.
The study’s hypothesis is that durvalumab, when administered with CCRT and as adjuvant 
therapy following CCRT, will improve PFS when compared to CCRT combined with placebo.
4.2.5
Rationale for treatment duration
After completion of SoC CCRT, administration of durvalumab/placebo will continue up to 
24 cycles (total) or until RECIST 1.1-defined PD or histopathologic confirmation of local 
tumor progression, or until another discontinuation criterion is met. The rationale for the 
duration of durvalumab treatment is approximately 80% of progression events occur within 
CCI
CCI
CCI


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the first 24 cycles of SoC treatment (Elit et al 2009, Fuglsang et al 2015, Wiebe et al 2012). In 
the PACIFIC study, no new safety signals were observed with durvalumab after 6 months of 
treatment. Based on these observations, no new safety signals are expected with 24 cycles of 
durvalumab administration. 
4.2.6
Rationale for stratification factors
Stratified randomization prevents imbalance between treatment groups for known factors that 
influence prognosis or treatment responsiveness. In this study, randomization will be stratified 
by disease stage status (FIGO (2009) Stage <III and node positive, FIGO (2009) Stage ≥III 
and node negative, or FIGO (2009) Stage ≥III and node positive), and region (United States, 
Canada, European Union, South Korea, and Japan) versus rest of world. Cervical cancer 
disease stage status and nodal status are known prognostic factors in cervical cancer (Pecorelli 
et al. 2009 and reviewed in sections 2.2.2 and 2.2.3) Region was grouped with the intention to 
accommodate potential differences in initial imaging approach at diagnosis (including 
PET/CT) and use of radiation therapy. 
4.3
Justification for dose
4.3.1
Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, pre-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors and from a Phase I study performed in Japanese patients with 
advanced solid tumor 
. There were 10 patients with cervical cancer in Study 
1108, with an ORR of 20% (2/10).
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 every 3 weeks (q3w), durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a 
particular regimen given the linearity seen at doses higher than 3 mg/kg. The expected half-
life with doses ≥3 mg/kg q2w is approximately 21 days. A dose-dependent suppression in 
peripheral sPD-L1 was observed over the dose range studied, consistent with engagement of 
durvalumab with PD-L1. A low level of immunogenicity has been observed. No patients have 
experienced immune-complex disease following exposure to durvalumab. (For further 
information on immunogenicity, please see the current durvalumab IB).
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a 
CCI


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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 antidrug antibody (ADA) impact; and 
(d) achieve PK exposure that yielded maximal anti-tumor activity in animal models.
Given the similar 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.
4.3.2
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data Study 1108 
(N=292; doses= 0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population PK analysis 
indicated only minor impact of body weight (WT) on the PK of durvalumab (coefficient of 
≤0.5). The impact of body weight (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.
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed her last 
scheduled visit or last scheduled procedure shown in the SoA.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
In the event that a roll-over or safety extension study is available at the time of the final data 
cutoff (DCO) and database closure, patients currently receiving treatment with durvalumab 
may be transitioned to such a study, and the current study would reach its end. The roll-over 
or safety extension study would ensure treatment continuation with visit assessments per its 
protocol. Any patient who would be proposed to move to such a study would be given a new 
Informed Consent.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to 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 screen 
failures; refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
“Randomized” patients are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.


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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.
Capability of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol
2.
Provision of signed and dated, written informed consent form prior to any 
mandatory study specific procedures, sampling, and analyses
3.
Provision of signed and dated written genetic informed consent prior to collection 
of sample for genetic analysis
The ICF process is described in Appendix A 3.
Age
4.
Females age ≥18 years at the time of screening. For patients aged <20 years and 
enrolled in Japan, a written informed consent should be obtained from the patient 
and her legally acceptable representative.
Type of patient and disease characteristics
5.
Histologically confirmed cervical adenocarcinoma, cervical squamous carcinoma, 
or cervical adenosquamous carcinoma and the following requirements: 

FIGO (2009) Stages IB2 to IIB, node positive (N≥1) -OR- FIGO (2009) Stages 
IIIA to IVA with any N stage (N≥0) (refer to Appendix K)

Nodal staging may be either surgical or by imaging (CT or MRI) with 
pathological lymph node size defined by a short-axis diameter* of ≥10mm 
(axial plane)

No evidence of metastatic disease (M0)
*Short-axis diameter is the longest diameter perpendicular to the long-axis diameter
6.
World Health Organization (WHO)/ECOG performance status (PS) of 0 or 1 at 
enrollment and randomization
7.
At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 TL at 
baseline. Tumor assessment by CT scan or MRI must be performed within 28 days 
prior to randomization.


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8.
Suitability and fitness for CCRT as determined by the Investigator
9.
Adequate organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.5 × 109 /L

Platelet count ≥75 × 109/L

Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in 
consultation with their physician and AstraZeneca.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 × ULN

Creatine clearance (CrCl) ≥60 mL/min calculated by Cockcroft-Gault equation 
(using actual body weight) or by measured 24-hour urine collection
Females:
Creatinine CL = 
Weight (kg) × (140 - Age) × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
10.
Life expectancy of at least 12 weeks
Weight
11.
Body weight >30 kg
Sex
12.
Female
5.2
Exclusion criteria 
Medical conditions
1.
Diagnosis of small cell (neuroendocrine) histology or mucinous adenocarcinoma 
cervical cancer
2.
Intent to administer a fertility-sparing treatment regimen
3.
Evidence of metastatic disease per RECIST 1.1 including lymph nodes ≥15 mm 
(short axis) above the L1 cephalad body, in the inguinal region or outside the 
planned radiation field.


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4.
Patients who have undergone a previous hysterectomy, including a supracervical 
hysterectomy, or will have a hysterectomy as part of their initial cervical cancer 
therapy
5.
History of allogeneic organ transplantation
6.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to 
this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Patients with any chronic skin condition that does not require systemic therapy

Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician

Patients with celiac disease controlled by diet alone
7.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI 
conditions associated with diarrhea, or psychiatric illness/social situations that 
would limit compliance with study requirement, substantially increase risk of 
incurring AEs or compromise the ability of the patient to give written informed 
consent
8.
History of another primary malignancy except for

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of IP and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease
9.
History of active primary immunodeficiency


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10.
Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in 
line with local practice), hepatitis B (known positive HBV HBsAg result), 
hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 
antibodies). Patients with a past or resolved HBV infection (defined as the presence 
of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. 
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA.
11.
Brain metastases or spinal cord compression. Patients with suspected brain 
metastases at screening should have an MRI (preferred) or CT each preferably with 
IV contrast of the brain prior to study entry. Brain metastases will not be recorded 
as RECIST TLs at baseline. 
12.
QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms from 
1 ECG.
13.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients
14.
Prior history or presence of vesicovaginal, colovaginal, or rectovaginal fistula.
Prior/concomitant therapy
15.
Prior chemotherapy or radiation therapy for the management of cervical cancer
16.
Exposure to immune-mediated therapy prior to the study for any indication 
including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-
PD-L2 antibodies, or therapeutic anticancer vaccines
17.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable.
18.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 
Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up 
to 30 days after the last dose of IP
19.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
20.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab. The following are exceptions to this criterion:


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
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra 
articular injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent

Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication)
Prior/concurrent clinical study experience
21.
Participation in another clinical study with an investigational product (IP) 
administered in the last 28 days
22.
Previous IP assignment in the present study
23.
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
24.
Prior randomization or treatment in a previous durvalumab clinical study regardless 
of treatment arm assignment
Other exclusions
25.
Female patients who are pregnant or breastfeeding or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of study treatment
26.
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions, and 
requirements
27.
Genetics research study (optional): 
Exclusion criteria for participation in the optional (DNA) genetics research 
component of the study include:

Previous allogeneic bone marrow transplant

Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection


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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 nonsterilized male partner must use at least 1 highly
effective method of contraception (Table 4) from the time of screening 
throughout the total duration of the drug treatment and the drug washout period 
(90 days after the last dose of study treatment). 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. 
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) 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 


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Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).
Patients should follow the local prescribing information for their SoC CCRT relating to the 
contraception, the time limits for such precautions, and any additional restrictions for agents.
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.
2.
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 
study treatment or until alternate anticancer therapy is started. 
3.
Restrictions relating to concomitant medications are described in Section 6.4
5.4
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (ie, not randomized 
patients). Patients may be rescreened a single time, but they may not be re-randomized. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) 


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publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
6.
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to durvalumab + SoC CCRT or placebo + SoC 
CCRT.
6.1
Treatments administered
6.1.1
Investigational products
AstraZeneca will supply durvalumab (MEDI4736). Further details about the study treatments 
are in Table 5. EBRT + brachytherapy, cisplatin, and the saline solution for the placebo will 
be supplied locally. Under certain circumstances when local sourcing is not feasible, an SoC 
treatment may be supplied centrally through AstraZeneca. 


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Form Doc Number: AZDoc0070547 Parent Doc Number: 
AZDoc0017426
Table 5
Study treatments
Durvalumab
Placebo
Chemoradiotherapy (Standard of care)
EBRT + 
brachytherapy
Chemotherapyf
Study treatment 
name:
Durvalumab 
(MEDI4736)a
Saline solution
External beam 
radiotherapy and 
brachytherapy
Cisplatin
Dosage formulation:
500-mg vial solution 
for infusion after 
dilution, 50 mg/mL
Sterile solution of 
0.9% (w/v) sodium 
chloride for 
injection
As sourced locally
As sourced locally
Route of 
administration 
IV
IV
Whole pelvic or 
pelvic and para-
aortic radiation and 
brachytherapyb
IV
Dosing instructions:
1500 mg IV q4w
Dosing to match 
durvalumab
See Appendix G for 
treatment details
40 mg/m2 q1w × 5 
weeks 
Pre- and post-
hydration with 1-2 L 
of IV fluid is 
recommended with 
IV supplementation 
of Mg. Anti-emetics 
are recommendedc, d


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Form Doc Number: AZDoc0070547 Parent Doc Number: 
AZDoc0017426
Table 5
Study treatments
Durvalumab
Placebo
Chemoradiotherapy (Standard of care)
EBRT + 
brachytherapy
Chemotherapyf
Packaging and 
labeling
Study treatment will 
be provided in 
500-mg vials. Each 
vial will be labeled 
in accordance with 
Good 
Manufacturing 
Practice (GMP) 
Annex 13 and per 
country regulatory 
requirement.a
Sourced locally by 
site
n/a
Sourced locally by 
site 
Provider
AstraZeneca
Sourced locally by 
site
Sourced locally by 
sitee
Sourced locally by 
sitee
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. 
b
Pelvic and paraaortic radiotherapy is added based on extent of disease at baseline.
c
Standard antiemetic regimens consist of a steroid and 5HT-antagonist, with or without a substance P antagonist such as aprepitant.
d
An additional 6th week of platinum agent will be administered per investigator discretion
e
Under certain circumstances when local sourcing is not feasible, an SoC treatment may be supplied centrally through AstraZeneca.
Abbreviations: EBRT External beam radiotherapy; Gy Grey unit; IV Intravenous; n/a Not applicable; qxw Every x weeks; SoC Standard of care; w/v 
Weight/volume.
f
For patients who were treated with carboplatin prior to Protocol Version 3, please see Section 6.1.1.2.2


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6.1.1.1
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% w/v polysorbate 80; 
it has a pH of 6.0. The nominal fill volume is 10.0 mL. IP vials are stored at 2°C to 8°C (36°F 
to 46°F) and must not be frozen. Drug product should be kept in secondary packaging until 
use to prevent excessive light exposure.
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique. Total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
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 in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500 mg 
of durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. The IV bag should be covered with an opaque or 
transparent coloured sleeve (e.g. amber) after preparation by the unblinded pharmacist prior to 
dispensing to other study personnel to maintain double-blind conditions.
If 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 in-line filter.
Standard infusion time is 1 hour (± 5min). In the event that there are interruptions during 
infusion, the total allowed infusion time should not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used, after the contents of the IV bag are fully administered or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.


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If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded. 
Order of administration
After randomisation to receive durvalumab/placebo + SoC CCRT, patients will receive 
durvalumab/placebo via IV infusion over 1 hour (± 5min). It is recommended that a 60-minute 
observation period take place after durvalumab/placebo is administered, at least for Cycle 1. 
If no issues are observed following durvalumab/placebo administration during the first cycle, 
reduction of the observation period to 30 minutes is recommended at the Investigator’s 
discretion.
Durvalumab/Placebo administration will be followed by SoC chemotherapy via IV infusion as 
indicated in Section 6.1.1.1, with radiation therapy given on the same day. If there is not 
enough time to administer cisplatin it must be administered within 1 calendar day of the 
durvalumab infusion. This will allow for flexibility in timely administration of the treatment 
regimen, as radiation therapy and durvalumab/placebo can be given on C1D1, and cisplatin 
given on C1D2 and similarly for subsequent cycles
Cisplatin  should only be given on a day that external-beam radiation is scheduled. Radiation 
therapy can occur before or after durvalumab and the platinum agent are administered and 
should be given on the same day if possible. Treatment should preferably be given on a 
Monday, Tuesday or Wednesday. Cisplatin should not be given on a day of brachytherapy 
treatment. 
All patients should be planned to receive 5 doses of cisplatin regardless of the radiation 
fractionation schedule planned. An additional 6th dose of platinum chemotherapy can be 
administered per investigator discretion.
6.1.1.2
Standard of care
The SoC chemotherapy agent for CCRT will either be locally sourced or centrally supplied by 
AstraZeneca and will be administered according to prescribing information or treatment 
guidance in general use by the Investigating site. Under certain circumstances when local 
sourcing is not feasible, AstraZeneca will centrally supply the drug, and it will be labeled with 
local language translated text in accordance with regulatory guidelines.
6.1.1.2.1 Cisplatin
If a patient develops a toxicity related to cisplatin, the SOC TMGs (Appendix J) should be 
followed. Patients are not permitted to switch between cisplatin and carboplatin. 


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6.1.1.2.2 Carboplatin
In prior versions of this protocol carboplatin AUC2 was given for initial treatment or if 
cisplatin was intolerable. Subjects recruited to the study under this regimen may continue 
unchanged, as clinically indicated. Carboplatin is to be given AUC 2 q1w × 5 weeks, and an 
additional 6th week will be administered per investigator discretion. Antiemetics are 
recommended. Standard antiemetic regimens consist of a steroid and 5HT-antagonist, with or 
without a substance P antagonist such as aprepitant. 
6.1.1.3
Placebo 
Placebo will be sourced locally. The placebo should be prepared such that the volume matches 
that expected for a durvalumab infusion, this requires the addition of 30ml of a sterile solution 
of 0.9%(w/v) sodium chloride for injection to the IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose The volume of saline solution added will be 30.0 mL or same volume as 
durvalumab if weight falls to ≤30 kg. The IV bag should be covered with an opaque or 
transparent coloured sleeve (e.g. amber) after preparation by the unblinded pharmacist prior to 
dispensing to other study personnel to maintain double-blind conditions. Infusion time is 1 
hour (± 5min) and should be delivered through an IV administration set with a 0.2- or 0.22-μm 
in-line filter.
6.1.2
Dose and treatment regimens
Table 6 shows the dosing regimen for the study. 
Table 6
Treatment regimen
Week
Baseline
C1a
C2a
C3a
C4a
C5 to PDa,b
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
Day
1
q28d ±3 days unless dosing needs to be held for toxicity reasons
Durvalumab/placebob
X
X
X
X
X
SoC cisplatin
40 mg/m2 q1w × 5 weeksc(± 1 
day except cycle 1)
SoC EBRTd,e
Appendix G
SoC brachytherapy
Appendix G
a
These cycles refer to the 28-day cycles of administration of durvalumab/placebo.
b
During the combination portion of treatment, durvalumab will be administered first. If there is not enough time to 
administer cisplatin afterward on that day, it must be administered within 1 calendar day of the durvalumab infusion.
c
An additional 6th week of platinum agent will be administered per investigator discretion
d
Chemotherapy, radiotherapy and brachytherapy should ideally be completed within 56 days and up to 59 days. 
e
Radiotherapy should start on C1D1 following Durvalumab/placebo infusion on the same day. Refer to footnote b of this 
table..
Abbreviations: C Cycle; CR Complete response; EBRT External Beam Radiotherapy; Gy Gray unit; PD Progression of 
disease; PR Partial response; qxw Every x weeks; q28d Every 28 days; SD Stable disease; SoC Standard of care.




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6.1.3
Duration of treatment and criteria for treatment through progression
All treatment will be administered beginning on Day 1 until completion of planned therapy, 
clinical progression or RECIST 1.1-defined radiological progression or histopathologic 
progression on biopsy 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 radiological progression may continue to receive study treatment at the discretion 
of the Investigator and patient. 
A follow-up scan is to be collected no earlier than 4 weeks after and no later than 12 weeks 
after the RECIST 1.1-defined PD. This follow-up scan is evaluated using the criteria outlined 
in Appendix F. Patients will not be permitted to continue randomized therapy if progression 
occurs after response (CR or PR as defined by RECIST 1.1) in the target lesions (regardless of 
the appearance of new lesions) (ie, the response and progression events both occurred in the 
target lesions while receiving randomized therapy during the same treatment period). Patients 
may not continue on durvalumab/placebo if there is histopathological determination of 
progression. 
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 IP.
For all patients who are treated through progression, the Investigator should ensure patients do 
not have any significant, unacceptable, or irreversible toxicities that indicate continuing.
Crossover within the study will not be permitted.
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 PS to >1.

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.


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
The patient still fulfills the eligibility criteria for this study (see Section 5.1 and 
5.2), with the exception of inclusion criteria 7 and 9 and exclusion criteria 16, 17, 
18, 22, 23, and 25. 
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. Alternatively, PD may be determined by histopathological determination of tumor 
progression on biopsy.
Post final data cut off 
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 (total of 24 cycles). For patients 
continuing to receive durvalumab treatment following the final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor 
the patients’ safety laboratory results prior to and periodically during treatment with 
durvalumab in order to manage AEs in accordance with the durvalumab Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5). 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab may be 
transitioned to such a study, and the current study would reach its end. The roll-over or safety 
extension study would ensure treatment continuation with visit assessments per its protocol. 
Any patient who would be proposed to move to such a study would be given a new Informed 
Consent.
6.1.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the temperature 
of the storage area. Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the study monitor upon detection. A calibrated 
temperature monitoring device will be used to record the temperature conditions in the drug 
storage facility. Storage conditions stated in the IB may be superseded by the label storage. 
The IP label on the pack/bottle/carton for SoC specifies the appropriate storage for these 
agents.


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6.2
Measures to minimize bias: randomization and blinding
6.2.1
Subject enrollment and randomization
Patients will be randomized in a 1:1 ratio to durvalumab + SoC CCRT or placebo + SoC 
CCRT. Randomization will be stratified by disease stage status (FIGO (2009) Stage <III and 
node positive, FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node 
positive), and region [United States, Canada, European Union, South Korea, and Japan] versus 
rest of the world.
All patients will be centrally assigned to randomized study treatment using an interactive web 
response system (/IWRS). Before the study is initiated, the telephone number and/or the log-in 
information and directions for the IWRS will be provided to each site. 
If a patient withdraws from the study, then her enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening. 
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:

Obtain signed informed consent before any study specific procedures are 
performed. If laboratory or imaging procedures were performed for alternate 
reasons prior to signing consent, these can be used for screening purposes with 
consent of the patient. However, all screening laboratory and imaging results must 
have been obtained within 28 days of randomization. For patients with a single TL, 
if biopsy ≤3 months old is collected (in place of an archived sample) prior to 
screening imaging for baseline tumor assessment, allow approximately 2 weeks 
before imaging scans are acquired.

Obtain a unique 7-digit enrollment number (E-code), through the IWRS in the 
following format (ECCNNXXX: CC being the country code, NN being the center 
number, and XXX being the patient enrollment code at the center). This number is 
the patient’s unique identifier and is used to identify the patient on the electronic 
case report forms (eCRFs).

Determine patient eligibility (see Sections 5.1 and 5.2)

Obtain signed informed consent for genetic research study (optional)
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:


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
Obtain a unique randomization number via the IWRS. Numbers will start at 001 and 
will be assigned strictly sequentially by IWRS as patients are eligible for entry into 
the study. The system will randomize the eligible patient to 1 of the 2 treatment 
arms.

Obtain tumor sample and send for centralized PD-L1 testing.
If the patient is ineligible and not randomized, the IWRS should be contacted to terminate the 
patient in the system.
Treatment should start no more than 3 working days after being randomized. The day patients 
begin treatment will be designated C1D1. Patients must not be randomized and treated unless 
all eligibility criteria have been met.
6.2.2
Procedures for handling incorrectly enrolled or randomized subjects
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 randomized 
or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented and that the potential benefit:risk profile remains positive for the patient.
6.2.3
Methods for assigning treatment arms
The actual treatment given to patients will be determined by the randomization scheme in the 
IVRS/IWRS. The randomization scheme will be produced by a computer software program 
that incorporates a standard procedure for generating randomization numbers. 
One randomization list will be produced for each of the randomization strata. A blocked 
randomization will be generated, and all centers will use the same list in order to minimize 
any imbalance in the number of patients assigned to each treatment arm.
Patients will be identified to the IWRS per country regulations. Randomization codes will be 
assigned strictly sequentially, within each stratum, as patients become eligible for 
randomization. The IWRS will provide the kit identification number to be allocated to the 
patient at the randomization visit and subsequent treatment visits.


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6.2.4
Methods for ensuring blinding
The IWRS will provide to the unblinded pharmacists the kit identification number to be 
allocated to the patient at the dispensing visit. Blinded and unblinded access and notifications 
will be controlled using the IWRS. Investigators will remain blinded to each patient’s 
assigned study treatment throughout the course of the study. To maintain this blind, an 
otherwise uninvolved 3rd party will be unblinded and responsible for the reconstitution and 
dispensation of all study treatment and will endeavour to ensure that there are no differences 
in time taken to dispense following randomization.
In the event that the treatment allocation for a patient becomes known to the Investigator or 
other study staff involved in the management of study patients, or needs to be known to treat 
an individual patient for an AE, the Sponsor must be notified promptly by the Investigator and 
if possible, before unblinding.
The IWRS will be programmed with blind-breaking instructions. The blind may be broken if, 
in the opinion of the Investigator, it is in the patient’s best interest for the Investigator to know 
the study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management of 
the patient’s condition (eg, antidote available). In this case, the Sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and CRF (electronic or paper), as applicable. Study 
unblinding should not occur until database lock and all decisions on the evaluability of the 
data from each individual patient have been made and documented.
6.3
Treatment compliance
The administration of all IPs should be recorded in the appropriate sections of the eCRF.
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations 
should be recorded in eCRF. Dose reductions are not allowed.
The IP 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 90-
day follow-up period following the last dose of study treatment. 


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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). For SoC agents, please refer to the local prescribing information with regards 
to warnings, precautions, and contraindications.
General Concomitant Medication and Supportive Care Guidelines for Radiotherapy
Patients should receive full supportive care, including transfusions of blood and blood 
products, supplemental iron, antibiotics, anti-emetics, etc., when appropriate at the discretion 
of the treating physician. Because it has been observed that hemoglobin levels below 10-12 
g/dL during radiotherapy are associated with decreased local control, blood transfusions 
should be offered to and used to treat patients at the discretion of treating physicians prior to 
or during radiotherapy. There should be no radiotherapy treatment delays due to a low 
hemoglobin levels. Trials evaluating epoeitin alpha (Procrit, Epogen) and radio-chemotherapy 
in cervical cancer have indicated that epoeitin alpha may be associated with an increased risk 
for thromboembolism, and thus, may not be used in this study. 
In particular, patients should be told of the typical defecation pattern. At the first sign that 
their stools become softer than usual or they have any increase in stool frequency over what is 
normal for them, they should begin taking over-the-counter loperamide as directed by their 
physician(s). Patients should understand that if they do not start taking loperamide at the start 
of diarrhea, the diarrhea may become severe and last several days. Persistent diarrhea or any 
evidence of hematochezia should prompt a stool evaluation for fecal leukocytes and/or 
Clostridium difficile toxin & ova/parasite evaluation. Diphenoxylate/ atropine prescriptions 
are permitted. Loperamide will be recommended during the study in order to prevent diarrhea 
that may ultimately lead to intravenous infusion of fluids or hospitalizations. Diarrhea that is 
suspected to be associated with durvalumab should be treated according to the Toxicity 
Management Guidelines .


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Patients should call their doctor if they have any questions about taking loperamide, if they 
believe they are not achieving adequate control of diarrhea, or if they are feeling extremely 
weak, lightheaded, or dizzy (symptoms of dehydration). Side effects of loperamide include 
tiredness, drowsiness, or dizziness. If they experience these side effects, they should avoid 
driving a motorized vehicle or operating machinery. Before using any laxative, patients should 
consult their physician. Patients should make an extra effort to drink lots of fluids (several 
glasses of water, fruit juices, soda, soup, etc.) every day while they participate in this study
Table 7
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly while the patient 
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study
Should not be given concomitantly while the patient 
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly while the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding TLs, for palliative intent is acceptable 
[eg, by local surgery or radiotherapy])
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the Sponsor


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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 cisplatin is permitted 

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.
Abbreviations: CTLA-4 Cytotoxic T lymphocyte associated protein 4; IP Investigational product; PD-1 Programmed 
cell death protein 1; PD-L1 Programmed death ligand 1.
Table 8
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for 
those medications identified as “prohibited,” 
as listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
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


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Inactivated viruses, such as those in the 
influenza vaccine
Permitted
6.4.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
6.4.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-
clinically or in patients. As durvalumab is a monoclonal antibody and therefore a protein, it 
will be degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance. It is therefore not expected that durvalumab will induce or 
inhibit the major drug metabolizing cytochrome P450 pathways. As a result, there are no 
expected 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.
6.4.3
Rescue medication
As a result of immune-mediated adverse events (imAEs) that could potentially be experienced 
by patients on durvalumab, steroids and other immunosuppressant rescue medication has to be 
made available to this patient population. The 2 products that fall into the category of 
immunosuppressants are infliximab (eg, for colitis) and mycophenolate (eg, for hepatitis). 
AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications to the 
sites if local regulations prevent the use of infliximab and mycophenolate in this indication, as 
they are considered off-label for the management of immunotherapy related toxicities. These 
rescue medications must be receipted, controlled, and administered by the unblinded 
pharmacist and stored according to the labeled storage conditions, with temperature 
excursions reported accordingly by the unblinded pharmacist. If required for use as a result of 
an imAE, then the IWRS will provide to the unblinded pharmacists the kit identification 
number to be allocated to the patient at the time. Blinded and unblinded access and 
notifications will be controlled using the IWRS.
6.5
Dose modification
Dose delays are permitted for immuno-oncology (IO) therapy (see Dosing Modification and 
Toxicity Management Guidelines). However, dose reduction is not permitted. For Standard 
of care, please refer to section 8.4.5.2


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6.6
Treatment after the end of the study
After the final analysis, AstraZeneca will continue to supply open-label study medication to 
patients who had not completed 24 doses of study therapy up to the time that they discontinue 
the treatment for whatever reason (see Section 6.1.2).
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
An individual patient will not receive any further IP (durvalumab + SoC CCRT or placebo + 
SoC CCRT) 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 SoC agent 

Pregnancy or intent to become pregnant

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits)

Initiation of alternative anticancer therapy including another investigational agent

Clinical progression or RECIST 1.1-defined radiological progression (refer to 
Appendix F) and Investigator determination that the patient is no longer benefiting 
from treatment with IP

Histopathological determination of tumor progression on biopsy

Completion of planned therapy (24 cycles)


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7.1.1
Procedures for discontinuation of study treatment
Discontinuation of study treatment, for any reason, does not impact the patient’s participation 
in the study. A patient who decides to discontinue IP will always be asked about the reason(s) 
for discontinuation and the presence of any AE. The patient should continue attending 
subsequent study visits, and data collection should continue according to the study protocol. If 
the patient does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information. This follow-up could be 
a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs).
Patients who permanently discontinue drug for reasons other than progression (per RECIST 
1.1 as assessed by investigator tumor assessments or histopathologic confirmation of local 
tumor progression) should continue to have RECIST scans and physical exam including 
pelvic examination performed q20w ±1w after randomization and continue q12w±1w through 
164 weeks and then q24w±2w thereafter until progression (per RECIST 1.1 as assessed by 
investigator tumor assessments or histopathologic confirmation of local tumor progression) 
plus an additional follow-up scan or death (whichever comes first) as defined in the SoAs.
If a patient is discontinued for 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. 
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IWRS.
7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4), such that there is insufficient information to 
determine the patient’s status at that time. Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 


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than “lost to follow-up”. Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked, this includes those patients 
who withdrew consent or are classified as “lost to follow-up.”
Lost to follow-up - site personnel should check hospital records, the patient’s current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status. (The applicable eCRF 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 eCRF modules will be updated.)
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn their 
consent to survival follow-up. Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow-up AEs outside of the clinical study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to:
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 Appendix C 2)
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 


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The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture (WBDC) system will be used for data collection and query handling.
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
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, 
including any extra assessments that may be required, will be described in the Laboratory 
Manual. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1
Efficacy assessments 
This study will evaluate the primary endpoint of PFS using either RECIST 1.1 as assessed by 
investigator tumor assessments or histopathologic confirmation of local tumor progression. 
Efficacy assessments of ORR, CR rate will be derived (by AstraZeneca) using RECIST 1.1 
assessments or histopathologic confirmation of local progression. OS, incidence of local 
progression, distant disease progression and secondary malignancy will also be evaluated.
The assessment of PFS, incidence of local progression and distant disease recurrence will be 
performed by periodic clinical and radiological assessment to evaluate for metastatic relapse 
or loco-regional recurrence. During the first 164 weeks (about 3 years) after randomization, 
q12w (starting at W20) assessments will include interval history for new signs or symptoms, a 


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physical examination including pelvic examination, and radiological tumor assessments as per 
RECIST 1.1 or histopathologic assessment. During Years 4 and 5, patients will be assessed 
every 24 weeks and then annually until a PFS endpoint has been met or closure of the study. 
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV 
contrast, of the chest, abdomen, and pelvis collected during screening/baseline and at regular 
(follow-up) intervals during study treatment. Any other areas of disease involvement should 
be additionally imaged based on the signs and symptoms of individual patients. 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 resume the 
subsequent assessments following the original imaging visit schedule (relative to the date of 
randomization). Treatment continues until completion of planned therapy, clinical progression 
or RECIST 1.1-defined radiological progression (refer to Appendix F) or histopathologic 
progression on biopsy unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. Scanning continues throughout treatment until RECIST 1.1-
defined radiological progression plus an additional follow-up scan if clinically feasible. If 
progressive disease is determined through histopathologic progression on biopsy, a scan is 
required within 28 days of biopsy. 
A physical exam can include a pelvic examination with or without speculum, bimanual 
examination, rectovaginal examination, abdominal examination and optional pap smear and
should be performed following the same schedule as tumor assessments by imaging. Any 
lesion detected on physical exam that is within the radiation field and suspected to be 
progressive disease will be biopsied. Lesions identified as progressive disease by RECIST on 
CT or MRI do not require a biopsy. Lesions with histopathologic confirmation of disease will 
be reported as a response of PD. Radiological assessments should be obtained on all patients 
within 28 days of progression confirmed by histopathology. If the physical examination and 
biopsy are performed as unscheduled assessments and there is no evidence of active cervical 
cancer on histopathology, the patient will not be reported as a PD and will continue with all 
study procedures according to the Schedule of Assessments (Table 1).
8.1.1
Central reading of scans
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization for QC and storage. Guidelines for 
image acquisition, de-identification, storage at the investigative site as source data, and 
transfer to the imaging CRO will be provided in a separate document. A BICR of images will 
be performed, results of these independent reviews will not be communicated to Investigators, 
and results of Investigator RECIST 1.1 assessments will not be shared with the central 
reviewers. The management of patients will be based in part on the results of the RECIST 1.1 


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assessment conducted by the Investigator. Further details of the BICR will be documented in 
the Independent Review Charter.
8.1.2
Survival assessments
Assessments for survival must be made every 3 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 study treatment, will be collected.
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the primary PFS analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO.
8.1.3
Patient-reported Outcomes (PROs)
PROs allow for an understanding of treatment effect from the patients’ perspective. In this 
study, PROs will be used to capture the patient experience of symptoms, functioning and 
HRQoL and will aid in understanding of the benefit/risk evaluation. The following PRO 
instruments will be administered in this study: EORTC core quality of life questionnaire 
(EORTC QLQ-C30 v3) and supplemental cervical cancer module (EORTC QLQ-CX24, 
Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events 
(PRO-CTCAE), Patient Global Impression of Change (PGIC), Patient Global Impression of 
Severity (PGIS) and EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) (see 
Appendix H). PROs will be administered according to the SoAs.
8.1.3.1
EORTC QLQ-C30 and QLQ-CX24
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group in 1993. It 
consists of 30 items and measures symptoms, functioning, and global health status/quality of 
life (QoL) (Aaronson et al 1993) for all cancer types. Items are grouped into 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea and vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a 2-item global measure of health status/QoL (see Appendix H). 
The EORTC QLQ-CX24 is a 24-item complementary module to the QLQ-C30, designed 
specifically for use in cervical cancer. Items are grouped into three multi-item scales 
(symptom experience, body image, and sexual/vaginal functioning) and six single-item scales 
(lymphedema, peripheral neuropathy, menopausal symptoms, sexual activity, sexual worry, 
and sexual enjoyment) (Greimel et al 2006). 


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8.1.3.2
PRO-CTCAE
The PRO-CTCAE is included to address tolerability from the patients’ perspective. It was 
developed by the National Cancer Institute. The PRO-CTCAE will only be administered in 
those countries where a linguistically validated version exists. It was developed in recognition 
that collecting treatment-related 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 
treatment-related symptom onset, frequency, and severity in comparison with patient ratings 
(Basch et al 2009, Litwin et al 1998, Sprangers and Aaronson 1992). These treatment-related 
symptoms have been converted to patient-friendly terms (e.g., the Common Terminology 
Criteria for Adverse Event [CTCAE] term “myalgia” has been converted to “aching 
muscles”). Items capture the presence, frequency, severity and/or interference with usual 
activities, depending upon the AE. The items included in the PRO-CTCAE have undergone 
extensive qualitative review among experts and patients. Not all items are administered in any 
clinical study. In this study, only items that are considered relevant for the study, site of 
cancer, and cancer treatment are selected (see Appendix H). 
8.1.3.3
PGIC
The Patient Global Impression of Change (PGIC) is a single item included to assess how a 
patient perceives her overall change in health status since the start of study treatment. Patients 
choose from among seven response options ranging from “much better” to “much worse” (see 
Appendix H).
8.1.3.4
PGIS
The Patient Global Impression of Severity (PGIS) is a single item to assess how a patient 
perceives her overall severity of symptoms at the time of assessment. Patients choose from 
among five response options ranging from “no symptoms” to “very severe” (see Appendix H).
8.1.3.5
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) and visual 
analogue scale (VAS)
The EQ-5D-5L (Appendix H) is a standardized measure of health status developed by the 
EuroQol Group to provide a simple, generic measure of health for clinical and economic 
appraisal (EuroQol Group 1990). Applicable to a wide range of health conditions and 
treatments, it provides a simple, descriptive profile and a single index value for health status 
that can be used in the clinical and economic evaluation of health care as well as in population 
health surveys. The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 response options (no 
problems, slight problems, moderate problems, severe problems, and extreme problems) that 
reflect increasing levels of difficulty (EuroQol Group 2013).


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The patient will be asked to indicate her current health state by selecting the most appropriate 
level in each of the 5 dimensions. The questionnaire also includes a visual analog scale, where 
the patient will be asked to rate current health status on a scale of 0 to 100, with 0 being the 
worst imaginable health state (Appendix H).
8.1.3.6
Administration of patient reported outcome questionnaires
Patients will perform the PRO assessments using an electronic tablet (ePRO) during clinic 
visits.
Each site 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 SoAs. If technical or other issues prohibit completion on 
the device, an appropriate back-up option may be considered with prior approval from 
AstraZeneca.
It is important that the site staff explains the value and relevance of hearing directly from 
patients how they feel. The following best practice guidelines should be followed:
The PRO questionnaires must be administered and completed at the clinic prior to treatment 
administration performed at the site and ideally before any discussions of health status to 
avoid biasing the participant’s responses to the questions. As feasible, site staff should also 
ensure PRO questionnaires are completed prior to other study procedures, such as collection 
of laboratory samples and before discussion of disease progression to avoid biasing the 
patient’s responses to the questions. 

It is permitted for the baseline ePROs to be completed prior to C1D1 as long as first 
of dose of Durvalumab and CCRT is given within 3 days of ePRO completion

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 and will not be shared with the site staff. Therefore, if the participant 
has any medical problems, he/she should discuss them with the doctor or research 
nurse separately from the ePRO assessment.

The research nurse or appointed site staff must train the patient on how to use the 
ePRO device using the materials and training provided in the ePRO device.


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
The research nurse or appointed site staff must remind patients that there are no 
right or wrong answers, and the research nurse or appointed site staff should avoid 
clarifying items to avoid introducing bias. 

Patients must not receive help from relatives, friends, or clinic staff deciding on 
answers to the PRO questionnaires. The responses are the participant’s alone.  Site 
staff must not read or complete the PRO questionnaires on behalf of the patient. If 
the patient is unable to read the questionnaire (eg, is blind, illiterate or unable to 
read in the available language), that patient should be exempted from completing 
PRO questionnaires but may still participate in the study. Patients exempted in this 
regard should be flagged appropriately by the site staff in the source documents 
and eCRF.
A key aspect of study success is to have high PRO compliance. Therefore, it is essential to 
follow the SoAs, and that sites make sure the device is charged and fully functional at all 
times in order to minimize missing data.
8.1.4
Health care resource use
Health care resource use will be captured including inpatient admissions, ICU, and length of 
stay in hospital using the HOSPAD eCRF. The module is for all non-study protocol-related 
hospital admissions; any routine hospital visits for study protocol-related requirements do not 
need to be captured.
The assessment of health care resource use will increase the understanding regarding the 
relationship between treatment and tumour related cancer symptoms on resource use, such as 
the need for palliative procedures to address obstruction and bleeding. This will be captured 
and analysed to inform submissions to payers. 
8.1.4.1
Administration of health care resource assessment
The site should complete the HOSPAD eCRF every time a patient is hospitalized up to and 
including the post study treatment discontinuation follow up visit. If the patient discontinues 
study treatment for reasons other than RECIST progression, the “HOSPAD” eCRF should 
continue to be captured until progression has been confirmed. Study mandated visits should 
not be included as a hospital admission.
8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the 
SoAs). Full physical examinations will include assessments of the head, eyes, ears, nose, and 


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throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at 
screening only. Targeted physical examinations are to be utilized by the Investigator on the
basis of clinical observations and symptomatology. Situations in which physical examination 
results should be reported as AEs are described in Section 8.3.7. 
8.2.2
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs. 
First infusion
On the first infusion day, patients will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of 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 1 hour ±5 minutes)
If the infusion takes longer than 1 hour, 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 study treatment. 
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 eCRF page.
Patients receiving SoC will be monitored pre-dose and as clinically indicated with every 
infusion or administration.
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 eCRF.


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8.2.3
Electrocardiograms
A resting 12-lead ECG 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.
At screening Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) 
should be recorded. For subsequent visits in case of clinically significant ECG abnormalities, 
including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief 
period (eg, 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.4
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
the SoAs). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. 
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy 
test). Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 9 (clinical chemistry), Table 
10 (hematology), and Table 11 (urinalysis).


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Other safety tests to be performed at screening include assessment for HBV surface antigen, 
HCV antibodies, and HIV antibodies.
HPV status will be recorded at screening, if available.
The following laboratory variables will be measured:
Table 9
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
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 screening, 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 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.
Abbreviations: AE Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; T3
Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone.
Table 10
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to 
be assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed 
within 3 days prior to Day 1), and as clinically indicated.


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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 11
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red and white blood cells. 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law. Cases where a participant shows elevations in liver biochemistry may require 
further evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN 
may need to be reported as SAEs. Please refer to Appendix E for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law
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 study treatment (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.
8.2.5
WHO/ECOG performance status
WHO/ECOG PS 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.


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3.
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4.
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair
5.
Dead 
Any significant change from baseline or screening must be reported as an AE.
8.2.6
Early subject review for safety
It is recommended that patients are contacted 2 weeks after receiving the first 3 cycles of 
durvalumab (Cycle 1 Day 14 [±24 hours], Cycle 2 Day 14 [±24 hours], and Cycle 3 Day 14 
[±24 hours]) to ensure early identification and management of toxicities. 
8.2.7
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/ILD are observed, toxicity management as described in detail in the 
Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5) will be applied. 
The results of the full diagnostic workup (including high-resolution computed tomography 
[HRCT], blood and sputum culture, hematological parameters, etc) will be captured in the 
eCRF. It is strongly recommended to perform a full diagnostic workup, to exclude alternative 
causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or 
pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be 
considered and the Dosing Modification and Toxicity Management Guidelines should be 
followed.
Pneumonitis 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.


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Saturation of peripheral oxygen 
Other items

When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers, which are related to 
disease progression. 
(iii)
Additional Clinical chemistry: C-reactive protein (CRP), lactate 
dehydrogenase (LDH)
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, 
see Section 8.3.3.
8.3.1
Method of detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event 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 study treatment). If 
an event that starts post the defined safety follow-up period noted above is considered to be 
due to a late onset toxicity to study treatment, then it should be reported as an AE or SAE as 
applicable.


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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.
8.3.3
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the patient’s last AE assessment or other assessment in the 
study are followed up by the Investigator for as long as medically indicated (this may be 
beyond the 90 days after the last dose of study treatment), but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum common terminology criteria for adverse events (CTCAE) grade 
reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE


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
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 National Cancer Institute (NCI) CTCAE version 5 
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 can be downloaded from the Cancer Therapy Evaluation Program website 
(http://ctep.cancer.gov). 
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?”
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.


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8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit/you were 
last asked?” or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol (CSP) mandated laboratory tests and vital signs 
will be summarized in the clinical study report (CSR). Deterioration as compared to baseline 
in protocol-mandated laboratory values and vital signs should therefore only be reported as 
AEs if they fulfill any of the SAE criteria or are the reason for discontinuation of study 
treatment.
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 8.3.9and 8.3.10.
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new 


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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.
8.3.10
New cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are 
those that are not the primary reason for the administration of the IP and have been identified 
after the patient’s inclusion in this study.
8.3.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined follow-
up period after the administration of the last dose of study treatment, must be reported as 
follows:

Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF in the Statement of Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study Monitor/Physician as 
an SAE within 24 hours. It should also be documented in the Statement of Death 
page in the eCRF. The report should contain a comment regarding the co 
involvement of PD, if appropriate, and should assign main and contributory causes 
of death.

Deaths with an unknown cause should always be reported as an SAE. It should also 
be documented in the Statement of Death page in the eCRF. A postmortem 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 time frames.
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of study treatment should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started post the defined safety follow-up period and 
the event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE.
8.3.12
Adverse events of special interest
AESIs are events of scientific and medical interest specific to the further understanding of 
durvalumab safety profile and require close monitoring and rapid communication by the 
investigators to AstraZeneca. An AESI can be serious or non-serious. All AESIs will be 
recorded in the eCRF. Serious AESIs will be recorded and reported as per Section 8.4.1


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AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An imAE is defined as an AESI that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is 
no clear alternate etiology. 
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:

Diarrhea/colitis and intestinal perforation

Pneumonitis/ILD

Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism and type I diabetes mellitus)

Hepatitis/transaminase increases

Nephritis/blood creatinine increases

Pancreatitis/serum lipase and amylase increases

Rash/dermatitis(including pemphigoid)

Myocarditis

Myositis/polymyositis

Immune thrombocytopenia 

Rare/less frequent imAEs including neuromuscular toxicities such as myasthenia 
gravis and Guillain-Barré syndrome 

Other inflammatory responses that are rare or 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, and 
rheumatological events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.


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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 her clinical judgment in treating these types of toxicities. These guidelines 
apply to AEs considered causally related to the study drug/study regimen by the reporting 
Investigator.
8.3.13
Safety data to be collected following the final Data Cutoff 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.
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.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day (ie, immediately but no later than 
24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day (ie, immediately but no later than 24 hours of when he or she becomes aware of it).


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Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture system, an automated email alert is sent to the designated AstraZeneca representative.
If the electronic data capture system is not available, then the Investigator or other study site 
staff reports an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of an SAE, see Appendix B of the Clinical Study 
Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca unless the 
pregnancy is discovered before the study patient has received any study drug.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see 
the SoAs).
8.4.3
Overdose
8.4.3.1
Durvalumab 
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 eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.

For overdoses associated with an SAE, the standard reporting timelines apply, see 
Section 8.3.2. For other overdoses, reporting must occur within 30 days.
8.4.3.2
Standard of Care
Please refer to the local prescribing information for treatment of cases of overdose if any 
overdose is associated with an AE or SAE please record the AE/SAE diagnosis or symptoms 
in the relevant AE modules only of the eCRF.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (initial fatal/life-threatening or follow-up fatal/life-
threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE 
associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.


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The definition of a medication error can be found in Appendix B.
8.4.5
Management of durvalumab-related toxicities 
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are 
permitted 

All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
All toxicities will be graded according to NCI CTCAE, version 5. 
8.4.5.1
Specific toxicity management and dose modification information - durvalumab 
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitor durvalumab. 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. Guidelines for the management of immune-mediated reactions, 
infusion-related reactions, and non-immune-mediated reactions for durvalumab are provided 
in the Dosing Modification and Toxicity Management Guidelines. The most current version of 
these guidelines is also maintained within the Site Master File. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines).
Following the first dose of 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 


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Investigator in the exercise of her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to durvalumab regimen by the reporting 
Investigator.
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician.
8.4.5.2
Specific toxicity management and dose modification information -
chemoradiotherapy
Investigators should follow toxicity management guidelines for chemotherapy and radiation 
therapy (Appendix J). All effort should be taken to follow the guidelines to ensure optimal and 
timely medical care for the patients. If the guidelines are not able to be followed, justification 
should be clearly documented in the electronic database. For specific information regarding 
the individual agents used in this study, please refer to the local prescribing information for 
the relevant agent.
Every effort should be made to continue a patient on CCRT definitive SoC therapy. In the 
case of clinically significant toxicity possibly due to SoC or durvalumab, durvalumab dosing 
can be delayed one cycle. For further information on durvalumab toxicity management and 
dose modification see section 8.4.5.1 and the Sponsor study physician may also be contacted. 
8.5
Pharmacokinetics
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.5.1
Collection of samples
Blood samples for determination of durvalumab concentration in serum will be obtained 
according to the SoAs. 
Samples for determination of durvalumab concentration in serum will be analyzed by a 
designated third party on behalf of AstraZeneca. Samples will be collected, labeled, stored, 
and shipped as detailed in the Laboratory Manual. Full details of the analytical method used 
will be described in a separate Bioanalytical Validation Report.
8.5.1.1
Collection of samples to measure for the presence of antidrug antibodies
The presence of ADA will be assessed in serum samples taken according to the SoAs. 
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
durvalumab using validated assays. Tiered analysis will be performed to include screening, 


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confirmatory, and titer assay components, and positive negative cut points previously 
statistically determined from drug-naïve validation samples will be employed
8.5.2
Storage and destruction of pharmacokinetic/antidrug antibody samples
Durvalumab PK and ADA samples will be destroyed within 5 years of CSR finalization.
PK and ADA samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca-assigned Biobank; see 
details in the Laboratory Manual).
For China: PK and ADA samples collected in China will be stored and disposed according to 
local laws and regulations. PK and ADA samples collected in China will be destroyed after 
finalization of bioanalytical report or completion of CSR
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
8.7.1
Optional exploratory genetic sample
 
 
 
 
CCI


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This sample will not be collected in China. 
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 15 
years or as per local regulations from the date of the last patient’s last visit (LPLV), after 
which they will be destroyed. DNA is a finite resource that may be used up during analyses. 
The results of any further analyses will be reported either in the CSR itself or as an addendum, 
or separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
By participating in this study the patient consents to the mandatory collection and use of 
donated biological samples as described here. 
8.8.1
Tumour samples:
8.8.1.1
Tumor sample collection:
Several tumour biopsy samples are requested for this study as described below:
MANDATORY: A newly acquired sample is preferred if available per site’s routine clinical 
practice; otherwise, archival sample ≤3 months old prior to screening can be provided. 
Samples should be collected via a core needle (18 gauge or larger) or be collected as an 
excisional or incisional tumor biopsy sample. 
Please refer to the Laboratory Manual for specific instructions and guidelines regarding tumor 
sample collection.
OPTIONAL: The collection of an additional biopsy sample upon progression is optional but 
strongly encouraged.
All optional tumour sample will not be collected in China.
Details for collection, storage, and shipment of biologic samples are presented in a separate 
Laboratory Manual. 
8.8.1.2
PD-L1 expression assessment
PD-L1 is a potential biomarker for checkpoint inhibitor therapy in metastatic previously 
treated cervical cancer. However, it is unknown whether this is true in locally advanced 
cervical cancer. Previous studies demonstrate about 88% of cases in this population are ≥ 1 % 


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positive for PD-L1 (Emeka et al 2017). Additionally, the addition of concurrent 
chemoradiotherapy can result in a shift towards an increase in PD-L1 expression. Therefore, 
to further evaluate the PD-L1 as a potential biomarker, pretreatment tumor PD-L1 expression 
will be evaluated in all randomized patients. Data will be compared between arms to 
determine if baseline PD-L1 status is prognostic and/or predictive of outcomes associated with 
durvalumab + SoC CCRT versus placebo + SoC CCRT. 
8.8.2
Exploratory biomarkers
Blood samples for exploratory biomarker analyses will be obtained according to the schedules 
presented in the SoAs. Details for collection, volumes, storage, and shipment of biologic 
samples are presented in a separate Laboratory Manual. 
Baseline (preferred to be collected prior to dosing at C1D1) and/or on-treatment measures will 
be correlated with outcomes. Note that samples will be obtained from patients randomized to 
each treatment arm. Comparisons will be made between baseline measures to determine if 
biomarkers (or combination of markers) are prognostic or predictive of outcomes associated 
with durvalumab + SoC CCRT versus placebo + SoC CCRT therapies, subgrouped by 
histology. 
Additional sample collections and analyses may be completed at select study sites by 
site-specific amendment. All samples collected for such exploratory analyses will be stored at 
site, a reference laboratory, or AstraZeneca facilities and may be used for subsequent research 
relevant to evaluating response to therapy.
The exploratory biomarker plan is described by sample type below.
8.8.2.1
Microsatellite instability and tumor mutation burden
Tumor tissue remaining after PD-L1 testing will be analyzed retrospectively for microsatellite 
instability (MSI) and tumor mutation burden (TMB) using a Next Generation Sequencing 
(NGS)-based method such as whole exome sequencing (WES) or a targeted NGS assay. The 
MSI-H/MSS status and TMB will be determined based on the MSI events or somatic variants 
detected in the tumor sequence data and correlated with efficacy as an exploratory objective. 
Blood-based MSI testing may also be performed in cases of insufficient tissue material, 
unsuccessful tissue-based MSI/TMB testing or for evaluation of blood-based MSI/TMB with 
clinical outcomes and other biomarkers.
Note: This sample will not be collected in China.


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8.8.2.2
Tumor biomarkers
Based on availability of tissue (described in section 8.8.1.1), additional exploratory 
biomarkers might be analysed by immunohistochemistry (IHC). A primary goal is to measure 
CD8 and/or CD4/FoxP3 protein expression in an effort to enumerate cytotoxic versus 
regulatory T cells. Based on availability of tissue, a panel of additional, immune-relevant 
markers expressed on tumor-infiltrating lymphocytes or on tumor cells may be assessed. 
Markers of special interest include, but are not limited to, CXCL9 and LAG3.
Other tissue-based approaches may be pursued including messenger ribonucleic acid (mRNA) 
profiling and in situ hybridization (eg, detection of IFNg signaling genes), molecular profiling, 
and/or somatic variant detection methodologies.
Note: Above tumor biomarker sample will not be collected in China.
8.8.2.3
Whole blood gene expression (PAXgene RNA)
Whole blood samples will be obtained for RNA analysis. Total RNA will be prepared for 
quantification of mRNA and/or micro-RNA expression using quantitative reverse 
transcription PCR, microarray, sequencing, or similar technology. Focus is likely to be given 
to the expression of immunomodulatory genes. Baseline and/or on-treatment correlations with 
outcome data will be completed on select candidates, predictive markers with the aim of 
identifying useful expression thresholds for identifying patients likely to receive benefit.
Note: This sample will not be collected in China.
8.8.2.4
Plasma - ctDNA mutations
Blood samples will be collected for analysis of circulating tumor deoxyribonucleic acid 
(ctDNA) in plasma. ctDNA samples will be collected at baseline, during treatment, at disease 
progression, and during follow-up after discontinuation of study treatment, as specified in the 
Schedule of Assessments (Table 1 & Table 2). Analyses will include, but not be limited to 
evaluating baseline sensitizing mutations to treatment and correlations with clinical outcomes, 
changes in levels and variant frequencies of ctDNA and potentially minimal residual disease. 
Plasma may also be evaluated for relevant cytokines, chemokines and other immune-related 
biomarkers.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
Note: This sample will not be collected in China. 


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8.8.3
Management of biomarker data
The results may be pooled with biomarker data from other studies to evaluate biological 
responses across indications and to compare results in monotherapy versus combination 
settings.
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study Investigator, general physician, or any other third party, unless 
required to do so by law. The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
8.8.4
Storage, re-use, and destruction of biomarker samples
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to therapy as described in the exploratory 
analyses section.
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 to generate 
hypotheses to be tested in future research.
For China: The stained tissue slides (PD-L1 and H&E slides) will be retained at Covance as 
raw data for a minimum of 10 years after study closure and repatriated or discarded at the end 
of the retention period. Collected tissue slides for PD-L1 testing, if unstained, will be 
repatriated to the sites or discarded 5 years after study drug approved for marketing in China.
8.8.5
Labeling and shipment of biological samples
The Principal Investigator will ensure that samples are labeled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix C “IATA 6.2 Guidance Document.”


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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.
8.8.6
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of receipt of sample shipments.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered with the AstraZeneca Biobank Team during the entire life cycle.
9.
STATISTICAL CONSIDERATIONS 
The primary aim of the study is to compare the efficacy and safety of durvalumab + SoC 
CCRT to placebo + SoC CCRT in terms of PFS in patients with FIGO (2009) Stage IB2 to 
IVA cervical cancer.

Analyses will be performed by AstraZeneca or its representatives. 

Refer to SAP for details.

The SAP will be signed off before review of any potential treatment-revealing data 
is undertaken (this includes blinded delivery reviews and data monitoring 
committee reviews). For all situations, a full draft of SAP should be available to 
ensure sufficient time to prepare for any blinded or unblinded data review. A first 
draft of the SAP will be available before the first patient is enrolled.
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated. More detail will be 
provided in the SAP.


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9.1
Statistical hypotheses
The formal statistical analysis will be performed to test the main hypotheses: 

H0: No difference between durvalumab + SoC CCRT and placebo + SoC CCRT

H1: Difference between durvalumab + SoC CCRT and placebo + SoC CCRT
The primary objective of this study is to assess the efficacy of durvalumab + SoC CCRT 
compared with placebo + SoC CCRT in terms of PFS as assessed by investigator tumor 
assessments and histopathologic confirmation of local tumor progression. A key secondary 
objective is to assess the efficacy in terms of OS.
9.2
Sample size determination 
Approximately 714 patients will be randomized 1:1 to durvalumab + SoC CCRT or placebo + 
SoC CCRT to obtain approximately 227 PFS events in the ITT population. The randomization 
will be stratified according to disease stage status (FIGO (2009) Stage <III and node positive, 
FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node positive), and 
region [United States, Canada, European Union, South Korea, and Japan] versus rest of the 
world.
The PFS analysis will occur when approximately 227 PFS events have occurred across the 
durvalumab + SoC CCRT and placebo + SoC CCRT treatment arms. If the true HR is 0.65 
(likely to correspond to a 11% increase in the proportion of patients progression-free at 
3 years from 65% to 76%) (Rose et al 1999), this analysis will have 90% power to 
demonstrate a statistically significant difference for PFS, assuming a 2-sided 5% significance 
level. Assuming non-uniform recruitment, a 3-year PFS rate of 65% for placebo + SoC CCRT 
and an exponential distribution, recruitment of 714 patients in 18 months would be expected 
to yield 227 PFS events approximately 53 months following recruitment of the first patient. In 
addition, the sample size has been derived on the assumption that 5% of patients will drop out 
at an exponential rate within 36 months following the randomization of the first patient.
If the true OS HR is 0.65, the study is also sized to provide 89%  power for the OS endpoint in 
the comparison of durvalumab + Soc CCRT versus placebo + SoC CCRT, assuming a 2-sided 
5% significance level allowing for 1 interim analyses conducted at approximately 86% of the 
target events. The final OS analysis will occur at the earlier of 227 death events or 71 months 
following recruitment of the first patient. Assuming the same recruitment assumptions for PFS 
and a 3-year OS rate of 70% for placebo + SoC CCRT (Rose et al 1999), 227 deaths would be 
expected to occur 61 months following the recruitment of the first patient. The boundaries of 


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the treatment comparison will be derived based upon the actual number of OS events observed 
at that time. 
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
Full analysis set (ITT population)
PFS (3 year), OS, ORR, CR rate, DoR in Patients with a CR, Incidence 
of Local Progression, Distant Disease Progression, and Secondary 
Malignancy,)
Full analysis set (ITT population)
PFS, OS
PD-L1 positive analysis set
Demography
Full analysis set (ITT population)
PK data
PK analysis set
PROs
Full analysis set (ITT population)
Safety data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital Signs
Safety analysis set
Abbreviations: AE Adverse event; CR rate Complete response rate; ITT Intent-to-treat; ORR Objective response 
rate; OS Overall survival; PFS Progression-free survival; PK Pharmacokinetics; PRO Patient-reported outcomes;.
9.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients (ITT population). The FAS 
will be used for all efficacy analyses (including PROs). Treatment arms will be compared on 
the basis of randomized study treatment, regardless of the treatment actually received. Patients 
who were randomized but did not subsequently go on to receive study treatment are included 
in the analysis in the treatment arm to which they were randomized. The responders analysis 
set will include the subset of patients the FAS, who achieve an objective response.
9.3.2
Safety analysis set
The safety analysis set (SAS) will consist of all patients who received at least 1 dose of study 
treatment (durvalumab or placebo). Safety data will not be formally analyzed but summarized 
using the SAS according to the treatment received; that is, erroneously treated patients (eg, 


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those randomized to treatment A but actually given treatment B) will be summarized 
according to the treatment they actually received.
9.3.3
PK analysis set
All patients who receive at least 1 dose of durvalumab per the protocol for whom any 
post-dose data are available and who do not violate or deviate from the protocol in ways that 
would significantly affect the PK analyses will be included in the PK analysis set. The 
population will be defined by the Study Physician, Pharmacokineticist, and Statistician prior 
to any analyses being performed.
9.3.4
PD-L1 positive analysis set 
The PD-L1 positive analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 positive as defined ≥1% based on either tumor or immune cell staining.
9.4
Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
9.4.1.1
RECIST 1.1-based endpoints
The analysis of the secondary endpoints ORR, and CR rate, will be based on investigator 
assessments using RECIST 1.1 or pathologic assessment of local disease progression. In 
addition, the key secondary endpoint (OS) and other secondary endpoints (Incidence of Local 
Progression, Distant Disease Recurrence, and Secondary Malignancy) will also be analyzed.
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments. Baseline will be assessed within the 28 days prior to enrolment. If a patient has 
had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression, in which case the response will be 
assigned as PD).
Blinded independent central review
The BICR of all radiological imaging data will be carried out using RECIST version 1.1. All 
images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required. For each patient, the BICR 


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will define the overall visit response data (CR, PR, SD, PD, or NE) and the relevant scan dates 
for each timepoint (ie, for visits where response or progression is/is not identified). If a patient 
has had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of not evaluable (NE; unless there is evidence of progression, in which case the 
response will be assigned as PD). Endpoints (of PFS) will be derived from the overall visit 
response date and the scan dates.
Further details of the BICR will be documented in the Imaging Charter.
Pathological confirmation of local progression
At response assessment physical exams, patients will be evaluated for local progression. Any 
lesion detected on physical exam that is not evaluable through RECIST 1.1 and is within the 
radiation field and suspected to be progressive disease will be biopsied. Lesions with 
histopathologic confirmation of disease will be reported as a response of PD. If there is no 
evidence of active cervical cancer on biopsy, the patient will not be reported as PD, and will 
continue with all study procedures according to the Schedule of Assessments (Table 1). If 
there is evidence of active cervical cancer on biopsy, the date of progression will be the date 
of the physical exam that triggered the biopsy. 
Please refer to Appendix F for the definitions of CR, PR, SD, and PD.
9.4.1.2
Primary endpoint - progression-free survival
PFS (per RECIST 1.1 as assessed by investigator tumor assessments or histopathologic 
confirmation of local tumor progression) will be defined as the time from the date of 
randomization until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from therapy or receives 
another anticancer therapy prior to progression (ie, date of event or censoring – date of 
randomization + 1). Progression free survival events will be classified as either local 
progression, distant recurrence, secondary malignancy, or death. Patients who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment at which the RECIST 1.1 assessment and response evaluation physical exam were 
evaluable. However, if the patient progresses or dies after 2 or more missed visits, the patient 
will be censored at the last date of assessment which the RECIST 1.1 assessment and response 
evaluation physical exam were evaluable. If the patient has no evaluable visits or does not 
have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, 
then they will be treated as an event with date of death as the event date. An assessment will 
be considered non evaluable if, in the absence of progression by RECIST 1.1, a physical exam 
is not performed, or if a physical exam is performed and progression is suspected and a biopsy 
result is not reported. Similarly, in the absence of histopathologic confirmation of local tumor 


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progression, an assessment will be considered non-evaluable if the RECIST visit assessment is 
not performed. 
The PFS time will always be derived based on scan/physical exam dates and not visit dates.
PFS assessments/scans contributing toward a particular visit may be performed on different 
dates within a 4 week window for the specific timepoint assessment. The following rules will 
be applied:

For progression by histopathologic evidence of disease, date of progression will be 
determined based on the date of the physical exam which showed suggested 
progression.

For on-study tumor assessments, the date of progression will be determined based 
on the earliest date of the scan for RECIST 1.1 defined radiological progression or 
progression seen on physical exam. 

For BICR sensitivity analysis, date of progression will be determined based on the 
earliest of the dates of the component that triggered the progression on the first set 
of scans that indicates progression for the adjudicated reviewer selecting PD, or of 
either reviewer where both reviewers select PD as a timepoint response, and there is 
no adjudication for central review (BICR) data. 

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment where both the RECIST 
1.1 assessment and response evaluation physical exam were evaluable within a 4 
week time frame. 
9.4.1.3
Progression Free Survival (3 years)
Progression Free Survival (3 years) will be defined as the Kaplan-Meier estimate of PFS at 3 
years. 
9.4.1.4
Progression free survival in PD-L1 positive patients
PFS (per RECIST 1.1 as assessed by investigator tumor assessments or histopathologic 
confirmation of local tumor progression) in PD-L1 positive patients (≥1% based on either 
tumor or immune cell staining) will be defined as for the primary endpoint as the time from 
the date of randomization until the date of objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the patient withdraws from therapy 
or receives another anticancer therapy prior to progression (ie, date of event or censoring –
date of randomization + 1). 


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9.4.1.5
Overall survival
OS is defined as the time from the date of randomization until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If patients are confirmed to be alive or if 
the death date is after the DCO date, these patients will be censored at the date of DCO. Death 
dates may be found by checking publicly available death registries
9.4.1.6
Overall survival in PD-L1 postive patients
OS in PD-L1 positive patients (≥1% based on either tumor or immune cell staining) will be 
defined as the time from the date of randomization until death due to any cause. Any patient 
not known to have died at the time of analysis will be censored based on the last recorded date 
on which the patient was known to be alive.
9.4.1.7
Objective response rate
ORR (per RECIST 1.1 using investigator assessments or pathologic assessment of local 
disease progression) is defined as the number (%) of patients with at least 1 visit response of 
CR or PR. Data obtained up until progression, or the last evaluable assessment in the absence 
of progression, will be included in the assessment of ORR. Patients who go off treatment 
without progression, receive a subsequent therapy, and then respond will not be included as 
responders in the ORR. 
9.4.1.8
Complete response rate
CR rate (per RECIST 1.1 using investigator assessments or pathologic assessment of local 
disease progression) is defined as the disappearance of all TLs and non-target lesions and no 
evidence of new lesions, which encompasses RECIST 1.1 staging in addition to a physical 
exam to evaluate for recurrence. 
9.4.1.9
Incidence of Local Progression, Distant Disease Progression, Secondary 
Malignancy 
The incidence of local progression, distant disease progression, secondary malignancy, and 
death will each be considered separately and defined as the number and percentage of patients 
with documented evidence of local progression, distant disease recurrence, secondary 
malignancies, and death. The time from randomization to the date of first documented local 
progression, distant disease recurrence/secondary malignancy or death from any cause will 
also be summarized. 


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For the summaries, if two recurrence events (local progression and distant disease 
progression) occur within 2 months of each other, then this is referred to as a simultaneous 
event and will be considered a single event. In this situation the worst case will be taken as the 
event ‘type’, but the date of recurrence will be the earliest of the two events. For example, if 
local progression and distant recurrence are reported within a 2 month period then for the 
analysis and reporting of Incidence of Local Progression, Distant Disease, and Secondary 
Malignancy and time to date of first local progression, distant disease progression, secondary 
malignancy or death from any cause, the event will be counted as distant disease recurrence 
but the date will be the earliest date of the two events.
Distant disease progression, secondary malignancy, and deaths are considered to be competing 
risks for local progression. Local progression and death are considered to be competing risks 
for distant disease recurrence/secondary malignancy. From the time to event endpoint, distant 
disease recurrences and secondary malignancies will be summarized together. 
Local progressions will be determined by RECIST 1.1 or histopathologic confirmation of 
disease, more details can be found in Section 9.4.1.1. Distant disease recurrence should be 
diagnosed by RECIST 1.1 or histopathological confirmation of disease when metastatic lesion 
is easily accessible for biopsy. 
Secondary malignancies must be confirmed by biopsy. If a biopsy is not able to performed 
then the suspected secondary malignancy will be counted as a distant disease recurrence for 
the summary.
9.4.1.10
Duration of response for Complete Responders 
Duration of response in complete responders (per RECIST 1.1 using Investigator assessments, 
physical examination, and histopathological confirmation of local disease progression) will be 
defined as the time from the date of the first documented CR  to the first date of documented 
progression or death in the absence of disease progression. The end of response should 
coincide with the date of progression or death from any cause used for the PFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing towards 
the assessment visit. If a patient does not progress following a CR, then their DoR will be 
censored at the PFS censoring time. Duration of response for complete responders will not be 
defined for those patients who do not have a documented response of CR.
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), physical 
examinations, laboratory findings, vital signs, and exposure. These will be collected for all 


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patients. Data from all cycles of treatment will be combined in the presentation of safety data. 
“On treatment” will be defined as assessments between date of start dose and 90 days 
following discontinuation of study treatment (ie, the last dose of study treatment). For AEs, on 
treatment (or treatment-emergent AEs) will be defined as any AEs that started after dosing or 
prior to dosing and which worsens following exposure to the treatment.
AEs observed up until 90 days following discontinuation of study treatment or until the 
initiation of the first subsequent therapy following discontinuation of study treatment 
(whichever occurs first) will be used for the reporting of the AE summary tables. This will 
more accurately depict AEs attributable to study treatment only as the number of AEs up to 
90 days following discontinuation of durvalumab + SoC CCRT or placebo + SoC CCRT are 
likely to be attributable to subsequent therapy. However, to assess the longer-term toxicity 
profile, AE summaries will also be produced containing AEs observed up until 90 days 
following discontinuation of durvalumab + SoC CCRT or placebo + SoC CCRT. Any events 
in this period that occur after a patient has received further therapy for cancer (following 
discontinuation of study treatment) will be flagged in the data listings.
The SAS will be used for reporting of safety data.
A separate data listing of AEs occurring more than 90 days after discontinuation of study 
treatment will be produced. These events will not be included in AE summaries.
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, hematology, ECGs, 
and physical examinations, the baseline value will be the latest result obtained prior to the 
start of study treatment. 
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 only include evaluable patients, ie, those 
who had sufficient data to have the possibility of an abnormality.
For example:


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
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline to be evaluable, the 
patient need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.4.3
Calculation or derivation of patient-reported outcome variables
All items/questionnaires will be scored according to published scoring guidelines.
9.4.3.1
EORTC-QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and global health status/QoL scale. The EORTC QLQ-C30 will be scored according 
to the EORTC QLQ-C30 Scoring Manual (Fayers et al 2001). Briefly, outcome scores are 
computed by standardizing the average of the items (i.e., a raw score) making up the scale. 
Outcome scores are computed using a linear transformation of the raw score such that scores 
range from 0 to 100.
Higher scores on the global measure of health status/QoL and functional scales indicate better 
health status/function, but higher scores on symptom scales represent greater symptom 
severity. For each subscale, if <50% of the subscale items are missing, then the subscale score 
will be divided by the number of non-missing items and multiplied by the total number of 
items on the subscales (Fayers et al 2001). If at least 50% of the items are missing, then that 
subscale will be treated as missing. Missing single items are treated as missing. The reason for 
any missing questionnaire will be identified and recorded. If there is evidence that the missing 
data are systematic, missing values will be handled to ensure that any possible bias is 
minimized.
At each post-baseline assessment, the change from baseline in symptom, functional, and 
global measure of health status/QoL scale scores will be calculated.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated. Change in symptoms, functioning 
and global health status from baseline will be categorised as improved, stable or worsened as 
shown in Table 13. A minimum clinically relevant change is defined using the cut off value of 
10 points (Osoba et al 1998). Specifically, a clinically meaningful improvement in a symptom 
is defined as a decrease in the score from baseline of ≥10, while a clinically meaningful 


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deterioration in a symptom is defined as an increase in the score from baseline of ≥10. In 
contrast, a clinically meaningful improvement in a functional scale or global heath status is 
defined as an increase in the score from baseline of ≥10, while a clinically meaningful 
deterioration in a a functional scale or global heath status is defined as a decrease in the score 
from baseline of ≥10.
Table 13
Visit responses for EORTC QLQ-C30
Score
Change from baseline
Visit response
Symptom scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
Functional scales and global health 
status/QoL
≥+10
Improved
≤-10
Worsened
Otherwise
Stable
9.4.3.2
EORTC QLQ-CX24
The QLQ-CX24 consists of 24 questions that can be combined to produce three multi-item 
scales (symptom experience, body image, and sexual/vaginal functioning) and six single-item 
scales (lymphedema, peripheral neuropathy, menopausal symptoms, sexual activity, sexual 
worry, and sexual enjoyment). The scales and single item measures are also scored from 0 to 
100. In sexual activity and sexual enjoyment, higher scores indicate better functioning, 
however, in the other scales and single-items, higher scores reflect more problematic 
functioning or status. 
At each post-baseline assessment, the change from baseline in symptom and functional scale 
scores will be calculated.
The cut-off for a minimum clinically meaningful improvement will be defined in the SAP. 
Threshold values may also be derived in an exploratory fashion using both distribution-based 
methods and anchor-based methods, where the anchors are the PGIC and PGIS. Details will 
be provided in the SAP. At each post-baseline assessment, change in symptoms/functioning 
from baseline will be categorized as improved, stable, or worsened using the pre-specified 
clinically meaningful cut-off defined in the SAP.
9.4.4
Patient-reported outcomes version of the Common Terminology Criteria 
for Adverse Events
The PRO-CTCAE items are not currently scored. The data will be descriptively summarized. 


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9.4.5
Patient Global Impression of Change and Patient Global Impression of 
Severity
The response options of the PGIC are scored as follows: Much Better (+3), Moderately Better 
(+2), A Little Better (+1), No Change (0), A Little Worse (-1), Moderately Worse (-2) and 
Much Worse (-3).
The response options of the PGIS are scored using a 6-point scale: 1 = None; 2 = Very Mild; 3 
= Mild; 4 = Moderate; 5 = Severe; 6 = Very Severe.
9.4.6
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L)
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems, and extreme 
problems). A unique EQ-5D health state is referred to by a 5-digit code allowing for a total of 
3,125 health states. For example, state 11111 indicates no problems on any of the 5 
dimensions. These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses). 
Where EQ-5D-5L values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be 
applied (Oemar and Oppe 2013).
9.4.7
Definition of compliance and evaluability rates
Compliance rates for the PRO questionnaires should be 85%; this rate will be monitored as the 
trial goes on. Compliance with the EORTC QLQ-C30 and EORTC QLQ-CX24 will be 
calculated separately for each questionnaire:
Compliance rate= number of evaluable forms
number of expected forms × 100
Evaluability rates for the EORTC QLQ-C30 and EORTC QLQ-CX24 will also be calculated 
separately for each questionnaire:
Evaluability rate = number of evaluable forms
number of received forms × 100
An expected form = a questionnaire that is expected to be completed at a scheduled 
assessment time, that is, a questionnaire from a patient who has not withdrawn from the study 
at the scheduled assessment time but excluding patients in countries with no available 
translation. 


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An evaluable form = a questionnaire with a completion date and at least 1 subscale that is non-
missing. 
A received form = a questionnaire that has been received and has a completion date and at 
least 1 individual item completed.
9.4.8
Calculation or derivation of health care resource use
To investigate the impact of treatment and disease on health care resource use the following 
variables will be captured:

Planned and unplanned hospital attendances beyond trial protocol mandated visits 
(including physician visits, emergency room visits, day cases and admissions) 

Primary sign or symptom the patient presents with

Length of hospital stay

Length of any time spent in an intensive care unit (ICU)
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalisation or 
start of study drug if the start of study drug is after start date of hospitalisation (length of 
hospital stay = end date of hospitalisation – start date of hospitalisation + 1). Patients with 
missing discharge dates will be calculated as the difference between the last day with 
available data and the start date of hospitalisation. The length of ICU stay will be calculated 
using the same method.
9.4.9
Calculation or derivation of pharmacokinetic variables
9.4.9.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model may be developed using a non-linear mixed-effects modeling
approach. The impact of physiologically-relevant patient characteristics (covariates) and
disease on PK may be evaluated. The relationship between the PK exposure and the effect on
safety and efficacy endpoints may be evaluated (as data allow). The results of such an
analysis will be reported in a separate report. The PK, pharmacodynamics, demographic,
safety, and efficacy data collected in this study may also be combined with similar data from
other studies and explored using population PK and/or PK-pharmacodynamic methods.
9.4.9.2
Pharmacokinetic analysis
PK concentration data and summary statistics will be tabulated. PK parameters will be
determined from the raw data. The following PK parameters will be determined after the first


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and steady-state doses: peak and trough concentration (as data allow).
9.4.9.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab by treatment group. 
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
9.4.10
Calculation or derivation of biomarker variables
Biomarker status, will be assessed for evaluable patients in each cohort according to 
prespecified criteria that will be detailed in the SAP.
9.4.11
Calculation or derivation of pharmacogenetic variables
In the case of genetic data, only the date that the patient gave consent to participation in the 
genetic research and the date the blood sample was taken from the patient will be recorded in 
the eCRF and database. The genetic data generated from the study will be stored in the 
AstraZeneca Laboratory Information Management System database or other appropriate 
system. This database is a secure database, which is separate from the database used for the 
main study. Some or all of the dataset from the main study may be duplicated within the 
AstraZeneca Laboratory Information Management System database for exploratory genetic 
analysis. Data will be reported outside the CSR (please see Appendix C).
9.5
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock 
for the analysis of PFS and Clinical Study Protocol deviations identified. 
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be developed and finalized before database lock and will describe the patient populations to be 
included in the analyses and the procedures for accounting for missing, unused, and spurious 
data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
9.5.1
Efficacy analyses
The study has been sized to characterize the PFS benefit of durvalumab + SoC CCRT versus 
placebo + SoC CCRT. The analysis will be performed when approximately 227 PFS events 
have occurred across the durvalumab + SoC CCRT and placebo + SoC CCRT treatment arms 
(32% maturity).


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Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm. Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category. Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm. 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables. For efficacy variables, baseline is defined as 
the last visit prior to randomization.
All data collected will be listed. Efficacy and PRO data will be summarized and analyzed 
based on the FAS. PK data will be summarized and analyzed based on the PK analysis set. 
Safety data will be summarized on the safety analysis set.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
Table 14 details which endpoints are to be subjected to formal statistical analysis, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as primary 
for that endpoint. Note that all endpoints compare durvalumab + SoC CCRT versus placebo + 
SoC CCRT in all randomized patients (FAS; ITT population), unless otherwise indicated.
Table 14
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank analysis for:
Primary analysis using Investigator RECIST 1.1 assessments or 
histopathologic confirmation of local tumor progression
Sensitivity analyses using BICR assessments (RECIST 1.1) or 
histopathologic confirmation of local tumor progression
PFS (3 year)
Kaplan Meier estimate of PFS at 3 years


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Endpoints analyzed
Notes
PFS in PD-L1 positive 
patients
Overall survival
OS in PD-L1 positive patients
Stratified log-rank analysis for:
PFS in PD-L1 positive patients
Stratified log-rank analysis for:
Overall survival
Stratified log-rank analysis for:
OS in PD-L1 positive patients
Objective response rate
Secondary analysis for the ITT population 
Logistic regression for:
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of local 
tumor progression
Complete response rate
Logistic regression for:
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of local 
tumor progression 
Duration of Response in 
Patients with a Complete 
Response
Summary statistics and KM plot by treatment arm for:
Secondary analysis for the ITT population using Investigator 
RECIST 1.1 assessments or histopathologic confirmation of local 
tumour progression in patients who have achieved a best objective 
response of complete response 
Incidence of local 
progression, distant disease 
progression, and secondary 
malignancy
Summary statistics and KM plot and cumulative incidence plot by 
treatment arm for:
Secondary analysis for the ITT population
Change from baseline 
(EORTC QLQ-C30 and 
EORTC QLQ-CX24) 
Average change from baseline using a Mixed Model Repeated 
Measurements (MMRM) analysis
EQ-5D-5L (health state utility 
values and Visual Analog 
Scale)
Summary statistics for health state utilities and visual analogue 
scale, including change from baseline.
healthcare resource use
Descriptive statistics (as appropriate, including means, median, 
ranges or frequencies and percentages)
Abbreviations: BICR Blinded independent central review; EORTC European Organisation for Research and 
Treatment of Cancer; FAS Full analysis set; ITT Intent-to-treat; KM Kaplan-Meier; PK Pharmacokinetic; 


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QLQ-C30 30 item core quality of life questionnaire; QLQ-CX24 Cervical cancer module; RECIST Response 
Evaluation Criteria in Solid Tumors.
9.5.1.1
Primary endpoint: Progression-free survival
The primary PFS analysis will be based on the programmatically derived RECIST 1.1 using 
the Investigator tumor assessments or histopathologic confirmation of local tumor 
progression. The effect of durvalumab + SoC CCRT versus placebo + SoC CCRT will be 
analyzed using a log-rank test stratified by disease stage status (FIGO (2009) Stage <III and 
node positive, FIGO (2009) Stage ≥III and node negative, or FIGO (2009) Stage ≥III and node 
positive) and region [United States, Canada, European Union, South Korea, and Japan] versus 
rest of world. In addition, PFS will be analysed using a stratified Cox proportional hazards 
model using the same strata as for the primary analysis by stratified log rank test and using the 
Efron approach for ties. The point estimate of the treatment effect, i.e. HR will be obtained by 
maximing the Cox partial likelihood functions, which is the product of the likelihood of each 
stratum. (an HR less than 1 will favor durvalumab + SoC CCRT). The 95% CI will be 
estimated using the profile likelihood approach. The 95% CI and HR from the stratified Cox 
proportional hazards model will be in support of the p-value from the stratified log rank test, 
no p-value will be reported from the stratified Cox proportional hazards model. 
Stratification variables will be defined according to data from the IWRS. If there are any 
patients who are mis-stratified, a sensitivity analysis may be carried out using the baseline 
data collected in the eCRF.
Kaplan-Meier plots of PFS will be presented by treatment arm and by treatment arm and 
disease stage status (FIGO (2009) Stage <III and node positive, FIGO (2009) Stage ≥III and 
node negative, or FIGO (2009) Stage ≥III and node positive) and region [United States, 
Canada, European Union, South Korea, and Japan] versus rest of world subgroups, where 
appropriate. Summaries of the number and percentage of patients experiencing a PFS event 
and the type of event (local progression, distant progression, or death) will be provided along 
with median PFS for each treatment.
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans and physical examinations are not performed at the protocol-scheduled 
timepoints. The midpoint between the time of progression and the previous evaluable 
assessment will be analyzed using a log-rank test. For patients whose death was treated as a 
PFS event, the date of death will be used to derive the PFS time used in the analysis. This 
approach has been shown to be robust even in highly asymmetric assessment schedules (Sun 
and Chen 2010).
Attrition bias will be assessed by repeating the PFS analysis, except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 


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progression immediately following 2 or more non-evaluable tumor assessments will be 
included. In addition, patients who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the subsequent therapy. This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring where the 
censoring indicator of the PFS analysis is reversed.
A sensitivity analysis will be performed by replacing the investigator assessments with the 
BICR assessments in the definition of PFS. The stratified log-rank test will be repeated on 
these data. The HR and CI will be presented. The methodology and acceptance thresholds will 
be documented in the SAP.
The assumption of proportionality will be assessed first by examining plots of complementary 
log-log (event times) versus log (time) and, if these raise concerns, by fitting a time-dependent 
covariate to assess the extent to which this represents random variation. If a lack of 
proportionality is evident, the variation in treatment effect will be described by presenting 
piecewise HR calculated over distinct time-periods. In such circumstances, the HR can still be 
meaningfully interpreted as an average HR over time unless there is extensive crossing of the 
survival curves. If lack of proportionality is found, this may be a result of treatment-by-
covariate interactions, which will be investigated. In addition, the Kaplan-Meier curve along 
with landmark analyses (eg, 1-year PFS rate) will also help in understanding the treatment 
benefit.
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using Investigator 
tumor assessments or histopathologic confirmation of local tumor progression) between 
durvalumab + SoC CCRT and placebo + SoC CCRT in the following (but not limited to) 
subgroups of the FAS:

Age at randomization (<65 versus ≥65 years of age) 

PD-L1 status (≥1% vs < 1%)

Disease stage status (FIGO (2009) Stage <III and node positive, FIGO (2009) Stage 
≥III and node negative, or FIGO (2009) Stage ≥III and node positive) 

Intent to administer cisplatin or carboplatin

Race (Asian versus non-Asian)

Region [United States, Canada, European Union, South Korea, and Japan] versus 
rest of the world

HPV status (HPV 16, HPV 18 versus other)


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Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms. The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors. Forest 
plot will be performed.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made, since all these analyses will be considered supportive of the analysis of PFS.
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Additionally, for each subgroup, the HR (durvalumab + SoC CCRT:placebo + SoC CCRT) 
and 95% CI will be calculated from a Cox proportional hazards model, with treatment as the 
only covariate. These will be presented on a Forest plot including the HR and 95% CI from 
the overall population. 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and PFS will not be formally analyzed. In 
this case, only descriptive summaries will be provided. 
9.5.1.2
Progression Free Survival (3 year)
PFS (3 year) will be summarized (using the Kaplan-Meier curve) and presented by treatment 
arm.
9.5.1.3
Progression-free survival in PD-L1 positive patients
PFS in PD-L1 positive patients will be analyzed using a stratified log-rank test, using the same 
methodology as for the primary PFS endpoint. The effect of durvalumab + SoC CCRT versus 
placebo + SoC CCRT will be estimated by the HR together with its corresponding CI and p-
value using the same methodology as described for PFS in the subset of patients with PD-L1 
status of ≥1%. Kaplan-Meier plots will be presented by treatment arm. Summaries of the 
number and percentage of patients experiencing a PFS event and type of event (local 
progression, distant progression, or death) will be provided along with median PFS for each 
treatment.
9.5.1.4
Overall survival
OS in the ITT population will be analyzed using a stratified log-rank tests, using the same 
methodology as described for the primary PFS endpoint. The effect of durvalumab + SoC 
CCRT versus placebo + SoC CCRT will be estimated by the HR together with its 
corresponding CI and p-value using the same methodology as described for PFS. Kaplan-
Meier plots will be presented by treatment arm. Summaries of the number and percentage of 


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patients who have died, those still in survival follow-up, those lost to follow-up, and those 
who have withdrawn consent will be provided along with the median OS for each treatment.
9.5.1.5
Overall survival in PD-L1 positive patients
OS in PD-L1 positive patients will be analyzed using a stratified log-rank tests, using the same 
methodology as described for the primary PFS endpoint. The effect of durvalumab + SoC 
CCRT versus placebo + SoC CCRT will be estimated by the HR together with its 
corresponding CI and p-value using the same methodology as described for PFS. Kaplan-
Meier plots will be presented by treatment arm. Summaries of the number and percentage of 
patients who have died, those still in survival follow-up, those lost to follow-up, and those 
who have withdrawn consent will be provided along with the median OS for each treatment.
9.5.1.6
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using the investigator 
tumor assessments and histopathologic confirmation of local tumor progression. The ORR 
will be compared between durvalumab + SoC CCRT and placebo + SoC CCRT using logistic 
regression models, adjusting for the same factors as the primary endpoint. The results of the 
analysis will be presented in terms of an odds ratio together with its associated profile 
likelihood CI and p-value (based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to the model). This analysis will be performed in the ITT 
population.
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). Overall visit response data will be listed for all patients (ie, the FAS). For 
each treatment arm, best overall response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE). No formal statistical analyses are planned for BoR.
9.5.1.7
Complete response rate
The CR rate as obtained from complete responses will be compared between durvalumab + 
SoC CCRT and placebo + SoC CCRT using logistic regression models, by using the same 
methodology as described for the ORR endpoint. This analysis will be performed in the ITT 
population. Summaries will be produced that present the number and percentage of patients 
with a tumor response of CR.
9.5.1.8
Incidence of Local Progression, Distant Disease Progression, and Secondary 
Malignancy 
The actual number and percentage of patients with a progression free survival event will be 
presented by treatment arm according to whether the progression free survival event was a 


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local progression, distant progression, secondary malignancy, or death.
Time to first local progression, time to first distant disease progression or first secondary
malignancy, and time to death will be analyzed separately using KM plots. As discussed in 
Section 9.4.1.9, distant disease progression, secondary malignancy, and death are considered 
to be competing risks for local progression. Patients with distant disease progression, 
secondary malignancy, or death will be censored in the KM plot for local progression. Local 
progression and death are considered to be competing risks for distant disease recurrence and 
secondary malignancy, patients with local progression or death will be censored in the KM 
plot for distant disease progression or secondary malignancy. 
The cumulative incidence of local progression, distant disease progression or secondary 
malignancy, and deaths will be compared between the two treatment groups using competing 
risk analysis (Gray test, Fine and Gray 1999). Death will be considered a competing risk for 
local progression and distant disease progression or secondary malignancy. In addition, distant 
disease progression and secondary malignancy will be considered to be competing risks for 
local progression and local progression will be considered to be a competing risk for distant 
disease progression and secondary malignancy. Hazard ratios and 95% confidence intervals 
from competing risks regression analysis (Fine and Gray 1999) adjusted for treatment and 
stratification factors will also be presented -- more details of the analysis will be given in the 
SAP.
9.5.1.9
Duration of complete response
Duration of response in patients who have a best objective response of CR will be derived for 
each treatment arm based on the RECIST 1.1 Investigator assessments or physical exam and 
on histopathological confirmation of local tumour progression. Descriptive data will be 
provided by treatment arm for DoR in patients with CR, including the associated Kaplan-
Meier curves (without any formal comparison of treatment arms or p-value attached).
9.5.1.10
Patient-reported outcomes
All PRO analyses will be based on the FAS. For change from baseline summaries, evaluable 
patients will have both a baseline and at least 1 post-dose value recorded.
EORTC QLQ-C30
The mean change in symptom and functional scale and the global measure of health 
status/QoL scale scores from baseline will be analyzed for each measure using a mixed model 
for repeated measures. Full details of this and appropriate sensitivity analyses will be 
described in full in the SAP.


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Summaries of the original and the change from baseline values of each symptom scale/item, 
the global health status/QoL score, and each functional domain will be reported by visit for 
each treatment arm. Graphical presentations may also be produced as appropriate. Summaries 
of the number and percentage of patients in each response category at each visit for each 
ordinal item will also be produced for each treatment arm.
EORTC-QLQ-CX24
The mean change from baseline will be analyzed for each EORTC-QLQ-CX24 score using a 
mixed model for repeated measures. Full details of this and appropriate sensitivity analyses 
will be described in full in the SAP.
Summaries of the original and the change from baseline values of each symptom and 
functional domain will be reported by visit for each treatment arm. Graphical presentations 
may also be produced as appropriate. Summaries of the number and percentage of patients in 
each response category at each visit for each ordinal item will also be produced for each 
treatment arm.
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics. Further details 
will be provided in the SAP.
PGIC and PGIS
PGIC and PGIS data will be presented using summaries and descriptive statistics. Further 
details will be provided in the SAP.
EQ-5D-5L
Descriptive statistics and graphs will be reported for health state utility index values (United 
Kingdom base case).
To support future economic evaluations of the study treatment, additional appropriate analyses 
may be undertaken, for example, mean health state utility pre- and post-treatment, and pre-
and post-progression. These will be outlined in a separate Payer Analysis Plan.
9.5.1.11
Health care resource use
The potential impact the disease and treatment has on health care resource use will be 
analysed for the purposes of submissions to payers. Descriptive statistics (as appropriate, 
including means, median, ranges or frequencies and percentages) will be provided for each 
arm on the different types of hospital admissions, the length of stay of people admitted in to 
hospital for at least one overnight stay and length of stay of people admitted to intensive care / 
high dependency units, as well as the primary sign or symptom the patient presents with. To 


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support submissions to payers, additional analyses may be undertaken and these will be 
outlined in a separate Payer Analysis Plan. 
9.5.2
Safety analyses
Safety is a secondary endpoint in this study. All safety analyses will be performed on the 
safety population. Safety and tolerability data will be presented by treatment arm using the 
safety population. Safety data will be summarized descriptively and will not be formally 
analyzed.
Data from all cycles of treatment will be combined in the presentation of safety data. AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient. The number of patients experiencing 
each AE will be summarized by treatment arm and CTCAE grade. Additionally, data 
presentations of the rate of AEs per person-year at risk may be produced. 
Other safety data will be assessed in terms of AEs (including SAEs), physical examinations, 
laboratory findings, vital signs, and exposure. Exposure to durvalumab + SoC CCRT and 
placebo + SoC CCRT will be summarized. Time on study, dose delays and dose reductions 
will also be summarized. At the end of the study, appropriate summaries of all safety data will 
be produced, as defined in the SAP.
9.5.3
Pharmacokinetic data
PK concentration data will be listed for each patient in the durvalumab arm and each dosing 
day, and a summary will be provided for all evaluable durvalumab-treated patients patients.
9.5.4
Immunogenicity data
Immunogenicity results will be listed by patient, and a summary will be provided by the 
number and percentage of patients who develop detectable anti-drug antibodies by treatment 
group. The immunogenicity titer and neutralizing ADA data will be listed for samples 
confirmed positive for the presence of anti-drug antibodies by treatment group. 
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety may be evaluated, if the data allow. A detailed plan 
will be written by the AstraZeneca Clinical Pharmacology group or designee.
9.5.5
Pharmacokinetic/pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach.


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9.5.6
Biomarker data
The relationship of PD-L1 expression and, if applicable, of exploratory biomarkers to clinical 
outcomes (including but not restricted to) of PFS, and OS will be presented.
PD-L1 expression determined by IHC will be reported in the CSR. 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.
9.5.7
Methods for multiplicity control
The multiple testing procedure (MTP) will define which significance levels should be applied 
to the interpretation of the raw p-values for the primary endpoint of PFS and the key 
secondary endpoint of OS.
The overall 5% type I error rate will first be allocated to test the primary endpoint of PFS for 
durvalumab + SoC CCRT versus placebo + SoC CCRT. If the primary endpoint of PFS is 
significant, 5% alpha will be recycled to the lower level I the hierarchy, where the 5% alpha 
will be used for the test of OS for durvalumab + SoC CCRT versus placebo + SoC CCRT. 
The primary endpoint of PFS will be tested once. The key secondary endpoint of OS will be 
tested at 2 timepoints: 1 interim analysis and 1 final analysis. The tests including the interim 
and the final analysis that are for the comparison of durvalumab + SoC CCRT versus placebo 
+ SoC CCRT for the analyses of OS will be considered as one test family. As long as 1 test in 
the family can be rejected, the family is rejected. Thus, the assigned total alpha to the family 
will be recycled to the next MTP level. Details of the interim analyses are provided in Section 
9.6.
The details of the multiple testing procedure will be provided in the SAP.
9.6
Interim analyses 
No PFS interim analysis is planed in this study.
There will be an interim analysis performed for OS. The OS interim will occur at the time of 
the PFS analysis, if it is positive. It is anticipated that approximately 86% of the OS events 
will be available for this OS IA (approximately 195 of 227 OS events). If exactly 86% of the 
target events are available at the time of the interim analysis, with overall 2-sided alpha level 
of 5.0%, the 2-sided alpha to be applied at the interim analysis and final analysis would be 
3.1% and 4.1%, respectively.


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If the criteria for statistical significance is met for PFS but not OS at the time of the analysis 
for PFS, follow-up will continue until the earlier of 227 OS events or 71 months following 
randomization of the first patient, at which point OS will be retested. 
The SAP will describe the planned interim analysis in greater detail.
9.6.1
Data monitoring committee
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC composed of independent experts will be convened to confirm the safety and 
tolerability of the proposed dose and schedule of durvalumab + SoC CCRT. The first safety 
review will take place when the first 25 total patients across both treatment arms have 
completed SoC CCRT and have had at least 28 days of follow-up. The second safety review 
will take place when the first 60 total patients across both treatment arms have completed SoC 
CCRT and have had at least 28 days of follow-up. Safety reviews will be carried out by the 
IDMC in an unblinded manner. After review of the unblinded data, the IDMC will make a 
recommendation on whether the study should continue recruitment as planned or hold 
recruitment.
An additional safety review for Japanese patients will take place when the first 9 patients in 
Japan have completed SoC CCRT and had 28 days of follow-up. This review will be carried 
out by the IDMC in an unblinded manner. After review of the unblinded data, the IDMC will 
make a recommendation on whether the study should continue recruitment as planned or hold 
recruitment in Japan.
In addition, the IDMC will meet approximately every 6 months thereafter to continue safety 
monitoring. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
9.7
China Cohort
In China, recruitment will continue until approximately 105 Chinese patients have been 
randomised, irrespective of whether or not the overall study enrolment has been reached. It is 
anticipated that this target may not be met before the global recruitment of approximately 714 
is achieved. 


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A patient randomized in the China cohort will be included in both the global FAS and the 
China FAS. Per China National Medical Products Administration (NMPA) guidance, in 
addition to the evaluation of the overall data for primary, secondary and safety objectives, 
evaluation of consistency in efficacy and safety in China and Asia population is required to 
facilitate the benefit-risk assessment for Chinese patients.  Hence, the safety and efficacy data 
in China cohort will be analyzed separately where the same endpoint definitions and analysis 
methods (as detailed in Section 9.5) are applied.
Details of this analysis will be in a China supplementary SAP. 


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10.
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