A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With Gemcitabine+Cisplatin for Neoadjuvant Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients With Muscle-Invasive Bladder Cancer.
Phase: PHASE3
Conditions: Muscle Invasive Bladder Cancer
Sponsor: AstraZeneca

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
1 (233)
Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D933RC00001
Version
7.0 
Date
29 Jan 2024
A Phase III, Randomized, Open-Label, Multi-Center, Global Study to 
Determine the Efficacy and Safety of Durvalumab in Combination with 
Gemcitabine+Cisplatin for Neoadjuvant Treatment Followed by Durvalumab 
Alone for Adjuvant Treatment in Patients with Muscle-Invasive Bladder 
Cancer (NIAGARA)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifying Number(s):
EudraCT 2018-001811-59
EU CT number:   2023-510015-19-00
Protocol Number:
Amendment Number: 6
Study Intervention: Durvalumab 
Study Phase: 3 
Short Title: A Phase III Study of the Efficacy and Safety of Neoadjuvant Durvalumab + 
Gemcitabine + Cisplatin Followed by Adjuvant Durvalumab in Patients with MIBC
Acronym: NIAGARA
International Coordinating Investigator
Barts Cancer Institute, Barts and The London 
School of Medicine and Dentistry, Queen Mary 
University of London, Charterhouse Square, 
London EC1M 6BQ
Urology Coordinating Investigator
Department of Oncology & Metabolism
The Medical School
Beech Hill Road
Sheffield, UK S10 2RX
PPD
PPD

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
2 (233)
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY
Document
Date
Amendment 6 (Version 7)
29-Jan-2024
Amendment 5 (Version 6)
22-Jun-2023
Amendment 4 (Version 5)
01-Jun-2021
Amendment 3 (Version 4)
20-Jul-2020
Amendment 2 (Version 3)
09-Dec-2019
Amendment 1 (Version 2)
23-Apr-2019
Original Protocol (Version 1) 
02-Aug-2018
Amendment 6 (29-Jan-2024)
Overall Rationale for the Amendment: The primary reason for this amendment is to remove 
the censoring rule for two consecutive missed visits from the primary analysis of the primary 
endpoint EFS to minimize loss of clinically relevant events. Instead, a supportive sensitivity 
analysis applying this rule will be conducted. This is in line with European Medicines Agency 
guideline on methodological considerations for the evaluation of anticancer products (European 
Medicines Agency Guideline, 2013). Per FDA guidance (U.S. Department of Health and Human 
Services et al, 2018), a sensitivity analysis applying this censoring rule can be done if not used 
for the primary analysis.
This and other changes incorporated in this amendment are described in the following table. In 
addition, minor text clarifications, administrative changes, have been made; as these changes 
were minor, they are not listed in detail in the table below.
Section # and Name
Description of Change
Brief Rationale
Substantial/ Non-
substantial
Title Page – EU CTR 
Number
Updated EU CTR Number
New EU CTR Number issued 
Non-
substantial
Section 9.3.1.2 (Dual 
primary endpoint for 
event-free survival 
[EFS]), Section 9.4 
(Methods for statistical 
analyses, Table 18)
Removal of “However, if 
the patient progresses or 
experiences recurrent 
disease or dies after 2 or 
more missed visits, the 
patient will be censored at 
the time of the latest 
evaluable disease 
assessment.”
Removing two missed visit 
rule from primary endpoint 
EFS to minimize loss of 
clinically relevant events.
Substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
3 (233)
Addition of sensitivity 
analyses
"Analysis where subjects 
who take subsequent anti-
cancer therapy prior to the 
EFS event will be censored 
at their last evaluable 
assessment prior to taking 
the subsequent therapy –
attrition bias (ITT)"
“Analysis using the 2 
missed visit censoring rule –
attrition bias (ITT)” 
In Table 18 of section 9.4
Section 9.3.3 Calculation 
or derivation of patient-
reported outcome 
variables
Removal of “Also, if global 
health status/QoL, function, 
or symptom deteriorates or 
the patient dies after 2 or 
more missed PRO 
assessment visits, the 
patient will be censored at 
the time of the last PRO 
assessment where global 
health status/QoL, function, 
or symptom could be 
evaluated prior to the 2 
missed visits”
To be consistent with the 
EFS change
Substantial
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
4 (233)
TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................2
TABLE OF CONTENTS .....................................................................................4
1.
PROTOCOL SUMMARY .................................................................................11
1.1
Schedules of activities (SoAs)............................................................................11
1.2
Synopsis.............................................................................................................28
1.3
Schema ..............................................................................................................37
2.
INTRODUCTION .............................................................................................39
2.1
Study rationale ...................................................................................................39
2.1.1
Rationale for durvalumab as a potential therapy for MIBC.................................41
2.2
Background........................................................................................................42
2.2.1
Immunotherapies................................................................................................42
2.2.2
Durvalumab .......................................................................................................44
2.3
Benefit/risk assessment ......................................................................................44
2.3.1
Potential benefits................................................................................................44
2.3.1.1
Durvalumab .......................................................................................................44
2.3.1.2
Durvalumab in combination with chemotherapy.................................................45
2.3.2
Overall risks.......................................................................................................45
2.3.2.1
Durvalumab .......................................................................................................46
2.3.2.2
Durvalumab in combination with chemotherapy.................................................46
2.3.3
Overall benefit/risk.............................................................................................48
3.
OBJECTIVES AND ENDPOINTS ....................................................................48
4.
STUDY DESIGN...............................................................................................52
4.1
Overall design....................................................................................................52
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................54
4.2
Scientific rationale for study design....................................................................54
4.2.1
Rationale for study design..................................................................................54
4.2.2
Rationale for efficacy study endpoints................................................................55
4.2.3
Rationale for other study endpoints ....................................................................55
4.2.4
Safety monitoring rationale ................................................................................56
4.2.5
Rationale for gemcitabine and cisplatin as comparator .......................................56
4.3
Justification for dose ..........................................................................................57
4.3.1
Durvalumab monotherapy dose rationale............................................................57
4.3.1.1
Durvalumab q4w dose rationale .........................................................................57
4.3.1.2
Durvalumab q3w dose rationale .........................................................................59
4.3.2
Gemcitabine plus cisplatin dose rationale ...........................................................59
4.3.2.1
Split-dose rationale.............................................................................................60

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
5 (233)
4.4
End of study definition.......................................................................................60
5.
STUDY POPULATION.....................................................................................61
5.1
Inclusion criteria ................................................................................................61
5.2
Exclusion criteria ...............................................................................................65
5.3
Lifestyle restrictions...........................................................................................68
5.4
Screen failures....................................................................................................70
6.
STUDY TREATMENTS ...................................................................................71
6.1
Treatments administered ....................................................................................71
6.1.1
Investigational products .....................................................................................71
6.1.1.1
Order of administration ......................................................................................72
6.1.1.2
Durvalumab (MEDI4736) ..................................................................................72
6.1.1.3
Gemcitabine and cisplatin ..................................................................................73
6.1.2
Dose and treatment regimens..............................................................................73
6.1.2.1
Durvalumab (MEDI4736) ..................................................................................75
6.1.3
Duration of treatment and criteria for treatment through progression..................75
6.1.4
Storage...............................................................................................................76
6.1.5
Surgical plan ......................................................................................................76
6.2
Measures to minimize bias: randomization and blinding.....................................77
6.2.1
Patient enrollment and randomization.................................................................77
6.2.2
Procedures for handling incorrectly enrolled or randomized patients ..................79
6.2.3
Methods for assigning treatment arms ................................................................79
6.2.4
Methods for ensuring blinding............................................................................79
6.2.5
Methods for unblinding the study.......................................................................79
6.3
Treatment compliance ........................................................................................79
6.4
Concomitant therapy..........................................................................................80
6.4.1
Other concomitant treatment ..............................................................................83
6.4.2
Durvalumab drug-drug interactions....................................................................83
6.4.3
Rescue medication .............................................................................................83
6.5
Dose modification..............................................................................................84
6.6
Treatment after the end of the study ...................................................................85
7.
DISCONTINUATION OF TREATMENT PHASE OF STUDY AND 
PATIENT WITHDRAWAL...............................................................................85
7.1
Discontinuation of study treatment.....................................................................85
7.1.1
Procedures for discontinuation of study treatment ..............................................86
7.1.2
Procedures for discontinuation of study plan (no radical cystectomy).................86
7.2
Lost to follow-up................................................................................................87
7.3
Withdrawal from the study.................................................................................88
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................88
8.1
Efficacy assessments..........................................................................................89

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
6 (233)
8.1.1
Tumor assessments.............................................................................................89
8.1.1.1
Investigator RECIST 1.1 imaging review ...........................................................89
8.1.1.2
Local biopsy review ...........................................................................................91
8.1.1.3
Local pathology review......................................................................................91
8.1.1.4
Central biopsy review.........................................................................................91
8.1.1.5
Central pathology review ...................................................................................91
8.1.1.6
Central imaging review ......................................................................................92
8.1.2
Survival assessments..........................................................................................92
8.1.3
Clinical outcome assessments.............................................................................92
8.1.3.1
EORTC QLQ-C30 .............................................................................................94
8.1.3.2
EQ-5D-5L..........................................................................................................95
8.1.3.3
PGIC..................................................................................................................95
8.1.3.4
PGIS ..................................................................................................................95
8.1.3.5
PRO-CTCAE .....................................................................................................96
8.2
Safety assessments .............................................................................................96
8.2.1
Clinical safety laboratory assessments................................................................97
8.2.2
Physical examinations ........................................................................................99
8.2.3
Vital signs and measurements.............................................................................99
8.2.4
Electrocardiograms ..........................................................................................100
8.2.5
WHO/ECOG performance status......................................................................100
8.2.6
Patient follow-up contact (Arm 2 only) ............................................................101
8.2.7
Clavien-Dindo assessment................................................................................101
8.2.8
Other safety assessments ..................................................................................102
8.3
Collection of adverse events.............................................................................102
8.3.1
Method of detecting AEs and SAEs..................................................................103
8.3.2
Time period and frequency for collecting AE and SAE information .................103
8.3.3
Follow-up of AEs and SAEs.............................................................................103
8.3.4
Adverse event data collection...........................................................................104
8.3.5
Causality collection..........................................................................................105
8.3.6
Adverse events based on signs and symptoms ..................................................105
8.3.7
Adverse events based on examinations and tests...............................................105
8.3.8
Hy’s law...........................................................................................................106
8.3.9
Disease recurrence or progression ....................................................................106
8.3.10
New cancers.....................................................................................................106
8.3.11
Deaths..............................................................................................................106
8.3.12
Adverse events of special interest.....................................................................107
8.3.13
Safety data to be collected following the final DCO of the study......................108
8.4
Safety reporting and medical management .......................................................108
8.4.1
Reporting of serious adverse events..................................................................108
8.4.2
Pregnancy ........................................................................................................108
8.4.2.1
Maternal exposure............................................................................................109
8.4.2.2
Paternal exposure .............................................................................................109
8.4.3
Overdose..........................................................................................................110
8.4.3.1
Durvalumab .....................................................................................................110
8.4.3.2
Gemcitabine and cisplatin ................................................................................110

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
7 (233)
8.4.4
Medication error...............................................................................................110
8.4.5
Management of IP-related toxicities .................................................................111
8.4.5.1
Specific toxicity management and dose modification information –
durvalumab ......................................................................................................111
8.4.5.2
Specific toxicity management and dose modification information -
gemcitabine and cisplatin .................................................................................112
8.5
Pharmacokinetics .............................................................................................113
8.5.1
Collection of samples.......................................................................................113
8.5.1.1
Collection of samples to measure for the presence of ADAs.............................113
8.5.2
Storage and destruction of pharmacokinetic/ADA samples...............................113
8.6
Pharmacodynamics ..........................................................................................113
8.7
Genetics ...........................................................................................................114
8.7.1
Optional exploratory genetic sample ................................................................114
8.7.2
Storage and destruction of genetic samples.......................................................114
8.8
Biomarkers.......................................................................................................114
8.8.1
Collection of tissue samples for central pathology review, stratification by 
PD-L1 expression, and biomarker research.......................................................115
8.8.2
Exploratory biomarkers....................................................................................116
8.8.3
Storage, re-use, and destruction of biomarker samples......................................118
8.8.4
Labeling and shipment of biological samples ...................................................118
8.8.5
Chain of custody of biological samples ............................................................118
8.8.6
Withdrawal of informed consent for donated biological samples ......................119
8.8.7
German biomarker sub-study ...........................................................................119
9.
STATISTICAL CONSIDERATIONS..............................................................120
9.1
Sample size determination................................................................................120
9.2
Populations for analyses...................................................................................122
9.2.1
Full analysis set (ITT population).....................................................................122
9.2.2
Cystectomy population.....................................................................................123
9.2.3
PD-L1-high analysis set ...................................................................................123
9.2.4
Safety analysis set ............................................................................................123
9.2.5
PK analysis set.................................................................................................123
9.3
Outcome measures for analyses........................................................................123
9.3.1
Calculation or derivation of efficacy variables..................................................123
9.3.1.1
Dual Primary endpoint: pathologic complete response (pCR)...........................123
9.3.1.2
Dual Primary endpoint: event-free survival (EFS) ............................................123
9.3.1.3
Secondary endpoints ........................................................................................124
9.3.2
Calculation or derivation of safety variables.....................................................126
9.3.2.1
Adverse events.................................................................................................126
9.3.2.2
Other significant adverse events .......................................................................126
9.3.2.3
Safety assessments ...........................................................................................126
9.3.3
Calculation or derivation of patient-reported outcome variables .......................127
9.3.4
Calculation or derivation of pharmacokinetic variables ....................................131
9.3.4.1
Population pharmacokinetics and exposure-response/safety analysis ................131

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
8 (233)
9.3.4.2
Pharmacokinetic analysis .................................................................................131
9.3.4.3
Immunogenicity analysis..................................................................................131
9.3.5
Calculation or derivation of biomarker variables ..............................................131
9.3.6
Calculation or derivation of pharmacogenetic variables....................................131
9.4
Methods for statistical analyses ........................................................................131
9.4.1.1
Multiple testing strategy...................................................................................134
9.4.1.2
Pathologic complete response (pCR)................................................................135
9.4.1.3
Event-free survival (EFS).................................................................................135
9.4.2
Analysis of secondary endpoints ......................................................................137
9.4.2.1
Proportion of patients alive and event free at 24 months after last 
randomization (EFS24) ....................................................................................137
9.4.2.2
Proportion of patients who achieve <P2............................................................137
9.4.2.3
Overall Survival (OS).......................................................................................137
9.4.2.4
Proportion of patients alive at 5 years after randomization (OS5) .....................137
9.4.2.5
Metastasis-free survival (MFS) ........................................................................137
9.4.2.6
Disease-specific survival (DSS) .......................................................................137
9.4.2.7
Disease-free survival (DFS) .............................................................................137
9.4.2.8
Proportion of patients who undergo radical cystectomy....................................137
9.4.2.9
Patient-reported outcomes................................................................................138
9.4.3
Safety analyses.................................................................................................140
9.4.4
Pharmacokinetic data .......................................................................................140
9.4.5
Immunogenicity data........................................................................................140
9.4.6
Pharmacokinetic/pharmacodynamic relationships.............................................141
9.4.7
Biomarker data.................................................................................................141
9.5
Interim analyses ...............................................................................................141
9.6
Independent data monitoring committee...........................................................142
10.
REFERENCES ................................................................................................144
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .......................................................................................154
LIST OF TABLES
Table 1
Schedule of assessments for screening and neoadjuvant treatment (all 
treatment arms)................................................................................................ 13
Table 2
Schedule of assessments for the adjuvant treatment phase (Arm 1)................... 18
Table 3
Schedule of assessments for the adjuvant phase visits (Arm 2) ......................... 22
Table 4
Schedule of assessments for patients who have discontinued treatment or
completed study visits/treatment...................................................................... 25
Table 5
Study objectives and endpoints......................................................................... 48
Table 6
PD-L1 status defined by scoring of Ventana PD-L1 (SP263) Assay ................. 53

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
9 (233)
Table 7
Highly effective methods of contraception (<1% failure rate)........................... 70
Table 8
Study treatments............................................................................................... 71
Table 9
Treatment scheme ............................................................................................ 73
Table 10 Prohibited concomitant medications................................................................. 81
Table 11 Supportive medications .................................................................................... 83
Table 12 Clinical chemistry ............................................................................................ 97
Table 13 Hematology...................................................................................................... 98
Table 14 Urinalysis......................................................................................................... 98
Table 15 Summary of outcome variables and analysis populations................................ 122
Table 16 Mean change and clinically meaningful change - EORTC QLQ-C30 ............. 128
Table 17 Best response in EORTC QLQ-C30 scores: FAS population .......................... 128
Table 18 Pre-planned statistical and sensitivity analyses to be conducted...................... 132
Table 19 Summary of methods of assessment ............................................................... 176
Table 20 RECIST 1.1 evaluation of target lesions......................................................... 183
Table 21 RECIST 1.1 evaluation of non-target lesions.................................................. 184
Table 22 RECIST 1.1 overall visit response.................................................................. 185
LIST OF FIGURES
Figure 1 Study design..................................................................................................... 38
Figure 2 Neoadjuvant dosing schedule ........................................................................... 74
Figure 3 Multiple testing procedure for controlling the type I error rate........................ 135
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................ 155
Appendix B
Adverse event definitions and additional safety information.................... 161
Appendix C
Handling of Human Biological Samples ................................................. 165
Appendix D
Genetics.................................................................................................. 168
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law.................................................................................. 171
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).......................... 176

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
10 (233)
Appendix G
International Airline Transportation Association (IATA) 6.2 Guidance 
Document...................................................................................................... 187
Appendix H
Patient-reported outcomes ...................................................................... 188
Appendix I
Abbreviations........................................................................................... 198
Appendix J
Protocol Amendment History .................................................................. 203
Appendix K
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .................................... 227
Appendix L
Country-specific Requirements ............................................................... 232

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
11 (233)
1.
PROTOCOL SUMMARY
1.1
Schedules of activities (SoAs)
The procedures for the screening and treatment periods in this study are presented in Table 1, 
Table 2, and Table 3, and the procedures for the follow-up period are presented in Table 4.
Whenever vital signs and blood draws are scheduled for the same nominal time, the assessments 
should occur in the following order: vital signs and then blood draws. The timing of the vital 
signs assessments should be such that it allows the blood draw (eg, pharmacokinetic [PK] blood 
sample) to occur at the timepoints indicated in the schedules of activities (SoAs). Whenever 
electrocardiograms (ECGs), vital signs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: ECG, vital signs, and then blood 
draws. The timing of the first 2 assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the timepoints indicated in the SoAs.
For durvalumab treatment

Patients may delay dosing under certain circumstances.

Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1), due to either an immune or a non-immune-
related adverse event (AE).

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.

If there is a dosing delay while on the every 3 weeks (q3w) schedule (neoadjuvant 
portion), it is advised to skip the durvalumab dose and resume dosing on Day 1 of 
the subsequent cycle. If there is a dosing delay during the adjuvant portion of 
therapy, dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of tumor 
efficacy 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 Brochure [IB] for durvalumab). 

In the event that durvalumab is discontinued or delayed as part of the toxicity 
management guidance, gemcitabine and cisplatin (G+C) may still be administered 
as scheduled.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
12 (233)
For gemcitabine and cisplatin neoadjuvant treatment

Patients may delay and subsequently resume dosing per local standard clinical 
practice. Patients will also be permitted to skip Day 8 chemotherapy per local toxicity 
management standards for chemotherapy. 

If dosing must be delayed for reasons other than treatment-related toxicity, dosing
will occur as soon as feasible. In the event that Cycle 1 of the chemotherapy 
schedule is delayed, durvalumab should follow the chemotherapy schedule and 
should be administered on Day 1 of each cycle.

In the event that G+C chemotherapy is discontinued due to treatment-related
toxicity, patients should proceed to radical cystectomy when clinically feasible, 
and the remaining durvalumab monotherapy neoadjuvant doses should be 
skipped. Adjuvant therapy with durvalumab may continue following radical 
cystectomy. Note: If the Investigator feels that a patient would benefit from 
administering the remaining neoadjuvant durvalumab cycles without 
chemotherapy, AstraZeneca should be consulted for an exception to this rule.

In the event that creatinine clearance drops below 60 mL/min, the cisplatin dose may 
be divided into 2 administrations, as per local practice, for management of renal 
toxicity.
The study treatment phase of this study includes neoadjuvant, adjuvant, and surgical phases:

Neoadjuvant therapy: patients receive G+C chemotherapy ± durvalumab

Surgery: radical cystectomy

Adjuvant therapy: patients receive durvalumab or no treatment (patients required to 
attend scheduled study visits)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
13 (233)
Table 1
Schedule of assessments for screening and neoadjuvant treatment (all treatment arms)
Screening
C1
1 cycle = 3 weeks 
(21 days) 
C2
1 cycle = 3 weeks 
(21 days)
C3
1 cycle = 3 
weeks (21 days)
C4
1 cycle = 3 
weeks (21 days)
Pre-
radical 
cystectomy
Radical 
cystectomy 
(≥14 days to 
56 days 
after last 
dose of neo-
adjuvant 
therapy)
For 
details, 
see 
Section
Week
-4 to -1
1
2
4
5
7
8
10
11
Day
-28 to -1
1
8
1
8
1
8
1
8
Window (days)
NA
+3
±2
+3
±2
+3
±2
+3
±2
Informed consent
Informed consenta
X
5.1
Randomization
Xb
6.2.1
Study procedures
Physical examination (full)
X
8.2.2
Targeted physical examination 
(based on symptoms)
X
X
X
X
X
X
X
X
8.2.2
Vital signsc
X
X
X
X
X
X
X
X
X
8.2.3
ECG (resting 12-lead)d
X
As clinically indicated
8.2.4
Concomitant medications
<----------------------------------------------------------------------------------------------------------------------------------------------------->
6.4
Demography, including baseline 
characteristics and tobacco use
X
5.1, 5.2
Eligibility criteria
X
X
5.1, 5.2
Medical/surgical history
X
5.1
Laboratory assessments
Clinical chemistrye,f
X
Xg
X
X
X
X
X
X
X
Table 12
Hematologye, f
X
Xg
X
X
X
X
X
X
X
Table 13
Coagulation parameters
Xg
Table 13
TSH (reflex free T3 or free T4h)
X
Xi
X
X
X
Table 12
Hepatitis B and C and HIV
X
8.2.1

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
14 (233)
Screening
C1
1 cycle = 3 weeks 
(21 days) 
C2
1 cycle = 3 weeks 
(21 days)
C3
1 cycle = 3 
weeks (21 days)
C4
1 cycle = 3 
weeks (21 days)
Pre-
radical 
cystectomy
Radical 
cystectomy 
(≥14 days to 
56 days 
after last 
dose of neo-
adjuvant 
therapy)
For 
details, 
see 
Section
Week
-4 to -1
1
2
4
5
7
8
10
11
Day
-28 to -1
1
8
1
8
1
8
1
8
Window (days)
NA
+3
±2
+3
±2
+3
±2
+3
±2
Urinalysis
X
As clinically indicated
8.2.1
Pregnancy testj
X
X
X
X
X
8.2.1
Pharmacokinetics
Durvalumab PK sample (serum) 
(Arm 1 only)
Xk
Xl
Xl
8.5
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
X
X
8.2.5
AE/SAE assessmentm
<---------------------------------------------------------------------------------------------------------------------------------------------------->
8.3
IP administration
Durvalumab (Arm 1 only) f,n
X
X
X
X
6.1.2.1
Gemcitabinen
X
X
X
X
X
X
X
X
6.1.1.3
Cisplatinn
X
Xo
X
Xo
X
Xo
X
Xo
6.1.1.3
Other assessments and assays
Durvalumab immunogenicity 
assessment (ADA and 
neutralizing antibodies) (Arm 1 
only)
Xl
Xl
Xl
8.5.1.1
Tumor biopsy (newly acquired or 
archival ≤3 months old)p
Xa
8.8.1
Radical cystectomy
X
6.1.5
Tumor assessments: pathology 
testing 
Xq
8.8.1

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
15 (233)
Screening
C1
1 cycle = 3 weeks 
(21 days) 
C2
1 cycle = 3 weeks 
(21 days)
C3
1 cycle = 3 
weeks (21 days)
C4
1 cycle = 3 
weeks (21 days)
Pre-
radical 
cystectomy
Radical 
cystectomy 
(≥14 days to 
56 days 
after last 
dose of neo-
adjuvant 
therapy)
For 
details, 
see 
Section
Week
-4 to -1
1
2
4
5
7
8
10
11
Day
-28 to -1
1
8
1
8
1
8
1
8
Window (days)
NA
+3
±2
+3
±2
+3
±2
+3
±2
Optional additional tumor 
biopsies
The collection of additional tumor biopsies upon progression of patients in Arm 1 
and Arm 2 is strongly encouraged. 
8.8.1
Urine sample for biomarkerr
X (pre-dose)
Xs
8.8.2
Urine sample for cytologyt
X (pre-dose)
Xs
8.8.2
Blood sample for PaxGene-RNA 
analysisu
X
8.8.2
Serum sample for biomarkers
X
8.8.2
Plasma for ctDNA/circulating 
soluble factorsu
X
X (pre-dose)
X
Xs
8.8.2
Blood sample for genetic analysis 
(Gx) (optional)v
X
8.7
Distribute ePRO device
X
8.1.3
ePRO device training
X
8.1.3
EORTC QLQ-C30, PGIS, and 
EQ-5D-5L
To be completed at C1D1 and every 4 weeks thereafter
8.1.3.1, 
8.1.3.2, 
8.1.3.4
PRO-CTCAEw
To be completed at C1D1 and every 2 weeks thereafter
8.1.3.4
PGIC
To be completed at 4 weeks post-C1D1 and every 4 weeks thereafter
8.1.3.3
Efficacy evaluations
Neoadjuvant tumor assessments: 
RECIST 1.1
Xx
Xy
8.1, 
Appendix
Fz
a
Informed consent includes consent for study procedures and biopsy of baseline tumor tissue for PD-L1 status and pathology testing; genetic testing of tissue obtained at 
baseline and from radical cystectomy tumor tissue is an optional part of the informed consent. Informed consent of study procedures may be obtained prior to the 28-day 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
16 (233)
screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization. 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, with the exception of the patient’s tumoral PD-L1 status (must be obtained within ≤3 months before screening).
b
Every effort should be made to minimize the time between randomization and starting treatment; the maximum interval is 3 working days.
c
Vital signs will be evaluated per Section 8.2.3.
d
Any clinically significant abnormalities detected require triplicate ECG results obtained over a brief period (eg, 30 minutes).
e
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated.
f
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or 
Investigator prior to dosing; a creatinine clearance determination is required prior to each Day 1and Day 8 dose of cisplatin (if applicable).
g
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. For 
coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed at baseline on Day 1 (unless performed within 3 days prior 
to Day 1).
h
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
i
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
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then every 3 weeks. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician 
or Investigator prior to commencing an infusion. 
k
Pre-dose (within 60 minutes before start of infusion) and post-dose (within 10 minutes after the end of infusion). 
l
Pre-dose (within 60 minutes before start of infusion) only.
m
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
n
In Arm 1 only, durvalumab will be administered first; G+C infusion will start approximately 1 hour after the end of the durvalumab infusion. If there are no clinically 
significant concerns after the first cycle, reduction of the observation period may be at the Investigator’s discretion (suggested 30 minutes). 
o
This is required for patients with borderline renal function only. In the event that creatinine clearance drops below 60 mL/min, the cisplatin dose may be divided into 
2 administrations, as per local practice, for management of renal toxicity.
p
Archival tissue must be from a tumor sample when the patient has confirmed MIBC (ie, non-MIBC samples will not be acceptable). This tumor specimen should be of 
sufficient quantity to allow for prospective PD-L1 IHC evaluation, retrospective evaluation of muscle invasive disease, and other exploratory biomarker analyses.
q
A specimen from radical cystectomy must be provided for local and central pathological review; additional samples should also be collected for exploratory analyses for all 
surgical procedures (including a partial cystectomy). 
r
Urine biomarker sample will be done by central laboratory.
s
Collect in the morning prior to radical cystectomy or within 7 days immediately prior to radical cystectomy. Also, to be done upon progression or end of treatment if patient 
terminates the study prior to radical cystectomy.
t
Cytology will be done by local laboratory.
u
Also to be collected at recurrence or progression. If a patient is discontinued from treatment prematurely during the neoadjuvant phase (prior to cystectomy) due to either 
progression or recurrence, PaxGene and ctDNA/circulating soluble factors samples should also be collected.
v
The sample for genetic research will be obtained at Day 1 pre-dose. 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.
w
PRO-CTCAE will only be administered in those countries where a linguistically validated version is available.
x
A CT (preferred) or MRI of the chest, abdomen, and pelvis must be performed within 28 days prior to and as close as possible to randomization, and this scan is designated 
as the “Neoadjuvant Baseline” scan (ie, lesions are classified as neoadjuvant baseline Target Lesions or Non-Target Lesions). Lesions in the wall of distensible organs are 
not reproducibly measurable and should be classified NTLs.
y
A neoadjuvant follow up scan must be performed upon completion of neoadjuvant chemotherapy prior to surgery; consideration should be given to scheduling this scan as 
part of the pre-surgical workup, to confirm patient is still eligible for a radical cystectomy.
=z
For patients who are medically precluded from, refuse, or withdraw from a radical cystectomy, refer to Section 8.1.1 for tumor assessment schedule
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
17 (233)
ADA  Antidrug antibody; AE  Adverse event; BP  Blood pressure; C  Cycle; CT  Computed tomography; ctDNA  Circulating tumor DNA; D  Day; ECG  Electrocardiogram; 
ECOG Eastern Cooperative Oncology Group; EORTC QLQ-C30  European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire; 
ePRO Electronic patient reported outcome; EQ-5D-5L  EuroQol 5-dimension, 5-level health state utility index; G+C  gemcitabine and cisplatin; HIV  Human immunodeficiency
virus; IP  Investigational product; LFT  Liver function test; MIBC  Muscle-invasive bladder cancer; MRI  Magnetic resonance imaging; NA  Not applicable; PD-L1 Programmed 
cell death-ligand 1; PGIC  Patient Global Impression of Change; PGIS  Patient Global Impression of Severity; PK Pharmacokinetic(s); PRO-CTCAE Patient-reported outcomes 
version of the Common Terminology Criteria for Adverse Events; SAE  Serious adverse event; T3 Triiodothyronine; T4  Thyroxine; TSH Thyroid-stimulating hormone; 
WHO World Health Organization.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
18 (233)
Table 2
Schedule of assessments for the adjuvant treatment phase (Arm 1)
C1
1 cycle = 
4 weeks 
(28 days)
C2
1 cycle = 
4 weeks 
(28 days)
C3
1 cycle = 
4 weeks 
(28 days)
C4
1 cycle = 
4 weeks 
(28 days)
C5
1 cycle = 
4 weeks 
(28 days)
C6
1 cycle = 
4 weeks 
(28 days)
C7
1 cycle = 
4 weeks 
(28 days)
C8
1 cycle = 
4 weeks 
(28 days)
For 
details, 
see 
Section
Week
NA
1
5
9
13
17
21
25
29
Day
42 days after 
radical 
cystectomy
1
1
1
1
1
1
1
1
Window (days)
(±14 days)
(±3 days, tumor assessment ±7 days) 
Study procedures
Targeted physical examination (based on 
symptoms)
X
X
X
X
X
X
X
X
8.2.2
Vital signsa
X
X
X
X
X
X
X
X
8.2.3
ECG (resting 12-lead)b
As clinically indicated
8.2.4
Concomitant medications
<------------------------------------------------------------------------------------------------------------------>
6.4
Laboratory assessments
Clinical chemistryc
X
X
X
X
X
X
X
X
Table 12
Hematologyc
X
X
X
X
X
X
X
X
Table 13
Coagulation parameters (Arm 1 only)
X
Table 13
TSH (reflex free T3 or free T4)d
X
X
X
X
X
X
X
X
Table 12
Urinalysis
As clinically indicated
8.2.1
Pregnancy teste
Xe
Xe
Xe
X
X
X
X
X
8.2.1
Pharmacokinetics
Durvalumab PK sample (serum) (Arm 1 
only)
Xf
Xf
8.5
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
X
8.2.5
AE/SAE assessmentg
<------------------------------------------------------------------------------------------------------------------>
8.3

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
19 (233)
C1
1 cycle = 
4 weeks 
(28 days)
C2
1 cycle = 
4 weeks 
(28 days)
C3
1 cycle = 
4 weeks 
(28 days)
C4
1 cycle = 
4 weeks 
(28 days)
C5
1 cycle = 
4 weeks 
(28 days)
C6
1 cycle = 
4 weeks 
(28 days)
C7
1 cycle = 
4 weeks 
(28 days)
C8
1 cycle = 
4 weeks 
(28 days)
For 
details, 
see 
Section
Week
NA
1
5
9
13
17
21
25
29
Day
42 days after 
radical 
cystectomy
1
1
1
1
1
1
1
1
Window (days)
(±14 days)
(±3 days, tumor assessment ±7 days) 
IP administration
Durvalumab (Arm 1 only)
X
X
X
X
X
X
X
X
6.1.2.1
Other assessments and assays
Durvalumab immunogenicity assessment 
(ADA and neutralizing antibodies) (Arm 1 
only) 
X
X
8.5.1.1
Optional additional tumor biopsies
The collection of additional tumor biopsies upon recurrence in patients in Arm 1 and Arm 2 is 
strongly encouraged.
8.8.1
Clavien-Dindo assessment
90 days post-cystectomy (including a partial cystectomy, if performed)
8.2.7
Blood sample for PaxGene-RNA analysish
X
X
8.8.2
Serum sample for biomarkers
X
X
8.8.2
Plasma for ctDNA/circulating soluble 
factorsh
X
X
8.8.2
EORTC QLQ-C30, PGIS, PGIC, and 
EQ-5D-5L
To be completed at C1D1 and every 4 weeks thereafter
8.1.3.1-
8.1.3.4
PRO-CTCAEi
To be completed at C1D1 and every 2 weeks up to Week 13, then every 4 weeks thereafter
8.1.3.5

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
20 (233)
C1
1 cycle = 
4 weeks 
(28 days)
C2
1 cycle = 
4 weeks 
(28 days)
C3
1 cycle = 
4 weeks 
(28 days)
C4
1 cycle = 
4 weeks 
(28 days)
C5
1 cycle = 
4 weeks 
(28 days)
C6
1 cycle = 
4 weeks 
(28 days)
C7
1 cycle = 
4 weeks 
(28 days)
C8
1 cycle = 
4 weeks 
(28 days)
For 
details, 
see 
Section
Week
NA
1
5
9
13
17
21
25
29
Day
42 days after 
radical 
cystectomy
1
1
1
1
1
1
1
1
Window (days)
(±14 days)
(±3 days, tumor assessment ±7 days) 
Efficacy evaluations
Adjuvant assessments (RECIST 1.1)
Xj
Adjuvant tumor assessments occur every 12 weeks ±7 days after the date of radical cystectomy for 
the first 24 months, then every 24 weeks ±7 days for 36 months, and then every 52 weeks 
(annually) thereafter until progression, the end of study, death, study discontinuation, or Sponsor 
decision, whichever comes first.k During adjuvant treatment, the imaging schedule MUST be 
followed regardless of any delays in dosing. If an unscheduled assessment is performed and the 
patient has not progressed, every attempt should be made to perform the subsequent assessments 
according to the original imaging schedule. 
For patients who are medically precluded from, refuse, or withdraw from a radical cystectomy, refer 
to Section 8.1.1 for tumor assessment schedule.
6.1.3, 
8.1, 
Appendi
x F
a
Vital signs will be evaluated per Section 8.2.3.
b
Any clinically significant abnormalities detected require triplicate ECG results obtained over a brief period (eg, 30 minutes).
c
Serum or plasma clinical chemistry (including LFT monitoring) and hematology are to be collected q4w prior to the start of infusion for Arm 1 and as clinically indicated 
(may be performed more frequently if clinically indicated). Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion 
(within 3 days) and reviewed by the treating physician or Investigator prior to dosing.
d
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.
e
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then q4w. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or 
Investigator prior to commencing an infusion. 
f
Arm 1: Pre-dose (within 60 minutes before start of infusion) only.
g
For AEs/SAEs reported resulting from the radical cystectomy, additional information such as concomitant medications must be reported.
h
Also to be collected at recurrence or progression. If a patient is discontinued from treatment prematurely during the adjuvant phase due to either progression or recurrence, 
PaxGene and ctDNA/circulating soluble factors samples should also be collected.
i
PRO-CTCAE will only be administered in those countries where a linguistically validated version is available.
j
A CT (preferred) or MRI of the chest, abdomen, and pelvis must be performed 42 days (±2 weeks) after radical cystectomy and must be prior to the start of adjuvant therapy, 
and this scan is designated as the “Adjuvant Baseline” scan. In most instances, no lesions will be observed on the Adjuvant Baseline scans and ‘No Evidence of Disease’ will 
be recorded for the Adjuvant Baseline RECIST assessment; however, if any radiologically observable tumors exist, a fresh selection of Target and Non-Target lesions should 
be applied.
k
Where possible or feasible, radiological progression should be biopsy proven. Other imaging modalities (eg, bone scan, MRI scan) may be required to define progression in 
equivocal cases. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
21 (233)
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
ADA  Antidrug antibody; AE  Adverse event; BP  Blood pressure; C  Cycle; CT  Computed tomography; ctDNA  Circulating tumor DNA; D  Day; ECG  Electrocardiogram; 
ECOG Eastern Cooperative Oncology Group; EORTC QLQ-C30  European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire; 
EQ-5D-5L  EuroQol 5-dimension, 5-level health state utility index; IP  Investigational product; LFT  Liver function test; MRI  Magnetic resonance imaging; NA Not applicable; 
PGIC  Patient Global Impression of Change; PGIS  Patient Global Impression of Severity; PK  Pharmacokinetic(s); PRO-CTCAE Patient-reported outcomes version of the 
Common Terminology Criteria for Adverse Events; q4w  every 4 weeks; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; 
T3 Triiodothyronine; T4 Thyroxine; TSH  Thyroid-stimulating hormone; WHO  World Health Organization.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
22 (233)
Table 3
Schedule of assessments for the adjuvant phase visits (Arm 2)
C1
1 cycle = 
4 weeks 
(28 days)
C2
1 cycle = 
4 weeks 
(28 days)
C3
1 cycle = 
4 weeks 
(28 days)
C4
1 cycle = 
4 weeks 
(28 days)
C5
1 cycle = 
4 weeks 
(28 days)
C6
1 cycle = 
4 weeks 
(28 days)
C7
1 cycle = 
4 weeks 
(28 days)
C8
1 cycle = 
4 weeks 
(28 days)
For 
details, 
see 
Section
Week
NA
1
5
9
13
17
21
25
29
Day
42 days after 
radical 
cystectomy
1
1
1
1
1
1
1
1
Window (days)
(±14 days)
(±3 days, tumor assessment ±7 days) 
Study procedures
Targeted physical examination (based on 
symptoms)
X
X
X
X
8.2.2
Vital signsa
X
X
X
X
8.2.3
ECG (resting 12-lead)b
As clinically indicated
8.2.4
Concomitant medications
<------------------------------------------------------------------------------------------------------------------>
6.4
Laboratory assessments
Clinical chemistryc
X
X
X
X
Table 12
Hematologyc
X
X
X
X
Table 13
TSH (reflex free T3 or free T4)d
X
X
X
X
Table 12
Urinalysis
As clinically indicated
8.2.1
Pregnancy teste
Xe
Xe
8.2.1
Monitoring
WHO/ECOG performance status
X
X
X
X
8.2.5
AE/SAE assessmentf
<------------------------------------------------------------------------------------------------------------------>
8.3
Patient follow-up contact/patient review for 
safety
X
X
X
X
8.2.6
Optional additional tumor biopsies
The collection of additional tumor biopsies upon recurrence in patients is strongly encouraged.
8.8.1
Clavien-Dindo assessment
90 days post-cystectomy (including a partial cystectomy, if performed)
8.2.7
Blood sample for PaxGene-RNA analysisg
X
X
8.8.2

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
23 (233)
C1
1 cycle = 
4 weeks 
(28 days)
C2
1 cycle = 
4 weeks 
(28 days)
C3
1 cycle = 
4 weeks 
(28 days)
C4
1 cycle = 
4 weeks 
(28 days)
C5
1 cycle = 
4 weeks 
(28 days)
C6
1 cycle = 
4 weeks 
(28 days)
C7
1 cycle = 
4 weeks 
(28 days)
C8
1 cycle = 
4 weeks 
(28 days)
For 
details, 
see 
Section
Week
NA
1
5
9
13
17
21
25
29
Day
42 days after 
radical 
cystectomy
1
1
1
1
1
1
1
1
Window (days)
(±14 days)
(±3 days, tumor assessment ±7 days) 
Serum sample for biomarkers
X
X
8.8.2
Plasma for ctDNA/circulating soluble 
factorsg
X
X
8.8.2
EORTC QLQ-C30, PGIS, PGIC, and 
EQ-5D-5L
To be completed at C1D1 and every 4 weeks thereafter
8.1.3.1-
8.1.3.4
PRO-CTCAEh
To be completed at C1D1 and every 2 weeks up to Week 13, then every 4 weeks thereafter
8.1.3.5
Efficacy evaluations
Adjuvant assessments (RECIST 1.1)
Xi
Adjuvant tumor assessments occur every 12 weeks ±7 days after the date of radical cystectomy for 
the first 24 months, then every 24 weeks ±7 days for 36 months, and then every 52 weeks 
(annually) thereafter until progression, the end of study, death, study discontinuation, or Sponsor 
decision, whichever comes first.j During adjuvant treatment, the imaging schedule MUST be 
followed regardless of any delays in dosing. If an unscheduled assessment is performed and the 
patient has not progressed, every attempt should be made to perform the subsequent assessments 
according to the original imaging schedule. 
For patients who are medically precluded from, refuse, or withdraw from a radical cystectomy, refer 
to Section 8.1.1 for tumor assessment schedule.
6.1.3, 
8.1,
Appendi
x F
a
Vital signs will be evaluated per Section 8.2.3.
b
Any clinically significant abnormalities detected require triplicate ECG results obtained over a brief period (eg, 30 minutes).
c
Serum or plasma clinical chemistry (including LFT monitoring) and hematology are to be collected at any time during the visit for Arm 2, and as clinically indicated (may be 
performed more frequently if clinically indicated). 
d
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.
e
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then q4w. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or 
Investigator prior to commencing an infusion. For patients in Arm 2, pregnancy test will only be required for Cycle 1 and Cycle 3.
f
For AEs/SAEs reported resulting from the radical cystectomy, additional information such as concomitant medications must be reported.
g
Also to be collected at recurrence or progression. If a patient is discontinued from treatment prematurely during the adjuvant phase due to either progression or recurrence, 
PaxGene and ctDNA/circulating soluble factors samples should also be collected. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
24 (233)
h
PRO-CTCAE will only be administered in those countries where a linguistically validated version is available.
i
A CT (preferred) or MRI of the chest, abdomen, and pelvis must be performed 42 days (±2 weeks) after radical cystectomy and must be prior to the start of adjuvant therapy, 
and this scan is designated as the “Adjuvant Baseline” scan. In most instances, no lesions will be observed on the Adjuvant Baseline scans and “No Evidence of Disease” 
will be recorded for the Adjuvant Baseline RECIST assessment; however, if any radiologically observable tumors exist, a fresh selection of target and non-target lesions 
should be applied.
j
Where possible or feasible, radiological progression should be biopsy proven. Other imaging modalities (eg, bone scan, MRI scan) may be required to define progression in 
equivocal cases. 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
AE  Adverse event; C  Cycle; CT  Computed tomography; ctDNA  Circulating tumor DNA; D  Day; ECG  Electrocardiogram; ECOG Eastern Cooperative Oncology Group; 
EORTC QLQ-C30  European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire; EQ-5D-5L  EuroQol 5-dimension, 5-level health 
state utility index; LFT  Liver function test; MRI  Magnetic resonance imaging; NA  Not applicable; 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; q4w  every 4 weeks; RECIST 1.1  Response Evaluation 
Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH  Thyroid-stimulating hormone; WHO  World Health Organization.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
25 (233)
Table 4
Schedule of assessments for patients who have discontinued treatment or completed study visits/treatment
NOTE: If a patient is discontinued from study treatment either during or at the completion of the neoadjuvant phase and has not 
undergone a cystectomy or does not enter adjuvant phase, follow-up visits will be calculated from “time since last dose of treatment”, 
BUT it is anticipated that 30 and/or 60 days would have passed since last dose of treatment; therefore in those cases, study activities 
may be waived for the Day 30 and/or Month 2 visits (with the exception of AE/SAE follow-up as per section 8.3.2).  However, the 
Month 3 (90-day) visit must be performed and documented, even if delayed beyond the actual 90-days since last dose of treatment. In 
addition, a pregnancy test must be performed at this Month 3 visit if Day 30 visit (in which a pregnancy test is required) is not done. 
Time since last dose of treatment (Arm 1) or adjuvant phase study visits (Arm 2)
Evaluation
Day (±3)
Months (±1 week)
Month 12 
(±2 weeks)
Every 
6 months 
thereafter 
(±2 weeks)
For details, 
see Section
30
2a
3
6
9
Physical examination (full)
X
8.2.2
Vital signs (temperature, respiratory rate, blood pressure, and 
pulse)
X
8.2.3
Weight
X
Xa
X
8.2.3
Urinalysis
As clinically indicated
8.2.1
Pregnancy testb
X
As clinically indicated
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.4
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at 
initiation of subsequent anticancer therapyc
8.2.5
Subsequent anticancer therapyd
<------------------------------------------------------------------------------------------------------->
Survival statuse
X
X
X
X
X
8.1.2
Hematology
X
Xa
X
Table 13
Clinical chemistry
X
Xa
X
Table 12
TSH (reflex free T3 or free T4f)
X
Xa
X
Table 12
Durvalumab PK assessmentg  (Arm 1 only)
X
8.5

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
26 (233)
Time since last dose of treatment (Arm 1) or adjuvant phase study visits (Arm 2)
Evaluation
Day (±3)
Months (±1 week)
Month 12 
(±2 weeks)
Every 
6 months 
thereafter 
(±2 weeks)
For details, 
see Section
30
2a
3
6
9
Durvalumab immunogenicity assessment (ADA sampling) to 
identify ADA responsesg  (Arm 1 only)
X
8.5
Blood sample for PaxGene-RNA analysisk
Plasma for ctDNA/circulating soluble factorsk
As indicated
EORTC QLQ-C30, EQ-5D-5L, PGIC, and PGIS
X
X
X
Every 8 weeks until recurrence of disease, 
subsequent therapy, or study discontinuation 
(whichever occurs first).h
8.1.3.1, 
8.1.3.2, 
8.1.3.3, 
8.1.3.4
PRO-CTCAEi
X
X
X
8.1.3.4
Tumor assessment 
Tumor assessments occur every 12 weeks ±7 days after the date of radical cystectomy for 
the first 24 months, then every 24 weeks ±7 days for 36 months, and then every 52 weeks 
(annually) thereafter until progression, the end of study, death, study discontinuation, or 
Sponsor decision, whichever comes first.j During adjuvant treatment, the imaging schedule 
MUST be followed regardless of any delays in dosing. If an unscheduled assessment is 
performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments according to the original imaging schedule. 
For patients who are medically precluded from, refuse, or withdraw from a radical 
cystectomy, refer to Section 8.1.1 for tumor assessment schedule.
6.1.3, 8.1, 
Appendix F
a
Patients in Arm 2 will be required to have a follow-up call to collect AEs and concomitant medications. Weight, ECOG at 60 days, clinical chemistry, hematology, and TSH 
will not be required for this visit.
b
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. 
c
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.
d
Details of any treatment for bladder cancer (including surgery and radiation) post the last dose of IP must be recorded in the eCRF. At a minimum, the start date and 
description of the subsequent anticancer therapy should be collected. 
e
Patients may be contacted in the week following data cutoffs to confirm survival status. Details of any treatment for MIBC (including surgery) post 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 treatment with IP ends. 
h
Study sites will send reminders to patients to complete questionnaires during follow-up
i
PRO-CTCAE will only be administered in those countries where a linguistically validated version is available.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
27 (233)
j
Where possible or feasible, radiological progression should be biopsy proven. Other imaging modalities (eg, bone scan, MRI scan) may be required to define progression in 
equivocal cases. 
k
Also to be collected at recurrence or progression. If a patient discontinues from follow-up visits due to either progression or recurrence, PaxGene and ctDNA/circulating 
soluble factors samples should also be collected unless the patient previously collected these samples due to earlier progression or recurrence. 
ADA  Antidrug antibody; AE  Adverse event; CT  Computed tomography; ECOG  Eastern Cooperative Oncology Group; eCRF  Electronic case report form; 
EORTC QLQ-C30 European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire; EQ-5D-5L  EuroQol 5-dimension, 5-level 
health state utility index; IP  Investigational product; MIBC  Muscle-invasive bladder cancer; MRI  Magnetic resonance imaging; PGIC  Patient Global Impression of 
Change; PGIS Patient Global Impression of Severity; PK  Pharmacokinetic(s); PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; 
TSH Thyroid-stimulating hormone; WHO  World Health Organization.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
28 (233)
1.2
Synopsis
Protocol title: 
A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy 
and Safety of Durvalumab in Combination with Gemcitabine+Cisplatin (G+C) for Neoadjuvant 
Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients with 
Muscle-Invasive Bladder Cancer (NIAGARA)
Rationale:
The standard management for patients with muscle-invasive bladder cancer (MIBC) involves 
radical cystectomy and pelvic lymph node dissection. Several studies have demonstrated 
improved pathologic complete response (pCR), event-free survival (EFS), and overall survival 
(OS) with the integration of neoadjuvant, cisplatin-based combination chemotherapy when 
compared with radical cystectomy alone.
Despite improvements of pCR and survival rates with neoadjuvant chemotherapy, many patients 
will still develop recurrence and will ultimately die of metastatic bladder cancer. Recently, 
multiple programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) 
inhibitors have demonstrated activity in metastatic bladder cancer patients and have been granted 
approval in the platinum refractory setting, as well as pembrolizumab and atezolizumab 
accelerated approval in the first-line metastatic setting for patients unable to tolerate cisplatin 
chemotherapy (KEYTRUDA [package insert] 2018, TECENTRIQ [package insert] 2018). 
The benefits of adjuvant chemotherapy after radical cystectomy in patients with MIBC without 
clinically detectable metastases are unclear. There is limited evidence from adequately 
conducted, randomized, Phase III trials to support the use of adjuvant chemotherapy in patients 
immediately following surgery. However, in 2 separate meta-analyses conducted in 2013 (Leow 
et al 2014) and 2016 (Kim et al 2017), with 9 and 11 randomized controlled studies in MIBC, 
respectively, suggested an OS benefit in patients receiving adjuvant cisplatin-based 
chemotherapy. Multiple Phase III trials evaluating adjuvant PD-1 or PD-L1 inhibitors and 
Phase II trials reveal promising activity and safety for single-agent neoadjuvant pembrolizumab 
or atezolizumab are ongoing (Necchi et al 2018, Powles et al 2018).
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (subclass that 
inhibits binding of PD-L1 (B7 homolog 1, cluster of differentiation [CD]274) to PD-1 (CD279) 
and CD80 (B7-1). Nonclinical and clinical studies have indicated that blockade of the immune 
checkpoints PD-1/PD-L1 can have a positive effect on antitumor activity. Clinical benefit has 
been observed in a wide range of tumor types, including metastatic melanoma, squamous and 
nonsquamous non-small-cell lung cancer, head and neck squamous cell carcinoma, and 
urothelial carcinoma (UC).
The benefit of this class of compound and specifically durvalumab in bladder cancer has been 
demonstrated in a cohort of 182 patients with locally advanced or metastatic UC who progressed 
despite platinum-based chemotherapy (IMFINZI [package insert] 2017, Massard et al 2016). 
Durvalumab has been approved to treat locally advanced or metastatic urothelial carcinoma, 
unresectable stage III non-small cell lung cancer, and extensive-stage small cell lung cancer 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
29 (233)
(administered in combination with chemotherapy). Refer to the package insert (or label) for your 
specific country, as applicable. 
The addition of immunotherapy to chemotherapeutic agents has been shown to result in 
improved response rates relative to chemotherapy alone. Cytotoxic chemotherapy has been 
shown to modulate the immune response via several mechanisms, such as stimulating T cell 
activation by increasing the expression of MHC-1 molecules, stimulating dendritic cell 
maturation, inducing immunogenic cell death (a form of cell death that induces dendrites to 
stimulate tumor antigen presentation to T cells), and reducing the immunosuppressive function 
of regulatory T cells and myeloid-derived suppressor cells (Kodumudi et al 2010, Kroemer et al 
2013, Liu et al 2010, Zhang et al 2008). Combining a PD-L1 antagonist with cytotoxic agents 
may provide complementary benefit in mounting an effective antitumor immunity by promoting 
the antigen presentation, increasing the production of protective T cells, and overcoming 
immunosuppression in the tumor bed (Mellman et al 2011). In addition, a variety of approaches 
for combining PD-1 pathway blockers with other agents has been explored over the past few 
years in an effort to both improve the efficacy of treatment and/or position the treatment regimen 
for testing in patients who are treatment-naive with a variety of cancers (Langer et al 2016). The
rationale for the present study is that PD-L1 inhibition through exposure to durvalumab, in 
combination with chemotherapeutics such as G+C, may increase both the long-term response 
rate and the frequency of response by preventing the MIBC tumor cells (TCs) from evading 
immune-mediated antitumor response. Administering durvalumab may provide a benefit to this 
subgroup of patients by averting intrinsic resistance. Adjuvant durvalumab monotherapy may 
further improve time to disease relapse in these patients.
Objectives and endpoints:
Primary objectives:
Endpoints/variables:
To assess the efficacy of durvalumab + G+C 
combination therapy (neoadjuvant)/durvalumab 
alone (adjuvant) (Arm 1) compared to G+C 
combination therapy (neoadjuvant)/no adjuvant 
treatment (Arm 2) in terms of pCR and EFS in 
MIBC patients 
pCR using assessments per central pathology 
review
EFS using assessments per BICR or by central 
pathology review if a biopsy is required for a 
suspected new lesion
Secondary objectives:
Endpoints/variables:
To assess the efficacy of Arm 1 versus Arm 2 in 
terms of EFS at 24 months in MIBC patients 
EFS24 using assessments per BICR or by 
central pathology review if a biopsy is required 
for a suspected new lesion

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
30 (233)
To assess the efficacy of Arm 1 compared to Arm 2 
in terms of pathologic response at radical 
cystectomy and EFS in MIBC patients 
pCR using assessments per local pathology 
review
Proportion of patients who achieve <P2 per 
local pathology review
EFS using assessments per local Investigator or 
local biopsy review if a biopsy is required for a 
suspected new lesion
EFS24 using assessments per local Investigator 
or local biopsy review if a biopsy is required for 
a suspected new lesion
To assess the efficacy of Arm 1 versus Arm 2 in 
MIBC patients 
Metastasis-free survival and disease-specific 
survival per Investigator assessments or local
biopsy review if a biopsy is required for a 
suspected new lesion
Overall survival (OS)
OS at 5 years
Disease-free survival in patients who undergo 
radical cystectomy
Proportion of patients who undergo radical
cystectomy
PFS2 as defined by local standard clinical 
practice
To assess the efficacy of Arm 1 versus Arm 2 in 
terms of pCR and EFS in MIBC patients in the 
PD-L1-high subgroup
pCR using assessments per central pathology 
review
EFS using assessments per BICR or by central 
pathology review if a biopsy is required for a 
suspected new lesion
To assess disease-related symptoms, physical 
function, and other HRQoL in Arm 1 versus Arm 2 
using the EORTC QLQ-C30 questionnaire
Adjusted mean change from baseline and time 
to definitive clinically meaningful deterioration 
in EORTC QLQ-C30 scale/item scores 
(prioritized domains: fatigue and pain, physical 
functioning, global health status/quality of life)
To assess the PK of durvalumab when used in 
combination with G+C
Serum concentration of durvalumab and 
non-compartmental PK parameters (such as 
peak and trough concentrations, as data allow; 
sparse sampling)
To investigate the immunogenicity of durvalumab 
when used in combination with G+C 
Presence of ADAs for durvalumab 
(confirmatory results: positive or negative)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
31 (233)
Safety objective:
Endpoints/variables:
To assess the safety and tolerability profile of Arm 1 
versus Arm 2 in MIBC patients
AEs, laboratory findings, vital signs, and ECGs
Exploratory objectives:
Endpoints/variables:
To assess patient-reported treatment-related 
symptoms or tolerability of Arm 1 versus Arm 2 
using PRO-CTCAE
PRO-CTCAE (items pre-selected based on 
systemic treatment arms) – descriptive summary 
of responses
To assess overall health status and overall severity 
of disease-related symptoms in patients in Arm 1 
versus Arm 2 using the PGIC and PGIS 
questionnaires, respectively
PGIC and PGIS – descriptive summary of 
responses
To explore the impact of treatment and disease state 
on health state utility using the EQ-5D-5L
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on 
patient-reported data
To evaluate tumor-based biomarkers and 
associations with efficacy parameters, potentially 
including, but not limited to, microsatellite stability, 
tumor mutational burden, and other immune-related 
biomarkers
Association of tumor-based assessments with 
efficacy and clinical parameters
To evaluate circulatory-based and urine-based 
biomarkers and associations with efficacy 
parameters, including, but not limited to, ctDNA
Association of ctDNA, whole blood gene 
expression, and urine biomarkers with efficacy 
and clinical parameters
ADA Antidrug antibody; AE Adverse event; BICR Blinded Independent Central Review; ctDNA Circulating 
tumor DNA; ECG Electrocardiogram; EFS Event-free survival; EFS24 Proportion of patients alive and event 
free at 24 months using local pathology or BICR; EORTC QLQ-C30 European Organization for Research and 
Treatment of Cancer 30-item Core Quality of Life Questionnaire; EQ-5D-5L EuroQol 5-dimension, 5-level 
health state utility index; G+C gemcitabine plus cisplatin; HRQoL Health-related quality of life; 
MIBC Muscle-invasive bladder cancer; OS  Overall survival; pCR Pathologic complete response; PD-
L1 Programmed cell death-ligand 1; PFS2 Time from the date of randomization to the earliest date of 
progression which occurs on subsequent therapy following an EFS event or death; PGIC Patient Global 
Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; 
PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events.
Overall design:
This is a Phase III, randomized, open-label, multi-center, global study to evaluate durvalumab 
(MEDI4736) in combination with G+C chemotherapy (neoadjuvant) followed by durvalumab 
alone (adjuvant) versus G+C (neoadjuvant) followed by no adjuvant treatment in patients with 
MIBC. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
32 (233)
Study period:

Estimated date of first patient enrolled Q4 2018

Estimated date of last patient completed Q2 2026
Number of patients:
Approximately 1050 patients globally will be randomized in a 1:1 ratio to receive durvalumab + 
G+C combination therapy q3w (Arm 1) or G+C combination therapy q3w (Arm 2) for 4 cycles 
of neoadjuvant chemotherapy prior to radical cystectomy. Following radical cystectomy and 
during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy every 4 weeks 
(q4w) for 8 additional cycles, and patients in Arm 2 will receive no adjuvant treatment. 
Recruitment for patients with borderline renal function will be limited to up to 20% of the 
targeted global population. Recruitment for patients with T2N0 disease will be limited to 
approximately 40% of the targeted global population (for both treatment arms); once the 40% 
cap has been reached, only clinical stage T2-T4aN1M0 or T3-T4aN0M0 patients will be allowed 
to be enrolled onto the study.
Randomization will be stratified by clinical tumor stage T2N0 versus >T2N0 (including T2N1, 
T3 and T4a) to reflect prognostic stage II versus IIIa, respectively; renal function (adequate renal 
function versus borderline renal function), and PD-L1 status (high versus low/negative, based on 
Ventana assay; see Table 6). Patients will provide a tumor tissue sample at screening to 
determine PD-L1 status for stratification.
Treatments and treatment duration:
Neoadjuvant therapy
Patients randomized to the 2 treatment arms, Arm 1 or Arm 2, will be treated according to their 
renal function. 
Patients with adequate renal function (creatinine clearance [CrCl] ≥60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg intravenous (IV), cisplatin 70 mg/m2, 
gemcitabine 1000 mg/m2; Day 8: gemcitabine 1000 mg/m2; every 21 days for 4 cycles.

Arm 2: Day 1: cisplatin 70 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2; every 21 days for 4 cycles.
Patients with borderline renal function (CrCl ≥40 mL/min to <60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg IV, cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; 
Day 8: gemcitabine 1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.

Arm 2: Day 1: cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
33 (233)
*In scenarios when patients are unable to complete the intended 4 cycles of chemotherapy 
prior to radical cystectomy, patients will be permitted to receive less than 4 cycles of 
chemotherapy, at the discretion of the Investigator and upon discussion with AstraZeneca.
Adjuvant therapy (regardless of renal status)

Arm 1: Day 1: durvalumab 1500 mg IV; every 28 days for 8 cycles.

Arm 2: No adjuvant treatment.
Durvalumab (Arm 1 only): Patients will receive durvalumab 1500 mg via IV infusion q3w for 
4 cycles as neoadjuvant treatment prior to radical cystectomy. Following radical cystectomy, 
patients will receive durvalumab 1500 mg q4w for 8 cycles as adjuvant treatment, unless specific 
study discontinuation criterion are met. Please note, if a patient’s weight falls to 30 kg or below 
(≤30 kg), the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab 
q3w (neoadjuvant treatment) or q4w (adjuvant treatment) after consultation between the 
Investigator and the 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 q3w 
(neoadjuvant treatment) or q4w (adjuvant treatment). 
Gemcitabine + cisplatin: Patients will receive neoadjuvant gemcitabine + cisplatin 
(1000 mg/m2, Days 1 and 8, q3w + 70 mg/m2, Day 1, q3w via IV infusion) for patients with 
adequate renal function (CrCl ≥60 mL/min) or split-dose gemcitabine + cisplatin (1000 mg/m2, 
Days 1 and 8, q3w + 35 mg/m2, Days 1 and 8, q3w via IV infusion) for patients with borderline 
renal function (CrCl ≥40 mL/min to <60 mL/min), starting on Week 1, for a maximum of
4 cycles, followed by radical cystectomy.
Duration of treatment:
Unless specific treatment discontinuation criteria are met, adjuvant treatment in Arm 1 will 
continue for a maximum of 8 cycles (durvalumab 1500 mg administered q4w) following radical 
cystectomy. Patients in Arm 2 will receive no adjuvant treatment.
Progression during treatment:
During the neoadjuvant treatment phase, patients who have Response Evaluation Criteria in 
Solid Tumors, version 1.1 (RECIST 1.1)-defined radiological progression may continue to the 
adjuvant portion of treatment if the progression event did not preclude the patient from having a 
radical cystectomy (ie, progression is local and/or limited to regional lymph nodes that will be 
removed at radical cystectomy). In the event progression precludes the patient from undergoing 
radical cystectomy (ie, distant metastases), the patient will proceed to follow-up.
During the adjuvant treatment phase, patients with proven recurrence (see Sections 8.1.1.1 and 
8.1.1.2) will proceed to follow-up. 
Progression during follow-up: 
Patients who do not have an event of progression during study visits and who develop 
PD/recurrence in the follow-up period are not eligible for retreatment. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
34 (233)
Follow-up of patients post-discontinuation of study drug:
Patients who have discontinued study treatment due to toxicity or symptomatic deterioration, 
clinical progression/recurrence, or who have commenced subsequent anticancer therapy will be 
followed up until RECIST 1.1-defined PD, biopsy-proven recurrence, if clinically feasible and 
safe, or death (whichever comes first) and for survival.
Survival:
All patients randomized in the study should be followed up for survival.
Independent data monitoring committee:
An independent data monitoring committee (IDMC) comprising independent experts will be 
convened and will meet approximately 6 months after the study has started or after the first 
90 patients have been randomized, whichever occurs first, to review safety assessments and 
make recommendations to continue, amend, or stop the study based on safety findings. The 
committee will meet approximately every 6 months thereafter. The IDMC will separately assess 
the safety of durvalumab + gemcitabine/cisplatin in Japanese patients for the initial data review 
meetings and make recommendation if additional separate safety reviews are required. For the 
interim analysis, the IDMC will review interim data and inform the Sponsor whether the interim 
boundaries specified in Section 9.4.3 are crossed.
Full details of the IDMC procedures, processes, and interim analyses can be found in the IDMC 
Charter.
Statistical methods:
The dual primary objectives of this study are to assess the efficacy of Arm 1 versus Arm 2 in 
terms of EFS as assessed by Blinded Independent Central Review (BICR) or by central 
pathology review if a biopsy is required for a suspected new lesion and pCR rate per central 
pathology review in MIBC patients.
pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as 
assessed per central pathology review using specimens obtained via radical cystectomy 
following the neoadjuvant treatment.
EFS, as assessed by BICR or by central pathology review if a biopsy is required for a suspected 
new lesion, is defined as the time from randomization to the first recurrence of disease 
post-radical cystectomy, time of first documented progression in patients who were precluded 
from radical cystectomy,  or time of expected surgery in patients who refuse to undergo a radical 
cystectomy or failure to undergo a radical cystectomy in participants with residual disease , or 
death due to any cause, whichever occurs first. A recurrence of disease includes local (pelvic) 
recurrence of UC, urinary tract recurrence of UC, or distant metastasis of UC. 
To control Type I error, the 5% 2-sided alpha used will be split into significance levels of 0.1% 
and 4.9% for pCR and EFS in MIBC patients respectively.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
35 (233)
The secondary objectives include: pCR using assessment per local pathology, EFS using 
assessments per local Investigator or local biopsy review if a biopsy is required for a suspected 
new lesion, disease-specific survival (DSS) in MIBC patients , OS, proportion of patients alive at 
5 years (OS5) in MIBC patients , disease-free survival (DFS) in MIBC patients  who undergo 
radical cystectomy, proportion of patients who achieve <P2 per local pathology review in MIBC 
patients, DFS in MIBC patients who undergo radical cystectomy, etc.
Unless otherwise specified, efficacy data will be summarized and analyzed on an 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 ITT population.
Approximately 1050 patients will be randomized in a 1:1 ratio to Arm 1 or Arm 2.
The randomization will be stratified according to the following 3 factors:

Clinical tumor stage T2N0 versus >T2N0 (including T2N1, T3 and T4a) to reflect 
prognostic stage II versus IIIa, respectively 

Renal function (adequate renal function versus borderline renal function)

PD-L1 status (high versus low/negative, based on Ventana assay; see Table 6)
The final analysis of the dual-primary endpoint of pCR will be performed approximately 6 
months after the last patient is randomized to the study.
The final analysis of the dual-primary endpoint of EFS will be performed when approximately 
451 EFS events in ITT have occurred across the 2 arms (43% maturity) or June 2025 
(approximately 45 months after the last subject is randomized), whichever occurs first. For the 
primary EFS endpoint in MIBC patients (Arm 1 versus Arm 2), two superiority interim analyses 
for EFS will be conducted: the first when the pCR analysis is conducted and the second when 
approximately 410 EFS events have occurred (39% maturity) across the 2 arms in ITT, or in 
April 2024, whichever occurs first. The latter interim is expected approximately 31 months after 
the last patient is randomized. The interim analyses will be assessed by an IDMC. Details of the 
plan and communication process will be provided in the statistical analysis plan (SAP) and in the 
IDMC charter.
Arm 1 versus Arm 2 (pCR in ITT)
It is assumed that the pCR for patients in Arm 2 is 35% (Grossman et al 2003). Under the 
alternative hypothesis, pCR is assumed to be 50% for Arm 1. With 525 patients in each arm, the 
study will have at least 95% power to demonstrate a statistically significant difference at a 2-
sided alpha level of 0.1%. Assuming a pCR rate of 35% in Arm 2, the smallest pCR rate that 
could be observed as being statistically significant at the time of pCR analysis is a 10-percentage 
point increase to 45% in Arm 1. 
Arm 1 versus Arm 2 (EFS in ITT)
The assumed EFS treatment effect under the alternative hypothesis is an average HR of 0.733 for 
Arm 1 versus Arm 2. This is based on the following assumptions:

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
36 (233)
An exponential model was assumed for EFS such that in patients who are assigned to the Arm 1, 
the overall median EFS is 38.0 months and the EFS rate at 24 months is 64.5%.
For Arm 2, an exponential model was assumed for EFS such that patients who are assigned to 
Arm 2, the overall median EFS is 27.8 months and the EFS rate at 24 months is 55%.
Based on a blinded event prediction, an estimated 451 EFS events (43% maturity) are expected 
to be observed at 45 months after the date of the last patient randomized. With 451 EFS events, 
the study will have at least 90% power to demonstrate a statistically significant difference at a 2-
sided overall alpha level of 4.90%, allowing two interim analyses to be conducted at 
approximately 67% and 91% of the target events. The smallest treatment difference that could be 
statistically significant will be an average HR of 0.82.
Arm 1 versus Arm 2 (OS in ITT)
The assumed OS treatment effect under the alternative hypothesis is an average HR of 0.76 for 
Arm 1 versus Arm 2. This is based on the following assumptions:

An exponential model was assumed for OS such that in all patients who are assigned 
to Arm 1, the overall median OS is 8.6 years (103 months), and the OS rate at 5 years 
is 66.8%.

For Arm 2, an exponential model was assumed for OS such that in all patients who are 
assigned to Arm 2, the overall median OS is 6.5 years (78 months), and the OS rate at 
5 years is 58.7%. 
The final analysis of OS based on approximately 428 OS events for the comparison of Arm 1 
versus Arm 2 (41% maturity, 428/1050), from ITT, is expected to occur 5 years (60 months) 
after the last patient is randomized to the study and will provide at least 80% power to 
demonstrate a statistically significant difference in OS at a 2-sided alpha level of 4.9%, allowing 
two interim analysis to be conducted at approximately 67% and 74% of the target events. The 
smallest treatment difference that could be statistically significant will be an HR of 0.82. 
Arm 1 versus Arm 2 (OS5 in ITT)
The statistical model assumptions for OS5 in the ITT of each arm are stated above.
The analysis of OS5 that is performed at the time of final analysis of OS will provide at least 
77% power to demonstrate a statistically significant difference in OS5 at a 2-sided alpha level of 
4.9%. 
pCR will be analyzed using a stratified logistic regression model adjusting for stratification 
factors:  clinical tumor stage T2N0 versus >T2N0 (including T2N1, T3 and T4a) to reflect 
prognostic stage II versus IIIa, respectively; renal function (adequate renal function versus 
borderline renal status); and PD-L1 status (high versus low/negative, based on Ventana assay; 
see Table 6). The result of the analysis will be presented in terms of an odds ratio together with a 
99.9% confidence interval (CI) and p-value.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
37 (233)
EFS will be analyzed using a stratified log-rank test, stratified for clinical tumor stage T2N0 
versus >T2N0 (including T2N1, T3 and T4a) to reflect prognostic stage II versus IIIa, 
respectively; renal function (adequate renal function versus borderline renal status); and PD-L1 
status (high versus low/negative, based on Ventana assay; see Table 6). The effect of treatment 
will be estimated by the HR together with the corresponding ([1-adjusted alpha] × 100%) CIs 
and p-values for EFS.
EFS24 will be analyzed using the Kaplan-Meier estimator of EFS at 24 months for each 
treatment to obtain the HR.
OS will be analyzed using a stratified log-rank test, stratified for clinical tumor stage T2N0 
versus >T2N0 (including T2N1, T3 and T4a) to reflect prognostic stage II versus IIIa, 
respectively; renal function (adequate renal function versus borderline renal status); and PD-L1 
status (high versus low/negative, based on Ventana assay; see Table 6.
OS5 will be analyzed using the Kaplan-Meier estimator of OS at 5 years for each treatment to 
obtain the HR.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.
Baseline will be the last assessment of the variable under consideration prior to the intake of the 
first dose of investigational product (IP), except for efficacy variables. For efficacy variables 
except DFS (including pCR rate, EFS, EFS24, proportion of patients who achieve <P2, 
metastasis-free survival (MFS), disease-specific survival (DSS), OS, OS5, the time from the date 
of randomization to the earliest date of progression which occurs on subsequent therapy 
following an EFS event or death (PFS2), proportion of patients who undergo radical cystectomy, 
PRO, demography, and PK data), baseline is defined as the last visit prior to randomization. A 
second (“adjuvant”) baseline scan will be performed 42 days (±2 weeks) following the date of 
radical cystectomy and prior to the start of adjuvant therapy for radiological assessments. 
Efficacy assessments of pCR and proportion of patients who achieve <P2 will be derived (by 
AstraZeneca) using local pathology review of the radical cystectomy sample.
Safety data from all cycles of treatment will be presented for neoadjuvant treatment and 
neoadjuvant followed by adjuvant treatment separately as appropriate. Adverse events (AEs; in 
terms of both Medical Dictionary for Regulatory Activities preferred terms and Common 
Terminology Criteria for Adverse Events [CTCAE] grade) will be listed individually by patient. 
The number of patients experiencing each AE will be summarized by treatment arm and CTCAE 
grade. Other safety data will be assessed in terms of physical examinations, laboratory 
assessments, vital signs, and ECGs. At the end of the study, appropriate summaries of all safety 
data will be produced, as defined in the SAP.
1.3
Schema
The general study design is summarized in Figure 1.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
38 (233)
Figure 1
Study design
a
Enrolment of patients with T2N0 disease is limited to approximately 40% of the targeted global population (for both treatment arms).
b
Patients with borderline renal function will receive split-dose G+C and will be limited to up to 20% of the targeted global population.
CrCl Creatinine clearance; Durva Durvalumab; G+C Gemcitabine and cisplatin; q3w Every 3 weeks; q4w Every 4 weeks; MIBC Muscle-invasive 
bladder cancer; PD-L1 Programmed cell death-ligand 1; R Randomization.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
39 (233)
2.
INTRODUCTION
Bladder cancer (BC) is the 9th most common cancer diagnosed worldwide, with an estimated 
429800 new cases each year and 165100 cancer-related deaths reported globally in 2012 (Ferlay 
et al 2015, Torre et al 2015). Bladder cancer is generally divided into muscle-invasive and 
non-muscle-invasive disease based on invasion of the muscularis propria. At the initial diagnosis 
of BC, 70% to 75% of cases are diagnosed as non-MIBC (NMIBC), and approximately 25% to 
30% are diagnosed as MIBC (Babjuk et al 2014, Boccardo and Palmeri 2006, Burger et al 2013).
Cisplatin-based neoadjuvant chemotherapy is the standard first-line (1L) treatment in patients 
with MIBC fit enough to receive this. The combination of neoadjuvant therapy and radical 
cystectomy has shown potential for an increase in pathologic complete response (pCR), 
event-free survival (EFS), and overall survival (OS) in patients with MIBC (Grossman et al 
2003, Sonpavde et al 2009). Grossman et al showed an increase in pCR rate of 38% in patients 
who had neoadjuvant therapy followed by cystectomy versus 15% in the cystectomy alone group 
and an increase of OS5 (Grossman et al 2003). Despite these measures, patients with MIBC still 
have high rates of disease recurrence and possible development of advanced cancer, with most 
recurrences occurring within the first 2 to 3 years after cystectomy (Chang et al 2017, Witjes et 
al 2016). Because of the significant rate of recurrence (approximately 56% in patients with 
pathological stage T3), the use of perioperative chemotherapy has been explored in an effort to 
eliminate distant micrometastatic disease and improve the outcomes achieved with radical 
cystectomy alone (Grossman et al 2003). However, there is still a significant unmet medical need 
for additional treatment options to improve survival in this patient population.
2.1
Study rationale
The standard management for patients with MIBC involves radical cystectomy and pelvic lymph 
node dissection. Several studies have demonstrated improved pCR, EFS, and OS with the 
integration of neoadjuvant, cisplatin-based combination chemotherapy when compared with 
radical cystectomy alone. The treatment recommendation since the NCCN 2018 guideline is 
cisplatin-based neoadjuvant chemotherapy with radical cystectomy surgery for patients with 
stage II and stage IIIa, according to AJCC 8th edition criteria.
The current AJCC 8th criteria reflect a modification to the previously defined stage III and IV 
patient populations.  In this updated version, T1-T4 patients with node-positive disease (regional 
lymph nodes) are now classified as IIIa (cN1 disease) and IIIb (N2/N3 disease); prior to this 
revision, all patients with node-positive disease were classified as stage IV. Also in 2018, the 
NCCN guidelines were revised to reflect the treatment approach of neoadjuvant chemotherapy 
followed by radical cystectomy plus lymphadenectomy, be offered to all stage IIIa patients, 
when feasible; previously patients with node-positive disease were not considered cystectomy 
candidates (Flaig, 2018). The rationale provided for this change reflects clinical data 
demonstrating a better prognosis for patients with cN1 disease compared with similar patients 
with N2 and N3 disease; it was also suggested that this patient population would benefit from a 
more aggressive approach. It is acknowledged therefore, that in addition to stage II patients, that 
all IIIa patients (T3-T4N0 and T1-T4N1) should now be offered treatment with potential curative 
intent; therefore, patients with T2-4N1 are being included in the study. Despite improvements of 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
40 (233)
pCR and survival rates with neoadjuvant chemotherapy, many patients will still develop 
recurrence and will ultimately die of metastatic bladder cancer. Recently, multiple programmed 
cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have demonstrated activity in 
patients with metastatic BC and have been granted approval in the platinum refractory setting as 
well as pembrolizumab and atezolizumab accelerated approval in the 1L metastatic setting for 
patients unable to tolerate cisplatin chemotherapy (KEYTRUDA [package insert] 2018, 
TECENTRIQ [package insert] 2018). 
The benefits of adjuvant chemotherapy after radical cystectomy in patients with MIBC without 
clinically detectable metastases are unclear. There is limited evidence from adequately 
conducted, randomized, Phase III trials to support the use of adjuvant chemotherapy in patients 
immediately following surgery. However, in 2 separate meta-analyses conducted in 2013 (Leow 
et al 2014) and 2016 (Kim et al 2017), with 9 and 11 randomized controlled studies in MIBC, 
respectively, suggested an OS benefit in patients receiving adjuvant cisplatin-based 
chemotherapy. Multiple Phase III trials evaluating adjuvant PD-1 or PD-L1 inhibitors and 
Phase II trials reveal promising activity and safety for single-agent neoadjuvant pembrolizumab 
or atezolizumab are ongoing (Necchi et al 2018, Powles et al 2018).
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin (Ig) G1 kappa 
(IgG1κ) subclass that inhibits binding of PD-L1 (B7 homolog 1 [B7-H1], cluster of 
differentiation [CD]274) to PD-1 (CD279) and CD80 (B7-1). Nonclinical and clinical studies 
have indicated that blockade of the immune checkpoints PD-1/PD-L1 can have a positive effect 
on antitumor activity. Clinical benefit has been observed in a wide range of tumor types, 
including metastatic melanoma, squamous and nonsquamous non-small-cell lung cancer 
(NSCLC), head and neck squamous cell carcinoma, and urothelial carcinoma (UC).
The benefit of this class of compound and specifically durvalumab in BC has been demonstrated 
in a cohort of 182 patients with locally advanced or metastatic UC who progressed despite 
platinum-based chemotherapy (IMFINZI [package insert] 2017, Massard et al 2016). 
Durvalumab has been approved to treat locally advanced or metastatic urothelial carcinoma, 
unresectable stage III non-small cell lung cancer, and extensive-stage small cell lung cancer 
(administered in combination with chemotherapy). Refer to the package insert (or label) for your 
specific country, as applicable.
The addition of immunotherapy to chemotherapeutic agents has been shown to result in 
improved response rates relative to chemotherapy alone. Cytotoxic chemotherapy has been 
shown to modulate the immune response via several mechanisms, such as stimulating T cell 
activation by increasing the expression of MHC-1 molecules, stimulating dendritic cell 
maturation, inducing immunogenic cell death (a form of cell death that induces dendrites to 
stimulate tumor antigen presentation to T cells), and reducing the immunosuppressive function 
of regulatory T cells and myeloid-derived suppressor cells (Kodumudi et al 2010, Kroemer et al 
2013, Liu et al 2010, Zhang et al 2008). Combining a PD-L1 antagonist with cytotoxic agents 
may provide complementary benefit in mounting an effective antitumor immunity by promoting 
the antigen presentation, increasing the production protective T cells, and overcoming 
immunosuppression in the tumor bed (Mellman et al 2011). In addition, a variety of approaches 
for combining PD-1 pathway blockers with other agents has been explored over the past few 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
41 (233)
years in an effort to both improve the efficacy of treatment and/or to position the treatment 
regimen for testing in patients who are treatment-naive with a variety of cancers (Langer et al 
2016). The rationale for the present study is that PD-L1 inhibition through exposure to 
durvalumab, in combination with chemotherapeutics such as gemcitabine plus cisplatin (G+C), 
may increase both the long-term response rate and frequency of response by preventing the 
MIBC tumor cells (TCs) from evading immune-mediated antitumor response. Administering 
durvalumab- may provide a benefit to this subgroup of patients by averting intrinsic resistance.
2.1.1
Rationale for durvalumab as a potential therapy for MIBC
Efficacy of immuno-oncology agents pembrolizumab, atezolizumab, nivolumab, and avelumab 
has been demonstrated in a number of recent studies (reviewed in Gill et al 2017).
The following immuno-oncology agents are currently approved in the US for treatment of UC:

Pembrolizumab (KEYTRUDA [package insert] 2018): 

For the treatment of patients with locally advanced or metastatic UC who are not 
eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 
(combined positive score ≥10), or in patients who are not eligible for any 
platinum-containing chemotherapy regardless of PD-L1 status

For the treatment of patients with locally advanced or metastatic UC who have 
disease progression during or following platinum-containing chemotherapy or 
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing 
chemotherapy

Avelumab (BAVENCIO [package insert] 2017), a PD-L1 inhibitor, for patients with 
locally advanced or metastatic UC who: 

Have disease progression during or following platinum-containing chemotherapy

Have disease progression within 12 months of neoadjuvant or adjuvant treatment 
with platinum-containing chemotherapy

Atezolizumab (TECENTRIQ [package insert] 2018), a PD-L1 blocking antibody 
indicated for the treatment of patients with locally advanced or metastatic UC who:

Are not eligible for cisplatin-containing chemotherapy, and whose tumors express 
PD-L1 (PD-L1 stained tumor-infiltrating immune cells [ICs] covering ≥5% of the 
tumor area), or are not eligible for any platinum-containing chemotherapy 
regardless of level of tumor PD-L1 expression

Have disease progression during or following any platinum-containing 
chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy
Approval of atezolizumab was based on a multinational Phase II study with 315 patients who 
experienced significant increases in objective response rate (ORR) and durability of responses 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
42 (233)
(Rosenberg et al 2016). In a recent Phase III study (KEYNOTE-045), pembrolizumab, a human 
anti-PD-L1 antibody, demonstrated a significant 3-month improvement in OS over 
chemotherapy as second-line treatment for platinum-refractory advanced UC (Bellmunt et 
al 2017). Presumably, the success of PD-L1 pathway blockade in UC is due to the high rate of 
PD-L1 expression in UC tumors. PD-L1 expression is also high in the tumors of patients with 
NMIBC who have had prior Bacillus Calmette Guerin (BCG) treatment (Lerner et al 2016). 
Collectively, existing efficacy data and PD-L1 expression data support the potential therapeutic 
effect of durvalumab in bladder cancer, including MIBC.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the Investigator Brochure (IB).
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004). 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The programmed cell death 1 (PD-1) receptor (CD279) is expressed on the 
surface of activated T cells (Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) 
and PD-L2 (B7-DC; CD273) (Okazaki and Honjo 2007). PD-1 and PD-L1/PD-L2 belong to the 
family of immune checkpoint proteins that act as co-inhibitory factors, which can halt or limit 
the development of T-cell response. When PD-L1 binds to PD1, an inhibitory signal is 
transmitted into the T cell, which reduces cytokine production and suppresses T-cell 
proliferation. TCs exploit this immune checkpoint pathway as a mechanism to evade detection 
and inhibit immune response.
PDL1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly overexpressed on TCs or on non-transformed cells in the tumor 
microenvironment (Pardoll 2012). PDL1 expressed on the TCs 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/PDL1 pathway represents an adaptive 
immune resistance mechanism that is exerted by TCs in response to endogenous antitumor 
activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on ICs. 
This activity overcomes PD-L1-mediated inhibition of antitumor immunity. While functional 
blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different from 
direct agonism of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of pre-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
43 (233)
PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, Iwai et al 
2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) with responses that tend to be 
more pronounced in patients with tumors that express PD-L1 (Powles et al 2014, Rizvi et al 
2015, Segal et al 2015). In addition, high mutational burden (eg, in bladder carcinoma; 
Alexandrov et al 2013) may contribute to the responses seen with immune therapy.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as with PD-L1 has promising clinical activity. 
Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an anti-PD-L1 agent, 
have been granted approvals by agencies such as the US Food and Drug Administration (FDA) 
and the European Medicines Agency for the treatment of a number of malignancies, including 
metastatic melanoma, squamous and NSCLC, squamous cell carcinoma of the head and neck, 
and UC. 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.
Immunotherapy with PD-1 (ie, PDCD1) or PD-L1 (ie, CD274) inhibitors has shown significant 
activity in advanced UC. Atezolizumab, a PD-L1 inhibitor, showed an ORR of 23% and median 
OS of 15.9 months (95% confidence interval [CI] 10.4 to not estimable). Treatment was 
generally well tolerated with only 8% of patients discontinuing therapy due to an adverse event 
(AE) (Balar et al 2017). Durvalumab monotherapy studies in patients with UC are ongoing.
Immunotherapy with PD-1 or PD-L1 has proven to be an important advance for patients with 
metastatic BC; however, initiating immunotherapy earlier in the treatment of BC may provide 
potential long-term benefit and improved outcomes for patients with MIBC.
Comprehensive genomic analysis of urothelial bladder cancers have provided an understanding 
of the molecular mutations underlying the disease. The most frequent recurrent mutations occur 
in genes controlling cell cycle and chromatin or receptor kinase signaling (Cancer Genome Atlas 
Research Network 2014). For UC patients treated with radical cystectomy, PIK3CA mutations 
correlate with a better prognosis than TP53 and CDKN2A alterations (Kim et al 2015). 
Deleterious mutations in DNA damage response and repair (DDR) genes, such as NBN and 
ERCC2, have also been implicated in the progression and/or prognosis of bladder cancer 
(Bellmunt et al 2007, Mullane et al 2016).
Genomic predictors have also been used retrospectively to analyze patient outcome data. An 
extensive panel of DDR genes (MSK-IMPACT) has been interrogated in UC patients to 
determine whether DDR pathway alterations are predictive of response to standard of care (SoC) 
(Teo et al 2017). The presence of DDR alterations is associated with increased response to 
neoadjuvant chemotherapy, improved outcome following platinum-based chemotherapy, and 
trends toward improved outcome after chemoradiation (Desai et al 2016, Iyer et al 2016, Teo et 
al 2017). Of note, analysis of the DDR gene panels in bladder tumors has been used to impute 
the overall tumor mutational burden (TMB) and has demonstrated an association between the 
prevalence of DDR aberrations and TMB (Teo et al 2017). The estimates for TMB have also 
been generated using the FoundationOne Assay and are reported to align with the distribution of 
TMB in TCGA bladder tumors and the MSK-IMPACT panel (Rosenberg et al 2016).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
44 (233)
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand 2 [PD-L2]) with PD-1 on T cells and 
CD80 (B7.1) on ICs. It is being developed by AstraZeneca/MedImmune for use in the treatment 
of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The 
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 interferon-gamma (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 antitumor immune response by binding to PD-L1 and shifting 
the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-
dependent cellular cytotoxicity and complement-dependent cytotoxicity. 
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12. Refer to the 
current durvalumab IB for a complete summary of nonclinical and clinical information including 
safety, efficacy, and pharmacokinetics (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 for information regarding the independent data monitoring committee (IDMC).
2.3.1
Potential benefits
2.3.1.1
Durvalumab
A total of 23 sponsored clinical studies have been or are being conducted with durvalumab as a 
single agent or in combination with other agents. As of 12 July 2017, an estimated 4067 patients 
had received at least 1 dose of durvalumab across a number of tumor types (refer to the current 
durvalumab IB).
The potential benefit of durvalumab in bladder cancer was demonstrated in a cohort of 
182 patients with locally advanced or metastatic UC who had progressed while on or after a 
platinum-based chemotherapy. The overall ORR based on Blinded Independent Central Review 
(BICR) was 17%. In patients who had received only 1 neoadjuvant or adjuvant prior therapy, the 
ORR was 24%. With a median follow-up time of 5.6 months, among the responding patients, 
45% had ongoing responses of 6 months or longer, and 16% had ongoing responses of 
12 months or longer (median DoR: not reached [range: 0.9+ months to 19.9+ months]). 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
45 (233)
2.3.1.2
Durvalumab in combination with chemotherapy
As a human mAb directed against PD-L1 (a ligand that is expressed in most types of cancer), 
durvalumab is expected to enhance the antitumor immune responses in patients with a number of 
cancers, including BC. PD-L1 is commonly expressed in UC specimens (Inman et al 2007), and 
95% of lymphocytes that invade bladder tumors express the PD-1 receptor. Urothelial expression 
of PD-L1 is also predictive of mortality following cystectomy in patients with organ-limited 
disease. PD-L1 expression is significantly associated with a higher grade and stage in UC 
patients (Inman et al 2007). High mutational burden in bladder carcinoma (Alexandrov et al 
2013) may contribute to the responses seen with immune therapy. In addition, the utilization of 
chemotherapy may potentially upregulate the expression of PD-L1. Based on these findings, an 
anti-PD-L1 antibody is being used therapeutically to enhance antitumor immune responses in 
patients with cancer. PD-L1 inhibition through exposure to durvalumab, in combination with 
chemotherapeutics such as G+C, may increase both the long-term response rate and frequency of 
response by preventing the MIBC TCs from evading immune-mediated antitumor response. 
Administering durvalumab may provide a benefit to this subgroup of patients by averting 
intrinsic resistance.
Studies evaluating PD-L1 inhibitors and other immunotherapy agents in combination with 
chemotherapy have yielded encouraging results (Langer et al 2016, Rizvi et al 2016, Horn et al 
2018). The PD-1 inhibitor pembrolizumab received FDA approval under accelerated assessment 
for the treatment of first line metastatic, nonsquamous NSCLC patients in combination with 
pemetrexed and carboplatin. Approval was based on impressive ORR (55% versus 29%) and 
progression-free survival (PFS) (13.0 versus 6 months) data and a compelling hazard ratio (HR) 
of 0.53 (95% CI 0.31, 10.3) for pembrolizumab plus carboplatin versus carboplatin alone 
(KEYTRUDA [package insert] 2018). Although these results relate to first-line treatment of 
patients with metastatic disease, these data are supportive of the theory that combining 
chemotherapy with immunotherapeutic agents has the potential to significantly improve clinical 
outcomes.
2.3.2
Overall risks
mAbs directed against immune checkpoint proteins, such as PD-L1, as well as those directed 
against PD-1, aim to boost endogenous immune responses directed against tumor cells. By 
stimulating the immune system, however, there is the potential for adverse effects on other 
tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or hormone therapy. These immune-mediated effects can occur in nearly any organ system 
and are most commonly seen as gastrointestinal (GI) AEs such as colitis and diarrhea; 
pneumonitis/interstitial lung disease (ILD); myocarditis; hepatic AEs such as hepatitis and 
transaminase increases; skin events such as pruritus, rash, and dermatitis; and endocrinopathies 
such as hypothyroidism and hyperthyroidism.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
46 (233)
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
hepatitis/transaminase increases, endocrinopathies (ie, events of hypophysitis/ hypopituitarism, 
adrenal insufficiency, hypothyroidism and hyperthyroidism, type I diabetes mellitus and diabetes 
insipidus), rash/dermatitis (including pemphigoid), nephritis/blood creatinine increases, 
myocarditis, myositis/polymyositis, immune thrombocytopenia, infusion-related reactions, 
hypersensitivity reactions, pancreatitis, serious infections, and other inflammatory responses that 
are rare/less frequent, including neuromuscular toxicities (eg, Guillain-Barré syndrome and 
myasthenia gravis) (see Section 8.3.12).
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of >20% include fatigue, nausea, decreased 
appetite, dyspnea, and cough. Approximately 10% of patients experienced an AE that resulted in 
permanent discontinuation of durvalumab, and approximately 6% of patients experienced a 
serious adverse event (SAE) that was considered to be related to durvalumab by the Study 
Investigator.
The majority of treatment-related AEs were manageable with dosing delays, symptomatic 
treatment, and, in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB.
2.3.2.2
Durvalumab in combination with chemotherapy
Safety and tolerability data for durvalumab and tremelimumab, a cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4) mAb of the IgG2 kappa isotype, in combination with standard 
first-line platinum-based chemotherapy in advanced solid tumors are being generated from 
2 ongoing Phase I studies: an AstraZeneca internal study (D419SC00001) and a Canadian 
Cancer Trials Group study (NCT02537418).
As of 12 July 2018, a total of 22 patients with advanced solid tumors have been treated with 
durvalumab and tremelimumab in combination with platinum-based chemotherapy in 
Study D419SC00001. All patients had at least 1 AE (regardless of causality). AEs (all grades) 
reported in >20% of patients were nausea (68.2%); neutrophil count decreased (63.6%); 
decreased appetite (50.0%); cough, diarrhea, and rash (36.4% each); anemia and pyrexia (31.8% 
each); constipation, dizziness, insomnia, myalgia, platelet count decreased, and pruritus (27.3% 
each); ALT increased, alopecia, dyspepsia, peripheral sensory neuropathy, vomiting, and white 
blood cell count decreased (22.7% each). All patients had AEs considered by the Investigator to 
be related to study treatment. SAEs were reported in a total of 10 patients (45.5%). With the 
exception of pneumonia and pyrexia (3 patients each) and diarrhea and neutrophil count 
decreased (2 patients each), all other SAEs were reported in 1 patient each. One patient had a 
fatal AE of lung infection, which was considered treatment related. A total of 13.6% of patients 
had AEs that led to permanent discontinuation of treatment.  

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
47 (233)
In the CCTG study (NCT02537418), a total of 488 cycles have been administered up to the data 
cutoff of October 2016, with 103 patients evaluable for non-hematologic AEs. Overall, all 
patients experienced at least 1 AE; 96% were considered by the Investigator as causally related 
to chemotherapy, 75% were considered as causally related to durvalumab, and 55% were 
considered as causally related to tremelimumab. A total of 69 events (26% of all events) were 
Grade ≥3, regardless of causality. Of these, 20 events were considered by the Investigator as 
causally related to durvalumab treatment, and 15 events were considered as causally related to 
tremelimumab treatment. SAEs were reported in 38% of patients (39/103) regardless of 
causality; 19% were considered by the Investigator as related to chemotherapy, 15% were 
considered as related to durvalumab, and 11% were considered as related to tremelimumab 
treatment. Note that some events considered related to durvalumab and tremelimumab treatment 
may be reported in the same patient(s).
Overall, the common AEs reported were of Grade 1 to 2 with the most commonly reported being 
fatigue (93%), nausea (72%), dyspnea (63%), constipation (59%), and cough (52%), regardless 
of causality. The most common chemotherapy-related AEs were fatigue (62%), nausea (58%), 
vomiting (32%), anorexia (28%), alopecia (27%), and peripheral sensory neuropathy (24%). The 
most common durvalumab-related AEs were fatigue (42%), rash maculo-papular (17%), nausea 
(16%), and diarrhea (12%). The most common tremelimumab‑related AEs were fatigue (26%), 
rash maculo-papular (13%), and diarrhea (11%). The most common Grade >3 events were 
fatigue (11 events), thrombotic events (9 events), dyspnea (7 events), lung infection (7 events), 
and diarrhea (7 events). Transient elevations in amylase and lipase were seen, but no patient had 
clinical or radiological evidence of pancreatitis. Thyroid-stimulating hormone (TSH) elevations 
of ≥5× the upper limit of normal (ULN) were documented in 10 patients (10%), and 6 patients 
required initiation of thyroid replacement therapy on study. Three of these patients with elevated 
TSH had a previous history of hypothyroidism. In all dose levels, dose delays of durvalumab 
were mostly for administrative reasons/patient request and neutropenia related to chemotherapy, 
while those for durvalumab ± tremelimumab were interrupted in 4 patients because of 
pneumonitis, colitis, or rash.
Seven patients (6.7%) discontinued durvalumab ± tremelimumab due to the following AEs: 
pneumonitis (3 patients) and hepatitis, myocarditis, hyperthyroidism, and limbic encephalitis 
(1 patient each).
There were 7 deaths within 30 days of the last dose of protocol therapy. Two of these were 
considered to be at least possibly related to durvalumab or tremelimumab; 1 patient had diarrhea, 
hyperthyroidism, and myocarditis, which was steroid responsive, but later declined active 
therapy. The cause of death has not yet been determined. The final post-mortem examination has 
not been reported. One patient had confusion and possible encephalitis. 
Overall in these 2 studies, toxicities related to the platinum-based chemotherapy core regimen 
and to durvalumab and tremelimumab were as expected for these agents. In general, the 
combination of immunotherapy agent durvalumab + tremelimumab with chemotherapy appears 
tolerable and manageable.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
48 (233)
External published data evaluating the use of an immune checkpoint inhibitor administered in 
combination with a conventional lung cancer chemotherapy have reported acceptable toxicity 
profiles. Toxicity data from the Impower133 study that combined atezolizumab (PD-L1) with 
carboplatin + etoposide as first-line therapy for extensive small-cell lung cancer demonstrated 
equivalent hematologic side effects in both groups and a similar incidence and types of 
immune-mediated AEs to those seen with atezolizumab alone (Horn et al 2018). Pembrolizumab 
(PD-1) has been administered in NSCLC trials in combination with various platinum-based 
doublets (ie, with carboplatin). Toxicity data specifically from the KEYNOTE-021 study 
revealed a higher incidence of non-hematologic chemotherapy AEs reported with combination 
therapy; however, the incidence of potential immune-mediated toxicity for the combination 
group was comparable to that observed with pembrolizumab monotherapy (Langer et al 2016). 
Additional data from another first-line NSCLC study (Rizvi et al 2016) evaluating nivolumab 
(PD-L1) in combination with 4 cycles of a platinum doublet (including gemcitabine and 
cisplatin) reported toxicities commonly described with platinum-based therapy and a rate of 
non-hematologic toxicities consistent with chemotherapy alone; in this study, there was, 
however, an increased frequency of immune-related AEs reported with the combination 
compared with nivolumab alone.
Overall, the above data demonstrate that anti-PD-L1 immunotherapy (including durvalumab) in 
combination with chemotherapy is reasonably well tolerated and has an acceptable safety profile.
2.3.3
Overall benefit/risk
The treatment options currently available for these patients remain limited, current standard
therapy is likely to result in modest improvements in long-term survival, and additional and 
alternative therapies are required for patients with MIBC. Therefore, there remains an unmet 
medical need for this patient population. In this study, gemcitabine and cisplatin will be 
combined with the PD-L1 inhibitor durvalumab to broaden the therapeutic effect of durvalumab 
monotherapy for the treatment of patients with MIBC.
3.
OBJECTIVES AND ENDPOINTS
Table 5
Study objectives and endpoints
Primary objective:
Endpoints/variables:
To assess the efficacy of durvalumab + G+C 
combination therapy (neoadjuvant)/durvalumab 
alone (adjuvant) (Arm 1) compared to G+C 
combination therapy (neoadjuvant)/no adjuvant 
(Arm 2) in terms of pCR and EFS in MIBC
patients 
pCR using assessments per central pathology 
review
EFS using assessments per BICR or by central 
pathology review if a biopsy is required for a 
suspected new lesion

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
49 (233)
Table 5
Study objectives and endpoints
Secondary objectives:
Endpoints/variables:
To assess the efficacy of Arm 1 versus Arm 2 in 
terms of EFS at 24 months in MIBC patients 
EFS24 using assessments per BICR or by central 
pathology review if a biopsy is required for a 
suspected new lesion
To assess the efficacy of Arm 1 compared to 
Arm 2 in terms of pathologic response at radical 
cystectomy and EFS in MIBC patients 
pCR using assessments per local pathology review
Proportion of patients who achieve <P2 per local
pathology review
EFS using assessments per local Investigator or 
local biopsy review if a biopsy is required for a 
suspected new lesion
EFS24 using assessments per local Investigator or 
local biopsy review if a biopsy is required for a 
suspected new lesion
To assess the efficacy of Arm 1 versus Arm 2 in 
MIBC patients 
Metastasis-free survival and disease-specific 
survival per Investigator assessments or 
Investigator biopsy review if a biopsy is required 
for a suspected new lesion
Overall survival (OS)
OS at 5 years
Disease-free survival in patients who undergo 
radical cystectomy
Proportion of patients who undergo radical 
cystectomy
PFS2 as defined by local standard clinical practice
To assess the efficacy of Arm 1 versus Arm 2 in 
terms of pCR and EFS in MIBC patients in the 
PD-L1-high subgroup
pCR using assessments per central pathology 
review
EFS using assessments per BICR or by central 
pathology review if a biopsy is required for a 
suspected new lesion
To assess disease-related symptoms, physical 
function, and other HRQoL in Arm 1 versus 
Arm 2 using the EORTC QLQ-C30 
questionnaire
Adjusted mean change from baseline and time to 
definitive clinically meaningful deterioration in 
EORTC QLQ-C30 scale/item scores (prioritized 
domains: fatigue and pain, physical functioning, 
and global health status/quality of life)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
50 (233)
Table 5
Study objectives and endpoints
To assess the PK of durvalumab when used in 
combination with G+C
Serum concentration of durvalumab and 
non-compartmental PK parameters (such as peak 
and trough concentrations, as data allow; sparse 
sampling)
To investigate the immunogenicity of 
durvalumab when used in combination with 
G+C 
Presence of ADAs for durvalumab (confirmatory 
results: positive or negative)
Safety objective:
Endpoints/variables:
To assess the safety and tolerability profile of 
Arm 1 versus Arm 2 in MIBC patients
AEs, laboratory findings, vital signs, and ECGs
Exploratory objectives:
Endpoints/variables:
To assess patient-reported treatment-related 
symptoms or tolerability of Arm 1 versus Arm 2 
using PRO-CTCAE
PRO-CTCAE (items pre-selected based on 
systemic treatment arms) – descriptive summary of 
responses
To assess overall health status and overall 
severity of disease-related symptoms in patients 
in Arm 1 versus Arm 2 using the PGIC and 
PGIS questionnaires, respectively
PGIC and PGIS – descriptive summary of 
responses
To explore the impact of treatment and disease 
state on health state utility using the EQ-5D-5L
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on 
patient-reported data
To evaluate tumor-based biomarkers and 
associations with efficacy parameters, 
potentially including, but not limited to, 
microsatellite stability, tumor mutational burden, 
and other immune-related biomarkers
Association of tumor-based assessments with 
efficacy and clinical parameters
To evaluate circulatory-based and urine-based 
biomarkers and associations with efficacy 
parameters, including, but not limited to, ctDNA
Association of ctDNA, whole blood gene 
expression, and urine biomarkers with efficacy and 
clinical parameters
ADA Antidrug antibody; AE Adverse event; BICR  Blinded Independent Central Review; ctDNA Circulating 
tumor DNA; ECG  electrocardiogram; EFS event-free survival; EFS24 proportion of patients alive and event 
free at 24 months using local pathology or BICR; EORTC QLQ-C30  European Organization for Research 
and Treatment of Cancer 30-item Core Quality of Life Questionnaire; EQ-5D-5L EuroQol 5-dimension, 
5-level health state utility index; G+C  gemcitabine plus cisplatin; HRQoL health-related quality of life; 
MIBC muscle-invasive bladder cancer; OS Overall survival; pCR pathologic complete response; PD-
L1 Programmed cell death-ligand 1; PFS2 Time from the date of randomization to the earliest date of 
progression which occurs on subsequent therapy following an EFS event or death; PGIC Patient Global 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
51 (233)
Impression of Change; PGIS Patient Global Impression of Severity; PK Pharmacokinetics; PRO-
CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
52 (233)
4.
STUDY DESIGN
4.1
Overall design
This is a Phase III, randomized, open-label, multi-center, global study to determine the efficacy 
and safety of durvalumab + G+C combination therapy versus G+C for the neoadjuvant and 
adjuvant treatment of patients with histologically or cytologically documented, resectable MIBC 
(ie, T2N0/1M0-T4aN0/1M0) and transitional cell carcinoma (TCC; transitional cell and mixed 
transitional/nontransitional cell histologies) of the urothelium (excluding renal pelvis and ureters) 
who are candidates for radical cystectomy and have not received prior systemic chemotherapy or 
immunotherapy for treatment of MIBC. 
Approximately 1050 patients globally will be randomized in 1:1 ratio to receive durvalumab + 
G+C combination therapy every 3 weeks (q3w) (Arm 1) or G+C combination therapy q3w 
(Arm 2) for 4 cycles of neoadjuvant chemotherapy prior to radical cystectomy. Following the 
radical cystectomy and during adjuvant therapy, patients in Arm 1 will receive durvalumab 
monotherapy q4w for 8 additional cycles and patients in Arm 2 will receive no adjuvant 
treatment. Crossover from Arm 1 to Arm 2 will not be permitted.
Patients randomized to the 2 treatment arms, Arm 1 or Arm 2, will be treated according to their 
renal function. Recruitment for borderline renal function patients will be limited to up to 20% of 
the targeted global population.
Recruitment for patients with T2N0 disease will be limited to approximately 40% of the targeted 
global population (for both treatment arms); once the 40% cap has been reached, only T2-
4N1M0 and T3-4N0M0 patients will be allowed to be enrolled onto the study
Neoadjuvant therapy
Patients with adequate renal function (CrCl ≥60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg intravenously (IV), cisplatin 70 mg/m2, 
gemcitabine 1000 mg/m2; Day 8: gemcitabine 1000 mg/m2; every 21 days for 4 cycles.

Arm 2: Day 1: cisplatin 70 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2; every 21 days for 4 cycles.
Patients with borderline renal function (CrCl ≥40 mL/min to <60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg IV, cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; 
Day 8: gemcitabine 1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.

Arm 2: Day 1: cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.
*In scenarios when patients are unable to complete the intended 4 cycles of chemotherapy 
prior to radical cystectomy, patients will be permitted to receive less than 4 cycles of 
chemotherapy, at the discretion of the Investigator and upon discussion with AstraZeneca.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
53 (233)
Adjuvant therapy (regardless of renal status)

Arm 1: Day 1: durvalumab 1500 mg IV; every 28 days for 8 cycles.

Arm 2: No adjuvant treatment. 
Patients will receive 4 cycles of study treatment in the neoadjuvant setting prior to radical
cystectomy. After radical cystectomy and adequate recovery, patients will continue to receive up 
to a maximum of 8 cycles of durvalumab monotherapy or no adjuvant treatment based on the 
original randomized treatment assignment prior to neoadjuvant treatment.
Randomization will be stratified by clinical tumor stage T2N0 versus >T2N0 (including T2N1, 
T3 and T4a) to reflect prognostic stage II versus IIIa, respectively; renal function (adequate renal 
function versus borderline renal function; see Inclusion Criteria 7); and PD-L1 status (high 
versus low/negative, based on Ventana assay; see Table 6). Patients will provide a tumor tissue 
sample at screening (Table 6) to determine PD-L1 status for stratification. 
Table 6
PD-L1 status defined by scoring of Ventana PD-L1 (SP263) Assay
PD-L1 Interpretation
Staining description
PD-L1 status is determined by the percentage of tumor cells with any membrane staining 
above background by the percentage of tumor-associated ICs with staining (IC+) at any 
intensity above background. The percent of tumor area occupied by any tumor-associated ICs 
(Immune Cells Present, ICP) is used to determine IC+, which is the percent area of ICP 
exhibiting PD-L1 positive IC staining is also evaluated.
High
PD-L1 status is considered high if any of the following are met:

≥25% of tumor cells exhibit membrane staining

ICP >1% and IC+ ≥25%

ICP = 1% and IC+ = 100%
Low/Negative
PD-L1 status is considered low/negative if:

None of the criteria for PD-L1 high status are met
PD-L1  Programmed cell death-ligand 1.
Source: VENTANA PD-L1 (SP263) Assay Package Insert.
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.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
54 (233)
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 patients become infected with SARSCoV-2 or similar pandemic infection) 
which would prevent the conduct of study-related activities at study sites, thereby compromising 
the study site staff or the patient’s ability to conduct the study. The investigator or designee 
should contact the study Sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain compliance 
with Good Clinical Practice, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the Informed Consent Form (ICF) should be signed at the patient’s 
next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated study physician.

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix K (Changes Related to Mitigation of Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis).
4.2
Scientific rationale for study design
4.2.1
Rationale for study design
Durvalumab, along with other PD-1/PD-L1 inhibitors, has already been established as treatment 
regimens for patients with locally advanced or metastatic UC, and there exists strong rationale 
that durvalumab could also be effective in earlier stages of BC such as localized MIBC. 
Furthermore, there is growing evidence that the addition of immunotherapy to 1L 
chemotherapeutic agents can improve clinical benefit when compared to the standard 
chemotherapy options alone (Langer et al 2016). In May 2017, the PD-1 inhibitor 
pembrolizumab received FDA approval under accelerated assessment for the treatment of 1L 
metastatic, nonsquamous NSCLC patients in combination with pemetrexed and carboplatin. 
Approval was based on impressive ORR (55% versus 29%) and PFS (13.0 months versus 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
55 (233)
6 months) data and a compelling HR of 0.53 (95% CI: 0.31, 10.3) for pembrolizumab plus 
carboplatin versus carboplatin alone (KEYTRUDA [package insert] 2018). Although these 
results relate to 1L treatment of patients with metastatic disease, these data are supportive of the 
theory that combining chemotherapy with immunotherapeutic agents has the potential to 
significantly improve clinical outcomes. AstraZeneca has therefore designed the proposed Phase 
III study to evaluate the clinical utility of adding durvalumab to the established chemotherapy 
regimen in patients with MIBC.
4.2.2
Rationale for efficacy study endpoints
The primary aims of this study are to assess the efficacy of Arm 1 versus Arm 2 
(neoadjuvant/adjuvant) in MIBC patients in terms of EFS and to assess the efficacy of Arm 1 
versus Arm 2 (neoadjuvant) MIBC patients in terms of pCR rate.
EFS is defined as the time from randomization to the first recurrence of disease after radical 
cystectomy, the time of first documented progression in patients who are precluded from radical
cystectomy, time of documented residual disease in patients who refuse to undergo a radical 
cystectomy, or the time of death due to any cause, whichever occurs first. A recurrence of 
disease includes local (pelvic) recurrence of UC, urinary tract recurrence of UC, or distant 
metastases of UC. EFS will be assessed using computed tomography (CT)/magnetic resonance 
imaging (MRI) and pathology testing performed according to local standards and as clinically 
indicated.
pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as 
assessed per central pathology review using specimens obtained via radical cystectomy 
following the neoadjuvant treatment and will be calculated among patients within the ITT 
population
This Phase III study will be sized to detect evidence of improved efficacy. Based on available 
datasets regarding response characteristics, pCR and EFS, will be improved by the addition of 
G+C to durvalumab.
Other secondary and exploratory endpoints will be examined to further evaluate the antitumor 
effect of Arm 1 versus Arm 2, including EFS rate at 24 months (EFS24), metastasis-free survival 
(MFS), DSS as per Investigator assessments, proportion of patients who achieve <P2 as per local
pathology review, OS, and OS5.
Efficacy (pCR and EFS) is also being evaluated in the subset of patients characterized as 
PD-L1-high. This subset analysis is being performed based on available evidence from other 
clinical trials in MIBC, which have reported a survival benefit in objective response rate for the 
PD-L1-high population compared with the ITT population. Antitumor activity will be based on 
Investigator assessment according to disease assessment guidelines.
4.2.3
Rationale for other study endpoints
Biological samples will be used to explore potential biomarkers in tumor, plasma, urine, and/or 
serum, which may influence the progression of cancer (and associated clinical characteristics) 
and/or response.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
56 (233)
Blood samples will be taken to allow for research into PK of durvalumab and G+C, 
immunogenicity of durvalumab, and the relationship between durvalumab PK exposure and 
clinical outcomes, efficacy, AEs, and/or safety parameters.
In addition to assessing EFS and other clinical endpoints in the trial, it is important to examine 
the impact of neoadjuvant and adjuvant therapy on disease-related symptoms, physical function, 
and other health-related quality of life (HRQoL) of the patient to aid understanding of how 
clinical benefit relates to patient wellbeing and for considering in making risk-benefit 
evaluations. Moreover, patient reported outcomes assist in the documentation of symptoms and 
specifically what symptoms and impacts are most important to patients and how these relate to 
clinical outcomes. Disease-related symptoms, physical function, and other HRQoL will be 
assessed using the EORTC QLQ-C30 questionnaire. The rationale for selecting the EORTC 
QLQ-C30 is primarily because it has good coverage of the conceptual model of general cancer 
symptoms and impact concepts. The impact of treatment on the overall health status and overall 
severity of cancer symptoms will be assessed using the Patient Global Impression of Change 
(PGIC) and Patient Global Impression of Severity (PGIS) single-item questionnaires, 
respectively. PGIC and PGIS are useful for determining the responder threshold of other PRO 
measures such as the EORTC QLQ-C30. Finally, pre-selected questions from the 
patient-reported outcomes version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) items bank will be evaluated to characterize treatment-related adverse events or 
tolerability directly from patients’ perspective.
4.2.4
Safety monitoring rationale
The study design aims to minimize potential safety risks by intensive monitoring and ongoing 
safety monitoring at each office visit, during the conduct of the trial. In addition, an IDMC will 
assess the safety profile of G+C with or without durvalumab at regular intervals. See Section 9.6
for details on the IDMC.
Risk associated with durvalumab, G+C, and the combination of durvalumab and G+C are 
discussed in Section 2.3.2.
4.2.5
Rationale for gemcitabine and cisplatin as comparator
The standard management for patients with MIBC involves radical cystectomy and pelvic lymph 
node dissection. Several studies have demonstrated improved pCR, EFS, and OS with the 
integration of neoadjuvant, cisplatin-based combination chemotherapy when compared with 
radical cystectomy alone. Specifically, 2 large randomized studies have demonstrated 
improvement in survival with the integration of neoadjuvant, cisplatin-based combination 
chemotherapy, leading to the utilization of neoadjuvant chemotherapy in the perioperative setting 
for patients with MIBC (Grossman et al 2003, International Collaboration of Trialists 2011).
Despite the improvement in survival demonstrated in the randomized studies with the use of 
neoadjuvant MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or CMV (cisplatin, 
methotrexate, and vinblastine), concerns regarding the balance between the toxicity and the 
efficacy of these regimens have contributed, at least in part, to the reduced acceptance of 
neoadjuvant chemotherapy. In 2000, the results from a randomized Phase III study comparing 
G+C with standard MVAC in patients with metastatic BC were published. G+C was associated 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
57 (233)
with similar efficacy compared with MVAC, albeit with overall less toxicity, leading to the 
adoption of the regimen among the most commonly used systemic treatments for patients with 
metastatic disease. Pragmatically, yet in somewhat of a departure from the evidence-based 
oncology paradigm, the results from that study have also been used to justify the routine use and 
integration into standard practice guidelines of neoadjuvant G+C, despite lack of prospective 
randomized data in this setting (National Comprehensive Cancer Network 2019). Although there 
are no studies reporting level 1 data comparing MVAC to G+C in the neoadjuvant setting, 
retrospective analyses have reported no significant difference in pCR and OS between the 
2 treatment arms (Dash et al 2008, Galsky et al 2015).
4.3
Justification for dose
This study will utilize a fixed dose for durvalumab treatment (1500 mg q3w IV as neoadjuvant 
treatment and 1500 mg q4w IV as adjuvant treatment). Based on an average body weight of 
75 kg, a fixed dose of 1500 mg of durvalumab q4w is equivalent to 20 mg/kg q4w.
G+C will be dosed at 1000 mg/m2 IV on Days 1 and 8 q3w (gemcitabine) + 70 mg/m2 IV on 
Day 1 q3w (cisplatin) for patients with adequate renal function (creatinine clearance [CrCl] 
≥60 mL/min) and at 1000 mg/m2 IV on Days 1 and 8 q3w (gemcitabine) + 35 mg/m2 IV on 
Days 1 and 8 q3w (cisplatin) for patients with borderline renal function (CrCl ≥40 mL/min to 
<60 mL/min).
4.3.1
Durvalumab monotherapy dose rationale
4.3.1.1
Durvalumab q4w dose rationale
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, nonclinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study CD-ON-MEDI4736-1108 
(hereafter referred to as Study 1108) in patients with advanced solid tumors and from a Phase I 
trial performed in Japanese patients with advanced solid tumor (D4190C00002).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg q2w or 15 mg/kg q3w, durvalumab exhibited non-linear (dose-dependent) 
PK consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg 
q2w, suggesting near complete target saturation (membrane-bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is 
approximately 21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with PD-L1. A low level of 
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; European Medicines Agency 2013

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
58 (233)
Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man; 
Methodological consideration for using progression-free survival (PFS) or disease-free survival 
(DFS) in confirmatory trials. 2012. Available at URL: https://www.ema.europa.eu/en/appendix-
1-guideline-evaluation-anticancer-medicinal-products-man-methodological-consideration-using-
progression-free-survival-pfs-or-disease-free-survival-dfs-confirmatory-trials-scientific-
guideline.
EuroQol Group 1990
EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 
16(3):199-208.
Fairman et al 2014). Multiple simulations indicate that a similar overall exposure is expected 
following both 10 mg/kg q2w and 20 mg/kg q4w regimens, as represented by AUCss (4 weeks). 
Median Cmax,ss is expected to be higher with 20 mg/kg q4w (~1.5 fold), and median Ctrough,ss is 
expected to be higher with 10 mg/kg q2w (~1.25 fold). Clinical activity with the 20 mg/kg q4w 
dosing regimen is anticipated to be consistent with 10 mg/kg q2w with the proposed similar dose 
of 20 mg/kg q4w expected to (a) achieve complete target saturation in majority of patients; (b) 
account for anticipated variability in PK, pharmacodynamics, and clinical activity in diverse 
cancer populations; (c) maintain sufficient PK exposure in case of antidrug antibody (ADA) 
impact; and (d) achieve PK exposure that yielded maximal antitumor activity in animal models.
Given the similar area under the serum drug concentration-time curve (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.
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from 
Study 1108. Population PK analysis indicated only minor impact of body weight on PK of 
durvalumab (coefficient of ≤0.5). The impact of body weight-based (10 mg/kg q2w or 20 mg/kg 
q4w) and fixed dosing (750 mg q2w or 1500 mg q4w) of durvalumab was evaluated by 
comparing predicted steady-state PK exposures (AUCss,0-28, Cmax,ss, and Cmin,ss) using the 
population PK model. A fixed dose of 750 mg q2w was selected to approximate 10 mg/kg q2w 
and a fixed dose of 1500 mg q4w was selected to approximate 20 mg/kg q4w (based on median 
body weight of approximately 75 kg). A total of 1000 patients were simulated using body weight 
distribution of 40 to 110 kg. Simulation results demonstrate that body weight-based (10 mg/kg 
q2w) and fixed dosing (750 mg q2w) regimens yield similar median steady-state exposures and 
associated variability, supporting the potential switch of durvalumab from weight-based to fixed 
dose. Similar considerations hold for the q4w dosing regimens (20 mg/kg q4w versus 1500 mg 
q4w).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
59 (233)
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang 
et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being better for 7 of 
12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. Based on average body weight of 
75 kg, a fixed dose of 1500 mg q4w durvalumab (equivalent to 20 mg/kg q4w) is included in the 
current study.
Rationale for proposed Phase III dose and schedule
The proposed dosing schedule is aligned with the standard fixed dosing of durvalumab 1500 mg 
q4w, which is supported by efficacy and safety as well as tolerability data across multiple studies 
in multiple tumor types. To conform to the chemotherapy schedule in the study, we propose to 
use standard fixed dose of durvalumab 1500 mg at a q3w dosing interval for the first 4 cycles 
rather than the standard q4w schedule. The safety of a q3w dosing schedule in combination with 
chemotherapy has been explored in the ongoing Study D419SC00001, where tremelimumab is 
administered at 75 mg in combination with durvalumab 1120 mg q3w followed by durvalumab 
1120 mg q3w. The combination has been declared tolerable and manageable. The 1120-mg dose 
of durvalumab is the q3w equivalent of the standard 1500-mg q4w dose. The tremelimumab dose 
was not lowered proportionally to 56 mg because 75 mg is the lowest tested biologically 
effective dose. In this study, AstraZeneca proposes to use the Phase III fixed dose of 
durvalumab, so this study will combine durvalumab 1500 mg q3w with chemotherapy for 
4 cycles. The relative increase in dose density of durvalumab (ie, 1500 mg q3w instead of q4w) 
is supported by the fact that toxicities attributable to durvalumab do not appear dose dependent, 
and PK modeling reveals no meaningful differences in drug levels between q3w and q4w dosing. 
After chemotherapy, the dose will be durvalumab 1500 mg q4w.
Study BR.34 is a Phase II randomized trial of durvalumab and tremelimumab ± platinum-based 
chemotherapy in patients with metastatic (Stage IV) squamous or non-squamous NSCLC. Both 
Study BR.34 and the CCTG (NCT02537418) study are assessing tremelimumab 75 mg with 
durvalumab 1500 mg q3w in combination with platinum-based chemotherapy.
4.3.1.2
Durvalumab q3w dose rationale
PK modeling and simulation have been conducted to evaluate the switch from q4w dosing to 
q3w dosing for durvalumab. For durvalumab, median Cmax following the 5th dose of the q3w 
regimen and the 4th dose of the q4w regimen was 689 and 624 µg/mL, median trough 
concentration at Week 16 was 125 and 94.5 µg/mL, and AUC0-16wk was 28726 and 
22772 µg*day/mL for the q3w and q4w schedule, respectively. Therefore, PK modeling suggests 
that a q3w schedule does not impose a significant increased safety risk based on expected 
durvalumab exposures.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
60 (233)
4.3.2
Gemcitabine plus cisplatin dose rationale
A dose schedule (frequency) using a 21-day gemcitabine and cisplatin (G+C) regimen was 
selected based on better tolerability and similar efficacy compared with the G+C regimen 
administered on an every 28-day cycle. 
A randomized Phase III study of G+C (administered on an every-28-day cycle) compared with 
MVAC in patients with locally advanced and/or metastatic bladder cancer demonstrated similar 
efficacy between the 2 regimens when using gemcitabine 1000 mg/m2 on Days 1, 8, and 15 and 
cisplatin 70 mg/m2 on Day 2 (Von der Maase et al 2000). However, a high incidence of 
hematologic toxicity was reported, compromising the gemcitabine dose intensity; consequently, 
gemcitabine doses were modified in 37% of the G+C cycles in this Phase III study. A 
retrospective study comparing a 21-day cycle versus a 28-day cycle of G+C in patients with 
Stage IV transitional cell carcinoma demonstrated similar efficacy (overall response rates of 
59.7% and 55.6%, respectively, for the 21-day and 28-day regimen) and better tolerability 
(ie, reduced hematologic toxicity) with the use of a 21-day cycle; use of the 21-day regimen did 
not result in an increase in renal toxicity (Birgitte et al 2008). Another retrospective study 
evaluated the tolerability of a 21-day G+C regimen, specifically in elderly patients (≥65 years 
old) with urothelial cancer; 57% of patients received treatment in the neoadjuvant setting. 
Results demonstrated acceptable tolerability of this regimen with primary dose modifications 
only for the gemcitabine dose; 1 case of Grade IV renal toxicity was reported (Jan et al 2016). 
Although a large randomized Phase III has not been conducted to directly compare a 21-day and 
a 28-day G+C regimen in the neoadjuvant setting for UC, published results demonstrating 
similar efficacy, acceptable tolerability, and also the incorporation of the 21-day regimen into the 
current National Comprehensive Cancer Network bladder cancer guidelines (National 
Comprehensive Cancer Network 2019) as an acceptable regimen in the neoadjuvant setting, a 
21-day G+C regimen was selected for this study.
4.3.2.1
Split-dose rationale
Despite the standard, recommended treatment with cisplatin-based chemotherapy and radical 
cystectomy, significant limitations remain in the treatment of MIBC. Some patients with MIBC 
may be limited with regard to treatment options, as they are likely unable to tolerate the standard 
dose regimen of cisplatin due to impaired or borderline renal function (Dash et al 2006). For 
patients with borderline renal function or minimal dysfunction, a split-dose regimen of 
1000 mg/m2 IV q3w gemcitabine plus 35 mg/m2 IV on Day 1 and Day 8 q3w has been 
considered a reasonable option for patients who would otherwise have no option for treatment 
with neoadjuvant chemotherapy. This modified regimen has shown potential for an improvement 
in tolerability compared with current treatment options for patients with borderline renal 
function, has shown potential to avoid dosing delays, has demonstrated reduced toxicity, and has 
comparable benefit to the standard G+C dose in patients with adequate renal function 
(Abdelhafez and Williams 2017, Hussain et al 2012). 
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.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
61 (233)
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the schedule of activities (SoA).
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, all patients still on the study will be asked to transition to 
such a study for the purposes of OS, and the current study would reach its end. Any patient who 
would be proposed to move to such a study would be given a new informed consent.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
See Section 6.6 for a description of treatment options following the final DCO as well as 
following study completion. See Appendix A 6 for guidelines for the dissemination of study 
results.
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for any 
protocol related activity.
Food and Drug Administration requirements defines two completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was terminated. 
In the case of clinical studies with more than one primary outcome measure with different 
completion dates, this term refers to the date on which data collection is completed for all of the 
primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and AEs 
(for example, last participant’s last visit), whether the clinical study concludes according to the 
pre-specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of the 
study including the last visit or the last scheduled procedure shown in the SoA.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
62 (233)
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 the informed consent form 
(ICF). “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.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
apply:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
2.
Provision of signed and dated written ICF prior to any mandatory study specific 
procedures, sampling, and analyses. 
The ICF process is described in Appendix A 3.
Age
3.
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 his or her 
legally acceptable representative.
Type of patient and disease characteristics
4.
Patients with histologically or cytologically documented muscle-invasive TCC (also 
known as UC) of the bladder. 

Patients with transitional cell and mixed transitional/non-transitional cell 
histologies (adenocarcinoma, squamous cell)/variant transitional (eg, 
micropapillary, plasmacytoid, sarcomatoid, nested variant, lymphoepitheliod, 
nested variant) histologies. Patients with pure non-transitional cell variant 
histologies and any small cell histology are not eligible.  

Patients with clinical tumor stage T2-T4aN0/1M0 according to the American Joint 
Committee on Cancer Staging Manual (AJCC Cancer Staging Manual, 8th 
Edition) TCC of the bladder. cN1 disease is defined as the presence of a single 
lymph node in the true pelvis (perivesical, obturator, internal and external iliac, 
and sacral lymph node); lymph node must measure < 20 mm in the short axis 
(small volume metastasis) and be resectable, as per the planned lymphadenectomy 
procedure (see section 6.1.5 [surgical plan]). Lymph nodes with <10 mm short axis 
diameter are considered non-pathological per RECIST1.1.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
63 (233)
A single tumor (T)-stage is determined by the Investigator and is used for 
documentation of baseline disease characteristics and also for registering the patient 
for randomization (ie, for stratification purposes). Clinical staging, specifically for the 
determination of the clinical tumor stage (cT), is a composite of combined results 
obtained from a pathological assessment of the tumor (from a TURBT sample, 
confirming muscle invasion), an examination under anesthesia procedure (performed 
after the completion of the TURBT procedure), and results from a CT/MRI image. 
Patients should also meet the following additional criteria:

Must be planning and per the judgment of the Investigator medically fit for 
treatment with neoadjuvant therapy prior to radical cystectomy (ie, patients 
should not be randomized if they are not eligible or cannot receive any 
neoadjuvant treatment)

Must be planning and per the judgment of the Investigator medically fit to 
undergo a radical cystectomy at time of enrollment and randomization.

Have not received prior systemic chemotherapy or immunotherapy for treatment 
of MIBC. (Prior local intravesical chemotherapy is allowed regardless of time 
frame. Prior local intravesical immunotherapy (eg, BCG) is allowed if completed 
at least 6 weeks prior to the initiation of study treatment.)
5.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at 
enrollment.
6.
Tumor PD-L1 status, with immunohistochemistry (IHC) assay confirmed by a 
reference laboratory, must be known prior to randomization. As such, all patients must 
give valid written consent to provide a newly acquired MIBC tumor biopsy during 
screening (preferred) or provide an available archival MIBC tumor sample taken 
≤3 months prior to screening. Tumor lesions submitted must be when the patient was 
determined to have MIBC (ie, NMIBC samples will not be acceptable). Samples with 
limited tumor content are not acceptable. The tumor specimen submitted to evaluate 
PD-L1 status should be of sufficient quantity to allow for PD-L1 IHC, retrospective 
evaluation of muscle invasive disease, and other exploratory biomarker analyses and is 
preferred in formalin-fixed paraffin-embedded (FFPE) blocks. (Refer to Section 6.2.1
for information regarding obtaining tumoral PD-L1 status prior to the 28-day 
screening window.)
7.
Adequate organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.5×109/L

Platelet count ≥100×109/L

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
64 (233)

Serum bilirubin ≤1.5× ULN. This will not apply to patients with confirmed 
Gilbert’s syndrome, who will be allowed in consultation with their physician.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5×ULN

CrCl calculated by Cockcroft-Gault equation (using actual body weight) or 
measured by 24-hour urine collection for determination. (In cases where both are 
performed, measured 24-hour urine collection will be used to determine 
eligibility, providing an adequate collection was performed.)*
o
CrCl for Borderline Renal Function arm: ≥40 mL/min to <60 mL/min 
o
CrCl for Adequate Renal Function arm: ≥60 mL/min 
Cockcroft-Gault equation
Males:
Creatinine CL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL = 
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
8.
Must have a life expectancy of at least 12 weeks at randomization.
Weight
9.
Body weight >30 kg at enrollment and randomization
Reproduction
10.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause. The 
following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, 
or hysterectomy).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
65 (233)
*The method used to determine CrCl for study eligibility will be the same method used to 
determine cisplatin chemotherapy regimen used on study entry. If more than 1 evaluation of 
CrCl has been obtained during the screening period, the CrCl value closest to Cycle 1 Day 1 
should be entered into the interactive voice response system (IVRS)/interactive web response 
system (IWRS) for randomization purposes. See Section 6.2.1 for detailed requirements 
regarding IVRS/IWRS data entry for purposes of randomization.
5.2
Exclusion criteria
Patients are not eligible to be included in the study if any of the exclusion criteria apply:
Medical conditions
1.
Evidence of lymph node (N2-3) or metastatic TCC/UC (M1), extravesical TCC/UC 
that invades the pelvic and/or abdominal wall for bladder cancer (T4b), or primary 
non-bladder (ie, ureter, urethral, or renal pelvis) TCC/UC of the urothelium. Patients 
with cN1 and additional radiologically suspected lymph node metastasis within or 
outside the pelvis should be excluded if the short axis is ≥10 mm as per IV contrast-
enhanced CT or MRI scan. If an enlarged lymph node ≥10 and <15 mm can be 
confirmed pathologically (eg, by biopsy) as a non-cancer [benign] lesion and/or by 
positron emission tomography-CT, the patient may be considered eligible.
2.
Per the judgement of the Investigator, if a nephroureterctomy is required at the time of 
randomization for tumor of the mid ureter, renal pelvis, or collecting system
3.
If a ureteral tumor is present proximal to common iliacs that would require 
ureterectomy in addition to the planned cystectomy
4.
Inoperable tumor(s) with fixation to the pelvic wall on clinical exam.
5.
History of allogeneic organ transplantation that requires use of immunosuppressive 
agents. Patients with a history of allogenic stem cell transplantation are also excluded. 
6.
Active or prior documented autoimmune or inflammatory disorders (including but not 
limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis 
[with the exception of diverticulosis], autoimmune pneumonitis, autoimmune 
myocarditis systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener 
syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
66 (233)

Patients without active disease in the last 5 years may be included but only after 
consultation with AstraZeneca

Patients with celiac disease controlled by diet alone may be included but only 
after consultation with AstraZeneca
7.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, uncontrolled diabetes, symptomatic congestive heart failure, uncontrolled 
hypertension, uncontrolled angina, uncontrolled cardiac arrhythmia, active interstitial 
lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or 
psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs, or compromise the ability of 
the patient to give written informed consent. 
8.
History of a myocardial infarction within 6 months prior to randomization due to 
potential cardiotoxic effects observed with gemcitabine
9.
History of another primary malignancy, except for:

Prostate cancer (tumor/node/metastatsis) of stage ≤T2cN0M0 without biochemical 
recurrence or progression and who in the opinion of the Investigator are not 
deemed to require active intervention, or patients with incidental histologic 
findings of prostate cancer that has not been treated prior to the study and who do 
not require specific therapy for prostate cancer beyond the surgery described in 
the protocol and also are considered to be at low risk for recurrence per the 
Investigator

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of investigational product (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
10.
History of active primary immunodeficiency
11.
History of leptomeningeal carcinomatosis
12.
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 hepatitis B virus [HBV] surface 
antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive 
HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
67 (233)
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV ribonucleic acid (RNA).
13.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria 

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with 
AstraZeneca. 
14.
New York Heart Association Class III or IV heart failure (Criteria Committee NYHA 
1964). 
15.
(Exclusion Criterion 15 was removed in Protocol Amendment 2.)
16.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients
17.
Any medical contraindication to platinum (cisplatin)-based doublet chemotherapy, 
including:

CTCAE Grade ≥2 audiometric hearing loss

CTCAE Grade ≥2 peripheral neuropathy
Prior/concomitant therapy
18.
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. 
19.
Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette 
Guerin [BCG]), including but not limited to other anti-CTLA-4, anti-PD-1, 
anti-PD-L1, or anti-PD-L2 antibodies. 
20.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 
21.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP. 
22.
Prior pelvic radiotherapy treatment within 2 years of randomization to study.
23.
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab. The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
68 (233)

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
24.
Prior randomization or treatment in a previous durvalumab and/or tremelimumab 
clinical study regardless of the treatment arm (until the primary endpoint of that study 
has read out)
25.
Previous IP assignment in the present study
26.
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
27.
Participation in another clinical study with an IP administered during the last 28 days
Other exclusions
28.
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab. 
29.
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.
For procedures for withdrawal of incorrectly enrolled patients, see Section 6.2.2.
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1.
Female patient of childbearing 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 7) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (90 days after 
the last dose of durvalumab monotherapy). Non-sterilized male partners of a 
female patient of childbearing potential must use a male condom plus spermicide 
(except in countries where spermicide is not approved) 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. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
69 (233)
2.
Male patients with a female partner of childbearing potential

Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 
spermicide (except in countries where spermicide is not approved) from the time 
of screening throughout the total duration of the drug treatment and the drug 
washout period (90 days after the last dose of durvalumab monotherapy). Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male patients should refrain from sperm donation 
throughout this period.

Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 7). 
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution.

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago.

Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, 
or complete hysterectomy) are eligible.
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 7. Note 
that some contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 
where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel, 
which is considered highly effective]; and triphasic combined oral contraceptive pills).
All patients: Follow the local prescribing information related to contraception, the time limits 
for such precautions, and any additional restrictions for the chemotherapy agents (G+C).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
70 (233)
Table 7
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgesterel-releasing 
intrauterine system (eg, Mirena®)a

Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 

Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)

Combined Pill: Normal and low dose combined 
oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)

Minipill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone based pill
a
This is also considered a hormonal method.
3.
All patients: Patients should not donate blood or blood components while participating 
in this study and through 90 days after receipt of the final dose of durvalumab or until 
alternate anticancer therapy is started. 
4.
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
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.
If a patient who has failed screening is rescreened, a new E-code must not be assigned. Patients 
will reconfirm their consent to participate in the study by resigning and dating their original 
consent form(s), next to their original signature and date. All assessments except the tumor 
biopsy for PD-L1 testing must be repeated for rescreening, unless they are within 28 days of 
randomization. 
A minimal set of screen failure information is required in the CRF to ensure transparent 
reporting of screen failure patients; this includes demography, screen failure details, eligibility 
criteria, any SAEs, and PD-L1 biopsy/tumor sample (if the sample was sent to the central 
laboratory during screening).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
71 (233)
6.
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator) 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, gemcitabine, and cisplatin.
6.1
Treatments administered
6.1.1
Investigational products
AstraZeneca will supply durvalumab (MEDI4736). Neoadjuvant agents gemcitabine and 
cisplatin will be supplied locally. Under certain circumstances when local sourcing is not 
feasible, gemcitabine and cisplatin may be supplied centrally through AstraZeneca
Table 8
Study treatments
Treatment 1
Treatment 2
Study treatment 
name:
Durvalumab (MEDI4736)
Gemcitabine and cisplatina
Dosage 
formulation:
500-mg vial solution for infusion 
after dilution, 50 mg/mL
As sourced locally
Route of 
administration: 
IV
IV
Dosing 
instructions:
1500 mg IV q3w (neoadjuvant)b
1500 mg IV q4w (adjuvant, 
post-radical cystectomy)
Day 1 and Day 8 (gemcitabine 
1000 mg/m2 IV) of each 21-day cycle
(neoadjuvant) 
Day 1 and Day 8 (cisplatin 35mg/m2
IV) or Day 1 (cisplatin 70 mg/m2 IV) 
each 21-day cycle (neoadjuvant)
Packaging and 
labelling:
Study treatment will be provided in 
500-mg vials. Each vial will be 
labeled in accordance with GMP 
Annex 13 and per country regulatory 
requirements.c
Labels will be prepared in accordance 
with GMP and local regulatory 
guidelines. The labels will fulfil GMP 
Annex 13 requirements for labeling. 
Label text will be translated into local 
language.
Provider:
AstraZeneca
Sourced locally by sitea
a
Under certain circumstances when local sourcing is not feasible, G+C treatment may be supplied centrally 
through AstraZeneca.
b
Dosing of durvalumab will occur prior to the dosing of G+C chemotherapy
c
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. 
G+C  Gemcitabine and cisplatin; GMP  Good Manufacturing Practice; IV  Intravenous(ly); q3w  Every 3 weeks; 
q4w  Every 4 weeks.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
72 (233)
6.1.1.1
Order of administration
Immunotherapy administration will be followed by G+C chemotherapy via IV infusion as 
indicated in Section 6.1.1.3.
If corticosteroid anti-emetics are required, medications should be administered 30 minutes prior 
to chemotherapy, not prior to durvalumab. 
Patients in Arm 1 will receive durvalumab via IV infusion over 60 minutes. It is recommended 
that a 60-minute observation period take place after durvalumab is administered, at least for 
Cycle 1.
If no issues are observed following durvalumab administration during the first cycle, reduction of 
the observation period may be at the Investigator’s discretion (suggested 30 minutes). 
G+C chemotherapy is administered per local practice.
6.1.1.2
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume is 
10.0 mL. 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 original packaging until use to prevent prolonged light exposure. 
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator’s 
or site’s designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab (MEDI4736) vial to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm filter; acceptable configurations include an IV set containing an in-line filter or 
the attachment of a separate filter to the distal end of the IV tubing. 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. 
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
73 (233)
a 0.2- or 0.22-μm filter; acceptable configurations include an IV set containing an in-line filter or 
the attachment of a separate filter to the distal end of the IV tubing.
Standard infusion time is 1 hour; however, if 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 the infusion is 
completed, according to institutional policy to ensure the full dose is administered.
If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any unused 
portion must be discarded.
6.1.1.3
Gemcitabine and cisplatin
Gemcitabine and cisplatin will be locally sourced by AstraZeneca marketing companies and/or 
sites and will be infused 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 drugs, which will be labeled with local language translated 
text in accordance with regulatory guidelines.
6.1.2
Dose and treatment regimens
Patients will be randomized to the 2 treatment arms, Arm 1 or Arm 2, and will be treated 
according to their renal function based on randomization. Recruitment for patients with 
borderline renal function will be limited to up to 20% of the targeted global population.
Table 9
Treatment scheme
Treatment 
arm
Neoadjuvant therapy
1 cycle = 3 weeks (21 days)
Radical 
cystectomy
56 days 
(8 weeks)
Adjuvant therapy
1 cycle = 4 weeks 
(28 days)
Cycle 1
Week 1
Cycle 2
Week 4
Cycle 3
Week 7
Cycle 4
Week 10
Treatment will 
start 42-120 days 
following radical 
cystectomy
Durva + 
G+C
(Arm 1)
Durva + 
G+C
Durva + 
G+C
Durva + 
G+C
Durva + 
G+C
Durva x 8 cycles
G+C
(Arm 2)
G+C
G+C
G+C
G+C
No adjuvant 
treatment
Durva Durvalumab; G+C Gemcitabine and cisplatin.
Note: If there is a dosing delay for neoadjuvant chemotherapy, durvalumab doses should be held to ensure that 
dosing is administered on Day 1 of each cycle.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
74 (233)
Figure 2
Neoadjuvant dosing schedule
Note: Vertical arrows represent Day 1 of dosing for each cycle.
Neoadjuvant therapy
Patients with adequate renal function (CrCl ≥60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg IV, cisplatin 70 mg/m2, gemcitabine 1000 mg/m2; 
Day 8: gemcitabine 1000 mg/m2; every 21 days for 4 cycles. 

Arm 2: Day 1: cisplatin 70 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2; every 21 days for 4 cycles. 
Patients with borderline renal function (CrCl ≥40 mL/min to <60 mL/min)

Arm 1: Day 1: durvalumab 1500 mg IV, cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; 
Day 8: gemcitabine 1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.

Arm 2: Day 1: cisplatin 35 mg/m2, gemcitabine 1000 mg/m2; Day 8: gemcitabine 
1000 mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.
Results of serum creatinine and a determination of creatinine clearance must be available and 
reviewed by the treating physician or Investigator prior to dosing of cisplatin on Day 1 and 
Day 8 (if applicable, for patients on the cisplatin split dose regimen).
*In scenarios when patients are unable to complete the intended 4 cycles of chemotherapy 
prior to radical cystectomy, patients will be permitted to receive less than 4 cycles of 
chemotherapy, at the discretion of the Investigator and upon discussion with AstraZeneca.
Noncystectomy extension phase:
Patients in either treatment arm who fulfil the necessary criteria (see Section 6.1.5) may enter the 
noncystectomy extension phase after consultation and approval by AstraZeneca. Patients 
enrolled into Arm 1 who enter the noncystectomy extension phase may be administered
durvalumab 1500 mg (as monotherapy) every 28 days for a maximum of 8 doses (corresponding 
to a maximum exposure of 12 months) or until study-specific discontinuation criteria is met. For 
patients who enter the noncystectomy extension phase and subsequently undergo a radical 
cystectomy, further treatment should be discussed and agreed upon with AstraZeneca.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
75 (233)
Adjuvant therapy (regardless of renal status)

Arm 1: Day 1: durvalumab 1500 mg IV; every 28 days for 8 cycles.

Arm 2: No adjuvant treatment.
Adjuvant therapy is recommended to begin as soon as the patient recovers from radical 
cystectomy and within 120 days after and no earlier than 42 days after radical cystectomy. 
Cycle 1 Day 1 of the adjuvant treatment phase for patients in Arm 2 is recommended to occur as 
soon as the patient recovers from the radical cystectomy (no earlier than 42 days and no later 
than 120 days after radical cystectomy).
6.1.2.1
Durvalumab (MEDI4736)
This is a Phase III, randomized, open-label, multi-center, global study to evaluate durvalumab 
(MEDI4736) in combination with G+C chemotherapy (neoadjuvant) followed by durvalumab 
alone (adjuvant) versus G+C (neoadjuvant) followed by no adjuvant treatment in patients with 
MIBC. 
Approximately 1050 patients globally will be randomized in a 1:1 ratio to receive durvalumab + 
G+C combination therapy q3w (Arm 1) or G+C combination therapy q3w (Arm 2) for 4 cycles 
of neoadjuvant chemotherapy prior to radical cystectomy. Following radical cystectomy and 
during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy q4w via IV 
infusion over 60 minutes for 8 additional cycles. 
If a patient’s weight falls to 30 kg or below (≤30 kg), the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab q3w (neoadjuvant treatment) or q4w (adjuvant 
treatment) after consultation between the Investigator and the 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 q3w (neoadjuvant treatment) or q4w (adjuvant treatment). 
Patients in Arm 2 will receive no adjuvant treatment.
The order of administration of durvalumab and G+C is presented in Section 6.1.1.1.
6.1.3
Duration of treatment and criteria for treatment through progression
For patients in Arms 1 and 2, neoadjuvant treatment will be administered beginning on Day 1 of 
Cycle 1 q3w for 4 cycles 
Following radical cystectomy, Arm 1 patients will receive adjuvant treatment with durvalumab 
q4w for 8 cycles for up to a maximum of 8 cycles, unless specific study discontinuation criteria 
are met. 
Following radical cystectomy, Arm 2 patients will receive no additional treatment but will follow 
the visit schedule per Table 3, unless specific study discontinuation criteria are met.
During the neoadjuvant treatment phase, patients who have Response Evaluation Criteria in 
Solid Tumors, version 1.1 (RECIST 1.1)-defined radiological progression may continue to the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
76 (233)
adjuvant portion of treatment if the progression event did not preclude the patient from having a 
radical cystectomy (ie, progression is local and/or limited to regional lymph nodes that will be 
removed during the radical cystectomy/bilateral lymph node dissection procedure). In the event 
progression (ie, distant metastases) precludes the patient from undergoing radical cystectomy, 
the patient will proceed to follow-up, with no additional tumor assessments performed and the 
patient will be followed for OS. 
Following radical cystectomy, patients with proven recurrence (see Section 8.1.1.1) will proceed 
to follow-up. 
Crossover from Arm 1 to Arm 2 will not be permitted.
6.1.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is stored 
in a secured area, under refrigerated temperatures (2°C to 8°C), and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the temperature of 
the storage area. Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection. A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage facility. 
Storage conditions stated in the IB may be superseded by the label storage.
6.1.5
Surgical plan
Radical cystectomy is performed as soon as possible after completion of and recovering from 
neoadjuvant therapy and is recommended to occur within 56 days after the last dose of 
neoadjuvant chemotherapy. Radical cystectomy is not recommended earlier than 14 days after 
the last dose of neoadjuvant therapy. 
If it is anticipated that the radical cystectomy cannot be performed within the 56-day timeframe 
(8 weeks) from the last dose of neoadjuvant chemotherapy due to a medical reason and may be 
delayed up to 70 days (10 weeks), AstraZeneca should be consulted.
Male patients will undergo radical cystoprostatectomy and urinary diversion along with bilateral 
pelvic lymph node dissection. Female patients will undergo radical cystectomy. A hysterectomy 
and bilateral salpingectomy may be performed by the patient’s choice if no gross evidence of 
oncologic involvement is noted by the surgeon. Oophorectomy may be omitted if clinically 
indicated. Urinary diversion creation will be via an ileal conduit, ileal neobladder, Indiana 
Pouch, or as per local practice. Bilateral pelvic lymph node dissection will follow a minimum of 
the following template to include the 1) external iliac, 2) obturator, and 3) internal iliac nodes, 
and 4) common iliac nodes to the level of the ureteric crossing and must include a lymph node 
classified as cN1 at baseline if one was present. Removal of other nodes is per the surgeon’s 
discretion. The boundaries of the template will be the circumflex iliac vein and Cloquet’s node, 
laterally by the genitofemoral nerve, medially by the bladder, posteriorly by the obturator fossa, 
and proximally to the ureter. 
Radical cystectomy is a mandatory study procedure for all patients. If an alternative procedure is 
performed, it may result in a protocol deviation. However, if a patient is only able to undergo a 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
77 (233)
partial cystectomy based on Investigator and/or surgical assessment, these patients may proceed 
into the adjuvant phase to continue with the same assessments and study procedures, based on 
their treatment assignment at randomization.  
In a setting in which a patient refuses a radical cystectomy at the study specified time, after 
having a complete clinical response determined locally by multimodal assessment (see below) 
and without any additional intervention (eg, TURBT), he/she may be permitted to continue into a 
noncystectomy extension phase to continue with study procedures that mirror those for the 
adjuvant phase (including collection of samples for PK, ADA, and research lab testing, but 
without a Clavien-Dindo assessment), relevant to the arm to which they are randomized (see 
Table 2 for Arm 1 and Table 3 for Arm 2); this allowance is only permitted after consultation 
and agreement with AstraZeneca. Patients in Arm 1 who enter the noncystectomy extension 
phase may be administered durvalumab 1500 mg (as monotherapy) for a total of 8 doses (see 
Section 6.1.2); patients in Arm 2 will receive no additional treatment. Multimodal assessment for 
determining a complete clinical response includes:

Required: cystoscopy (with biopsies, per local practice and if feasible), examination 
under anesthesia, and CT/MRI

Should be obtained if feasible and per local practice: biopsies and urinalysis for 
cytology, PET-CT for patients enrolled with cN1
These assessments will need to be performed within 56 days of the last dose of neoadjuvant 
treatment to claim a complete response. 
6.2
Measures to minimize bias: randomization and blinding
6.2.1
Patient enrollment and randomization
All patients will be centrally/regional/local assigned to randomized study treatment using an 
IVRS/IWRS. Before the study is initiated, the telephone number and call-in directions for the 
IVRS and/or the log-in information and directions for the IWRS will be provided to each site. 
Note: If more than 1 evaluation of CrCl has been obtained during the screening period, the 
CrCl value closest to Cycle 1 Day 1 should be entered into the IVRS/IWRS for 
randomization purposes (see Section 5.1 for details). The method used to determine CrCl 
for study eligibility should be the same method used to determine cisplatin chemotherapy 
regimen used on study entry. CrCl values used in IVRS/IWRS will determine the 
chemotherapy regimen patients will initiate as neoadjuvant chemotherapy. Investigators 
are encouraged to determine CrCl as close to randomization as possible.
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Patients who withdraw after randomization will not be replaced.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
78 (233)
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, with the exception of the patient’s tumoral PD-L1 status 
(must be obtained within ≤3 months before screening). Informed consent of study 
procedures may be obtained prior to the 28-day screening window, if necessary, in 
order to permit tumor biopsy sample acquisition and analysis prior to randomization.

Obtain a unique 7-digit enrollment number (E-code), through the IVRS/IWRS in the 
following format 
 
 This number is the 
patient’s unique identifier and is used to identify the patient on the electronic case 
report forms (eCRFs).

Obtain tumor sample and send for PD-L1 expression analysis. (Obtaining the tumor 
biopsy sample should be given the highest priority and, as such, the sample may 
be obtained and sent for PD-L1 status evaluation prior to the 28-day screening 
window, but within ≤ 3 months before screening, in order to permit analysis prior 
to randomization.) PD-L1 status must be available in the IVRS/IWRS in order for the 
patient to be randomized, as it is a stratification factor.

Determine patient eligibility. Only patients who meet all eligibility criteria (see 
Section 5.1 and Section 5.2) and have a centrally identified PD-L1 status will be 
considered eligible for randomization.

Ensure PD-L1 status results are received by the IVRS/IWRS from the reference 
laboratory prior to randomization.

Determine a single tumor stage; a single tumor stage is determined by the Investigator 
and is used for documentation of baseline disease characteristics and also for 
registering the patient for randomization (ie, for stratification purposes) (See 
Section 5.1, item #4). 
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably trained 
delegate will:

Obtain a unique randomization number via the IVRS/IWRS. Numbers will start at 
 
and will be assigned 
 by IVRS/IWRS as patients are eligible for 
entry into the study. The system will randomize the eligible patient to 1 of the 
2 treatment arms.
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system. 
PPD
PPD
PPD

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
79 (233)
Patients will begin treatment on Day 1. Treatment should start no more than 3 working 
days after being randomized. Patients must not be randomized and treated unless all eligibility 
criteria have been met. 
If a patient withdraws from participation in the study, then his or her enrollment/randomization 
code cannot be reused. Withdrawn patients will not be replaced.
6.2.2
Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study medication. There can be no exceptions to this rule. Patients who are enrolled 
but are subsequently found not to meet all the eligibility criteria must not be randomized or 
initiated on treatment and must be withdrawn from the study.
When a patient does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform AstraZeneca immediately and a discussion 
should occur between AstraZeneca and the Investigator regarding whether to continue or 
discontinue the patient from treatment, taking into consideration the benefit/risk of study 
continuation for that patient. The AstraZeneca representative must ensure all decisions are 
appropriately documented. In situations where an agreement between the Investigator and 
AstraZeneca cannot be reached regarding the treatment plan, the patient should have their study 
treatment stopped and be withdrawn from the study.
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 IVRS/IWRS per country regulations. Randomization codes will 
be assigned 
, within each stratum, as patients become eligible for 
randomization. The IVRS/IWRS will provide the kit identification number to be allocated to the 
patient at the randomization visit and subsequent treatment visits. 
6.2.4
Methods for ensuring blinding
Not applicable; this is an open-label study.
6.2.5
Methods for unblinding the study
Not applicable; this is an open-label study.
6.3
Treatment compliance
Any change from the dosing schedule, dosing delays/interruptions, dose reductions, and dose 
discontinuations should be recorded in eCRF.
PPD

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
80 (233)
The Investigational Product Storage Manager is responsible for managing the IP from receipt by 
the study site until the destruction or return of all unused IP. The Investigator(s) is responsible 
for ensuring that the patient has returned all unused IP.
6.4
Concomitant therapy
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical treatment phase of the study (final study visit), including 
the 90-day follow-up period following the last dose of durvalumab (Arm 1) or adjuvant treatment 
phase visit (Arm 2). 
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
EXCEPTION: The following medications, administered for the purpose of performing the 
on-study radical cystectomy procedure, are exempt. Although not an inclusive list, examples of 
exempted therapies include bowel preparations, sedatives/anxiolytics, anesthesia, analgesics, 
neuromuscular blockers (and reversal agents), electrolyte solutions, anti-emetics, vasopressor 
support (eg, epinephrine, norepinephrine).
Concomitant medications that are administered in the peri-operative period of an on-study 
radical cystectomy, however, must be recorded if any of the following criteria are met:

Medications administered in the peri-operative period that were used to treat an 
unexpected adverse event/complication, occurring peri-operatively

Medications administered in the peri-operative period that contributed to an 
unexpected adverse event/complication, occurring post-operatively 

Medications administered as surgical prophylaxis, including antibiotics administered 
peri-operatively 

Medications administered during the surgery about which the Sponsor has requested 
specific additional information as part of documentation pertaining to a particular 
patient or as a program-wide requirement
Medications and fluids for chemo-immunotherapy infusions:
Any medication administered as a pre-medication for a gemcitabine, cisplatin, and durvalumab 
infusion is to be recorded as a concomitant medication; examples include anti-emetics (including 
a corticosteroid), medications used as prophylaxis for infusion/hypersensitivity reactions, and 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
81 (233)
antipyretics. Additionally, IV fluids containing electrolytes (ie, potassium chloride, magnesium 
sulfate) used in conjunction with the administration of cisplatin are to be recorded; plain IV 
solutions (ie, sodium chloride-containing solutions) are exempt from this requirement. Mannitol 
(as an osmotic diuretic), if administered with a cisplatin infusion, must also be recorded.
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 (Table 10 and Table 11). Refer also to the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5). 
For gemcitabine and cisplatin, please refer to the local prescribing information with regard to 
warnings, precautions, and contraindications.
Table 10
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Both treatment arms (Arms 1 and 2):
Any investigational anticancer therapy 
other than those under investigation in 
this study
Should not be given concomitantly whilst the patient is on 
study treatment OR during the adjuvant phase study visits for 
Arm 2 (see Table 3).
mAbs against CTLA-4, PD-1, or PD-
L1 other than those under investigation 
in this study
Should not be given concomitantly whilst the patient is on 
study treatment OR during the adjuvant phase study visits for 
Arm 2 (see Table 3).
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or 
biologic or hormonal therapy for 
cancer treatment other than those 
under investigation in this study
Should not be given concomitantly whilst the patient is on 
study treatment OR during the adjuvant phase study visits for 
Arm 2 (see Table 3). (Concurrent use of hormones for non-
cancer-related conditions [eg, insulin for diabetes and 
hormone replacement therapy] is acceptable. 
Live attenuated vaccines 
Should not be given through 90 days after the last dose of 
durvalumab
Should not be given through 3 months after the last of 
chemotherapy (gemcitabine and cisplatin) (Rubin et al 2014)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
82 (233)
Table 10
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Experimental arm (Arm 1-durvalumab in neoadjuvant and adjuvant phases):
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.

Use prior to imaging procedures in patients with 
contrast allergies. 

Short-term premedication for patients receiving 
combination chemotherapy agents, in which the 
prescribing information for the agent requires the use 
of steroids for documented hypersensitivity reactions.

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).
Investigators should attempt to limit the use of steroids for 
prevention of chemotherapy-induced nausea and vomiting to 
the day of treatment (ie, Days 1 and 8 only), if possible.
Epidermal growth factor receptor 
(EGFR) tyrosine kinase inhibitors 
(TKIs)
Should not be given concomitantly. 
Should be used with caution in the 90 days post last dose of 
durvalumab.
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with 1st generation EGFR TKIs) has been reported 
when durvalumab has been given concomitantly.
Herbal and natural remedies that may 
have immune-modulating effects
Should not be given concomitantly unless agreed by the 
Sponsor
CTLA-4 cytotoxic T-lymphocyte-associated antigen 4; IP Investigational product; PD-1 Programmed cell death-1; 
PD-L1 Programmed cell death ligand-1.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
83 (233)
Table 11
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)
Should be used, when necessary, for all patients
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 CRF.
6.4.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-clinically 
or in patients. As durvalumab is a mAb and therefore a protein, it will be degraded to small 
peptides and amino acids and will be eliminated by renal and reticuloendothelial clearance. It is 
therefore not expected that durvalumab will induce or inhibit the major drug metabolizing 
cytochrome P450 pathways. As a result, there are no expected PK drug-drug interactions. The 
MOA of durvalumab involves binding to PD-L1, and therefore significant pharmacodynamic 
drug interactions with the commonly administered concomitant medications are not expected. 
Despite this, appropriate clinical monitoring in all of the planned clinical studies will be 
conducted to evaluate any potential drug-drug interactions.
6.4.3
Rescue medication
As a result of immune-mediated adverse events (imAEs) that could potentially be experienced by 
patients on durvalumab, immunosuppressant rescue medication has to be made available to this 
patient population. The 2 products that fall into this category are infliximab (eg, for colitis) and 
mycophenolate (for hepatitis). AstraZeneca supply chain will be responsible for sourcing these 
2 rescue medications to the sites if local regulations prevent the use of infliximab and 
mycophenolate in this indication, as they are considered off-label for management of 
immunotherapy related toxicities. These rescue medications must be received, controlled, and 
administered by the pharmacist and stored according to the labelled storage conditions, with 
temperature excursions reported accordingly by the pharmacist. If required for use as a result of 
an imAE, then the IVRS/IWRS will provide to the pharmacists the kit identification number to 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
84 (233)
be allocated to the patient at the time. Access and notifications will be controlled using the 
IVRS/IWRS.
6.5
Dose modification
For durvalumab treatment

Patients may delay dosing under certain circumstances. However, dose reduction is 
not permitted.

Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1), due to either an immune or a 
non-immune-related AE.

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.

If there is a dosing delay while on the q3w schedule (neoadjuvant portion), it is 
advised to skip the durvalumab dose and resume dosing on Day 1 of the 
subsequent cycle. If there is a dosing delay during the adjuvant portion of therapy, 
dosing intervals of subsequent cycles may be shortened as clinically feasible in 
order to gradually align treatment cycles with the schedule of tumor efficacy and 
PRO assessments. Subsequent time between 2 consecutive doses cannot be less 
than 21 days, based on the half-life of durvalumab (see current IB for 
durvalumab). 

In the event that durvalumab is discontinued or delayed as part of the toxicity 
management guidance, gemcitabine and cisplatin (G+C) may still be administered 
as scheduled.
For gemcitabine and cisplatin neoadjuvant treatment

Patients may delay and subsequently resume dosing per local standard clinical 
practice. Patients will also be permitted to skip Day 8 chemotherapy per local toxicity 
management standards for chemotherapy. 

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible. In the event that Cycle 1 of the chemotherapy 
schedule is delayed, durvalumab should follow the chemotherapy schedule and 
should be administered on Day 1 of each cycle.

In the event that G+C chemotherapy is discontinued due to treatment-related
toxicity, patients should proceed to radical cystectomy when clinically feasible, 
and the remaining durvalumab monotherapy neoadjuvant doses should be 
skipped. Adjuvant therapy with durvalumab may continue following radical
cystectomy. Note: If the Investigator feels that a patient would benefit from 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
85 (233)
administering the remaining neoadjuvant durvalumab cycles without 
chemotherapy, AstraZeneca should be consulted for an exception to this rule.

In the event that creatinine clearance drops below 60 mL/min, the cisplatin dose may 
be divided into 2 administrations, as per local practice, for management of renal 
toxicity.
6.6
Treatment after the end of the study
Patients still on the study following the final DCO and database closure may continue to be 
followed for OS. Patients will be transitioned to a roll-over or safety extension study for 
follow-up for OS.
7.
DISCONTINUATION OF TREATMENT PHASE OF STUDY AND 
PATIENT WITHDRAWAL
7.1
Discontinuation of study treatment 
An individual patient will not receive any further IP (durvalumab, gemcitabine, or cisplatin) 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 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) for durvalumab or as defined 
in the local prescribing information for gemcitabine or cisplatin. 

A radical cystectomy procedure is not performed (see Section 6.1.5) either due to a 
medical decision by the investigator or a patient refusal, and entry into the 
noncystectomy extension phase is not applicable

RECIST 1.1-defined progression that precludes the patient from undergoing a radical
cystectomy; local progression during the neoadjuvant phase might not be a precluding 
event.

This is also applicable for patients who enter the noncystectomy extension phase 
with plans for a delayed cystectomy.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
86 (233)

Proven recurrence, either by RECIST 1.1-defined radiological progression or positive 
tumor biopsy from suspected recurrence (see Sections 8.1.1.1 and 8.1.1.2) following 
radical cystectomy.

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 
other than treatment described in this protocol. Patients enrolled in Arm 2, which are 
given treatment outside of the protocol-defined therapy during the adjuvant phase, 
should continue tumor assessments until progression or recurrence but discontinue all 
other adjuvant phase visit assessments.
See the SoA for data to be collected at the time of treatment discontinuation and follow-up and 
for any further evaluations that need to be completed.
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 Table 4).
Patients who permanently discontinue drug for reasons other than disease progression/recurrence 
should continue to have disease assessments performed every 12 weeks ±7 days after the date of 
radical cystectomy for the first 24 months, then every 24 weeks ±7 days for 36 months, and then 
every 52 weeks (annually) thereafter until recurrence either by RECIST 1.1-defined radiologic 
progression (see Section 8.1.1.1) or a tumor biopsy for suspected new lesions, the end of study, 
death, study discontinuation, or Sponsor decision, whichever comes first, as defined in Table 1, 
Table 2, and Table 4.
7.1.2
Procedures for discontinuation of study plan (no radical cystectomy)
For patients with confirmed progression during the neoadjuvant phase outside of the pelvis or 
patients with cN1 disease at study entry for which the node is no longer considered resectable, 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
87 (233)
who are therefore precluded from undergoing a radical cystectomy, no additional imaging will be 
required, and the patient will be entered into the follow-up phase with plans to follow for OS 
only (see Table 4). 
Patients who do not have a radical cystectomy performed for medically excluded reasons will be 
entered into the follow-up phase. Further disease assessments in these patients are outlined in 
Section 8.1.1.
Patients who refuse to proceed with a radical cystectomy will be managed as follows:

Patients in either treatment arm who are determined to be in complete response (see 
Section 6.1.5) and who enter into a noncystectomy extension phase with a plan for a 
potential delayed cystectomy will be discontinued if they meet progression or medical 
exclusion criteria, or if they refuse a delayed radical cystectomy, in case of disease 
recurrence.

Patients with residual disease will be entered into follow-up with no additional scans 
and followed for OS only.
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed (see Section 4.4), such that there is insufficient information to determine 
the patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than “lost 
to follow-up.” Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. If contact with a missing patient is re-established, the 
patient should not be considered lost to follow-up and evaluations should resume according to 
the protocol.
In order to support key end point of EFS analysis, the survival status of all patients in the full 
analysis set (FAS) and the safety analysis set (SAS) 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 CRF modules will be updated.)

In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
88 (233)
applicable local laws to obtain a current survival status. (The applicable CRF modules 
will be updated.)
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice 
to further treatment.
Patients who withdraw consent for further participation in the study will not receive any further 
IP or further study observation, with the exception of follow-up for survival, which will continue 
until the end of the study unless the patient has expressly withdrawn their consent to survival 
follow-up. Note that the patient may be offered additional tests or tapering of treatment to 
withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and
the presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to:

All further participation in the study including any further follow-up (eg, survival 
contact telephone calls)

Withdrawal to the use of any samples (see Section 8.8.6)
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoAs (Table 1, Table 2, Table 3, and 
Table 4). Patients in both Arms 1 and 2 are to follow the assessments, with the exceptions noted. 
The Investigator will ensure that data are recorded on the electronic CRFs. 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 electronic CRFs. A copy of the completed 
electronic CRFs 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. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
89 (233)
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA.
8.1
Efficacy assessments
This study will evaluate the dual primary endpoints of pCR and EFS. Efficacy assessments of 
pCR (primary) will be derived (by AstraZeneca) using central pathology review of the radical
cystectomy sample. The efficacy assessments of EFS (primary) and EFS24 will be derived (by 
AstraZeneca) using BICR assessments according to RECIST 1.1 or by central pathology review 
if a biopsy is required for a suspected new lesion. 
Additional secondary objectives will be OS, OS5, PFS2 as defined by local standard clinical 
practice, and proportion of patients who undergo radical cystectomy. The proportion of patients 
who achieve <P2 will be derived (by AstraZeneca) using local pathology assessments of radical
cystectomy samples.
8.1.1
Tumor assessments 
pCR efficacy assessment will be done by central pathology review of radical cystectomy samples 
(Sections 8.1.1.2 and 8.1.1.5). EFS efficacy assessment will be assessed by either RECIST 1.1 on 
imaging scans (Sections 8.1.1.1 and 8.1.1.6) or by pathology on biopsy samples if required 
(Sections 8.1.1.2 and 8.1.1.3).
8.1.1.1
Investigator RECIST 1.1 imaging review
Radiological efficacy will be assessed by RECIST 1.1. There will be 2 baseline assessments, the 
first for the neoadjuvant phase and the second for the adjuvant phase. A first “Neoadjuvant 
Baseline” scan should be collected during pre-randomization screening (Day -28 to -1) for 
disease staging and for use as a RECIST 1.1 baseline for the post-neoadjuvant/pre-radical
cystectomy follow-up scan (performed upon completion of neoadjuvant chemotherapy prior to 
surgery; consideration should be given to scheduling this scan as part of the pre-surgical workup, 
to confirm patient is still eligible for a radical cystectomy) (Table 1). 
A second “Adjuvant Baseline” scan should be collected 42 days (±2 weeks) after radical
cystectomy and ideally should be performed as close as possible and must be prior to the first 
date of adjuvant treatment (Table 2). In most instances, no lesions will be observed on the 
Adjuvant Baseline scans and ‘No Evidence of Disease’ will be recorded for the Adjuvant 
Baseline RECIST assessment. 
If any radiologically observable tumors are identified, a new selection of Target and/or 
Non-Target lesions are recorded. A follow-up scan should be performed at least 4 weeks later, as
an assessment using RECIST 1.1 criteria and then every 12 weeks, thereafter. The use of an 
earlier scan is in place to allow early confirmation of a metastatic lesion. Additionally, a new 
lesion can be evaluated pathologically at any time, when feasible, to confirm metastatic disease.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
90 (233)
On-study adjuvant tumor assessments occur every 12 weeks ±7 days after the date of radical
cystectomy for the first 24 months, then every 24 weeks ±7 days for 36 months, and then every 
52 weeks (annually) thereafter until unequivocal progression, the end of study, death, study 
discontinuation, or Sponsor decision, whichever comes first. If a new lesion is radiologically 
equivocal, treatment should continue and the lesion should be assessed at a subsequent scan no 
earlier than 6 weeks later or at the next scheduled imaging visit to determine if it becomes 
unequivocal. If measurable, in order for a previously equivocal new lesion to become 
unequivocal at a subsequent scan, the long axis diameter of the previously new equivocal 
non-nodal lesion or the short axis diameter of the previously new equivocal nodal lesion should 
show an increase of at least 5 mm. If the event of progression is confirmed on the subsequent 
follow-up scan, the date of progression corresponds to the first evidence of progression. Other 
imaging modalities (eg, bone scan, MRI scan) may be required to define progression in 
equivocal cases. During adjuvant treatment, the imaging schedule must be followed regardless of 
any delays in dosing. 
Tumor assessment for patients not undergoing a radical cystectomy
For patients with confirmed progression during the neoadjuvant phase outside of the pelvis or 
progression of a lymph nodein the true pelvis that is determined to be unresectable, and who are 
therefore precluded from undergoing a radical cystectomy, no additional imaging will be 
required, and the patient will be entered into the follow-up phase with plans to follow for OS 
only (see Table 4). 
Patients who refuse to proceed with a radical cystectomy will have tumor assessments performed 
as follows:

Patients in either treatment arm who are determined to be in complete clinical response 
(see Section 6.1.5) and who enter into a noncystectomy extension phase with a plan 
for a potential delayed cystectomy will have a scan obtained 12 weeks after the last 
scan that was performed in the neoadjuvant phase, and then every 12 weeks ±7 days 
for the first 24 months, then every 24 weeks ±7 days for 36 months, and then every 
52 weeks (annually) thereafter until unequivocal progression, the end of the study, 
death, study discontinuation, or Sponsor decision, whichever comes first. These 
follow-up scans will use the initial neoadjuvant baseline scan as a baseline scan for 
RECIST 1.1 assessments. If an unscheduled assessment is performed and the patient 
has not progressed, every attempt should be made to perform the subsequent 
assessments according to the original imaging schedule. For patients who discontinue 
treatment due to toxicity or other reasons in the absence of unequivocal recurrence, 
tumor assessments should continue according to the schedules of assessments.

Patients with local progression during the noncystectomy extension phase, who 
are not precluded from undergoing a delayed radical cystectomy, will have a 
post-cystectomy (adjuvant) baseline scan obtained and additional scans performed 
according to the on-study adjuvant schedule.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
91 (233)

Patients who are medically precluded from undergoing a delayed radical 
cystectomy will not undergo any additional scans and will be entered into 
follow-up for evaluation of OS only.

For patients who refuse a delayed radical cystectomy procedure in case of 
recurrence, no additional scans will be performed, and the patient will be entered 
into follow-up for evaluation of OS only.

Patients who refuse a radical cystectomy or are medically excluded and are without 
confirmation of a complete clinical response will be considered to have at least 
microscopic residual disease and will have progression (EFS) declared at time of 
expected surgery. 

Patients who refuse a radical cystectomy and have evidence of residual tumor as per 
findings on the post-neoadjuvant scan will be considered to have gross macroscopic 
residual disease and will have progression (EFS) declared at time of expected surgery.

Patients with residual disease (microscopic or macroscopic) and who refuse radical 
cystectomy will be entered into follow-up with no additional scans and therefore will 
not have an “Adjuvant Baseline” scan or adjuvant treatment and will be followed for 
evaluation of OS only.
8.1.1.2
Local biopsy review
Where possible or feasible, suspected progression/recurrence events should be biopsy proven as 
soon as feasible. If a biopsy is performed and the histopathological assessment reveals the 
presence of recurrent tumor, progression will be recorded using the date of biopsy.
8.1.1.3
Local pathology review
Local pathology review of radical cystectomy specimen to assess the pathological stage will be 
based on American Joint Committee on Cancer tumor-node-metastasis classification of 
carcinomas of the urinary bladder.
8.1.1.4
Central biopsy review
Where possible or feasible, suspected progression/recurrence events should be biopsy proven as 
soon as feasible. If a biopsy is performed and the histopathological assessment reveals the 
presence of recurrent tumor, progression will be recorded using the date of biopsy.
8.1.1.5
Central pathology review
Central pathology review of radical cystectomy specimen to assess the pathological stage will be 
performed at the discretion of AstraZeneca. Guidelines for sample requirements will be provided 
in a separate document. A central pathology review will be based on American Joint Committee 
on Cancer tumor node metastasis classification of carcinomas of the urinary bladder.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
92 (233)
8.1.1.6
Central imaging review
All images, including unscheduled visit scans, will be collected on an ongoing basis and sent to 
an AstraZeneca-appointed Contract Research Organization (CRO) for quality control 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 at the discretion of AstraZeneca. The results of these independent 
reviews will not be communicated to Investigators, and the results of Investigator RECIST 1.1 
assessments will not be shared with the central reviewers. The management of patients will be 
based in part upon the results of the RECIST 1.1 assessment conducted by the Investigator. 
Further details of the BICR will be documented in the Independent Review Charter (also referred 
to as “Imaging Charter”). 
Scans obtained for routine clinical management of the patient that are submitted to an imaging 
Contract Research Organization (iCRO) after investigator assigned RECIST 1.1 progression, 
may be centrally reviewed.
8.1.2
Survival assessments
Assessments for survival must be made at Months 3, 6, and 9 (±1 week); Month 12 (±2 weeks); 
and then every 6 months thereafter (±2 weeks) following treatment discontinuation or adjuvant 
phase study visits (Table 4). Survival information may be obtained via telephone contact with the 
patient or the patient’s family, or by contact with the patient’s current physician. The details of 
first and subsequent therapies for cancer, after discontinuation of treatment, will be collected. 
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cutoff for the primary analysis and all subsequent survival analyses to provide complete survival
data. These contacts should generally occur within 7 days of the data cutoff. If patients are 
confirmed to be alive or if the death date is after the data cutoff date, these patients will be 
censored at the date of data cutoff. Death dates may be found by checking publicly available 
death registries, where allowed by local regulations.
8.1.3
Clinical outcome assessments
Patient reported outcome (PRO) is a general term referring to all outcomes and symptoms that 
are directly reported by the patient. PROs have become important in evaluating the impact of 
treatment on disease-related symptoms, physical function, and other HRQoL and in assessing 
treatment-related symptoms. The following PROs will be administered in this study: European 
Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire 
(EORTC QLQ-C30, core questionnaire), EuroQol 5-Dimension 5-Level health state utility index 
(EQ-5D-5L), PGIC, PGIS, and selected questions from the PRO-CTCAE items bank. See 
questionnaires in Appendix H.
The PRO instruments will be completed by the patients using a handheld electronic patient 
reported outcome (ePRO) device at study sites or at home. It will take approximately 20 to 
30 minutes for patients to complete the questionnaires, therefore, the burden to the patient should 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
93 (233)
be moderate. The PRO questionnaires must be completed by the patient as per the SoAs 
(Table 1, Table 2, Table 3, and Table 4) to the best of their ability. The PRO questionnaires will 
be administered on the days specified in the SoAs (Table 1, Table 2, Table 3, and Table 4). The 
EORTC QLQ-C30 should always be completed prior to the other questionnaires.
Data from the PRO assessments will not be routinely reviewed by the treating physicians 
throughout the study. Patients will first be informed of this when they fill out the consent form 
that is required in order to participate in the trial. The form will include information explaining 
that the PRO information gathered via the device is not routinely reviewed by their healthcare 
provider and they should therefore report any concerning symptoms directly to their physician. 
Patients will then be reminded of this each time they complete the assessment on the handheld 
device. When the patient logs onto the device to complete the assessments, a message screen will 
show advising the patient to consult their healthcare provider if they have any concerning 
symptoms. The patient will not be able to continue with the PRO assessments until they have 
acknowledged that they have read this message. The exact message text states:
“Please Note: If you are having any symptoms, health issues or other concerns, please be sure to 
discuss these with your doctor or nurse. The answers you provide to the questions are for 
research purposes only and are not being routinely reviewed by the members of your healthcare 
team. Please note to always share any and all information with your doctor, including 
information about the answers you will provide in this questionnaire that may help address your 
safety concerns.”
Finally, such warning will also be implemented into the training material to the site 
professionals, who will also verbally pass the message to the patients. It is important that the
significance and relevance of the data are explained carefully to participating patients so that 
they are motivated to comply with data collection. 
The following instructions should be followed when collecting PRO data via an electronic 
device:

It is vital that the PRO reporting is initiated at randomization, as specified in the SoAs 
(Table 1, Table 2, Table 3, and Table 4) to capture the effect of study treatment.

PRO questionnaires should be completed at home or at study sites prior to any other 
study procedures (following informed consent) and before discussion of disease 
progression/recurrence to avoid biasing the patient’s responses to the questions.

When each instrument is due to be completed, the following order should be observed: 
EORTC QLQ-C30, PGIC, PGIS, EQ-5D-5L, and then PRO-CTCAE.

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. It is 
important that the ePRO device is charged and fully functional.

The research nurse or appointed site staff must remind patients that there are no right 
or wrong answers and avoid introducing bias by not clarifying items.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
94 (233)

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 or illiterate), 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 in the Review of PRO/Questionnaire/Diary 
(REVPRDI) eCRF. 

The patient should not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires.

Site staff must administer questionnaires available in the language that the patient 
speaks and understands. Questions should not be read in an available language and 
translated into another language for the patient.

The research nurse or appointed site staff must monitor compliance since minimizing 
missing data is a key aspect of study success. 

The research nurse or appointed site staff must check compliance at each study visit 
(or more frequently to identify problems early). Reminders should be sent to the 
patient at home as needed to ensure compliance with the assessment schedules.

If compliance drops to 85% or below, they will be flagged in the routine compliance 
report generated by the ePRO system, and a check-in call from the study site to ask the 
patient if he or she has any difficulties is highly recommended. A solution to 
enhance/resolve compliance should be discussed with the patient. Discussions and 
compliance review should be reflected in source documents. 

The reason why a patient could not complete assessments will be documented in the 
source documents and the REVPRDI eCRF.
8.1.3.1
EORTC QLQ-C30
The EORTC QLQ-C30 questionnaire (Appendix H) is included as a well-established instrument 
for assessing general cancer symptoms, physical functioning, and other HRQoL/health status in 
cancer clinical studies. It includes 30 items grouped into 9 multi-item scales: 5 functional scales 
(physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea 
and vomiting), and a global health and quality-of-life (QoL) scale. It also includes 6 single-item 
symptom measures: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties. For each of the 15 domains, final scores are transformed such that they range from 
0 to 100, where higher scores indicate greater functioning, greater HRQoL, or greater level of 
symptoms (Aaronson et al 1993).
The EORTC QLQ-C30 will be assessed based on the SoAs (Table 1, Table 2, Table 3, and 
Table 4) using a handheld device at study sites or at home.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
95 (233)
8.1.3.2
EQ-5D-5L
The EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L) is a standardized 
measure of health status developed by the EuroQol Group in order to provide a simple, generic 
measure of health for clinical and economic appraisal (EuroQol Group 1990). Applicable to a 
wide range of health conditions and treatments, it provides a simple descriptive profile and a 
single index value for health status that can be used in the clinical and economic evaluation of 
health care as well as in population health surveys. Since 2009, the EuroQol group has been 
developing a more sensitive version of the EQ-5D (the EQ-5D-5L), which expands the range of 
responses to each dimension from 3 to 5 levels of increasing severity (Herdman et al 2011).
The EQ-5D-5L questionnaire (Appendix H) 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 unable to/extreme 
problems) that reflect increasing levels of difficulty.
The patient will be asked to indicate his/her current health state by selecting the most appropriate 
level in each of the 5 dimensions. The questionnaire also includes a visual analogue 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.
The EQ-5D-5L will be assessed based on the SoAs (Table 1, Table 2, Table 3, and Table 4) 
using a handheld device at study sites or at home.
8.1.3.3
PGIC
The PGIC item (Appendix H) is included to assess how a patient perceives their overall change 
in health status since the start of study treatment. Patients will be asked, “Overall, how would 
you rate the change in your health status since starting this Study?” and will choose from seven 
response options ranging from “Much Better” to “Much Worse.”
The PGIC will be completed based on the SoAs (Table 1, Table 2, Table 3, and Table 4) using a 
handheld device at study sites or at home.
8.1.3.4
PGIS
The PGIS item (Appendix H) is included to assess how a patient perceives the overall severity of 
cancer symptoms over the past 1 week. Patients will be asked to choose the response that best 
describes the severity of their overall cancer symptoms over the past week. The response options 
are: no symptoms, very mild, mild, moderate, severe, and very severe. This item is included to 
aid in the interpretation of other PRO measures and to evaluate the overall impact of treatment 
on the global severity of bladder cancer symptoms. 
The PGIS will be completed based on the SoAs (Table 1, Table 2, Table 3, and Table 4) using a 
handheld device at study sites or at home.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
96 (233)
8.1.3.5
PRO-CTCAE
The PRO-CTCAE system has been developed by the National Cancer Institute (NCI). The 
PRO-CTCAE will only be administered in those countries where a linguistically validated 
version is available: currently English, Danish, German, Italian, Japanese, Korean, and Spanish. 
All applicable translations available during the study will be used. PRO-CTCAE is an item bank 
of symptoms experienced by patients while undergoing treatment of their cancer. It was 
developed in recognition that collecting symptom data directly from patients using PRO tools 
can improve the accuracy and efficiency of symptomatic AE data collection. This was based on 
findings from multiple studies demonstrating that physicians and nurses underestimate symptom 
onset, frequency, and severity in comparison with patient ratings (Basch et al 2009; Litwin et al 
1998; Sprangers et al 1992). To date, 81 symptoms of the CTCAE (version 4) have been 
identified to be amenable to patient reporting. These symptoms have been converted to patient 
terms (eg, CTCAE term “myalgia” converted to “aching muscles”). For several symptoms, like 
fatigue and pain, additional questions are asked about symptom frequency, severity, and 
interference with usual activities. For other symptoms like rash, additional questions focus on the 
presence on the body. The items included in the PRO-CTCAE have undergone extensive 
qualitative review among experts and patients. Using cognitive testing methods, these items and 
the additional questions for some of the symptoms have been extensively evaluated by cancer 
patients, so that symptoms of interest are clear, comprehendible, and measurable. Not all items 
are administered in any one clinical trial. The intention is to only ask patients to complete those 
items, which are considered relevant for the trial, site of cancer, and cancer treatment.
The items pre-selected for this study are based on analysis of the relevant core symptom set from 
NCI, treatment-related symptoms of durvalumab monotherapy, and side effects of G+C derived 
from the literature. Also, 7 of the 8 symptoms (fatigue, diarrhea, cough, shortness of breath, 
musculoskeletal/muscle pain, rash, pruritus, and fever) associated with immune-related adverse 
events (irAEs) reported in 5 immunotherapy product labels identified and recommended by the 
FDA for assessing treatment tolerability in immunotherapy clinical trials (Howie et al 2018) 
were included. Note that fever is not currently available in the PRO-CTCAE items bank. To 
minimize patient burden, some items considered too general (abdominal pain and headache) and 
non-therapy specific in the NCI Core Cancer Symptom list (anxiety, cognitive disturbance, 
depression, insomnia, neuropathy, painful urination, painful urination, change in usual urine 
color, urinary frequency, etc) have not been selected. The Free Text item in the PRO-CTCAE 
instrument is not included in the study, as the utility of this information and the analysis method 
have not been established. The full list of items is available in Appendix H.
The PRO-CTCAE assessments will be based on the SoAs (Table 1, Table 2, Table 3, and 
Table 4) using a handheld device at study sites or at home.
8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
97 (233)
8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the times indicated in the assessment schedules and as clinically indicated (see the 
SoAs).
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Urine pregnancy 
tests may be performed at the site using a licensed test (urine or serum pregnancy test). 
Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the
Investigator. 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 12 (clinical chemistry), Table 13
(hematology), and Table 14 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.
The following laboratory variables will be measured:
Table 12
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Calcium
TSHe
Creatinined
T3 freef (reflex)
Gamma glutamyltransferasec
T4 freef (reflex)
Glucose
Urea or blood urea nitrogen, depending on local practice
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
Gamma-glutamyltransferase, magnesium, testing are to be performed at baseline on Day 1 (unless all screening 
laboratory clinical chemistry assessments are performed within 3 days prior to Day 1), and if clinically 
indicated.
d
Creatinine testing is performed on Day 1 and Day 8 of each treatment cycle and if clinically indicated during 
the neoadjuvant phase. During the adjuvant phase, creatinine testing is performed according to Table 2 and 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
98 (233)
Table 3. Laboratory clinical chemistry assessments performed at the beginning of a cycle are obtained within 3 
days prior to Day 1. Creatinine clearance will be calculated using Cockcroft-Gault (using actual body weight) 
at baseline/screening only to ensure initial appropriate treatment assignment based on baseline renal function. 
Sites are required to determine a creatinine clearance prior to each dose of cisplatin for subsequent cycles. 
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.
AE Adverse event, ALT Alanine aminotransferase; AST Aspartate aminotransferase, T3  Triiodothyronine, 
T4 Thyroxine, TSH  Thyroid-stimulating hormone.
Table 13
Hematology
Absolute neutrophil counta
Platelet count
Absolute lymphocyte counta
Total white cell count
Hemoglobin
Note: For coagulation parameters, activated partial thromboplastin time [either as a ratio or as an absolute value, in 
seconds] and international normalized ratio are to be assessed at baseline on Neoadjuvant Cycle 1 Day 1 
(unless all screening laboratory hematology assessments are performed within 3 days prior to Day 1), Adjuvant 
Cycle 1 Day 1 (for patients in Arm 1 only), and as clinically indicated.
a
Can be recorded as absolute counts or as percentages. If entered as a percentage, the percentage of neutrophils 
with total white cell count has to be provided.
Table 14
Urinalysis
Bilirubin
Glucose
Blood
Protein
Note: Urinalysis should be done at screening and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells. 
If a patient shows an AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a 
Hy’s law case or if any of the individual liver test parameters fulfill any of the SAE criteria.
All patients should have further chemistry profiles performed following Table 4 after permanent 
discontinuation of treatment (Arm 1) or adjuvant phase study visits (Arm 2).
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.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
99 (233)
8.2.2
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 8.3.7. 
If any PRO assessments occur when the patient is attending a site visit (Section 8.1.3), then the 
PRO assessments should be completed by the patient prior to the performance of any physical 
examination.
8.2.3
Vital signs and measurements
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) and height will be 
assessed according to the SoAs (Table 1, Table 2, Table 3, and Table 4). Body weight is 
recorded once at each visit when vital signs are evaluated. Body surface area is calculated at the 
beginning of each cycle in the neoadjuvant phase only, for the purpose of chemotherapy dose 
calculations.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, the vital sign values should be entered into the CRF.
Neoadjuvant treatment phase
First infusion
On the first infusion day, patients in Arm 1 will be monitored and vital signs collected/recorded 
in the eCRF prior to, during, and after infusion of durvalumab as presented in the bulleted list 
below. Patients in Arm 1 will have vital signs monitored and recorded prior to start of 
chemotherapy per local standards. 
Arm 1 only
Vital signs will be collected from patients before, during, and after durvalumab infusion at the 
following times (based on a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then vital signs should follow the principles as 
described above or be taken more frequently if clinically indicated. A 1-hour observation period 
is recommended after the first infusion of durvalumab with monitoring per local standards. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
100 (233)
Arm 2 
Arm 2 will have vital signs monitored and recorded prior to start of chemotherapy per local 
standards throughout the neoadjuvant phase.
Subsequent infusions
BP, pulse, and other vital signs should be measured and collected/recorded in the eCRF prior to 
the start of treatment. Patients should be carefully monitored, and BP and other vital signs should 
be measured during and post-infusion as per institution standard and as clinically indicated. Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
CRF page.
Adjuvant treatment phase 
Arm 1
Patients in Arm 1 will have vital signs collected/recorded in the eCRF prior to the start of 
durvalumab infusion and should be carefully monitored, and vital signs should be measured per 
local standards and as clinically indicated. 
Arm 2
For patients in Arm 2, vital signs will be collected/recorded in the eCRF once per study visit. 
8.2.4
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs). ECGs should be obtained after the patient has been in a supine position for 
5 minutes and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value ≥470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the 
finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.5
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see the SoAs) based on the following:
0.
Fully active; able to carry out all usual activities without restrictions
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (eg, light housework or office work)
2.
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
101 (233)
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
Patient follow-up contact (Arm 2 only)
Patients randomized to Arm 2 will be contacted for information regarding ongoing and new AEs 
and concomitant medications for adjuvant phase visits 2, 4, 6, and 8. Patients are not required to 
return to the study site for these specified visits but must be contacted and available to provide 
information regarding AEs and concomitant medications to the Investigator.  
8.2.7
Clavien-Dindo assessment
Clavien-Dindo assessment will be utilized for grading surgical complications. The highest grade 
complication, which occurs within 90 days after the cystectomy (including a partial cystectomy, 
if performed), will be recorded at the time specified in the SoAs (Table 2 and Table 3). 
Investigators will indicate which AE resulted in a surgical complication grade reported. The 
following classification will be used:
Grade
Definition
Grade 0
No events observed.
Grade I
Any deviation from the normal post-operative course without the need for 
pharmacological treatment or surgical, endoscopic, and radiological interventions.
Allowed therapeutic regimens are drugs as anti-emetics, antipyretics, analgesics, 
diuretics, electrolytes, and physiotherapy. This grade also includes wound 
infections opened at the bedside.
Grade II
Requiring pharmacological treatment with drugs other than such allowed for 
Grade I complications.
Blood transfusions and total parenteral nutrition are also included.
Grade III
Requiring surgical, endoscopic, or radiological intervention
  Grade IIIa
Intervention not under general anesthesia
  Grade IIIb
Intervention under general anesthesia
Grade IV
Life-threatening complication (including CNS complications) requiring IC/ICU 
management
  Grade IVa
Single organ dysfunction (including dialysis)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
102 (233)
  Grade IVb
Multiorgan dysfunction
Grade V
Death of a patient
a
Brain hemorrhage, ischemic stroke, subarrachnoidal bleeding, but excluding transient ischemic attacks.
Source: Dindo et al 2004
CNS central nervous system; IC intermediate care; ICU intensive care unit.
8.2.8
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed. 
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected.

Physical examination

Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed.

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:
(i)
ILD markers (KL-6, SP-D) and β-D-glucan
(ii)
Additional clinical chemistry: CRP, LDH 
8.3
Collection of adverse events
The 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.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
103 (233)
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 AEs, see 
Section 8.3.3. 
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.2
Time period and frequency for collecting AE and SAE information 
AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up 
period is completed (90 days after the last dose of treatment (Arm 1) or adjuvant phase study 
visits (Arm 2). If an event that starts post the defined safety follow-up period noted above is 
considered to be due to a late onset toxicity to study drug then it should be reported as an AE or 
SAE as applicable.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix B. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs are provided in 
Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs/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’ last visit 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 treatment (Arm 1) or adjuvant phase study visits (Arm 2) but without further recording in the 
CRF. AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
104 (233)
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria 

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 8.3.5

Description of the SAE
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
105 (233)
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.5
Causality collection
The Investigator will assess causal relationship between the IP and each AE and will answer 
“yes” or “no” to the question, “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that, for SAEs that could be associated with any study procedure, the causal relationship is 
implied as “yes.”
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or the care provider, reported in response to the 
open question from the study site staff, “Have you had any health problems since the previous 
visit/you were last asked?,” or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to recording 
a list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the clinical study protocol-mandated laboratory tests and vital signs will be 
summarized in the clinical study report (CSR). Deterioration as compared to baseline in 
protocol-mandated laboratory values and vital signs should therefore only be reported as AEs if 
they fulfill any of the SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible, the reporting Investigator uses the 
clinical 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/recurrence, should not be reported as an AE.
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 Section 8.3.9).

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
106 (233)
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 recurrence or progression
Disease recurrence or 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 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 treatment (Arm 1) or adjuvant phase study 
visits (Arm 2), must be reported as follows:

Death clearly resulting from disease progression/recurrence 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/recurrence 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/recurrence, if appropriate, and should assign main and 
contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
post mortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual time frames.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of treatment (Arm 1) or adjuvant phase study visits (Arm 2) should be documented 
in the Statement of Death page. If the death occurred as a result of an event that started after the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
107 (233)
defined safety follow-up period and the event is considered to be due to a late onset toxicity to 
study drug, then it should also be reported as an SAE.
8.3.12
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring. An AESI may be serious or 
non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of the IP.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An imAE is defined as an AESI that is associated with drug exposure and 
is consistent with an immune-mediated MOA and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions in regard to an event being an imAE, the Investigator should 
promptly contact the Study Physician.
AESIs/imAEs observed with anti PD-L1/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis and rare/less frequent imAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab IB. More specific guidelines for their evaluation and treatment are described 
in detail in the Dose Modification and Toxicity Management Guidelines (see Section 8.4.5). 
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting Investigator.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
108 (233)
8.3.13
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5). All data after the final DCO and database closure 
will be recorded in the patient notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of treatment [Arm 1] or adjuvant phase study visits [Arm 2]) after the 
final DCO and database closure must be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP or to the study 
procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within 1 day (ie, immediately but no later than 
24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
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).
If the EDC system is not available, then the Investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone. The AstraZeneca representative will 
advise the Investigator/study site staff how to proceed. Investigators or other site personnel send 
relevant CRF modules by fax to the designated AstraZeneca representative.
For further guidance on the definition of a SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the patient has received any study drug

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
109 (233)

Pregnancies in the partner of male patients (see Section 5.3 for lifestyle restrictions for 
male patients with a female partner of childbearing potential and Section 8.4.2.2 for 
restrictions on male patients fathering a child)
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, and ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the 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.
The PREGREP module in the CRF is used to report the pregnancy, and the PREGOUT is used to 
report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab. Please follow the local prescribing information 
relating to contraception and the time limit for such precautions for gemcitabine and cisplatin.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
of durvalumab should, if possible, be followed-up and documented.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
110 (233)
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner. Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) prior to use.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see the 
SoAs).
8.4.3
Overdose
8.4.3.1
Durvalumab
Use of durvalumab in doses in excess of that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of durvalumab, and 
possible symptoms of overdose are not established. 

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.3.2. 
For other overdoses, reporting must occur within 30 days.
8.4.3.2
Gemcitabine and cisplatin
For patients receiving neoadjuvant gemcitabine and cisplatin, refer to the local prescribing 
information for treatment of cases of overdose. If any overdose is associated with an AE or SAE 
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 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
111 (233)
associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B.
8.4.5
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities:

Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).

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.

Patients should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression/recurrence, concomitant medications, or infections). This 
includes gemcitabine- or cisplatin-induced toxicity. In the event that toxicities are 
clearly attributed to chemotherapy, both chemotherapy and durvalumab should be 
delayed.

In the absence of a clear alternative etiology, all events should be potentially immune 
related and the TMGs should be followed (see Section 8.4.5.1).

In the event that the AE has clear immune-related etiology, G+C chemotherapy may 
still be administered as scheduled while durvalumab administration is delayed per 
TMGs (see Section 8.4.5.1).

In the event that G+C chemotherapy is discontinued due to treatment-related toxicity, 
patients should proceed to radical cystectomy when clinically feasible, and the 
remaining durvalumab monotherapy neoadjuvant doses should be skipped. Adjuvant 
therapy with durvalumab may continue following radical cystectomy. Note: If the 
Investigator feels that a patient would benefit from administering the remaining 
neoadjuvant durvalumab cycles without chemotherapy, AstraZeneca should be 
consulted for an exception to this rule.
All toxicities will be graded according to NCI CTCAE, version 5.0.
8.4.5.1
Specific toxicity management and dose modification information – durvalumab
Comprehensive TMGs have been developed to assist investigators with the recognition and 
management of toxicities associated with use of the immune-checkpoint inhibitors, durvalumab 
(MED4736; PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). Given the similar 
underlying mechanism of toxicities observed with these 2 compounds, these TMGs are 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
112 (233)
applicable to the management of patients receiving either drug as monotherapy or both drugs in 
combination. Additionally, these guidelines are applicable when either drug is used alone or both 
drugs are used in combination and is administered concurrently or sequentially with other 
anticancer drugs (ie, antineoplastic chemotherapy, targeted agents) are as part of a protocol-
specific treatment regimen. The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions that 
may be observed with checkpoint inhibitor monotherapy or combination checkpoint inhibitor 
regimens, with specific instructions for checkpoint inhibitor-specific dose modifications 
(including discontinuation) and treatment interventions. Investigators are advised, however, to 
use local practice guidelines and consult local references for the management of toxicities 
observed with other anticancer treatment (see Section 8.4.5.2).
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document entitled, “Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab Monotherapy),” 
and is maintained within the Site Master File. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related.
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines).
Following the first dose of the IP, subsequent administration of durvalumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines. These guidelines have been prepared by the Sponsor to assist the Investigator in the 
exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply 
to AEs considered causally related to durvalumab monotherapy 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 - gemcitabine 
and cisplatin
Chemotherapy- related toxicity management and dose adjustments, including dose delays and 
reductions, should be performed and follow standard clinical practice.
In the event that an AE can reasonably be attributed to chemotherapy, dose adjustment of 
chemotherapy should be attempted before modifying the administration of durvalumab.
In the event that chemotherapy is delayed, durvalumab should also be delayed. Every effort 
should be made to ensure patients receive at least 4 cycles of neoadjuvant therapy across all 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
113 (233)
treatment arms in the study, if conditions allow. In the event of unfavorable tolerability, patients 
who are unable to complete the study specified number of neoadjuvant treatment cycles patients 
may receive less than 4 cycles.
8.5
Pharmacokinetics
8.5.1
Collection of samples
Blood samples for the 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 ADAs
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, 
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/ADA 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 backup PK samples may be used for future exploratory biomarker research (in this 
case, residual backup PK samples will be shipped to AstraZeneca-designated Biobank; see 
details in the Laboratory Manual).
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
114 (233)
8.7
Genetics
8.7.1
Optional exploratory genetic sample
If the patient agrees to participate in the optional genetic research study, a blood sample will be 
collected. Participation is optional. Patients who do not wish to participate in the genetic research 
may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient. Signed informed consent will be required to obtain a replacement sample unless 
it was included in the original consent.
See Appendix D for information regarding genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in Appendix D or in the Laboratory 
Manual.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.
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, after which they will be destroyed. 
DNA is a finite resource that may be used up during analyses. The results of any further analyses 
will be reported either in the CSR itself or as an addendum or separately in a scientific report or 
publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
By participating in this study, the patient consents to the mandatory collection and use of donated 
biological samples as described here. Tissue samples will be obtained from all screened patients.
Mandatory tumor and blood biomarkers to be evaluated to support the exploratory objectives of 
the study are described in Section 8.8.2. Alternative biomarkers may be evaluated as determined 
by additional data associated with disease progression/recurrence or response to durvalumab.
Biomarker assessments that may have the potential to identify patients likely to respond to 
treatment with durvalumab (determined from other durvalumab studies) will be investigated to 
determine a patient’s biomarker status and for possible correlation with efficacy endpoints.
Pre-randomization tumor PD-L1 expression will be evaluated in all patients. Putative 
associations with clinical endpoints will be assessed. Baseline tumor requirements are briefly 
described in Section 8.8.1. Based on availability of tissue, additional exploratory biomarkers may 
also be evaluated as described in Section 8.8.2.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
115 (233)
Comparisons of PD-L1 expression in tumor will be made between arms to determine if PD-L1 
status is prognostic or predictive of outcomes associated with durvalumab + G+C combination 
therapy and/or G+C. The results may be pooled with biomarker data from other durvalumab 
studies to evaluate biological responses across indications and to compare results in monotherapy 
versus combination settings.
Samples will be taken at the times presented in the study plans in Table 1 and Table 2. For 
sample requirement, refer to the Laboratory Manual.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to immunotherapy as described in the exploratory 
analyses section.
8.8.1
Collection of tissue samples for central pathology review, stratification by PD-L1 
expression, and biomarker research
There are 2 mandatory requirements for the provision of tissue samples:

MANDATORY (screening stage): Provision of a FFPE tumor biopsy for the purpose 
of PD-L1 expression analyses and for enabling exploratory analyses as described in 
the proceeding section. A newly acquired tumor biopsy is strongly preferred; however, 
if not feasible with an acceptable clinical risk, an archival MIBC tumor sample taken 
≤3 months prior to screening can be submitted. A tumor tissue block is preferred. If a 
tissue block is unavailable, unstained sections from the tissue block may be submitted. 
This sample must be shipped to the central laboratory prior to dosing. The collection 
of tumor tissue is mandated when the patient has MIBC, which is defined as tumor 
invasion into the muscularis propria and must be submitted with the local pathology 
report confirming invasion into the muscular propria. Please refer to the Laboratory 
Manual for detailed instructions and guidelines regarding sections.

Samples should be collected during cystoscopy or transurethral resection of 
bladder tumor and placed in formalin and processed to a single 
paraffin-embedded block, as described in the Laboratory Manual. Whenever 
feasible, additional samples beyond those mandated for PD-L1 analyses should be 
obtained and processed as described in the Laboratory Manual. 

Newly acquired or archived specimens with limited tumor content and fine needle 
aspirates are inadequate for defining tumor PD-L1 status, hence, are not accepted.

MANDATORY (treatment stage): The collection of the radical cystectomy specimen 
at radical cystectomy to assess the pathological stage and to determine the rate of 
down-staging. Please refer to the Pathology Manual for detailed instructions and 
guidelines regarding this section.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
116 (233)

OPTIONAL: The collection of additional tumor biopsies upon progression or 
recurrence of patients in Arm 1 and Arm 2 is strongly encouraged. If the biopsy is 
performed, the tumor biopsy must be submitted to centrally confirm histopathological 
finding. Please see Covance laboratory manual for detailed instructions and guidelines.
Patients will be permitted, upon discussion with the study team, to be provided their PD-L1 
status if requested after an event that is considered an EFS event. 
Please refer to the Laboratory Manual for further details of requirements including sample 
quality control and shipping.
A brief description of exploratory tumor markers likely to be explored by IHC or RNA analysis 
is provided in Section 8.8.2. 
To meet the requirement for FDA approval of a companion diagnostic, sections of the tumor will 
be retained at Ventana or Ventana-approved laboratory for potential additional studies, as 
requested by the FDA, to support potential test approval.
8.8.2
Exploratory biomarkers
Blood, tumor, and urine samples for exploratory biomarker analyses will be obtained according 
to the schedules presented in the SoAs. Details for collection, volume, storage, and shipment of 
biologic samples are presented in a separate Laboratory Manual. 
Baseline 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 Arm 1 versus Arm 2, 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 the 
site, at a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The exploratory biomarker plan is described by sample type below.
Tumor markers (in FFPE tumor block)
Tissue obtained as part of screening procedures for establishing PD-L1 status at radical 
cystectomy and/or progression/recurrence may be analyzed for additional markers by IHC. 
Markers evaluated may change based on the best available information at the time of the 
biomarker analysis. Markers of special interest include, but are not limited to, Ox40, GITR, 
PD-L2, Tim-3, CD137, CD8, and Lag3-.
Tissues obtained may also be assessed for somatic mutations, microsatellite instability, TMB, 
neo-antigen prediction, T-cell receptor clonality and/or for an IFN-γ gene expression signature 
(eg, -IFN-γ, CXCL9, LAG3, and CD274) and other RNA biomarkers by targeted RNAseq and/or 
other gene expression methodologies. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
117 (233)
For genomic DNA that has been extracted, genotyping of immunomodulatory genes such as 
PD-1, PD-L1, CTLA-4, and human leukocyte antigen loci may be completed to determine 
whether natural variation within such genes is associated with the likelihood of clinical benefit 
and/or with the likelihood of drug-related AEs. Genes associated with solid tumor development, 
disease progression/recurrence, or likelihood of tumor response to chemotherapy may likewise 
be investigated. Genotyping will occur retrospectively, data will not be shared with patients, and 
results will not impact treatment decisions.
Whole blood gene expression (PaxGene-RNA)
Whole blood samples will be obtained from all patients at the timepoints described in Table 1, 
Table 2, and Table 3. RNA will be prepared for quantification of RNA and/or micro-RNA 
expression using reverse transcription-quantitative polymerase chain reaction, microarray, 
sequencing, or similar technology.
Focus is likely to be given to the expression of immunomodulatory genes. Correlations with 
outcome data will be completed on select candidates and predictive markers, with the aim of 
identifying useful expression thresholds for identifying patients likely to receive benefit.
Other biomarkers
Plasma, serum, and urine samples will be taken at the timepoints described in Table 1, Table 2, 
and Table 3 for additional exploratory plasma (ctDNA/circulating soluble factors), serum 
biomarkers, and urine biomarkers.
Urine-based markers
Urine must be obtained at the timepoints described in Table 1. These samples will be used to 
evaluate urine cytology, exploratory biomarkers, which may be predictive of pathological 
response prior to radical cystectomy, or other clinical endpoints. 
Serum-based markers
Serum will be obtained to explore the expression of cytokines and chemokines, including but not 
limited to IFN-γ, interleukin (IL)-18, CXCL9, and CXCL10. 
Similarly, the concentrations of a battery of IC ligands, receptors, or other soluble factors may be 
assessed. Proteins of special interest include CTLA-4, PD-1, B7-1, B7-2, and IL-6R.
Plasma-based markers (ctDNA, circulating soluble factors)
Plasma will be obtained from all patients as described in the SoAs. The concentrations of a panel 
of relevant cytokines, chemokines, and other immune-related markers may be assessed. Plasma 
may also be used to evaluate mutant circulating tumor DNA. Overall mutational burden and/or 
somatic mutations/genomic alterations in plasma may be assessed using next generation or 
similar technologies. Such measurements may be correlated with response.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
118 (233)
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study Investigator, general physician, or any other third party unless required 
to do so by law. The patient’s samples will not be used for any purpose other than those 
described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication nor 
report.
8.8.3
Storage, re-use, and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the CSR in a separate report. The results of 
this biomarker research may be pooled with biomarker data from other studies involving 
durvalumab to generate hypotheses to be tested in future research.
8.8.4
Labeling and shipment of biological samples
The Principal Investigator at each center will ensure that samples are labeled and shipped in 
accordance with the Laboratory Manual and the Biological Substance, Category B, Regulations 
(materials containing or suspected to contain infectious substances that do not meet Category A 
criteria); see Appendix C “IATA 6.2 Guidance Document.”
Any sample 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.
8.8.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle 
(Appendix C).
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 sample shipment.
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. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
119 (233)
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
8.8.6
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:

Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples

Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of, or destroyed and the action documented

Ensure that the organization(s) holding the samples is/are immediately informed about 
the withdrawn consent and that samples are disposed of or destroyed, the action is 
documented.

Ensure that the patient and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or destroyed and the action 
documented and the study site is informed.
8.8.7
German biomarker sub-study
In addition to planned biomarker analyses performed for the overall study patient population, a 
biomarker sub-study will be performed at select sites (approximately 15) in Germany to assess 
additional immune, mutational and/or molecular subtyping biomarkers from tumor samples 
collected at baseline and again at the time of cystectomy (Appendix L 1). Association and 
correlation with biomarker results and clinical responses (therapy response, outcomes) will be 
investigated. The sub-study is intended to collect samples from approximately 50 patients (if 
feasible), recruited from participating NIAGARA sites located in Germany only. Participation in 
this sub-study for these patients is optional and will require a separate consent process. 
Analysis of the exploratory biomarker data within this sub-study will be analyzed and reported 
independently from the NIAGARA study. Prioritization is given to the biomarker analyses 
required for the parent NIAGARA study. Additional sub-study analyses will only be performed 
if there is sufficient tissue available.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
120 (233)
9.
STATISTICAL CONSIDERATIONS
All statistical analyses will be performed by AstraZeneca or its representatives.
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 3 months 
of the first randomized patient and any subsequent amendments will be documented, with final 
amendments completed prior to reporting of data.
The dual primary objectives of this study are to assess the efficacy of Arm 1 versus Arm 2 
(neoadjuvant/adjuvant) in terms of EFS as assessed per BICR or by central pathology review if a 
biopsy is required for a suspected new lesion and pCR rate (neoadjuvant) as assessed per central 
pathology review in ITT. To achieve these objectives, the multiple testing procedure (MTP) for 
controlling the type I error rate will be utilized (see Section 9.4.1.1).
Depending on the extent of any impact, summaries of data related 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.
9.1
Sample size determination
This study will plan to enroll and screen approximately 1400 patients at approximately 150 sites 
in order to randomize approximately 1050 eligible patients in a 1:1 ratio to receive either 
durvalumab + G+C combination therapy (neoadjuvant)/durvalumab alone (adjuvant) in Arm 1 or 
G+C combination therapy (neoadjuvant)/no adjuvant treatment in Arm 2.
The study is sized to characterize the pCR rate and EFS benefit of Arm 1 versus Arm 2 in MIBC 
patients who have not received prior systemic chemotherapy.
Statistical assumptions are made using a pCR rate of 35% and 50% for patients enrolled on the 
control arm and experimental arms, respectively, (see below) for ITT. 
Non-uniform accrual of patients (with k=2) is assumed when estimating the analysis times. The 
total proportion of patients randomized at time t [t ≤22 months] following the start of the study is 
assumed to be (t/22)2. 
The final analysis of the primary pCR will be performed approximately 6 months after the last 
patient is randomized to the study.
The final analysis of the dual-primary endpoint of EFS will be performed when approximately 
451 EFS events in ITT have occurred across the 2 arms (43% maturity) or June 2025 
(approximately 45 months after the last patient is randomized), whichever occurs first.
Arm 1 versus Arm 2 (pCR in ITT)
It is assumed that the pCR for patients (ITT) in Arm 2 is 35% (Grossman et al 2003). Under the 
alternative hypothesis, pCR is assumed to be 50% for Arm 1. With 525 patients in each arm, the 
study will have at least 95% power to demonstrate a statistically significant difference at a 2-

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
121 (233)
sided alpha level of 0.1%. Assuming a pCR rate of 35% in Arm 2, the smallest pCR rate that 
could be observed as being statistically significant at the time of pCR analysis is a 10-percentage 
point increase to 45% in Arm 1.
Arm 1 versus Arm 2 (EFS in ITT)
The assumed EFS treatment effect under the alternative hypothesis is an average HR of 0.733 for 
Arm 1 versus Arm 2. This is based on the following assumptions:
An exponential model was assumed for EFS such that in patients who are assigned to the Arm 1, 
the overall median EFS is 38.0 months and the EFS rate at 24 months is 64.5%.
For Arm 2, an exponential model was assumed for EFS such that patients who are assigned to 
Arm 2, the overall median EFS is 27.8 months and the EFS rate at 24 months is 55%.
Based on a blinded event prediction an estimated 451 EFS events (43% maturity) are expected to 
be observed at 45 months after the date of the last patient randomized. With 451 EFS events, the
study will have at least 90% power to demonstrate a statistically significant difference at a 2-
sided overall alpha level of 4.90%, allowing two interim analyses to be conducted at 
approximately 67% and 91% of the target events. The smallest treatment difference that could be 
statistically significant will be an average HR of 0.82.
Arm 1 versus Arm 2 (OS in ITT)
The assumed OS treatment effect under the alternative hypothesis is an average HR of 0.76 for 
Arm 1 versus Arm 2. This is based on the following assumptions:

An exponential model was assumed for OS such that in all patients who are assigned 
to Arm 1, the overall median OS is 8.6 years (103 months), and the OS rate at 5 years 
is 66.7%.

For Arm 2, an exponential model was assumed for OS such that in all patients who are 
assigned to Arm 2, the overall median OS is 6.5 years (78 months) and the OS rate at 
5 years is 58.7%. 
The final analysis of OS based on approximately 428 OS events for the comparison of Arm 1 
versus Arm 2 (41% maturity, 428/1050), from ITT, is expected to occur approximately 5 years 
(60 months) after the last patient is randomized to the study and will provide at least 80% power 
to demonstrate a statistically significant difference in OS at a 2-sided alpha level of 4.9%, 
allowing two interim analysis to be conducted at approximately 67% and 74% of the target 
events. The smallest treatment difference that could be statistically significant will be an HR of 
0.82.
Arm 1 versus Arm 2 (OS5 in ITT)
The statistical model assumptions for OS5 in the ITT of each arm are stated above.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
122 (233)
The analysis of OS5 that is performed at the time of the final analysis of OS will provide at least 
77% power to demonstrate a statistically significant difference in OS5 at a 2-sided alpha level of 
4.9%. 
9.2
Populations for analyses
Definitions of the analysis sets for each outcome variable are provided in Table 15.
Table 15
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy data
pCR rate
Full analysis set (ITT population)
PD-L1-high analysis set
EFS
Full analysis set (ITT population)
PD-L1-high analysis set
Proportion of patients who achieve <P2, EFS24, MFS, DSS, OS, OS5, 
PFS2, proportion of patients who undergo radical cystectomy
Full analysis set (ITT population)
PROs
Full analysis set (ITT population)
DFS
Cystectomy population
Demography
Full analysis set (ITT population)
PK data
PK analysis set
Safety data
Exposure
Safety analysis set
AEs
Safety analysis set
ECOG performance status
Safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
AE Adverse event; DFS  Disease-free survival; DSS  Disease-specific survival; ECOG  Eastern Cooperative 
Oncology Group; EFS Event-free survival; EFS24 Proportion of patients alive and event free at 24 months; 
ITT Intent-to-treat; MFS  Metastasis-free survival; OS5 Proportion of patients alive at 5 years; 
pCR Pathologic complete response; PFS2 Time from the date of randomization to the earliest date of 
progression which occurs on subsequent therapy following an EFS event or death; PK Pharmacokinetic; 
PRO Patient-reported outcome.
9.2.1
Full analysis set (ITT population)
The FAS will include all randomized patients. Unless otherwise specified, 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.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
123 (233)
9.2.2
Cystectomy population
The Cystectomy population will include all patients in FAS who undergo radical cystectomy. 
Unless otherwise specified, the analysis set will be used for DFS only. Treatment arms will be 
compared on the basis of randomized study treatment, regardless of the treatment actually 
received.
9.2.3
PD-L1-high analysis set
The PD-L1-high analysis set will include the subset of patients in the FAS whose PD-L1 status is 
PD-L1-high as defined by Ventana SP263 assay in Table 6.
9.2.4
Safety analysis set
The SAS will consist of all patients who received at least 1 dose of study treatment. Safety data 
will not be formally analyzed but summarized according to the treatment received, that is, 
erroneously treated patients (eg, those randomized to treatment A but actually given treatment B) 
will be summarized according to the treatment they actually received.
9.2.5
PK analysis set
All patients who receive at least 1 dose of IP per the protocol for whom any post-dose data are 
available and who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses will be included in the PK analysis set. The population will be defined by 
the Study Physician, Pharmacokineticist, and Statistician prior to any analyses being performed.
9.3
Outcome measures for analyses
9.3.1
Calculation or derivation of efficacy variables
9.3.1.1
Dual Primary endpoint: pathologic complete response (pCR)
The dual primary endpoint of pCR is the pCR assessment in ITT per central pathology review.
pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as 
assessed using specimens obtained via radical cystectomy following the neoadjuvant treatment. 
pCR will be assessed per central pathology review and local pathology review. The 
denominators for pCR in the ITT will be MIBC patients in the ITT.
9.3.1.2
Dual Primary endpoint: event-free survival (EFS)
The dual primary endpoint of EFS is the EFS assessment in ITT per BICR or by central 
pathology review if a biopsy is required for a suspected new lesion.
EFS is defined as the time from randomization to the first recurrence of disease after radical
cystectomy, the time of first documented progression in patients who are medically precluded 
from a radical cystectomy, or time of expected surgery in patients who refuse to undergo a 
radical cystectomy or failure to undergo a radical cystectomy in participants with residual 
disease, or the time of death due to any cause, whichever occurs first. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
124 (233)

A recurrence of disease includes local (pelvic) recurrence of UC, urinary tract 
recurrence of UC, or distant metastasis of UC. In the event that progression is 
confirmed via biopsy or subsequent scans (the confirmation of suspected new lesions 
initially identified in the scans if applicable), the date of recurrence will be the earliest 
date among the initial detection of radiological unequivocal new lesion, or the 
pathological confirmation of new lesion if biopsy is performed to confirm suspected 
new lesion post cystectomy, or the death due to any causes.

Patients who are suspected of having microscopic disease (ie, no evidence on imaging) 
or who have documented macroscopic disease (confirmed by imaging) at the 
completion of neoadjuvant therapy and who refuse to proceed with a radical 
cystectomy, are declared as progressed, with EFS being declared at the time of 
expected surgery

For patients who fulfill criteria for a complete clinical response, refuse an initial 
radical cystectomy and are entered in a noncystectomy extension phase, EFS is 
defined as time to the first recurrence of disease following a delayed radical 
cystectomy (if performed). For patients who are medically precluded from or refuse a 
delayed radical cystectomy, EFS is confirmed at time of unequivocal progression.
EFS will be assessed using CT/MRI and pathology testing performed according to local 
standards and as clinically indicated. 
Patients who take subsequent therapy prior to their last evaluable RECIST assessment or 
progression or death will not be censored at their last evaluable RECIST assessment prior to 
taking the subsequent therapy. Patients who have not progressed or experienced recurrent disease 
or died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable disease assessment. If the patient has no evaluable visits or does not have 
baseline disease assessment (ie, a baseline scan) prior to neoadjuvant treatment, they will be 
censored at Day 1 unless they die within 112 days of randomization.
The EFS time will always be derived based on assessment dates and not visit dates.
9.3.1.3
Secondary endpoints
Proportion of patients alive and event free at 24 months after randomization
The EFS24 will be defined as the Kaplan-Meier estimate of EFS at 24 months after 
randomization, as assessed per BICR or by central pathology review if a biopsy is required for a 
suspected new lesion and per local Investigator or local biopsy review if a biopsy is required for 
a suspected new lesion.
Proportion of patients who achieve <P2
The proportion of patients who achieve <P2 is defined as the proportion of patients whose 
pathological staging at radical cystectomy was P0 (T0N0M0)/Pa/P1/Cis as assessed per local 
pathology review using specimens obtained via radical cystectomy following the neoadjuvant 
treatment.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
125 (233)
The denominator for this endpoint will be the number of patients in the ITT population (MIBC 
patients).
Overall Survival (OS)
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. In order to minimize confounding of OS, 
patients randomized to Arm 2 will not be allowed to cross over to Arm 1.
Note: Survival calls will be made following the date of data cutoff for the analysis (these 
contacts should generally occur within 7 days of the data cutoff date). If patients are confirmed 
to be alive or if the death date is after the data cutoff date, these patients will be censored at the 
date of data cutoff. Death dates may be found by checking publicly available death registries, 
where allowed by local regulations.
Proportion of patients alive at 5 years after randomization (OS5)
The OS5 will be defined as the Kaplan-Meier estimate of OS at 5 years after randomization.
Metastasis-free survival 
MFS is defined as the time from date of randomization until the first recognition of distant 
metastases or death, whichever occurs first. Patients who were alive and free from metastases 
were censored at the time of the latest date of assessment from their last evaluable disease 
assessment.
Disease-specific survival 
DSS is defined as the time from the date of randomization until death due to BC. Any patient not 
known to have died due to BC at the time of analysis will be censored based on the last recorded 
date on which the patient was known to be alive. 
Disease-free survival
DFS is defined as the time from the date of radical cystectomy to the first recurrence of disease 
post radical cystectomy, or death due to any cause, whichever occurs first. DFS will be assessed 
in patients who undergo radical cystectomy and are disease free at adjuvant baseline visit per 
BICR assessment.
Proportion of patients who undergo cystectomy
Proportion of patients who undergo cystectomy is defined as the proportion patients who 
undergo radical cystectomy after the neoadjuvant treatment. The denominator will be patients in 
the ITT population.
Time from randomization to subsequent progression or recurrence post-EFS event (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest date of 
progression which occurs on subsequent therapy following an EFS event or death. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
126 (233)
The date of subsequent progression will be recorded by the Investigator in the eCRF and defined 
according to local standard clinical practice and may involve any of the following: objective 
radiological imaging, symptomatic progression, or death. Patients who are alive and for whom a 
subsequent disease progression post-EFS event has not been observed should be censored at the 
last time known to be alive and without a subsequent disease progression.
9.3.2
Calculation or derivation of safety variables
9.3.2.1
Adverse events
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.
Any AE occurring before treatment with durvalumab will be included in the data listings but will 
not be included in the summary tables of AEs. Any AE occurring within 90 days of 
discontinuation of any IP may be included in the AE summaries, but the majority of those 
summaries will omit the AEs observed after a patient has received further therapy for cancer. 
Supporting AE summaries for any AE occurring within 90 days of completion of adjuvant visit 
and for any AE occurring from radical cystectomy to 90 days post-radical cystectomy, including 
Clavien-Dindo assessment, will also be provided to support the above AE summaries. Further 
details will be provided in the SAP. Any events in this period that occur after a patient has 
received further therapy for cancer (following discontinuation of durvalumab) 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 IP will be 
produced. These events will not be included in AE summaries.
9.3.2.2
Other significant adverse events
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 AEs leading to discontinuation. Based on the 
expert’s judgment, significant AEs of particular clinical importance may, after consultation with 
the Global Patient Safety Physician, be considered other significant adverse events (OAEs) and 
reported as such in the CSR. A similar review of laboratory/vital signs/ECG data and physical 
examinations 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.
9.3.2.3
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, 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:

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
127 (233)

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 formulas:

Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 
0.02)
The denominator used in laboratory summaries will only include evaluable patients, ie, those 
who had sufficient data to have the possibility of an abnormality.
For example:

If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline to be evaluable, the 
patient need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.3.3
Calculation or derivation of patient-reported outcome variables
All items/questionnaires will be scored according to published scoring guidelines listed in the 
SAP. All PRO analyses will be based on the FAS.
EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined into 5 functional scales 
(physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), and global health status/QoL scale. The EORTC QLQ-C30 will be scored 
according to the EORTC QLQ-C30 Scoring Manual (Fayers 2001). An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales, each of the 
functional scales, and the global measure of health status scale in the EORTC QLQ-C30 
according to the EORTC QLQ-C30 Scoring Manual. Higher scores on the global health status 
and functional scales indicate better health status/function, but higher scores on symptom scales 
represent greater symptom severity.
Definition of clinically meaningful changes - Visit Response and Best Overall Response
Definition of clinically meaningful changes in score compared with baseline will be evaluated. A 
clinically meaningful change is defined as an absolute change in the score from baseline of ≥10 
for scales from the EORTC QLQ-C30 (Osoba et al 1998). For example, a clinically meaningful 
improvement in physical functioning (as assessed by EORTC QLQ-C30) is defined as an 
increase in the score from baseline of ≥10, whereas a clinically meaningful deterioration is 
defined as a decrease in the score from baseline of ≥10. A clinically meaningful deterioration or 
worsening in pain (as assessed by EORTC QLQ-C30) may be defined as an increase in the score 
from baseline of ≥10. At each post-baseline assessment, the change in global health status/QoL, 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
128 (233)
symptoms, and functioning score from baseline will be categorized as improvement, no change, 
or deterioration as shown in Table 16.
Table 16
Mean change and clinically meaningful change - EORTC QLQ-C30
Score
Change from baseline
Visit response
EORTC QLQ-C30 global health 
status/quality of life scale score
≥10 point increase from baseline (ie, increase 
of at least 10)
Improvement
≥10 point decrease from baseline (ie, decrease 
of at least 10) 
Deterioration
Otherwise
No change
EORTC QLQ-C30 symptom 
scales
≥10 point increase from baseline (ie, increase 
of at least 10) 
Deterioration
≥10 point decrease from baseline (ie, decrease 
of at least 10)
Improvement
Otherwise
No change
EORTC QLQ-C30 functional 
scales
≥10 point increase from baseline (ie, increase 
of at least 10)
Improvement
≥10 point decrease from baseline (ie, decrease 
of at least 10) 
Deterioration
Otherwise
No change
A patient’s best overall response in symptoms, function, or global health status/QoL will be 
derived as the best response the patient achieved, based on evaluable PRO data collected during 
the study period. The criteria in Table 17 will be used to assign a best response in symptoms or 
function or global health status/QoL.
Table 17
Best response in EORTC QLQ-C30 scores: FAS population
Overall score response
Criteria
Improved
Patient meets 1 of the following criteria:
1.
Has 2 consecutive visit responses of “improvement” at least 
21 days apart
2.
Has 1 visit response of “improvement” and no further assessments
No Change
Patient does not qualify for an overall score response of “improved” and 
meets 1 of the following criteria:
1.
Has 2 consecutive visit responses of “no change” 
2.
Has 1 visit response of “no change” and no further assessments 
The 2 responses should be at least 21 days apart. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
129 (233)
Overall score response
Criteria
Deterioration
Patient does not qualify for an overall score response of “improved” or “no 
change” and meets 1 of the following criteria:
1.
Has 2 consecutive visit responses of “deterioration” at least 
21 days apart
2.
Has 1 visit response of “deterioration” and no further assessments 
3.
Has 1 visit response of “improvement”, “no change”, or 
“deterioration” followed by death within 2 PRO assessment visits
Other
Patient meets 1 of the following criteria:
1.
Does not qualify for one of the above.
2.
Has either no baseline or no post-baseline evaluable PRO 
assessments
Missing
Patient has no baseline and no post baseline evaluable PRO assessments
Time to definitive/sustained clinically meaningful deterioration in health-related QoL, 
functioning or symptoms 
Time to definitive or sustained clinically meaningful deterioration in global health status/QoL 
and functioning as measured by EORTC QLQ-C30 scales/items will be defined as the time from 
the date of randomization until the date of the first observation with ≥10-point decrease in score 
with no subsequent observations with <10-point decrease from baseline. Similarly, time to 
definitive clinically meaningful deterioration in symptoms as measured by EORTC QLQ-C30 
scales/items will be defined as the time from the date of randomization until the date of the first 
observation with ≥10-point increase in score with no subsequent observations with <10-point
increase from baseline. Sensitivity analysis will be performed by including death (by any cause) 
in the absence of a clinically meaningful deterioration, regardless of whether the patient 
discontinues study drug(s) or receives another anticancer therapy prior to global health 
status/QoL, function or symptom deterioration. Such deaths will be included as an event in the 
sensitivity analysis only if it occurs within 2 PRO assessment visits from the last available PRO 
assessment. Patients whose global health status/QoL, functioning, or symptoms (as measured by 
EORTC QLQ-C30) has not shown a clinically meaningful deterioration and who are alive at the 
time of the analysis will be censored at the time of their last PRO assessment where the global 
health status/QoL, function, or symptom could be evaluated.
The at-risk population for the analysis of time to global health status/QoL or functioning 
deterioration is defined as the subset of the FAS having baseline scores of ≥10. The at-risk 
population for the analysis of time to symptom deterioration is defined as the subset of the FAS 
having baseline scores ≤90.
Improvement rate – global health status/QoL, functioning, symptoms
Responses in symptoms for each visit (improvement, deterioration, and no change based on 
Table 16) as well as the best overall response will be calculated for each patient. The symptom 
improvement rate will be defined as the number (%) of patients with a best overall score 
response of “improved” in symptoms. The denominator will consist of a subset of the FAS who 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
130 (233)
have a baseline symptom score ≥10. Global health status/QoL or function improvement rate. The 
global health status/QoL or function improvement rate will be defined as the number (%) of 
patients with best overall response of “improved” in QoL or function. The denominator will 
consist of a subset of the FAS who have a baseline global health status/QoL or function score 
≤90.
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 
difficulty (no problems, slight problems, moderate problems, severe problems, and unable 
to/extreme problems). A unique EQ-5D-5L health state is referred to by a 5-digit code, allowing 
for a total of 3125 health states. For example, state 11111 indicates no problems on any of the 
5 dimensions. These data will be converted into a weighted health state index by applying scores 
from EQ-5D-5L 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 and 
described in detail in the SAP).
In addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health). This score is reported separately.
PGIC
The PGIC question is “Overall, how would you rate the change in your health status since 
starting this Study?” with response options for the PGIC as follows: Much Better (+3), 
Moderately Better (+2), A Little Better (+1), About the Same (0), A Little Worse (-1), 
Moderately Worse (-2), and Much Worse (-3). No scoring will be done using the assigned 
numerical values.
PGIS
PGIS assesses the overall severity of disease-related symptoms (eg, general cancer symptoms). 
The response options of the PGIS are as follows: No Symptoms = 0, Very Mild = 1, Mild = 2,
Moderate =3, Severe = 4, and Very Severe = 5. 
PRO-CTCAE
Refer to Appendix H for details on the PRO-CTCAE questions and responses.
PRO-CTCAE items are not combined into summary scores, and individual items will be 
descriptively summarized (eg, proportion of patients endorsing each response option). Further 
details will be provided in the SAP.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
131 (233)
9.3.4
Calculation or derivation of pharmacokinetic variables
9.3.4.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model may be developed using a non-linear mixed-effects modeling approach. 
If performed, the impact of physiologically relevant patient characteristics (covariates) and 
disease on PK will be evaluated. The relationship between the PK exposure and the effect on 
safety and efficacy endpoints may be evaluated. The results of such an analysis will be reported 
in a separate report. The PK, pharmacodynamics, demographic, safety, and efficacy data 
collected in this study may also be combined with similar data from other studies and explored 
using population PK and/or PK-pharmacodynamic methods.
9.3.4.2
Pharmacokinetic analysis
The non-compartmental analysis will not be conducted for this study due to sparse sampling. PK 
concentration data will be listed and summarized by visit using descriptive statistics.
9.3.4.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab. The immunogenicity 
titer and presence of neutralizing ADAs will be reported for samples confirmed positive for the 
presence of ADAs. The effect of immunogenicity as well as the effect of its neutralizing 
properties on PK, pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
9.3.5
Calculation or derivation of biomarker variables
Biomarker status, as defined in the secondary objectives, will be assessed for evaluable patients 
in each cohort according to prespecified criteria that will be detailed in the SAP.
9.3.6
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 (LIMS) database or other appropriate system. This 
database is a secure database, which is separate from the database used for the main study. Some 
or all of the dataset from the main study may be duplicated within the AstraZeneca LIMS 
database for exploratory genetic analysis. Data will be reported outside the CSR 
(see Appendix D).
9.4
Methods for statistical analyses
In ITT, the following formal statistical analysis of pCR and EFS (as dual primary endpoints) will 
be performed:

H0: No difference between Arm 1 and Arm 2 

H1: Difference between Arm 1 and Arm 2
The study has been sized to characterize the pCR rate and EFS benefit of Arm 1 versus Arm 2 in 
ITT.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
132 (233)
The final analysis of the primary pCR will be performed approximately 6 months after the last 
patient is randomized.
The final analysis of the primary EFS will be performed when 451 EFS events (43% maturity) in 
ITT are reached across both arms or in June 2025, whichever occurs first. This is expected 
approximately 45 months after the last patient is randomized.
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 except DFS (including pCR 
rate, EFS, EFS24, proportion of patients who achieve <P2, MFS, DSS, OS, OS5, PFS2, 
proportion of patients who undergo radical cystectomy, PRO, demography, and PK data), 
baseline is defined as the last visit prior to randomization. A second (“adjuvant”) baseline scan 
will be performed 42 days (±2 weeks) following the date of radical cystectomy and prior to the 
start of adjuvant therapy for radiological assessments. Efficacy assessments of pCR will be 
derived (by AstraZeneca) using central pathology review of the radical cystectomy sample.
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 analyses will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
Table 18 details which endpoints are to be subjected to formal statistical analysis, together with 
pre-planned sensitivity analyses, making it clear which analysis is regarded as primary for that 
endpoint. Note, all endpoints compare Arm 1 versus Arm 2 in all randomized patients (ITT 
population), unless otherwise indicated.
Table 18
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
pCR rate
Stratified logistic regression for:
Primary analysis using central pathology review: 

Arm 1 versus Arm 2 (ITT population)
Secondary analysis using Investigator assessment:

Arm 1 versus Arm 2 (ITT population)

Arm 1 versus Arm 2 (PD-L1-high population)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
133 (233)
Table 18
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
EFS
Stratified log-rank test for:
Primary analysis using BICR or by central pathology review if a biopsy is 
required for a suspected new lesion: 

Arm 1 versus Arm 2 (ITT population) 
Sensitivity analysis for the primary analysis using BICR or by central 
pathology review if a biopsy is required for a suspected new lesion: 

Using a Kaplan-Meier plot of time to censoring where the 
censoring indicator of the primary analysis is reversed - attrition 
bias (ITT)

Interval censored analysis - evaluation-time bias (, ITT)

Analysis where subjects who take subsequent anti-cancer therapy 
prior to the EFS event will be censored at their last evaluable 
assessment prior to taking the subsequent therapy – attrition bias 
(ITT)

Analysis using the 2 missed visit censoring rule - attrition bias 
(ITT)
Secondary analysis per local Investigator or local biopsy review if a 
biopsy is required for a suspected new lesion: 

Arm 1 versus Arm 2 (ITT population)

Arm 1 versus Arm 2 (PD-L1-high population).
EFS24
Hazard ratio using the Kaplan-Meier estimates of EFS24:

Arm 1 versus Arm 2 (ITT population)
Proportion of patients 
who achieve <P2
Stratified logistic regression using central pathology review:

Arm 1 versus Arm 2 (ITT population)
OS
A stratified log-rank test:

Arm 1 versus Arm 2 (ITT population)
OS5
Hazard ratio using the Kaplan-Meier estimates of OS5:

Arm 1 versus Arm 2 (ITT population)
Proportion of patients 
who undergo radical
cystectomy
Point estimate and 95% CI

Arm 1 versus Arm 2 (ITT population)
DFS
A stratified log-rank test based on BICR data:

Arm 1 versus Arm 2 (Cystectomy population)
MFS
A stratified log-rank test based on Investigator data:

Arm 1 versus Arm 2 (ITT population)
DSS
A stratified log-rank test based on Investigator data:

Arm 1 versus Arm 2 (ITT population)
EORTC QLQ-C30
Average change from baseline using a MMRM analysis

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
134 (233)
Table 18
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Time to 
definitive/sustained 
clinically meaningful 
deterioration (EORTC 
QLQ-C30)
Stratified log-rank test
BICR  Blinded Independent Central Review; CI  Confidence interval; DFS  Disease-free survival; 
DSS Disease-specific survival; EFS  Event-free survival; EFS24 Proportion of patients alive and event free at 
24 months; EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer Core Quality of 
Life Questionnaire; ITT  Intent-to-treat; MFS  Metastasis-free survival; MMRM  Mixed-model for repeated-
measures; OS5  Proportion of patients alive at 5 years; pCR  Pathologic complete response.
9.4.1.1
Multiple testing strategy
In order to strongly control the type I error at the 5% 2-sided alpha level, an MTP with 
gatekeeping strategy will be used across the dual primary endpoints (pCR rate and EFS). If the 
higher level hypothesis in the MTP is rejected for superiority, the following hypothesis will then 
be tested as shown in Figure 3.
Hypotheses will be tested using a multiple testing procedure with an alpha-exhaustive recycling 
strategy (Burman et al 2009). With this approach, hypothesis will be tested in a pre-defined order 
by first splitting the 5% alpha into 0.1% and 4.9% for pCR and EFS for Arm 1 versus Arm 2, 
respectively, in the ITT population as outlined in Figure 3.
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. Since the  
EFS in the ITT is tested at multiple timepoints (ie, 2 interims and final analysis), the EFS tests 
for the same comparison/population (ie, shown in first box in the MTP) will be considered as 1 
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 can be recycled to the next MTP level. This testing procedure 
stops when the entire test mass is allocated to non-rejected hypotheses. Implementation of this 
predefined ordered testing procedure, including recycling, will strongly control type I error at the 
5% (2-sided) alpha level among all key hypotheses. Figure 3 shows the multiple testing 
framework for the dual primary endpoints and key secondary endpoint. The details of the 
complete MTP and the alpha-exhaustive recycling procedure will be provided in the SAP.
The alpha level allocated to pCR and EFS (dual primary endpoints)  will be controlled at the 
superiority interim and final timepoints by using the Lan DeMets (Lan and DeMets 1983) 
spending function that approximates an O’Brien Fleming approach, where the alpha level 
applied at the interim depends on the proportion of information available.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
135 (233)
Figure 3
Multiple testing procedure for controlling the type I error rate
Durva  Durvalumab; EFS  Event-free survival; G+C Gemcitabine+cisplatin; ITT  Intention to treat; OS5 Proportion 
of patients alive at 5 years; pCR Pathologic complete response; vs  versus.
9.4.1.2
Pathologic complete response (pCR)
The primary analysis of pCR will be based on assessment per central pathology review. The pCR 
will be compared between Arm 1 and Arm 2 in ITT using logistic regression models adjusted for 
the stratification factors: clinical tumor stage T2N0 versus >T2N0 (including T2N1, T3 and T4a) 
to reflect prognostic stage II versus IIIa, respectively; renal function (adequate renal function 
versus borderline renal status); and PD-L1 status (high versus low/negative). The results of the 
analysis will be presented in terms of an odds ratio together with its corresponding 99.9% CI and 
p-value. 
Pathological response data will be listed and summarized over time for patients with adequate 
renal function. 
A secondary analysis, using pCR rate per local Investigator assessment, will be performed using 
the same methodology as for the analysis described above.
9.4.1.3
Event-free survival (EFS)
The primary EFS analysis will be based on assessments per the BICR or by central pathology 
review if a biopsy is required for a suspected new lesion. The analysis will be performed in ITT 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
136 (233)
using a stratified log-rank test adjusted for the stratification factors: clinical tumor stage T2N0 
versus >T2N0 (including T2N1, T3 and T4a) to reflect prognostic stage II versus IIIa, 
respectively; renal function (adequate renal function versus borderline renal status); and PD-L1 
status (high versus low/negative). The effect of treatment will be estimated by the HR together 
with its corresponding ([1-adjusted alpha] × 100%) CI and p-values. 
The HR and CI will be estimated from the stratified Cox proportional hazards model (Cox 1972).
All of the secondary analyses will be performed using the same methodology as for the primary 
analyses described above.
Kaplan-Meier plots of EFS will be presented by treatment arm. Summaries of the number and 
percentage of patients experiencing an EFS event and the type of event (progression, recurrence, 
or death) will be provided along with median EFS for each treatment.
Subgroup analyses will be conducted comparing EFS (per disease assessment using BICR 
assessments) between Arm 1 versus Arm 2 in the following subgroups of patients in ITT (but not 
limited to):  

Sex (male versus female)

Age at randomization (<65 versus ≥65 years of age)

Pathologic lymph node metastasis found at radical cystectomy (N0 versus N+)

All visible tumor removed during the TUBRT procedure prior to study entry (Yes 
versus No)
PD-L1 status (high versus low/negative), 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 EFS.
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate. A model will be constructed, containing treatment and the stratification factors, to 
ensure that any output from the Cox modelling is likely to be consistent with the results of the 
stratified log-rank test.
Additionally, for each subgroup, the HR (Arm 1: Arm 2) 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. 
The secondary analysis of EFS will be performed using the same methodology as for the primary 
analysis described above.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
137 (233)
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 EFS will not be formally analyzed. In this case, only 
descriptive summaries will be provided.
9.4.2
Analysis of secondary endpoints
9.4.2.1
Proportion of patients alive and event free at 24 months after last randomization 
(EFS24)
EFS24 will be summarized (using the Kaplan-Meier curve) and presented by treatment arm and 
will be compared between treatments by using the KM estimator of EFS at 24 months for each 
treatment to obtain the HR. Note: 24 months equates to study day 731.
9.4.2.2
Proportion of patients who achieve <P2
The primary analysis for proportion of patients who achieve <P2 will be based on assessment per 
local pathology review. The proportion of patients who achieve <P2 will be compared between 
Arm 1 and Arm 2 using logistic regression models adjusted for the stratification factors. The 
results of the analysis will be presented in terms of an odds ratio together with its corresponding 
95% CI and p-value.
9.4.2.3
Overall Survival (OS)
OS will be analyzed using stratified log-rank tests, using the same methodology as described for 
the primary EFS endpoint (see Section 9.4.1.3).
9.4.2.4
Proportion of patients alive at 5 years after randomization (OS5)
OS5 will be summarized using the same methodology as EFS24 (see Section 9.4.2.1).
9.4.2.5
Metastasis-free survival (MFS)
MFS will be analyzed using stratified log-rank tests, using the same methodology as described 
for the primary EFS endpoint (see Section 9.4.1.3). The effect of treatment will be estimated by 
the HR together with its corresponding 95% CI for the ITT population.
9.4.2.6
Disease-specific survival (DSS)
DSS will be analyzed using the same methodology as described for MFS (see Section 9.4.2.5
9.4.2.5).
9.4.2.7
Disease-free survival (DFS)
DFS will be analyzed using the same methodology as described for MFS (see Section 9.4.2.5
9.4.2.5).
9.4.2.8
Proportion of patients who undergo radical cystectomy
The proportion of patients who undergo radical cystectomy will be presented together with its 
corresponding 95% CI.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
138 (233)
9.4.2.9
Patient-reported outcomes
EORTC QLQ-C30
The main PRO measures identified in the secondary objectives are global health status/QoL, 
physical functioning, fatigue, and pain subscales of the EORTC QLQ-C30. However, separate 
analysis will be conducted for global health status/QoL, functions (physical, role, cognitive, 
social, and emotional), fatigue, and pain. PROs are not part of the main MTP and will be 
analyzed as supportive endpoints.
Summaries for compliance (the number of evaluable forms divided by the number of expected 
forms) for each treatment arm will be produced.
The primary assessment of global health status/QoL, functioning, and symptoms will be focused 
on the adjusted mean change from baseline using a mixed-model for repeated-measures 
(MMRM) analysis of all the post-baseline scores for each visit. The model will include 
treatment, visit, treatment by visit interaction, and stratification variables as explanatory 
variables, and the baseline score as a covariate. Adjusted mean change from baseline estimates 
per treatment arm and corresponding 95% CIs will be presented along with an overall estimate of 
the treatment difference, 95% CI, and p-value.
Supportive analysis of global health status/QoL, functioning, and symptoms will be time to 
definitive or sustained clinically meaningful deterioration analyzed using a stratified log-rank 
test as described for the primary EFS endpoint. Separate analysis will be conducted for global 
health status/QoL, functions, fatigue, and pain. The effect between Arm 1 and Arm 2 will be 
estimated by the HR together with its corresponding CI and p-value. Kaplan-Meier plots will be 
presented by treatment arm. Summaries of the number and percentage of patients who have an 
event as well as who were censored will be provided along with the medians for each treatment.
Summary tables of visit responses for each EORTC QLQ-C30-scale/item score (global health 
status/QoL, 5 functions and all symptoms) and for each visit (improvement, deterioration, and no 
change) will be presented by treatment arm. In addition, summary tables of the best overall 
response will be provided for the following domains by treatment arm: global health status/QoL, 
functions (physical, role, cognitive, emotional and social), fatigue and pain. Occurrence of 
symptom and QoL/function improvement based on the best overall response will be compared 
between treatment arms using a logistic regression model. The odds ratio, p-value, and 95% CI 
will be presented graphically on a forest plot.
Summaries of absolute and unadjusted change from baseline values of each EORTC QLQ-C30 
scale/item will be reported by visit for each treatment arm. Graphical presentations may also be 
produced as appropriate.
Alternative thresholds for meaningful change in the EORTC QLQ-C30 scales will be derived 
from anchor-based methods using the PGIS and/or PGIC. The analyses will be supplemented 
with empirical cumulative distribution function and probability density function curves as 
necessary. Details will be described further in the SAP.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
139 (233)
EQ-5D-5L
Descriptive statistics, graphs, and listings will be reported for health state utility index values 
(United Kingdom base case) and visual analogue scale by visits as well as the change in these 
scores from baseline. 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/recurrence.
PGIC
PGIC data will be presented using summaries and descriptive statistics based on the FAS. The 
proportion of patients in each response category at each visit will be presented by treatment arm. 
Further details will be provided in the SAP.
PGIS
PGIS data will be presented using summaries and descriptive statistics based on the FAS. The 
proportion of patients in each response category at each visit will be presented by treatment arm. 
Also, the change from baseline in the severity of general cancer symptoms will be presented as 
the proportion of patients with no change (eg, mild to mild), 1 category improvement (eg, mild to 
none), ≥2 category improvement (eg, severe to mild), 1 category deterioration (eg, none to mild), 
and ≥2 category deterioration (eg, mild to severe) at each visit by treatment arm. The data may 
be analyzed based on the following re-grouped categories: None (no symptoms), Mild (very mild 
and mild), Moderate, and Severe (very severe and severe). Further details will be provided in the 
SAP.
PRO-CTCAE
The PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS. Further details will be provided in the SAP.
PRO compliance
Summary measures of visit and overall compliance rates will be derived for each PRO 
questionnaire (EORTC QLQ-C30, PGIC, PGIS, EQ-5D-5L, and PRO-CTCAE, respectively). 
These will be based upon the following criteria:

Expected: Number of patients still under PRO follow-up expected to complete a 
questionnaire at a scheduled assessment time. For patients whose disease has 
progressed/recurred, the latest of progression/recurrence and safety follow-up will be 
used to assess whether the patient 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 patients/forms.

Received: Number of patients from whom a completed questionnaire with at least 
1 item completed was received plus those recorded as “subject too heavily affected by 
symptoms of disease under investigation” is answered as a reason for not completing 
the questionnaire.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
140 (233)

Evaluable: Number of patients for whom at least 1 subscale (eg, single-item subscale) 
can be determined or “subject too heavily affected by symptoms of disease under 
investigation” is answered as a reason for not completing the form.
Compliance rate (visit): Compliance will be calculated separately for each visit, including 
baseline, for each treatment arm as (Evaluable ÷ Expected) × 100.
Evaluable rate: Evaluability rate will be calculated separately for each visit, including baseline, 
for each treatment arm as (Evaluable ÷ Received) × 100.
Overall compliance rate: Patients are counted as Received/Evaluable if they have a 
Received/Evaluable baseline and at least 1 Received/Evaluable post-baseline questionnaire. 
Rates are expressed in percentages.
Missing values
Missing data will be handled based on the EORTC QLQ-C30 scoring manual.
9.4.3
Safety analyses
Safety and tolerability data will be presented by treatment arm using the SAS.
Data from all cycles of treatment will be combined in the presentation of safety data. AEs (both 
in terms of 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-years at risk may be 
produced. 
Other safety data will be assessed in terms of physical examination, laboratory assessments, vital 
signs, and ECGs. Exposure to durvalumab and G+C will be summarized. Time on study and 
durvalumab and G+C dosing delays will also be summarized. At the end of the study, 
appropriate summaries of all safety data will be produced, as defined in the SAP.
9.4.4
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary will be 
provided for all evaluable patients using the PK analysis set.
9.4.5
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 ADAs against durvalumab. The 
immunogenicity titer and neutralizing ADA data will be listed for samples confirmed positive for 
the presence of anti-durvalumab antibodies.
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow. A detailed plan will 
be written by the AstraZeneca Clinical Pharmacology group or designee.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
141 (233)
9.4.6
Pharmacokinetic/pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters may 
be investigated graphically or using an appropriate data modeling approach.
9.4.7
Biomarker data
The relationship of PD-L1 expression and, if applicable, of exploratory biomarkers to clinical 
outcomes (including but not restricted to) of pCR, EFS, EFS24, proportion of patients who 
achieve <P2, OS, OS5, MFS, DSS, and proportion of patients who undergo radical cystectomy 
may 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
Interim analyses
EFS
EFS will be tested at two interim time points and a final time point.
For the dual-primary EFS endpoint in MIBC patients (Arm 1 versus Arm 2), two superiority 
interim analyses for EFS will be conducted: the first when the pCR analysis is conducted and the
second based on a data cut-off when approximately 410 EFS events have occurred (39% 
maturity, 410/1050) across the 2 arms in ITT, or in April 2024 whichever occurs first 
(approximately 31 months after the last patient is randomized). The final analysis will be 
conducted when approximately 451 EFS events have occurred (43% maturity, 451/1050) across 
Arm 1 and Arm 2 or in June 2025 (approximately 45 months after the last patient is randomized), 
whichever occurs first.
The alpha level allocated to the EFS will be controlled at the interim and final time points using 
the Lan DeMets spending function that approximates an O’Brien Fleming approach, where the 
alpha level applied at the interim depends on the proportion of information available. The first 
interim analysis has been performed with 301 events and the 2-sided alpha of 0.69% (calculated 
assuming 509 total events as stated in the previous protocol) has been spent. Applying this alpha 
spent at the first interim analysis and considering the revised total of 451 events, if exactly 91% 
of the target 451 events are available at the time of the second interim analysis, with overall 2-
sided alpha level of 4.9%, the 2-sided alpha to be applied at the second interim analysis, and final 
analysis would be, 3.5%, and 3.9%, respectively. However, the derivation of actual rejection 
boundary for any interim analysis will use the observed number of events at the interim analysis 
and the number of events planned for the final analysis. For the planned final analysis, the 
rejection boundaries will be derived based on the observed number of events and previous 
rejection boundaries using the generalized Haybittle-Peto method (SAS manual), exhausting any 
remaining alpha for the analysis.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
142 (233)
OS
OS will be tested at 2 interim time points and a final time point in accordance with the 
hierarchical multiple testing strategy. 
The first interim analysis of OS will be conducted at the time when the second interim EFS 
analysis is conducted (but will only be tested if EFS is positive via the MTP). A second interim 
analysis will be conducted at the time when the final EFS analysis is conducted.  At the time of 
the first interim analysis, approximately 288 OS events are estimated to occur (27% maturity, 
288/1050) across Arm 1 and Arm 2. At the time of the second interim analysis, approximate 318 
OS events are estimated to occur (30% maturity, 318/1050) across Arm 1 and Arm 2. The final 
analysis will be conducted when approximately 428 OS events have occurred (41% maturity, 
428/1050) across Arm 1 and Arm 2, which is expected to be approximately 60 months after the 
last participant is randomized. 
The alpha level allocated to the OS will be interim and final time points using the Lan DeMets 
spending function that approximates an O’Brien Fleming approach, where the alpha level 
applied at the interim depends on the proportion of information available. If exactly 67% 
(288/428) and 74% (318/428) of the target events are available at the time of the first interim 
analysis and the second interim analysis, with overall 2-sided alpha level of 4.9%, the smallest 
treatment difference that could be statistically significant will be an average HR of 0.82, and the 
2-sided alpha to be applied at the first, the second interim analysis, and final analysis would be 
1.2%, 1.5%, 4.3 %, respectively.  
The derivation of actual rejection boundary for any interim analysis will use the observed 
number of events at the interim analysis and the number of events planned for the final analysis. 
For the planned final analysis, the rejection boundaries will be derived based on the observed 
number of events and previous rejection boundaries using the generalized Haybittle-Peto method 
(SAS manual), exhausting any remaining alpha for the analysis. The interim analyses will be 
assessed by an IDMC. Details of the plan and communication process will be provided in the 
SAP and in the IDMC charter.
9.6
Independent data monitoring committee
A data monitoring committee will be utilized for this study.
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 comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 90 patients have been randomized, 
whichever occurs first, to review safety assessments and make recommendations to continue, 
amend, or stop the study based on safety findings. The IDMC will separately assess the safety of 
durvalumab + gemcitabine/cisplatin in Japanese patients for the initial data review meetings and 
make recommendation if additional separate safety reviews are required. The committee will 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
143 (233)
meet approximately every 6 months thereafter. For the interim analysis, the IDMC will review 
interim data and inform the Sponsor whether the interim boundaries specified in Section 9.4.3
are crossed. Full details of the IDMC procedures, processes, and interim analyses can be found in 
the IDMC Charter.
Interim safety monitoring will be conducted by an IDMC. Details of the plan and communication 
process will be provided in an IDMC Charter.
The recommendations from the IDMC will not reveal the results of the analyses but will take the 
form of “Continue/Modify/Recommend early submission/Stop.”

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
144 (233)
10.
REFERENCES
Aaronson et al 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. JNCI 1993;85(5):365-76.
Abdelhafez and Williams 2017
Abdelhafez M, Williams M. Safety and efficacy of gemcitabine-cisplatin split dose as a 
neoadjuvant chemotherapy for muscle invasive bladder cancer. J Urol 2017;197(4S):e1194.
AJCC Cancer Staging Manual, 8th Edition
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al, editors. AJCC 
Cancer Staging Manual, Eighth Edition. American Joint Committee on Cancer (AJCC); 2017. 
Available upon request. 
Alexandrov et al 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature 2013;500:415-21.
Babjuk et al 2014
Babjuk M, Böhle A, Burger M, Compérat E, Kaasinen E, Palou J, et al. Guidelines on non 
muscle-invasive bladder cancer (Ta, T1, and CIS). EAU Guidelines Office, Arnhem, The 
Netherlands. European Association of Urology; 2014.
Bajorin et al 2021
Bajorin DF, Witjes JA, Gschwend JE, Schenker BP, Valderrama BP, Tomita Y, et al. Adjuvant 
Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 
2021;384(22):2102-2114.
Balar et al 2017
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as 
first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial 
carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389(10064):67-76.
Basch et al 2009
Basch E, Jia X, Heller G, Barz A, Sit L, Fruscione M, et al. Adverse symptom event reporting by 
patients vs clinicians: relationship with clinical outcomes. Journal of National Cancer Institute 
2009;101:1624-1632.
BAVENCIO [package insert] 2017
BAVENCIO [package insert]. New York, USA. 2017.
Bellmunt et al 2007
Bellmunt J, Paz-Ares L, Cuello M, Cecere FL, Albiol S, Guillem V, et al. Gene expression of 
ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-
based chemotherapy. Ann Oncol 2007;18(3):522-8.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
145 (233)
Bellmunt et al 2017
Bellmunt J, Powles T, Vogelzang N. A review on the evolution of PD-1/PD-L1 immunotherapy 
for bladder cancer: The future is now. Cancer Treat Rev 2017;54:58-67.
Bellmunt et al 2021
Bellmunt J, Hussain M, Gschwend J, Albers P, Oudard S, Castellano D, et al. Adjuvant 
atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a 
multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021;22(4):525-37
Birgitte et al 2008
Birgitte A, Sengelov L, Von der Maase H, et al. Gemcitabine and cisplatin in locally advanced 
and metastatic bladder cancer; 3 or 4 week schedule? Acta Oncologica 2008;47:110-9.
Boccardo and Palmeri 2006
Boccardo F, Palmeri L. Adjuvant chemotherapy of bladder cancer. Ann Oncol 
2006;17(Supplement 5):v129-32.
Brahmer et al 2012
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65.
Burger et al 2013
Burger M, Catto JWF, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology 
and Risk Factors of Urothelial Bladder Cancer. European Urology 2013;63(2):234-241.
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of Bonferroni 
based multiple tests. Stat Med 2009;28:739-61.
Cancer Genome Atlas Research Network 2014
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of 
urothelial bladder carcinoma. Nature 2014;507(7492):315-22.
Cathomas et al 2022
Cathomas R, Rothschild S, Hayoz S, Spahn M, Özdemir B, Kiss B, et al. Perioperative 
chemoimmunotherapy with durvalumab for operable muscle-invasive urothelial carcinoma 
(MIUC): Primary analysis of the single arm phase II trial SAKK 06/17. J Clin Oncol, 2022 
ASCO Annual Meeting Abstracts;40(16s): (suppl; abstr 4515).
Chang et al 2017
Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP, et al. Treatment of non-
metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. American 
Urological Association 2017;1-42.
Cox 1972
Cox DR. Regression models and life tables. J Royal Stst Society 1972;Series B 34(2):187-220.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
146 (233)
Criteria Committee NYHA 1964
Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood vessels. 
Nomenclature and criteria for diagnosis, 6th ed. Boston (MA), Little, Brown and Co.; 1964. 
(Available upon request).
Dash et al 2006
Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, et al. Impact of renal 
impairment on eligibility for adjuvant cisplatin based chemotherapy in patients with urothelial 
carcinoma of the bladder. Cancer 2006;107(3):506-13.
Dash et al 2008
Dash A, Pettus JA, Herr HW, Bochner BH, Dalbagni G, Donat SM, et al. A role for neoadjuvant 
gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective 
experience. Cancer 2008;113(9):2471-77.
Desai et al 2016
Desai NB, Scott SN, Zabor EC, Cha EK, Hreiki J, Sfakianos JP, et al. Genomic characterization 
of response to chemoradiation in urothelial bladder cancer. Cancer 2016;122(23):3715-23.
Dindo et al 2004
Dindo D, Demartines N, Clavien P. Classification of surgical complications: a new proposal with 
evaluation in a cohort of 6336 patients results of a survey. Ann Surg 2004;240(2):205-213.
Dunn et al 2004
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60.
European Medicines Agency 2013
Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man; 
Methodological consideration for using progression-free survival (PFS) or disease-free survival 
(DFS) in confirmatory trials. 2012. Available at URL: https://www.ema.europa.eu/en/appendix-
1-guideline-evaluation-anticancer-medicinal-products-man-methodological-consideration-using-
progression-free-survival-pfs-or-disease-free-survival-dfs-confirmatory-trials-scientific-
guideline.
EuroQol Group 1990
EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 
16(3):199-208.
Fairman et al 2014
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of 
durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid 
tumours. J Clin Oncol, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; abstr 2602). 
Fayers 2001
Fayers PM. Interpreting quality of life data: population-based reference data for the EORTC 
QLQ-C30. Eur J Cancer 2001;37(11):1331-4.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
147 (233)
Ferlay et al 2015
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and 
mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 
2015;136:E359-86.
Flaig et al 2018
Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK et al. Bladder 
Cancer, Version 5.2018: Featured update to the NCCN guidelines. J Nat Comp Cancer Network 
2018; 16(9): 1041-1053
Fleischer et al 2011
Fleischer F, Gaschler-Markefski B, Bluhmki E. How is retrospective independent review 
influenced by investigator-introduced informative censoring: a quantitative approach. Stat Med 
2011;30(29):3373-86.
Galsky et al 2015
Galsky MD, Pal SK, Chowdhury S, Harshman LC, Crabb SJ, Wong Y-N, et al. Comparative 
effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus 
cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer 2015;121(15):2586-
93. 
Gill et al 2017
Gill DM, Sonpavde G, Pal SK, Agarwal N. Which checkpoint inhibitor? An embarrassment of 
riches for bladder cancer. Immunotherapy. 2017;9(6):463-466.
Grossman et al 2003
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. 
Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally 
advanced bladder cancer. N Engl J Med 2003;349:859-66.
Herdman et al 2011
Herdman M, Gudex C, Lloyd A et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res: 1–10; 2011 Dec;20(10):1727-36.
Hirano et al 2005
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
2005;65(3):1089-96.
Horn et al 2018
Horn L, Mansfield AS, Szcaesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line 
atezolimab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 
2018;379(23):2220-2229.
Howie et al 2018
Howie LJ, Singh H, King-Kallimanis B, Roydhouse J, Theoret MR, Blumenthal GM, et al. 
Patient-reported outcomes in PD-1/PD-L1 inhibitor registration trials: FDA analysis of data 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
148 (233)
submitted and future directions. J Clin Oncol, 2018 ASCO-SITC Clinical Immuno-Oncology 
Symposium, 36 (suppl 5S; abstr 134).
Hussain et al 2012
Hussain SA, Palmer DH, Lloyd B, Collins SI, Barton D, Ansari J, et al. A study of split-dose 
cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer. Oncology Letters 
2012;3:855-59.
IMFINZI [package insert] 2017
IMFINZI [package insert]. Cambridge, England: AstraZeneca; 2017.
Inman et al 2007
Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, et al. PD-L1 (B7-H1) expression 
by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with 
localized stage progression. Cancer 2007;109(8):1499-5.
International Collaboration of Trialists 2011
International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer 
Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies 
Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract
Cancer Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada 
Clinical Trials Group, Finnbladder, Norwegian Bladder Cancer Study Group, et al. International 
phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for 
muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011; 
29(16):2171-7.
Iwai et al 2002
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99:12293-7.
Iyer et al 2016
Iyer G, Price J, Bourgeois S, Armstrong E, Huang S, Harari PM. Insulin growth factor 1 like 
receptor (IGF-1R). BMC Cancer 2016;16(1):773.
Jan et al 2016
Jan A, Dolan D, Lombardi K and Gupta S. Tolerability of Gemcitabine Plus Cisplatin for 
Treatment of Urothelial Cancer in the Elderly Population. Clin Genitourin Cancer 
2016;14.3:257-263.
Keir et al 2008
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704.
KEYTRUDA [package insert] 2018
KEYTRUDA [package insert]. New Jersey, USA. 2018.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
149 (233)
Kim et al 2015
Kim PH, Cha EK, Sfakianos JP, Iyer G, Zabor EC, Scott SN, et al. Genomic predictors of 
survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol 
2015;67(2):198-201.
Kim et al 2017
Kim HS, Jeong CW, Kwak C, Kim HH, Ku JH. Adjuvant chemotherapy for muscle-invasive 
bladder cancer: a systematic review and network meta-analysis of randomized clinical trials. 
Oncotarget 2017;8(46):81204-14. Available at URL: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655275/.
Klein et al 2007
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. 
Stat Med 2007;26(24):4505-19.
Kodumudi et al 2010
Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel 
chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor 
cells in tumor bearers. Clin Cancer Res 2010;16(18):4583-94.
Kroemer et al 2013
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu 
Rev Immunol 2013;31:51-72.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63.
Langer et al 2016
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. 
Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-
small-cell lung cancer: a randomized, phase 2 cohort of the open-label KEYNOTE-021 study. 
Lancet Oncol 2016;17(11):1497-1508.
Leow et al 2014
Leow JJ, Martin-Doyle W, Rajagopal PS, Patel CG, Anderson EM, Rothman AT, et al. Adjuvant 
chemotherapy for muscle-invasive bladder cancer: a 2013 updated systematic review and meta-
analysis of randomized trials. Eur Urol 2014;66(1):42-54.
Lerner et al 2016
Lerner SP, Bajorin DF, Dinney CP, Efstathiou JA, Groshen S, Hahn NM, et al. Summary and 
Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on 
Novel Therapeutics for Non-Muscle Invasive Bladder Cancer. Bl Cancer 2016;2(2):165-202.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
150 (233)
Litwin et al 1998
Litwin MS, Lubeck DP, Henning JM, et al. Differences in urologist and patient assessments of 
health related quality of life in men with prostate cancer: Results of the CaPSURE database. 
J Urol 1998;159:1988-92.
Liu et al 2010
Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the 
antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J 
Cancer 2010;102(1):115-23.
Massard et al 2016
Massard C, Gordon M, Sharma S, Rafii S, Wainberg Z, Luke J, et al. Safety and efficacy of 
durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, 
in patients with advanced urothelial bladder cancer. J Clin Oncol 2016;34(26):3119-25.
Mellman et al 2011
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 
2011;480(7378):480-9.
Mullane et al 2016
Mullane SA, Werner L, Guancial EA, Lis RT, Stack EC, Loda M, et al. Expression levels of 
DNA damage repair proteins are associated with overall survival in platinum-treated advanced 
urothelial carcinoma. Clin Genitourin Cancer 2016;14(4):352-9.
Narwal et al 2013
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. Clin 
Pharmacokinet 2013;52:1017–27.
National Comprehensive Cancer Network 2019
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Bladder 
Cancer. 2019. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed 06 March 2019.
Necchi et al 2018
Necchi A, Briganti A, Bianchi M, Raggi D, Giannatempo P, Luciano R, et al. Preoperative 
pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder 
carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. 
J Clin Oncol 2018;36(15_suppl):4507.
Ng et al 2006
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res 2006;23(6):1275–84.
Okazaki and Honjo 2007
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 
2007;19(7):813-24.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
151 (233)
Okudaira et al 2009
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-H1 
or B7-DC induces an antitumor effect in a mouse pancreatic cancer model. Int J Oncol 
2009;35(4):741-9.
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.
Pardoll 2012
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12:252-64.
Powles et al 2014
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558-62.
Powles et al 2017
Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy 
and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results 
from a phase 1/2 open-label study. JAMA Oncol 3(9): doi: 10.1001/jamaoncol.2017.2411. Epub 
2017 Sep 14.
Powles et al 2018
Powles T, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Pous AF, et al. A 
phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle 
invasive bladder cancer (ABACUS). J Clin Oncol 36(15_suppl):4506.
Qin et al 2016
Qin A, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current status 
of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 2016; 9:2169–70.
Rizvi et al 2015
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall 
cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.
Rizvi et al 2016
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab 
in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of 
Advanced Non-Small-Cell Lung Cancer. JCO 2016;34:2969-79.
Rosenberg et al 2016
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. 
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have 
progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, 
phase 2 trial. Lancet 2016;387(10031):1909-20.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
152 (233)
Rubin et al 2014
Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical 
practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 
2014;58(3):e44-100.
SAS manual
https://documentation.sas.com/doc/en/pgmsascdc/9.4_3.4/statug/statug_seqdesign_details31.htm.
Segal et al 2015
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of 
the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011.
Sonpavde et al 2009
Sonpavde G, Goldman BH, Speights, VO, Lerner SP, Wood DP, Vogelzang NJ, et al. Quality of 
pathologic response and surgery correlate with survival for completely resected bladder cancer 
following neoadjuvant chemotherapy. Cancer 2009;115(18):4104-09.
Sprangers et al 1992
Sprangers MA, Aaronson NK. The role of health care providers and significant others in 
evaluating the quality of life of patients with chronic disease: A review. J Clin Epidemiol. 
1992;45:743-760.
Stewart et al 2015
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification and 
characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3(9):1052-62.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein’s Method with the conventional approach for 
interval-censored data analysis. Stat Biopharm Res 2010;2(1):97-108.
TECENTRIQ [package insert] 2018
TECENTRIQ [package insert]. California, USA. 2018.
Teo et al 2017
Teo MY, Bambury RM, Zabor EC, Jordan E, Al-Ahmadie H, Boyd ME, et al. DNA damage 
response and repair gene alterations are associated with improved survival in patients with 
platinum-treated advanced urothelial carcinoma. Clin Cancer Res 2017;23(14):3610-8.
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-
54.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
153 (233)
Torre et al 2015
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. 
CA Cancer J Clin 2015;65:87-108.
U.S. Department of Health and Human Services et al 2018
U.S. Department of Health and Human Services Food and Drug Administration Oncology 
Center of Excellence Center for Drug Evaluation and Research (CDER) Center for Biologics 
Evaluation and Research (CBER), Clinical trial endpoints for the approval of cancer drugs and 
biologics: Guidance for industry. 2018. Available at URL: https:// www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-
biologics. 2018
VENTANA PD-L1 (SP263) Assay Package Insert
VENTANA PD-L1 (SP263) Assay. Ventana Medical Systems, Inc. Tucson, Arizona, USA. 
2017. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160046c.pdf.
Von der Maase et al 2000
Von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine 
and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or 
metastatic bladder cancer: results of a large, randomized, multinational, multicenter, Phase III 
study. J Clin Oncol 2000;18:3068–77.
Wang et al 2009
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012–24.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized 
clinical trials. Stat Med 1991;10(11):1665-77.
Witjes et al 2016
Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, et al. EAU Guidelines on 
muscle-invasive and metastatic bladder cancer. European Association of Urology (EAU) 
Guidelines. 2016.
Zhang et al 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Antitumor immunotherapy by blockade of the 
PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9.
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
154 (233)
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
155 (233)
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
156 (233)
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilizing medical devices investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to the sponsor of any (potential) serious breach 
of the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a subject or the reliability and robustness of the data generated in the clinical 
trial.

If any (potential) serious breach occurs in the course of the study, investigators or 
other site personnel will inform the appropriate AstraZeneca representatives 
immediately after he or she becomes aware of it.

In certain regions/countries, the sponsor has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about such breaches.

The sponsor will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. If EU Clinical Trials 
Regulation 536/2014 applies, the sponsor is required to enter details of serious 
breaches into the European Medicines Agency (EMA) Clinical Trial Information 
System (CTIS). It is important to note that redacted versions of serious breach reports 
will be available to the public via CTIS.

The investigator should have a process in place to ensure that:

the site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach

a (potential) serious breach is promptly reported to the sponsor or delegated party, 
through the contacts (e-mail address or telephone number) provided by the sponsor
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
157 (233)
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of the 
study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded 
from other aspects of the study.
If a patient’s partner becomes pregnant during or within 90 days after the last dose of 
durvalumab, the partner is asked to sign the “Adult Study Informed Consent Form for Pregnant 
Partners of Study Patients” and provide information about the pregnancy accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. The patient will give a separate agreement to allow any remaining specimens to be used 
for exploratory research. Patients who decline to participate in this optional research will indicate 
this in the ICF. If a patient withdraws consent to the use of donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples already have been 
analyzed at the time of the request, AstraZeneca will not be obliged to destroy the results of this 
research
A 4
Data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, their 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
158 (233)
general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s identity 
and might also have access to his or her genetic data. Also, regulatory authorities may require 
access to the relevant files. Even so, the patient’s medical information and the genetic files 
would remain physically separate.
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data sets 
transferred to the Sponsor will contain only the identifier; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of clinical study data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS within 
a year from global End of Trial Date in all participating countries, due to scientific reasons as 
otherwise statistical analysis is not relevant.
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on other 
websites according to the regulations of the countries in which the main study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
159 (233)
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for a minimum of 25 years after study archiving or as required by 
local regulations, according to the AstraZeneca Global retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written approval 
of AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study are defined as source documents. Source data are contained in source documents 
(original records or certified copies).
A 9
Study and site closure
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at undue 
risk because of clinically significant findings that: 

meet individual stopping criteria or are otherwise considered significant  

are assessed as causally related to study drug,  

are not considered to be consistent with continuation of the study 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
160 (233)
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/ 
IEC or local health authorities, the Sponsor’s procedures, or the GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
A 10
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
161 (233)
Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event (AE) is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a 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 unfavourable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
162 (233)
B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
B 6
CTCAE grade
The grading scales found in the revised National Cancer Institute CTCAE Version 5.0 will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the criteria recommended in the CTCAE manual that converts severity levels 
into CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version of CTCAE 
should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
163 (233)

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant or 
has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

occurred

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
164 (233)

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error (eg, medication prepared incorrectly, even if it was not actually given 
to the participant)

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as a 
solid tablet) 

Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature) 

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of
the above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
165 (233)
Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring 
of study sites, auditing or process checks, and contractual requirements of external laboratory 
providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end of 
a specified period as described in the informed consent.
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
166 (233)
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient

temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.ht
m)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
167 (233)

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
168 (233)
Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject’s DNA, ie, the entire 
genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on durvalumab continues but no longer than 
15 years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and if 
a subject declines to participate there will be no penalty or loss of benefit. The subject will not be 
excluded from any aspect of the main study.
Inclusion criteria

For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed 
consent for the genetic sampling and analyses.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
169 (233)
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Appendix C 2 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients pre-dose at the first 
dosing visit. Although DNA is stable, early sample collection is preferred to avoid introducing 
bias through excluding patients who may withdraw due to an AE, such patients would be 
important to include in any genetic analysis. If for any reason the sample is not drawn at the first 
dosing visit, it may be taken at any visit until the last study visit. Only one sample should be 
collected per patient for genetics during the study. Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality. Samples will be stored for a maximum of 15 years, from the 
date of last subject last visit, after which they will be destroyed. DNA is a finite resource that is 
used up during analyses. Samples will be stored and used until no further analyses are possible or 
the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample and 
corresponding data at the AstraZeneca genetics laboratories, or at the designated organisation. 
No personal details identifying the individual will be available to any person (AstraZeneca 
employee or designated organisations working with the DNA).
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, and 
permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
170 (233)
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate in 
the genetic component of the study the subject must sign and date both the consent form for the
main study and the genetic component of the study. Copies of both signed and dated consent 
forms must be given to the subject and the original filed at the study centre. The Principal 
Investigator(s) is responsible for ensuring that consent is given freely and that the subject 
understands that they may freely withdrawal from the genetic aspect of the study at any time.
Patient data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a subject’s identity 
and also have access to his or her genetic data. In addition, Regulatory authorities may require 
access to the relevant files, though the subject’s medical information and the genetic files would 
remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease. The researchers can only 
use this information for health related research purposes. Researchers may see summary results 
but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data in a 
suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
171 (233)
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. Specific guidance on managing liver abnormalities can be found in 
Section 8.2.1 of the Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP). 
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3 × ULN

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
172 (233)

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
For studies using central laboratories:
When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (and also to the AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
For studies using local laboratories:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
173 (233)

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting Study 
treatment (See Section 8.4 Safety Reporting)

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to this 
contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available in 
the Hy’s law lab kit should be used.

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP. The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
174 (233)

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
E 6
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment
This section is applicable to patients who meet PHL criteria on Study treatment having 
previously met PHL criteria at a study visit prior to starting Study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the subjects’ condition# compared with the 
last visit where PHL criteria were met.#

If there is no significant change, no action is required

If there is a significant change, notify the AstraZeneca representative, who will inform 
the central Study Team, then follow the subsequent process described in 
Appendix B 5.

A ‘significant’ change in the subject’s condition refers to a clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. 
The determination of whether there has been a significant change will be at the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
175 (233)
discretion of the Investigator, this may be in consultation with the Study Physician if 
there is any uncertainty.
E 7
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment, and has already 
met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the subject meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix E 6?
If No: Follow the process described in Appendix E 4.
If Yes: Determine if there has been a significant# change in the subject’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E 4.
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
176 (233)
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009). Investigator assessments will use the 
RECIST 1.1 guidelines described in this Appendix.  
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of target lesions 
(TLs), non-target lesions (NTLs), and new lesions (NLs) is provided in Table 19.
Table 19
Summary of methods of assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET/CT
CT  Computed tomography; FDG-PET/CT  18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI Magnetic resonance imaging. 
CT and MRI 
Computed tomography (CT) with intravenous (IV) contrast is the preferred imaging modality 
(although magnetic resonance imaging [MRI] with IV contrast is acceptable if CT is 
contraindicated) to generate reproducible anatomical images for tumor assessments (ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs). It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, imaging 
sequences, etc), imaging facility, tumor assessor (eg, radiologist), and method of tumor 
assessment (eg, RECIST 1.1) are used consistently for each patient throughout the study. The use 
of the same scanner for serial scans is recommended, if possible. It is important to follow the 
image collection/tumor assessment schedule as closely as possible (refer to the schedules of 
activities [SoAs]), and this on-study imaging schedule MUST be followed regardless of any 
delays in dosing or missed imaging visits. If an unscheduled assessment is performed (eg, to 
investigate clinical signs/symptoms of progression) and the patient has not progressed, every 
attempt should be made to perform the subsequent scan acquisitions at the next scheduled 
imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body scans 
should be performed with breath-hold scanning techniques, if possible. Therefore, CT of the 
chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
177 (233)
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. The modality used at follow-up should be the same as was used at baseline, 
and the lesions should be measured/assessed on the same pulse sequence. In general, local 
oncology diagnostic imaging parameters are applied for scan acquisition. It is beyond the scope 
of this appendix to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest-abdomen 
(-pelvis). Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients. Because a lesion later identified in a body part not 
scanned at baseline would be considered as an NL representing disease progression, careful 
consideration should be given to the extent of imaging coverage at baseline and at subsequent 
follow-up timepoints. This will enable better consistency not only of tumor measurements but 
also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) at 
baseline and follow-up visits vary according to the study, and these timepoints are specified in 
the SoAs. Examples include the following:

IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis)

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire 
liver and both adrenal glands) (-pelvis)

IV contrast-enhanced CT or MRI of the head and neck

IV contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when patients have sensitivity to IV 
contrast or have compromised renal function:
1.
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred)
2.
Chest CT without IV contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT 
IV contrast (iodine based) is medically contraindicated at any time during the study
3.
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the patient has compromised renal function

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
178 (233)
4.
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study
Specifically for this study in UC, staging and surveillance of malignancy in the upper urinary 
tract (renal pelvis, ureters) by CT urography may be applied according to local practice. Various 
techniques and scanning protocols for CT urography have been described (Potenta et al 2015; 
Zhang et al 2007).
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) with ≤5 mm slice thickness for optimal lesion 
measurements. Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses >5 mm. If this occurs, the minimum size of measurable lesions at baseline 
should be twice the slice thickness of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TLs. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of NLs. However, there is preference that a 
higher resolution modality such as CT be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the presence 
of new bone lesions. 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray 
at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).  
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone 
lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a bone scan 
that were not present on a previous bone scan; however, a newly observed equivocal hot-spot on 
a bone scan that cannot be verified with correlative imaging (CT, MRI, or X-ray) of the same 
anatomical region shall not be the only trigger for a progressive disease (PD) assessment at that 
timepoint.  

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
179 (233)
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) 
scans may be used as a method for identifying new extrahepatic lesions (but not intrahepatic 
lesions) for RECIST 1.1 assessments according to the following algorithm: NLs will be recorded 
where there is positive 18F-fluoro-deoxyglucose uptake1 not present on baseline or prior 
FDG-PET scan or in a location corresponding to an NL on a companion CT/MRI collected close 
in time to the FDG-PET scan. The PET portion of the PET/CT introduces additional data that 
may bias an Investigator if it is not routinely or serially performed. Therefore, if there is no 
baseline or prior FDG-PET scan available for comparison and no evidence of NLs on companion 
CT/MRI scans, then follow-up CT/MRI assessments should continue as per the regular imaging 
schedule to verify the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan are 
of limited use in anatomically based efficacy assessments, and it is therefore suggested that they 
should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV contrast) 
to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used for 
RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET portion 
of the CT introduces additional (PET) data that may bias an Investigator if it is not routinely or 
serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may not 
provide an accurate assessment of true tumor size. Tumors identified by ultrasound will need to 
be assessed by correlative CT or MRI anatomical scan.
Other Tumor Assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need to be 
assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1. 
                                               
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the surrounding tissue or liver is observed.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
180 (233)
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be used 
as part of the tumor response assessment as per RECIST 1.1.  
Furthermore, an overall assessment of complete response (CR; all other disease 
disappears/reverts to normal) would be changed to partial response (PR) if an effusion remains 
present radiologically.
Measurability of tumor lesions at baseline
RECIST 1.1 measurable lesions at baseline:
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please see 
additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatic lymph nodes.
Non-measurable lesions at baseline:

Truly non-measurable lesions include the following: 

Bone lesions (see exception below for soft tissue component)

Leptomeningeal disease

Ascites, pleural, or pericardial effusion

Inflammatory breast disease

Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline3).

Previously irradiated lesions4

Brain metastasis
Special considerations regarding lesion measurability at baseline:

Bone lesions
                                               
2 The short axis is defined as the longest in-plane axis perpendicular to long axis
3 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
4 Localized post-radiation changes that affect lesion sizes may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
181 (233)

Bone scan, PET scan or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used 
to confirm the presence or disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component 
meets the definition of measurability. 

Blastic bone lesions are considered non-measurable.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but 
if non-cystic lesions are present in the same patient, these should be selected over 
cystic lesions as TLs.
RECIST 1.1 TL selection at baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
identified as TL at baseline. TLs should be selected on the basis of their size (longest diameter 
for non-nodal lesions or short axis diameter for nodal lesions), but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), a 
segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TLs will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis diameter. 

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that 
coalesce should similarly be assessed by the longest axis diameter.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
182 (233)

Tumor lesions selected for fresh screening biopsy should not be selected as TLs, 
unless imaging occurred at least approximately 2 weeks after biopsy, allowing time for 
healing.

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
RECIST 1.1 NTL selection at baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions not recorded 
as TLs should be identified as NTLs at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumor response and progression 
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter for 
non-nodal lesions or short axis diameter for lymph node lesions. All measurements should be 
recorded in millimeters. The sum of the diameters for all TLs at each follow-up visit will be 
compared to the baseline sum of diameters (for response or stable disease [SD]) or to the 
smallest prior (nadir) sum of diameters (for progression). 
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into two or more parts, the sum of the diameters of those parts should be 
recorded. 

If two or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s). If the 
merged TLs are non-nodal lesions, record the long axis diameter of the merged lesion. 
If pathologic lymph nodes coalesce and are no longer individually separable within a 
conglomerate mass, the vector of the longest diameter of the coalesced mass should be 
used to determine the perpendicular vector for the maximal short axis diameter. 

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
183 (233)

If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion. The choice of “too large to measure” in the CRF will trigger an 
overall visit response of PD.

When a TL has had any intervention, the following apply:
o
Target Lesion Intervention may include radiotherapy, embolization, excisional 
biopsy, surgery, etc. that is not a part of study treatment and might adversely affect 
the size of that Target lesion
o
If an Intervention on a Target Lesion is ticked in the case report form, the diameter 
of the lesion is still recorded (0mm if no longer present) and is included in the sum 
of diameters. 
o
If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that Target lesion. 
o
If a Target Lesion has an Intervention, the only Overall Visit Responses allowed to 
be recorded by the Investigator are NE or PD, with PD if the sum of diameters 
exceeds a 20% increase and at least a 5mm absolute increase in the visit sum of 
diameters compared to the previous minimum (nadir) sum of diameters. 
o
No visit with a recorded Target Lesion Intervention can be used as the minimum 
(nadir) sum of diameters. 
Table 20
RECIST 1.1 evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters.
Stable disease (SD)
Neither sufficient decrease in sum of diameters to qualify for PR 
nor sufficient increase to qualify for PD.
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – This 
includes the baseline sum if that is the smallest on study. In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm from nadir.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (eg, missing anatomy) or had a lesion intervention at 
this visit. Note: If the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a TL 
response.
Not applicable (NA)
Only relevant if no TLs present at baseline.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
184 (233)
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded by 
the Investigator. 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. A 
modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be extremely 
rare.
Table 21
RECIST 1.1 evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline. All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non-CR/non-PD
Persistence of one or more NTLs.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
Not applicable (NA)
Only relevant if no NTLs present at baseline
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion.
RECIST 1.1 NL identification at follow-up
Details including the imaging modality, the date of scan, and the location of any NLs will be 
recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The finding of 
an NL should be unequivocal, ie, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor. If an NL is 
radiologically equivocal, for example, because of its small size, the treatment and tumor 
assessments should continue, and the lesion should be assessed at a subsequent scan no earlier 
than 6 weeks later to determine if it becomes unequivocal. If measurable, in order for a 
previously equivocal new lesion to become unequivocal at a subsequent scan, the long axis 
diameter of the previously new equivocal non-nodal lesion or the short axis diameter of the 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
185 (233)
previously new equivocal nodal lesion should show an increase of at least 5 mm. If a previously 
equivocal NL is assessed as unequivocal at a follow-up visit, then the progression date should be 
declared using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered an NL and will indicate disease progression.
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs is identical between RECIST 1.1 and RECIST 1.1 using the algorithm shown in Table 22.
Table 22
RECIST 1.1 overall visit response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/non-PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
NA
NA
No
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, 
NED No evidence of disease (only relevant if there were neither target lesions nor non-target lesions at baseline); 
NA Not applicable (only relevant if there were no target and/or non-target lesions at baseline), 
RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1.
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if 
ascites remains present radiologically.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:

For subjects with TLs (at baseline): CR, PR, SD, PD, or not evaluable (NE)

For subjects with NTLs only (at baseline): CR, non-CR/non-PD, PD, or NE

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
186 (233)

For subjects with no disease at baseline: no evidence of disease (NED; available as an 
option in the eCRF), PD, or NE
Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed iCRO for quality control, storage, and for Blinded Independent Central 
Review (BICR). Digital copies of all original scans should be stored at the Investigator site as 
source documents. Electronic image transfer from the sites to the iCRO is strongly encouraged. 
A BICR of images will be performed at the discretion of AstraZeneca. Results of these 
independent reviews will not be communicated to Investigators, and results of Investigator tumor 
assessments will not be shared with the central reviewers. The management of patients will be 
based solely upon the results of the tumor assessments conducted by the Investigator. Further 
details of the BICR will be documented in the Independent Review Charter, (also referred to as 
‘Imaging Charter’).
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.
Potenta et al 2015
Potenta SE, D’Agostino R, Sternberg KM, Tatsumi K, Perusse K. CT urography for evaluation 
of the ureter. RadioGraphics 2015;35:709-26.
Zhang et al 2007
Zhang J, Gerst S, Lefkowitz RA, Bach A. Imaging of bladder cancer. Radiol Clin N Am 
2007;45:183-205.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
187 (233)
Appendix G
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
188 (233)
Appendix H
Patient-reported outcomes

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
189 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
190 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
191 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
192 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
193 (233)
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)
Overall, how would you rate the change in your health status since starting this Study?
Please tick () one box only:

Much Better

Moderately Better

A Little Better

About the Same

A Little Worse

Moderately Worse

Much Worse

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
194 (233)
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS)
Please choose the response below that best describes the severity of your overall cancer symptoms over the past 7 days.

No Symptoms

Very Mild

Mild

Moderate

Severe

Very Severe

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
195 (233)
PRO-CTCAE

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
196 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
197 (233)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
198 (233)
Appendix I
Abbreviations 
Abbreviation or 
special term
Explanation
1L
first line
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BC
bladder cancer
BCG
Bacillus Calmette Guerin
BICR
Blinded Independent Central Review
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
CIS
carcinoma in situ
CMV
cisplatin, methotrexate, and vinblastine
CR
complete response
CrCl
creatinine clearance
CRF
case report form (electronic/paper)
CRO
Contract Research Organization
CSA
clinical study agreement
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4 
DCO
data cutoff
DDR
DNA damage response and repair
DFS
disease-free survival
DoR
duration of response
DSS
disease-specific survival
ECG
electrocardiogram

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
199 (233)
Abbreviation or 
special term
Explanation
ECOG
Eastern Cooperative Oncology Group
EFS
event-free survival
EFS24
proportion of patients alive and event free at 24 months
EGFR
epidermal growth factor receptor 
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer 30-item Core 
Quality of Life Questionnaire
ePRO
electronic patient reported outcome
EQ-5D-5L
FA
EuroQol 5-dimension, 5-level health state utility index
final analysis
FAS
full analysis set
FDA
Food and Drug Administration
FDG-PET
18F-fluoro-deoxyglucose positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
G+C
gemcitabine and cisplatin
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
hepatitis B virus surface antigen 
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life
IB
Investigator Brochure
IC
immune cell
ICF
informed consent form
ICH
iCRO
International Conference on Harmonisation
imaging Contract Research Organization
IDMC
independent data monitoring committee
IEC
Independent Ethics Committee
IFN-γ
interferon-gamma
Ig
immunoglobulin

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
200 (233)
Abbreviation or 
special term
Explanation
IHC
immunohistochemistry
IL
interleukin
ILD
interstitial lung disease
imAE
immune-mediated adverse event
IMP
investigational medicinal product
IP
investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous(ly)
IVRS
interactive voice response system
IWRS
interactive web response system
LIMS
Laboratory Information Management System
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MFS
metastasis-free survival
MIBC
muscle-invasive bladder cancer
MMRM
mixed-model for repeated-measures
MOA
mechanism of action
MRI
magnetic resonance imaging
MTP
multiple testing procedure
MVAC
methotrexate, vinblastine, adriamycin, and cisplatin
NCI
National Cancer Institute
NL
new lesion
NMIBC
non-muscle-invasive bladder cancer
NSCLC
non-small-cell lung cancer
NTL
non-target lesion
OAE
other significant adverse event
ORR
objective response rate
OS
overall survival
OS5
proportion of patients alive at 5 years
pCR
pathologic complete response
PD
progressive disease

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
201 (233)
Abbreviation or 
special term
Explanation
PD-1
programmed cell death-1
PD-L1
programmed cell death-ligand 1
PFS
progression-free survival
PFS2
Time from the date of randomization to the earliest date of 
progression which occurs on subsequent therapy following an EFS 
event or death
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PS
performance status
q3w
every 3 weeks
q4w
every 4 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
REVPRDI
Review of PRO/Questionnaire/Diary
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
safety analysis set
SD
stable disease
SoA
schedule of activities
SoC
Standard of care
TC
tumor cell
TCC
transitional cell carcinoma
TKI
tyrosine kinase inhibitors
TL
target lesion
TMB
tumor mutational burden
TMG
toxicity management guidelines
UC
urothelial carcinoma

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
202 (233)
Abbreviation or 
special term
Explanation
ULN
upper limit of normal
US
United States
WBDC
web based data capture
WHO
World Health Organization

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
203 (233)
Appendix J
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 5 (22-Jun-2023)
Overall Rationale for the Amendment: 
Following a review of the literature, there is a growing body of evidence that there is a slow 
down of progression events after 2 years in MIBC treated with chemotherapy and/or 
checkpoint-inhibitors, with the majority of events occurring within 12 months after radical 
surgery (Bajorin et al 2021Bajorin et al 2021Bajorin et al 2021, Bellmunt et al 2021, Cathomas 
et al 2022). As such, to ensure study completion, the statistical assumptions in terms of number 
of events and timing of these events have been updated. Hence, the protocol has been amended 
to reduce the total number of expected events at final analysis (FA) from 509 to 451 across the 
two arms with a corresponding reduction in the power from 93% to 90%. Calendar based data 
cut-offs for the second interim and final EFS analyses, which are set up based on the latest 
blinded event predictions, have also been introduced in case of further slowing down of the 
events. An interim analysis (IA) of OS has also been added at EFS IA2 (but will only be 
formally tested if EFS is statistically significant via the MTP).
This and other changes incorporated in this amendment are described in the following table. 
Administrative and formatting changes were made throughout the protocol.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
204 (233)
Section # and name
Description of change
Brief rationale
Substantial/ 
non-
substantial
Title Page – EU CTR 
Number
Added EU CTR Number
EU CTR applicable for studies 
transitioning to EU CTR.
Non-
substantial
Section 1.2 Synopsis, 
Study period
Updated text of the estimated 
date of last patient completed 
from Q4 2025 to Q2 2026
To update estimated dates based 
on the actual date of the last 
patient enrolled 
Non-
substantial
Section 1.2 Synopsis, 
Statistical methods, 
Section 9.1 Sample Size 
Determination, Section 
9.4 Methods for 
Statistical Analyses, 
Section 9.5 Interim 
Analyses
Changed number of events for 
final EFS analysis and also 
added calendar-based 
assessment timepoints for EFS 
IA2 and FA. In accordance 
with these changes, the study 
power and critical value were 
also updated, as were the 
information fraction values at 
the interim analyses
To account for the slowing 
down of EFS events after 2 
years
Substantial
Section 1.2 Objectives 
and Endpoints, Section 
8.9, Section 9.3.4, 
Table 1, Table 2, Table 
3, Table 4, Table 5
Removal of calculation of 
healthcare resource use 
(HOSPAD)
Collection of HOSPAD data 
was de-prioritized by 
AstraZeneca as assessment of 
health economics and hospital 
burden is no longer required for 
the submission
Non-
substantial
Section 1.2 Synopsis, 
Section 9.1 Sample size 
determination
The calculation method of the 
timing of targeted events has 
been changed. 
A blinded event prediction has 
been used to provide a more 
accurate prediction
Non-
substantial
Section 4.4
End of Study definition 
updated
EU CTR requirement.  To 
distinguish between US and EU 
end of the study definitions
Non-
substantial
8.1.1.6
Central Imaging 
Review 
Clarification regarding scans 
taken for routine clinical 
management after RECIST 1.1 
progression
Clarification concerning any 
post progression scans 
submitted to vendor which may, 
in some instances, be centrally 
reviewed
Non-
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
205 (233)
8.2.8 Other safety 
assessments
Removal of Tumor markers for 
Pneumonitis investigation
No specific tumor markers 
associated with metastatic 
bladder cancer presenting in the 
lung that would be relevant for 
ILD investigation have been 
identified
Non-
substantial
Section 9.3.1.2 (Dual 
primary endpoint for 
event-free survival 
[EFS])
Updated text to clarify EFS 
censoring rules  
1) at the time of radical 
cystectomy, patients will now 
be censored if the general 2 
missed visit rule applies rather 
than considering only the scan 
immediately after cystectomy
2) patients with no evaluable 
visits or baseline disease 
assessment prior to 
neoadjuvant treatment will not 
be censored at Day 1 if they die 
within 112 days of 
randomization  (rather than 2 
visits
Simplification of the censoring 
rules. Change to calendar days 
due to there only being 1 visit in 
the neoadjuvant phase
Non-
substantial
Section 9.5 Interim 
Analyses
Additional interim analysis of 
OS at EFS IA2 added 
To allow a formal test of OS if 
EFS at EFS IA2 is positive. 
Substantial
Section 9.5 Interim 
Analyses
Predicted OS events at the time 
of EFS IA2 have been added 
and predicted OS events at the 
EFS final analysis have been 
revised 
Updated blinded prediction with  
EFS IA2 added
Non 
substantial
Section 9.5 Interim 
Analyses
Text has been added to state 
that the actual alpha level will 
be based on the observed 
number of events and as such 
the final analysis alpha will be 
derived using the generalized 
Haybittle-Peto method
Clarification 
Non 
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
206 (233)
Appendix A1
Serious breach wording added 
Insertion of required EU CTR 
language to define how to 
identify and report serious 
breaches.
Non-
substantial
Appendix A6
Dissemination of Clinical 
Study Data 
Insertion of required EU CTR 
language to define when study 
results will be available
Non-
substantial
Appendix A7
Data Quality Assurance
Insertion of required EU CTR 
language" to update document 
retention period
Non-
substantial
Appendix F 
Deletion of "Evaluation of 
scans subsequent to RECIST 
1.1-defined progression" 
paragraph
Treatment through progression 
is not applicable in this study 
Non-
substantial 
Appendix L
Specific Country Requirements
Insertion of required EU-CTR 
language to capture applicable 
EU/EEA local CSP and country 
specific requirements that were 
previously approved by the 
respective country 
Non-
substantial
Amendment 4 (01-Jun-2021)
Overall Rational for the Amendment: Primary analysis, study objective and changes to the 
multiple testing plan now reflects the intention-to-treat (ITT) population rather than patients with 
adequate renal function, based on evolving data demonstrating no difference in outcomes for 
patients receiving a full or split cisplatin-dose regimen as part of a gemcitabine-cisplatin 
neoadjuvant regimen.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
207 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Section 1.1 (Schedule of 
Activities [SoAs]),
Table 1, Table 2, Table 
3, and Table 4 
Clarified footnotes to reflect 
collection of samples for 
ctDNA and PaxGene RNA. 
Samples for ctDNA and 
PaxGene only need to be 
collected at the time of a clinical 
event, defined as the time of 
progression or recurrence, 
occurring at any time during the 
study (neoadjuvant, adjuvant or 
follow-up). No additional 
samples are required beyond a 
progression or recurrence event.
Language indicating collection 
‘for any other reason or at end 
of the study’ has been removed.
Non-
substantial
Section 1.1 (Schedule of 
Activities [SoAs]),
Table 2 and Table 3
Section 8.2.7 (Clavien-
Dindo Assessments)
Updated language to reflect 
requirement for Clavien-Dindo 
assessment at 90 days, for all 
cystectomy procedures
Clavien-Dindo assessments, 
performed at 90 days following 
a cystectomy procedure, are to 
be determined for all surgical 
procedures, including both a 
radical and a partial cystectomy 
(performed either due to medical 
contraindication or 
investigator’s decision)
Non-
substantial
Section 2.2 
(Background)
Removal of Urothelial 
Carcinoma (UC) indication 
language, reflecting FDA 
approval in the US for locally 
advanced or metastatic disease 
AstraZeneca has voluntarily 
withdrawn the conditionally 
approved indication of 
durvalumab in the US for 
locally advanced or metastatic
UC after platinum-containing 
chemotherapy with consultation 
and guidance of the FDA.
Non-
substantial
Section 2.3.2.1 
(Durvalumab)
Updated text to reflect 
additional risks for 
durvalumab, based on current 
safety language.
The following risks have been 
added for Durvalumab: 
pemphigoid [reflected as 
rash/dermatitis (pemphigoid)] 
and immune thrombocytopenia
Non-
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
208 (233)
Section 3 (Objective and 
Endpoints)
Section 4.2.2. (Rationale 
for efficacy study 
endpoints)
Section 9.2 (Table 18) 
(Population Analyses)
Updated study objectives and 
study population
Primary analysis for pCR and 
EFS will be performed on the 
ITT population instead of 
patients in the adequate renal 
function cohort; now reflected 
as the primary study objective  
Reference to the adequate renal 
function population has been 
removed from all the secondary 
objectives.
Substantial
1.2 Synopsis 
8.1 Efficacy Assessments
9. Statistical 
Considerations 
(And throughout 
protocol, where 
applicable, except in 
Appendix J - Protocol 
Amendment History)
Regarding pCR and EFS 
endpoints, updated “co-
primary” endpoint(s) language 
to “dual primary” endpoint(s)
Dual primary endpoints is more 
appropriate than co-primary 
endpoints in the context of 
study’s statistical 
considerations.  
Non-
substantial
Section 8.4.5.1 (Specific 
toxicity management and 
dose modification 
information –
durvalumab)
Removal of text referencing 
toxicity management 
guidelines (TMG) link to the 
WebPortal
The on-line TMG WebPortal 
has been decommissioned due to 
lack of use. The TMGs for the 
management of Durvalumab 
(and Tremelimumab) are 
continued to be provided to sites 
as a separate Annex document
Non-
substantial
Section 9.3.1.2 (Dual 
primary endpoint for 
event-free survival 
[EFS])
Updated text to clarify window 
for post-cystectomy scan, 
Censoring rules for patients with 
scans 42 to 120 days post-
cystectomy (adjuvant baseline) 
are as follows:
If this scan is obtained during 
this interval and prior to the first 
study treatment (Arm 1) and 
within the 120 days, regardless 
of timing relative to the first 
study visit (Arm 2), the patient 
will not be censored
Non-
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
209 (233)
This interval aligns with text in 
section 6.1.2 (Dose and 
Treatment regimens)
Section 9.3.1.3 
(Secondary Endpoints)
Section 3 (Objectives 
and Endpoints)
Updated text to clarify 
additional survival endpoint
Overall survival (OS) added as a 
secondary endpoint (and also 
reflected in the secondary 
objective)
Substantial
Section 9.4 (Method of 
Statistical Analyses)
Section 1.2 (Synopsis)
Updated text to reflect 
population for primary analysis 
and also modified statistical 
analysis plan
Primary analysis is to be 
performed on ITT, to align with 
updated study objectives; 
changes to multiple testing plan 
and modified schedule for 
interim analyses have been 
added.
Substantial
Appendix K (Changes 
Related to Mitigation of 
Study Disruptions Due to 
Cases of Civil Crisis, 
Natural Disaster, or 
Public Health Crisis)
Added language describing 
COVID-19 assessment for 
patients receiving durvalumab
Guidance provided for 
recruitment of new patients, 
management of existing 
patients, administration of study 
treatment, and considerations for 
COVIV-19 vaccination.
Non-
substantial 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
210 (233)
Amendment 3 (20-July-2020)
Overall Rational for the Amendment: The primary reason for this amendment is to modify the 
patient population to include patients with clinical node-positive disease, specifically patients 
with cN1 disease. In addition to existing patients with node-negative disease (cT2-4aN0M0), 
patients with cT2-4aN1M0 are now included in the study population. In this context, the T2 cap 
is being clarified to only restrict enrollment of patients with cT2N0M0 disease; patients with 
cT2N1M0 disease are permitted to enroll onto the study.
Additionally, study mitigation language has been added which will provide sites with measures 
that may be implemented if a participant is not able to visit a study site to ensure that the clinical 
trial can continue whilst minimizing risk to the participant, maintaining compliance with GCP, 
and minimizing risks to the study integrity.
This and other changes incorporated in this amendment are described in the following table. In 
addition, minor text clarifications, administrative changes, and changes for consistency across 
the durvalumab program have been made; as these changes were minor, they are not listed in 
detail in the table below.
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Section 1.1 (Schedule of 
activities [SoAs]), Table 1 
to Table 4
Clarified requirement for 
conducting QLQ  and 
CTCAE assements in the 
timeframe between 
radical cystectomy and 
start of adjuvant phase
Clarification
Non-
substantial
Section 1.1 (Schedule of 
activities [SoAs]), Table 1 
to Table 4
Added footnote to tables 
1-3 to clarify requirement 
for collection  of 
PaxGene-RNA and 
ctDNA/circulating soluble 
factor samples 
For patients who are discontinued 
early from either the neoadjuvant or 
adjuvant phase due to recurrence, 
progression, or any other reason, 
PaxGene-RNA and 
ctDNA/circulating soluble factor 
samples are also to be collected 
Non-
substantial
Section 1.1 (Schedule of 
activities [SoAs]), Table 1 
to Table 4
Added language to 
indicate that patients who 
are discontinued from the 
neoadjuvant phase and 
will not enter into 
adjuvant phase, even if a 
It is recognized that for patients who
discontinue from study treatment 
either during or at the completion of 
the neoadjuvant phase and have not 
undergone a cystectomy, or do not 
enter adjuvant phase, the time 
Non-
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
211 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
cystectomy is performed, 
30 and 60-day follow up 
visits may be waived; 
however, a 
comprehensive 90-day 
visit must be performed
between the last dose of study drug 
and the first visit will often be longer 
than 30 and even 60 days, as required 
in the follow-up phase. For these 
patients, the 30 Day and Month 2 
follow-up visits can be waived; 
however, the Month 3 (90 day) visit 
is required to ensure comprehensive 
assessments (safety, concomitant 
medications and PK) are documented
Figure 1
Section 2.1 (Study 
rationale)
Updated footnote to 
reflect T2 cap limiting 
only enrollment of T2N0 
patients
The figure is updated to reflect that 
only T2N0 patients will be limited to 
enrollment. 
Substantial
Section 1.2 (Synopsis)
Section 4.1 (Overall 
design)
Updated text to clarify 
current stratification to 
accommodate cN1 
patients
. Randomization will be stratified by 
clinical tumor stage T2N0 versus 
>T2N0 (including T2N1, T3 and 
T4a) to reflect prognostic stage II 
versus IIIa, respectively.
Substantial
Section 2.1 (Study 
rationale)
Added language to reflect 
modification to study 
population to now include 
patients with cN1 disease
In accordance with current NCCN 
guidelines, patients with stage IIIa 
disease are now considered for 
neoadjuvant chemotherapy/radical 
cystectomy. Therefore, 
randomization will be stratified by 
clinical tumor stage T2N0 versus 
>T2N0 (including T2N1, T3 and 
T4a) to reflect prognostic stage II 
versus IIIa, respectively 
Substantial
4.1.1 Study conduct 
mitigation during study 
disruptions due to cases 
of civil crisis, natural 
disaster, or public health 
crisis
New wording was added 
which would give 
guidance on how the 
study could continue in 
the event of a serious 
disruption with details of 
mitigation that could be 
The impact of COVID-19 has 
highlighted the risk to continuity of 
clinical trials during times of study 
disruption, whether by civil crisis, 
natural disaster or public health 
crisis. This section details the 
measures that may be implemented if 
Substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
212 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Appendix K 
employed to ensure study 
continuity.
a patient is not able to visit a study 
site to ensure that the clinical trial 
can continue whilst minimizing risk 
to the patient, maintaining 
compliance with GCP, and 
minimizing risks to study integrity. 
These changes will only be initiated 
at a time of study disruption.
Section 5.1 (Inclusion 
criteria)
Section 6.1.5 (Surgical 
plan)
Updated text to reflect 
inclusion of patients with 
N1 disease
Patients with T2-T4aN1, in addition 
to patients with T2-T4aN0 patients, 
are now included in the patient 
population. Definition of clinical N1 
is provided. The single regional 
pelvic lymph node, in the opinion of 
the investigator, must be considered 
resectable per the surgical plan.
Substantial
Section 5.2 (Exclusion 
criteria)
Updated text to reflect N2 
and N3 patients are 
excluded
Only node-positive patients with N1 
disease are considered eligible. 
Modified exclusion reflects patients 
with N2 and N3 disease are not 
eligible
Substantial
Section 5.2 (Exclusion 
criteria)
Updated exclusion #9
Removed requirement for a prior 
prostatectomy 
Non-
substantial
Section 6.1.5 (Surgical 
plan)
Updated text to reflect 
recommendation  for 
PET-scan for N1 patients
For patients with N1 disease at study 
entry who are being considered for 
the non-cystectomy extension phase, 
a PET-CT is recommended in 
addition to a pelvic CT scan, as a 
confirmatory assessment, to confirm 
a complete clinical response (cCR)
Non-
substantial
Section 6.2.1 (Patient 
enrollment and 
randomization)
Updated text to reflect 
requirement of PD-L1 
sample to collected ≤ 3 
months prior to screening
Clarification 
Non-
substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
213 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Section 7.1.2 (Procedure 
for discontinuation of 
study plan-no radical 
cystectomy)
Section 8.1.1. 
(Investigator RECIST 1.1 
imaging review)
Updated text to 
discontinuation procedure 
for non-cystectomy 
patients with N1 disease
Patients who have N1 disease at 
study entry who are subsequently 
found to have an unresectable 
regional lymph node after 
randomization, will follow the 
procedures described for non-
cystectomy patients.
Non-
substantial
Section 8.1.1. 
(Investigator RECIST 1.1 
imaging review)
Updated text to reflect 
initial neoadjuvant 
baseline scan is the 
reference scan for patients 
entering into the extended 
noncystectomy phase
Clarification
Non-
substantial
Amendment 2 (09-December-2019)
Overall Rationale for the Amendment: The primary reason for this amendment was the 
addition of language to accommodate patients who have no radical cystectomy performed. This 
and other changes incorporated in this amendment are described in the following table. In 
addition, minor text clarifications, administrative changes, and changes for consistency across 
the durvalumab program have been made; as these changes were minor, they are not listed in 
detail in the table.
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Section 1.1 (Schedule of 
activities [SoAs]), 
Table 1 to Table 4
Section 1.2 (Synopsis)
Section 4.2.2 (Rationale 
for efficacy study 
endpoints)
Added language addressing 
patients who have no radical 
cystectomy performed
More details provided in the SoA 
tables and CSP sections outlining 
requirements for tumor assessment 
and EFS determinations, 
specifically for patients who do not 
undergo a radical cystectomy
Substantial 
Section 1.1 (Schedule of 
activities [SoAs]), 
Table 1
Added footnote “u” to indicate 
that the sample for genetic 
research may be obtained at 
any point during the study
To alleviate the burden of 
activities on Cycle 1 Day 1, and to 
align with standard practice in this 
program
Non-
substantial 
Section 1.1 (Schedule of 
activities [SoAs]), 
Table 1
Added language to footnote 
“w” (now “x”) and respective 
text in Section 8.1.1.1 to 
indicate that sites should 
consider scheduling the 
No specific timeframe is defined in 
the CSP as to when the 
post-neoadjuvant scan needs to be 
obtained relative to the last dose of 
neoadjuvant treatment; guidance 
Non-
substantial 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
214 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
post-neoadjuvant scan as part 
of the pre-surgical work-up
provided to suggest timing should 
coincide with pre-surgery 
work-up, if applicable
Section 1.1 (Schedule of 
activities [SoAs]), 
Table 1 and Table 2
Section 8.2.1 (Clinical 
safety laboratory 
assessments)
Added language requiring 
activated partial thromboplastin 
time and international 
normalized ratio be assessed on 
Cycle 1 Day 1 of both the 
neoadjuvant and adjuvant 
phases.
Assessment at adjuvant Cycle 1 
Day 1 is added as coagulation and 
hepatic function may have 
changed due to intervening 
procedures, including cystectomy.
Substantial
Section 1.2 (Synopsis)
Section 3 (Objective and 
endpoints)
Section 4.2.2 (Rationale 
for study endpoints)
Section 9.2 (Populations 
for analyses)
Section 9.2.4 (PD-L1-
high analysis set)
Section 9.4 (Methods for 
statistical analyses)
Added language to reflect 
efficacy objective for pCR and 
EFS for patients in the PD-L1-
high subgroup
Emerging clinical data from other 
studies using neoadjuvant PD/PD-
L1 inhibitors have demonstrated 
improved response rates in PD-L1 
high patients; this objective is also 
being incorporated into this study
Substantial
Section 1.2 (Synopsis)
Section 4.1 (Overall 
design)
Added language indicating a 
limit on recruitment of patients 
with T2 disease to 
approximately 40%, in both 
treatment arms
This limit is in place to align with 
previously published studies 
describing the distribution of 
patients with T2 and > T2 disease 
(and their corresponding pCR 
rates) for patients receiving 
neoadjuvant chemotherapy and 
thereby, to ensure that the 
statistical assumptions for pCR 
rates between the experimental and 
control groups are maintained, as 
reflected in Section 9.1 (Sample 
size determination).
Substantial 
Section 1.2 (Synopsis)
Section 6.1.3 (Duration 
of treatment and criteria 
for treatment through 
progression)
Clarified progression events 
that would or would not 
preclude patient from 
undergoing a radical 
cystectomy
Additional language provided to 
clarify progression events, in the 
context of both medical reasons 
and confirmed progression that 
would or would not preclude a 
patient from proceeding with a 
radical cystectomy.
Substantial 
Section 5.1 (Inclusion 
criteria)
Added language to clarify that 
clinical tumor staging is a 
composite assessment of results 
obtained from imaging, 
Clarification that a single clinical 
tumor stage needs to be derived 
based on all available data, 
regardless of the order in which 
Non-
substantial 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
215 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
pathology, and physical exam, 
to derive a single tumor stage at 
study entry
that information is being reviewed. 
A single tumor stage needs to be 
documented in the eCRF and 
IXRS at the time of randomization.
Section 5.2. (Exclusion 
criteria)

Exclusion Criterion 2: 
added language to clarify 
that additional work-up of 
a large lymph node, 
confirming a benign lesion, 
is acceptable for eligibility

Exclusion Criterion 14: 
removal of QTcF 
requirement at baseline 
due to low risk of 
QTc-prolonging effects 
with study treatment

Language added to allow sites 
to work-up a large nodal mass 
(short-axis between 10 and 
<15 mm), either 
pathologically (biopsy) or by 
PET-CT scan, to confirm the 
presence of a benign mass and 
allow the patient to be 
enrolled

Requirement for 
documentation of normal 
QTcF was initially retained 
due to concerns related to 
ECG effects related to 
gemcitabine; further 
assessment is that QTc-
prolonging effects is not a risk 
with any of the study 
treatments, and therefore is 
being removed.
Non-
substantial 
Section 6.1.2 (Dose and 
treatment regimens)
Added language describing the 
noncystectomy extension phase 
for patients who meet specific 
criteria
New provision added to allow 
patients in either treatment arm 
who have a complete clinical 
response at the completion of 
neoadjuvant treatment and refuse a 
radical cystectomy to transition 
into the noncystectomy extension 
phase, with approval from AZ, 
with assessments mirroring those 
in the adjuvant phase. For patients 
in Arm 1, this would include 
additional cycles of durvalumab
monotherapy.
Substantial 
Section 6.1.5 (Surgical 
Plan):

Added language indicating 
that AZ should be 
consulted for a patient who 
is unable to undergo a 
radical cystectomy within 
the 56-day timeframe, 
specifically for delays 
extending beyond 70 days 
(10 weeks)

Added language indicating 
that if a patient is 
confirmed to have a 
complete clinical response 
(by multi-modal 

Provision added to encourage 
sites to contact AZ if a radical 
cystectomy may be delayed 
beyond 10 weeks (the outer 
limit supported by guidelines), 
secondary to a medical issue.

New provision being added to 
allow patients who are 
determined to have a complete 
clinical response at the 
completion of neoadjuvant 
treatment and refuse a radical 
Substantial 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
216 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
assessment) and refuses a 
radical cystectomy, 
transition into the 
noncystectomy extension 
phase (instead of the 
follow-up phase) is 
permitted with approval by 
the Sponsor.
cystectomy to transition into a 
noncystectomy extension 
phase, with approval from 
Sponsor. 
Section 6.2.1 (Patient 
enrollment and 
randomization)
Added language to clarify that 
clinical tumor staging should 
be determined at screening
Updated text to reflect 
timeframe for collection of 
sample for PD-L1 testing is ≤3 
months (instead of 56 days)
Clarification
Clarification
Non-
substantial 
Section 6.4 
(Concomitant therapy)
Added language clarifying the 
requirements for recording 
concomitant 
medications/therapy 
administered during the 
surgical procedure
Medications routinely used to 
perform the surgery (eg, pre- and 
peri-operative medications) are 
now exempt from recording as a 
concomitant medication unless 
specific criteria are met, 
predominately related to the 
management or cause of an 
unexpected event occurring peri-or 
post-operatively.
Substantial 
Section 7.1 
(Discontinuation of 
study treatment)
Added language clarifying 
criteria for study treatment 
discontinuation for patients 
who have no radical 
cystectomy performed
Specific guidance provided 
describing disposition of patients 
who do not have a radical 
cystectomy performed
Substantial 
Section 8.1.1 
(Investigator RECIST 
1.1 imaging review)

Added language indicating 
a modified imaging plan 
for patients with a new 
tumor (target and non-
target lesion) detected on 
initial post-cystectomy 
(adjuvant baseline) scan

Added language to clarify 
tumor assessment (imaging 
plan) for patients who are 
precluded from or refuse a 
radical cystectomy
Clarification provided to indicate 
evaluation of a new lesion, 
detected at the adjuvant baseline 
scan
Clarification of tumor assessment 
and EFS determination provided 
for patients who are medically 
preclude from or refuse a radical 
cystectomy
Substantial 
Section 8.8.7 (German 
biomarker sub-study)
Added text describing a 
biomarker sub-study being 
performed at NIAGARA sites 
within Germany
Language added to reference a 
substudy being conducted 
evaluating additional exploratory 
immune, mutational, and/or 
molecular subtyping biomarkers
Substantial

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
217 (233)
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Section 9.3.1.2 (Co-
primary endpoint: event-
free survival (EFS))
Added language clarifying 
definition of EFS for patients 
who refuse a radical 
cystectomy procedure, 
specifically for patients with 
residual disease and for those 
achieving a complete response.
EFS definition has been updated, 
to align with updates on the 
definition provided by the FDA
Substantial 
Appendix A 
(Regulatory, ethical and 
study oversight 
considerations)
Added text regarding study 
termination and reporting 
requirements for SAEs as per 
TransCelerate protocol 
template 
Language explaining requirements 
for SAE reporting and reasons for 
study termination, added per 
program-wide template language
Non-
substantial
Appendix B (Adverse 
event definitions and 
additional safety 
information)
Added text regarding AEs for 
malignant tumors as per 
TransCelerate protocol 
template
Language describing AEs for 
malignant tumors added per 
program-wide template language
Non-
substantial
Appendix F (Guidelines 
for Evaluation of 
Objective Tumor 
Response Using 
RECIST 1.1 Criteria 
(Response Evaluation 
Criteria in Solid 
Tumors)
Removal of text describing 
requirement for obtaining a 
confirmatory scan once 
unequivocal progression is 
confirmed
Additionally updated text to be 
consistent with latest 
TransCelerate protocol 
template
Once unequivocal progression has 
been confirmed by imaging, no
additional scans are required.
Additional updates added per 
program-wide template language.
Substantial 
Non-
substantial
Amendment 1 (Version 2.0): 23-April-2019
Overall Rationale for the Amendment: Protocol version 2 (dated 23Apr19) was created based 
on feedback from investigators and regulatory agencies. The main drivers for the amendment 
included:

Clarification that the adjuvant phase is required for both treatment (Arm 1) and control 
arm (Arm 2)

Modification of adjuvant schedule to retain patients in Arm 2 by allowing for visits to 
alternate between in clinic visits and phone contacts

Primary/secondary endpoints updated to reflect EFS assessments by BICR AND central 
pathology review

Modification of Imaging Schedule for Control and Experimental Arms (Arms 1 and 2) 

Change of International Coordinating Investigator (ICI)

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
218 (233)
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Schedules of 
activities (SoAs): Table 1 
(Schedule of assessments 
for screening and 
neoadjuvant treatment [all 
treatment arms]):

Extended the assessment time for concomitant 
medications, urinalysis, adverse event (AE)/serious 
adverse event (SAE) assessment, and patient-
reported outcome (PRO)/hospital resource use 
module (HOSPAD) endpoints to include the pre-
radical cystectomy and radical cystectomy dates

Added row for coagulation parameters for 
clarification on time of collection

Changed tumor sample age from ≤3 years to ≤3 
months for programmed cell death-ligand 1 (PD-L1) 
testing

Moved urine biomarker and cytology from screening 
to Cycle 1 Day 1 (pre-dose)

Removed Cycle 3 Day 1 urine sample for biomarker 
and cytology

Removed blood sample for PaxGene-RNA analysis 
from screening

Moved serum sample for biomarkers from screening 
to Cycle 1 Day 1

Clarified patient global impression of change (PGIC) 
timepoint

For footnote “c,” added section link for vital signs

Clarified creatinine clearance requirements for 
cisplatin

Added row and footnote for urine biomarker to 
clarify what laboratories would perform the tests

Added row and footnote for urine cytology to clarify 
what laboratories would perform the tests

Changed timing for urine collection for biomarker 
and cytology for pre-cytology visit from within 2 
days to within 7 days immediately prior to radical 
cystectomy

For footnote “g,” added details for collection of 
coagulation parameters at baseline
To reflect the changes 
to the study based on 
this amendment and to 
provide clarification on 
adjuvant phase visits 
for treatment Arm 1 
and Arm 2

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
219 (233)
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Schedules of 
activities (SoAs): Table 2 
(Schedule of assessments 
for the adjuvant treatment 
phase [Arm 1]):

Renamed as schedule of assessments for the adjuvant 
treatment phase (Arm 1)

Baseline adjuvant scan time frame changed from 35 
to 42 days to allow patients a longer period to 
recover from cystectomy prior to the baseline 
adjuvant scan

Extended the assessment time for 
electrocardiograms, concomitant medications, 
urinalysis, AE/SAE assessment, and PRO/HOSPAD 
to include 42 days after radical cystectomy

Removed urine biomarker and cytology laboratory 
assessments

Added Clavien-Dindo assessment 90 days following 
radical cystectomy to collect surgical complications

Updated the patient-reported outcomes version of the 
Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) assessment timing to be completed at 
Cycle 1 Day 1 and every 2 weeks up to Week 13 
(instead of Week 12) then every 4 weeks thereafter

For footnote “g,” added text to indicate that AEs and 
medications related to the radical cystectomy will be 
recorded to provide clarification that AEs and 
concomitant medications related to the surgery need 
to be documented

For footnote “a,” added section link for vital signs

Updated adjuvant assessment to reflect change to 
every 24 weeks for 36 months, then every 52 weeks
(annually) thereafter
Table added to clarify 
adjuvant phase 
schedule for patients 
randomized to Arm 1
Section 1.1 Schedules of 
activities (SoAs): Table 3 
(Schedule of assessments 
for the adjuvant phase 
visits [Arm 2]):

Incorporated all relevant changes from Table 2 
(adjuvant schedule for Arm 1)

Clarified that for patients in Arm 2, pregnancy test 
will only be required for Cycle 1 and Cycle 3
Table added to clarify 
adjuvant phase 
schedule for patients 
randomized to Arm 2, 
which modified the 
adjuvant schedule of 
assessments to decrease 
the burden of on-site 
visits for patients 
randomized to Arm 2
Section 1.1 Schedules of 
activities (SoAs): Table 4 
(Schedule of assessments 
for patients who have 
discontinued treatment or 
completed study 
visits/treatment):

Removed Months 4 and 8, as no assessments are 
scheduled for these dates

Added footnote “a” at Month 2 to indicate patients 
in Arm 2 will have a follow-up call only at this visit

Removed weight from follow-up assessment at 
Month 6

Updated tumor assessment to reflect change to 
every 24 weeks for 36 months, then every 52 weeks 
(annually) thereafter

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
220 (233)
Section # and Name
Description of Change
Brief Rationale
Section 1.2 (Synopsis -
International 
Coordinating 
Investigator): 
Updated the International Coordinating Investigator from 
 to 
Section 2.3.1.2 
(Durvalumab in 
combination with 
chemotherapy): 
New section 
Section added for 
completeness of 
potential benefit for use 
of durvalumab in 
combination with 
chemotherapy
Section 2.3.2.2 
(Durvalumab in 
combination with 
chemotherapy): 
New section 
Section added for 
completeness of 
potential risk for use of 
durvalumab in 
combination with 
chemotherapy
Table 5 (Section 3 
[Objectives and 
Endpoints]):

Updated event-free survival (EFS) using assessments 
per Blinded Independent Central Review (BICR) 
endpoint to include “or by central pathology review 
if a biopsy is required for a suspected new lesion” to 
ensure that biopsy results can be incorporated into 
the EFS endpoint

Updated EFS and proportion of patients alive and 
event free at 24 months (EFS24) using assessments 
per local Investigator endpoints to include “or 
Investigator biopsy review if a biopsy is required for 
a suspected new lesion” to ensure that biopsy results 
can be incorporated into the EFS endpoint

Updated metastasis-free survival and disease-specific 
survival per Investigator assessments to include “or 
Investigator biopsy review if a biopsy is required for 
a suspected new lesion” to ensure that biopsy results 
can be incorporated into the EFS endpoint

Added “PFS2 (time from the date of randomization 
to the earliest date of progression which occurs on 
subsequent therapy following an EFS event or death) 
as defined by local standard clinical practice” 
endpoint to the following secondary objectives: to 
assess the efficacy of Arm 1 versus Arm 2 in muscle-
invasive bladder cancer (MIBC) patients with 
adequate renal function and to assess the efficacy of 
Arm 1 versus Arm 2 in MIBC patients

Clarified the secondary endpoint for European 
Organization for Research and Treatment of Cancer 
30-item Core Quality of Life Questionnaire (EORTC 
QLQ-C30) scale/item scores as the adjusted mean 
change from baseline and time to definitive clinically 
meaningful deterioration in EORTC QLQ-C30

Clarified the exploratory endpoints for the PRO-
CTCAE, PGIC, and patient global impression of 
severity as descriptive summary of responses
PPD
PPD

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
221 (233)
Section # and Name
Description of Change
Brief Rationale
Section 4.3.2 
(Gemcitabine plus 
cisplatin dose rationale):
Added text summarizing relevant studies confirming the 
dose and treatment schedule for the 21-day gemcitabine 
plus cisplatin regimen
Sections 4.4 (End of study 
definition) and 6.6 
(Treatment after the end 
of the study):
Added standard text summarizing roll-over and safety 
extension study options 
For clarity and 
completeness
Section 5.1 (Inclusion 
criteria):

Inclusion criterion 4: removed the time limit for 
prior intravesical chemotherapy for patients entering 
the study to allow for patients treated with 
intravesical chemotherapy following the 
transurethral resection of bladder tumors regardless 
of time frame

Inclusion criterion 6, changed tumor sample age for 
PD-L1 from ≤3 years to ≤3 months
Section 5.2 (Exclusion 
criteria):

Changes to Exclusion criterion 2 and 3: added to 
provide clarity regarding patient eligibility with 
respect to the extent of surgery allowed on study

Exclusion criterion 6, added autoimmune 
pneumonitis and autoimmune myocarditis to the list 
of autoimmune or inflammatory disorders 

Exclusion criterion 7, added uncontrolled angina to 
the list of uncontrolled intercurrent illnesses that are 
excluded

Exclusion criterion 8, added history of myocardial 
infarction within the past 6 months prior to 
randomization due to potential cardiotoxic effects 
observed with gemcitabine

Exclusion criterion 20, removed the note from this 
exclusion that patients should not receive live 
vaccine while receiving investigational product (IP) 
and up to 30 days after the last dose of IP

Exclusion criterion 22, added a 2-year time limit for 
prior pelvic radiotherapy
Section 5.3 (Lifestyle 
restrictions):

Clarified that male contraception of condom plus 
spermicide is applicable only in countries where 
spermicide is approved, since spermicide is not 
available in all countries

Clarified to follow the local prescribing information 
related to contraception for the chemotherapy agents 
(gemcitabine plus cisplatin)
Section 5.4 (Screen 
failures):
Added PD-L1 biopsy/tumor sample (if the sample was 
sent to the central laboratory during screening) as data 
collected on screen failures
Section 6.1.1.1 (Order of 
administration): 

Added instructions that if anti-emetics are required, 
then they should be administered 30 minutes prior to 
chemotherapy, not prior to durvalumab to provide 
clarity for use of anti-emetics

Added that gemcitabine + cisplatin (G+C) 
chemotherapy is to be administered per local practice

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
222 (233)
Section # and Name
Description of Change
Brief Rationale
Section 6.1.1.2 
(Durvalumab 
[MEDI4736]):

Updated information and preparation for study 
treatment 

Added language describing acceptable 
configurations for in-line filter setup for infusion 
administration
Section 6.1.1.3 
(Gemcitabine and 
cisplatin):
Clarified that these drugs are to be locally sourced by the 
sites instead of AstraZeneca
Section 6.1.2 (Dose and 
treatment regimens):

For neoadjuvant therapy, added the creatinine 
clearance requirements for cisplatin to provide 
clarity to sites for creatinine clearance verification 
prior to each cisplatin dose

For adjuvant therapy, added text to provide 
clarification for the start of Cycle 1 Day 1 for 
patients in Arm 2

For adjuvant therapy, changed starting time frame 
for adjuvant therapy from 28 to 42 days after radical 
cystectomy to allow patients a longer period to 
recover from cystectomy prior to the baseline 
adjuvant scan
Section 6.1.2.1 
(Durvalumab 
[MEDI4736]):
Updated information and preparation for study treatment
Section 6.1.3 (Duration of 
treatment and criteria for 
treatment through 
progression): 
Moved heading from under Surgical plan and clarified 
the duration of treatment for Arm 1 and Arm 2
Section 6.1.4 (Storage):
Added based on updated guidance
Table 9: 

Updated weeks based on schedules of assessments

Changed starting time frame for adjuvant therapy 
from 28 to 42 days following radical cystectomy to 
allow patients a longer period to recover from 
cystectomy prior to the baseline adjuvant scan
Section 6.2.2 (Procedures 
for handling incorrectly 
enrolled or randomized 
patients): 
Added clarification wording to require that the 
risk/benefit be part of the conversation between the 
Investigator and Sponsor when determining if a patient is 
to continue or discontinue treatment
Section 6.4 (Concomitant 
therapy): 
Added clarification for Arm 1 and Arm 2

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
223 (233)
Section # and Name
Description of Change
Brief Rationale
Table 10 (Prohibited 
concomitant 
medications):

Clarified the timelines for usage of prohibited 
medications for Arm 1 and Arm 2

Updated live attenuated vaccines prohibition from 
30 to 90 days after the last dose of durvalumab 
based on the half-life (to approximate 5 times the 
half-life)

Added time frame information for administration of 
live attenuated vaccines for G+C chemotherapy to 
provide clarification for the time frame for 
acceptable/safe vaccine administration based on 
current Infectious Diseases Society of America 
(IDSA) recommendations for patients receiving 
standard chemotherapy only

Clarified the limited use of steroids with 
durvalumab

Removed palliative radiotherapy for non-target 
lesions from supportive medication
Section 6.5 (Dose 
modification): 
Added clarifications
Section 7 
(Discontinuation of 
treatment phase of study 
and patient withdrawal):
Added “phase of study” to the section title to indicate that 
the section is applicable for both treatment arms 
Section 7.1 
(Discontinuation of study 
treatment):

Added clarification that a patient should discontinue 
study treatment if a radical cystectomy procedure is 
not performed (ie, a partial cystectomy or no 
cystectomy is performed)

Added clarification for Arm 2 since these patients 
receive no treatment

Removed discontinuation criterion: “clinical 
progression/recurrence and Investigator 
determination that the patient is no longer benefiting 
from treatment with IP.” Not applicable to this study, 
as patients would discontinue study treatment for 
Response Evaluation Criteria in Solid Tumors, 
version 1.1 (RECIST 1.1) progressive disease that 
precludes a patient from a cystectomy or proven 
recurrence in the adjuvant setting

Updated proven recurrence wording and added 
section link to Section 8.1.1.2
Section 7.1.1 (Procedures 
for discontinuation of 
study treatment):

Clarified the procedures for patients who
permanently discontinue drug for reasons other than 
disease progression/recurrence

Updated tumor assessment schedule to reflect 
change from “every 24 weeks thereafter” to “every 
24 weeks for 36 months, and then every 52 weeks 
(annually) thereafter”
Section 8.1 (Efficacy 
assessments):

Updated EFS and EFS24 using assessments per 
BICR to include “or by central pathology review if a 
biopsy is required for a suspected new lesion”

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
224 (233)
Section # and Name
Description of Change
Brief Rationale
Section 8.1.1 (Tumor 
assessments): 
Added section for further details for the subsections 
below
Section 8.1.1.1 
(Investigator RECIST 1.1 
imaging review):

Changed the timing for second “Adjuvant Baseline” 
scan from 35 to 42 days to allow patients a longer 
period to recover from cystectomy prior to the 
baseline adjuvant scan

Removed biopsy text and added details regarding 
additional scans if a new lesion is radiologically 
equivocal

Updated tumor assessment schedule to reflect 
change from “every 24 weeks thereafter” to “every 
24 weeks for 36 months, and then every 52 weeks 
(annually) thereafter”
Section 8.1.1.2 (Local 
biopsy review): 
Added section to describe the local biopsy review
Section 8.1.1.3 (Local 
pathology review): 
Added section to describe the local pathology review
Section 8.1.1.4 (Central 
biopsy review): 
Added section to describe the biopsy review
Section 8.1.2 (Survival 
assessments): 
Clarified timepoints for assessments
Section 8.1.3 (Clinical 
outcome assessments): 
Updated to include more information on compliance and 
clarify PRO administration best practice instructions
Table 12 (Clinical 
chemistry): 
Added footnote to clarify creatinine testing and creatinine 
clearance requirements for cisplatin
Table 13: 
Added clarification for percentages of neutrophils
Section 8.2.3 (Vital signs 
and measurements): 
Updated to provide clarification on vital signs required 
for Arm 1 and Arm 2 by neoadjuvant and adjuvant phases
Section 8.2.6 (Patient 
follow-up contact [Arm 2 
only]): 
Added section for follow-up in Arm 2
Section 8.2.7 (Clavien-
Dindo assessment): 
Added assessment for grading surgical complications
Sections 8.3.2 (Time 
period and frequency for 
collecting AE and SAE 
information), 8.3.3 
(Follow-up of AEs and 
SAEs), 8.3.11 (Deaths), 
and 8.3.13 (Safety data to 
be collected following the 
final DCO of the study): 
Changed collection time to 90 days after the last dose of 
treatment (Arm 1) or adjuvant study visits (Arm 2) to 
provide clarification that patients in Arm 2 will be 
followed with the same frequency and visit schedule as in 
Arm 1
Sections 8.4.5 
(Management of IP-
related toxicities) and 
8.4.5.2 (Specific toxicity 
management and dose 
modification information 
- gemcitabine and 
cisplatin): 
Added clarity for each IP versus durvalumab

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
225 (233)
Section # and Name
Description of Change
Brief Rationale
Section 8.4.5.1 (Specific 
toxicity management and 
dose modification 
information -
durvalumab): 
Added additional text providing language about the use, 
location, and applicability of the toxicity management 
guidelines
Section 8.8.1 (Collection 
of tissue samples for 
central pathology review, 
stratification by PD L1 
expression, and biomarker 
research):

Updated heading wording for clarity

Changed tumor sample age for PD-L1 from ≤3 years 
to ≤3 months

Added that sites should refer to the Pathology 
Manual for detailed instructions and guidelines for 
the mandatory (treatment stage) tissue sample

Clarified the instructions and guidelines for optional 
additional tumor biopsies

Removed text that the Ventana PD-L1 (SP263) assay 
would be used to determine PD-L1 status in all 
specimens
Section 8.8.2 
(Exploratory biomarkers):

Clarified tumor markers and added pathological 
staging analysis

Updated urine cytology wording

Updated serum-based markers wording

Clarified plasma-based markers assessment wording
Section 9 (Statistical 
considerations): 
Updated EFS using assessments per BICR to include “or 
by central pathology review if a biopsy is required for a 
suspected new lesion”
Section 9.1 (Sample size 
determination): 
Updated alpha and power for Arm 1 versus Arm 2 (EFS 
in MIBC patients with adequate renal function) and Arm 
1 versus Arm 2 (EFS in Intent-to-treat)
Table 15 (Summary of 
outcome variables and 
analysis populations): 
Added PFS2
Section 9.3.1.2 (Co-
primary endpoint: event-
free survival [EFS]):

Updated EFS using assessments per BICR to include 
“or by central pathology review if a biopsy is 
required for a suspected new lesion”

Added clarification in the event that progression is 
confirmed via biopsy or subsequent scans

Added clarification regarding censoring of patients 
who take subsequent therapy prior to their last 
evaluable RECIST assessment or progression or 
death
Section 9.3.1.3 
(Secondary endpoints):

Updated EFS using assessments per BICR to include 
“or by central pathology review if a biopsy is 
required for a suspected new lesion”

Clarified definition of metastasis-free survival

Added PFS2
Section 9.3.2.1 (Adverse 
events): 
Added wording on AE summaries for any AE within 90 
days of completion of adjuvant visit and any AE 
occurring from radical cystectomy

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
226 (233)
Section # and Name
Description of Change
Brief Rationale
Section 9.3.3 (Calculation 
or derivation of patient-
reported outcome 
variables): 
Updated the time to definitive/sustained clinically 
meaningful deterioration in health-related quality of life 
functioning or symptoms analysis
Table 16 (Mean change 
and clinically meaningful 
change - EORTC QLQ-
C30): 
Updated change from baseline definitions
Table 18 (Pre-planned 
statistical and sensitivity 
analyses to be conducted):

Updated EFS using assessments per BICR to include 
“or by central pathology review if a biopsy is 
required for a suspected new lesion”

Updated secondary analysis per local Investigator to 
include “or Investigator biopsy review if a biopsy is 
required for a suspected new lesion”

Updated endpoint from time to deterioration to time 
to definitive/sustained clinically meaningful 
deterioration (EORTC QLQ-C30)
Section 9.4.1.1 (Multiple 
testing strategy): 
Removed “per BICR” for EFS
Section 9.4.1.3 (Event-
free survival [EFS]):

Updated description for subgroup analysis of lymph 
node metastasis

Added PD-L1 status subgroup analysis

Updated attrition bias assessment analysis
Section 9.4.2.8 (Patient-
reported outcomes): 
Updated the analysis for EORTC QLQ-C30
Section 9.5 (Interim 
analyses): 
Added detail on the analysis of the co-primary endpoint 
pCR
Section 10 (References):

Added the following references based on the updates 
made to the main text: Birgitte et al 2008, Dindo et al 
2004, Horn et al 2018, Inman et al 2007, Jan et al 
2016, Rizvi et al 2016, Rubin et al 2014, and Von 
der Maase et al 2000

Updated National Comprehensive Cancer Network 
reference from 2017 to 2019
Appendix C (Handling of 
human biological 
samples): 
Updated based on new standard AstraZeneca template 
wording
Appendix F (Guidelines 
for evaluation of objective 
tumor response using 
RECIST 1.1 criteria 
[Response Evaluation 
Criteria in Solid 
Tumors]): 
Updated based on new standard AstraZeneca template 
wording
Appendix I 
(Abbreviations): 
Added CSP, CTLA-4, DCO, FDG-PET, IMP, NL, PFS2, 
REVPRDI, TC, and TMG
Global/other changes: 
Minor corrections and clarifications throughout the 
protocol to improve readability and correct errors

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
227 (233)
Appendix K
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These changes 
should only be implemented if allowable by local/regional guidelines and following agreement 
from the Sponsor. 
K 1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, telemedicine visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments as per local and regional regulations and/or guidelines 
regarding reconsent of study patients should be checked and followed. Reconsent may be verbal 
if allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the patient’s next contact with the study site). Visiting the study sites for the sole 
purpose of obtaining reconsent should be avoided.
Please note reconsent is not required in situations where alternative means of carrying out visits 
is already indicated as per protocol (irrespective of civil crisis, natural disaster or public health 
crisis) e.g. in Table 3 Schedule of Assessments for Arm 2 patients in adjuvant phase, where some 
visits are via virtual contact (not in-clinic).
K 2
Rescreening of Patients to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in previously 
screened patients. The investigator should confirm this with the designated study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrolment into the study or commencing of dosing with IP. If this delay is 
outside the screening window specified in Table 1 [Schedule of assessments for screening and 
neoadjuvant treatment (all treatment arms)] the patient will need to be rescreened to reconfirm 
eligibility before commencing study procedures. This will provide another opportunity to re-
screen a patient in addition to that detailed in Table 1. The procedures detailed in Table 1 must 
be undertaken to confirm eligibility using the same randomization number as for the patient.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
228 (233)
K 3
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile health 
devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by a 
telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact with the 
patients will allow adverse events, concomitant medication, and other information including 
efficacy data where relevant to be collected according to study requirements to be reported and 
documented.
K 4
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine visits will be captured by the qualified HCP from the study 
site or TPV service in the source documents, or by the patient themselves.
K 5
COVID-19 Risk Assessment 
The safety of patients is of primary importance. Any potential risks of participating in the study, 
particularly with the added challenges due to COVID-19 outbreak, should be weighed against the 
anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised to use clinical 
judgment in determining infection prevention precautions for study patients.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. Patients 
enrolling in this study may require more frequent visits to the site for study treatment 
administration and for study assessments compared to patients receiving standard of care. 
Therefore, several risk mitigation factors have been implemented related to study conduct during 
the COVID-19 outbreak, for patient management in an event of COVID-19, and actions to be 
taken on study treatment (see Section K 8). With these measures in place, it is considered that the 
anticipated potential benefits for the patients enrolled in this study outweigh the potential risks. 
All implemented measures prioritise trial patient safety and data validity; in case these two 
conflict with each other, trial participant safety should always prevail (see also European 
Medicines Agency Guidance on the management of clinical trials during the COVID-19 
[coronavirus] pandemic [
EMA 2020]). 
Notably, patients with active COVID-19 infection confirmed by local laboratory testing will not 
be eligible for study enrolment (see CSP Section 5.2, Exclusion Criterion 7). 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
229 (233)
K 6
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section K 9 provides a dose modification and 
management plan for patients with confirmed or suspected COVID-19 who are being treated 
with study intervention durvalumab. The risk-benefit assessment should be carefully considered 
for each patient enrolling in the study based on the known safety risks related to COVID-19, 
individual needs, and local guidelines and restrictions. Investigators must continue to use their 
best clinical judgment in determining the most optimal care for patients and utmost diligence in 
determining their eligibility for study participation, continued study treatment, and overall 
assessment of benefit/risk of study treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
K 7
New Patient Enrolment
Study sites may continue to recruit new patients into the study provided the following activities 
to preserve study integrity can be met:

Upon discussion with the site monitor, the study site has confirmed the ability to enrol 
and manage new patients effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 7 (see CSP Section 5.2), patients with uncontrolled intercurrent 
illness, including but not limited to, ongoing or active infection are not eligible for the study 
participation and hence such patients (including those who have confirmed COVID 19) should 
not be included for study participation.
K 8
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
patients’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
AEs, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 along with 
logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should be 
followed, and the End of Treatment Form(s) completed

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
230 (233)
K 9
Ongoing Patients
Patients receiving study intervention should continue to undergo safety assessments prior to 
dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, study 
intervention should be interrupted until such assessments can be completed.
K 9.1
If a Patient has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health authority 
or institutional guidance. 

Signs and symptoms of COVID-19 include but are not limited to new onset of fever, new 
or worsening cough, shortness of breath, difficulty breathing and sometimes abnormal 
chest imaging and may be similar to those of an imAE. 

In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is encountered 
for a participant. 

If COVID-19 is ruled out, study intervention may be resumed per the CSP.

If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
K 9.2
Patient with Confirmed COVID-19
Patients with confirmed COVID-19 (by local laboratory testing and/or combination of key 
symptoms) should have study intervention withheld and COVID-19 managed per local guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators are 
advised to apply clinical judgement regarding the use of corticosteroids as per the durvalumab 
TMGs. This includes also the consideration of alternate immunosuppressive agents other than 
corticosteroids for imAE management, depending on the individual patient’s presentation (
Curigliano et al 2020).
K 9.3
Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
231 (233)
The study clinical lead should be contacted if any additional guidance or clarification is needed.
K 9.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated COVID-
19 vaccines as well. Investigators should apply their discretion assessing the risk-benefit of other 
types of COVID-19 vaccines for patients in clinical trials. Ideally, administration of the vaccine 
should be done on a different day other than the day of study drug administration to differentiate 
any potential AEs seen from the vaccine and study drug. The administration of the vaccine and 
any potential AEs associated with the vaccine are to be documented on the concomitant 
medication and AE eCRFs, respectively.
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance on 
the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 2, 27 
March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
232 (233)
Appendix L
Country-specific Requirements
L 1
Germany
Section # and heading
Description of change with reason
8.8.7 German biomarker sub-study 
(participating sites only)
In addition to planned biomarker analyses 
performed for the overall study patient 
population, a biomarker sub-study will be 
performed at select sites (approximately 15) 
in Germany to assess additional immune, 
mutational and/or molecular subtyping 
biomarkers from tumor samples collected at 
baseline and again at the time of cystectomy.
Below is the wording captured in the German Local CSP:
In addition to planned biomarker analyses performed for the overall study patient population, a 
biomarker sub-study will be performed at select sites (approximately 15) in Germany to assess 
additional immune, mutational and/or molecular subtyping biomarkers from tumor samples 
collected at baseline and again at the time of cystectomy. Association and correlation with 
biomarker results and clinical responses (therapy response, outcomes) will be investigated. The 
sub-study is intended to collect samples from approximately 50-80 patients recruited as part of 
the NIAGARA study (total of 1050 patients globally), at sites located in Germany only. 
Participation in this sub-study for these patients is optional and will require a separate consent 
process. 
Sample Collection for Sub-Study 
In addition to the samples described in Section 8.8.1 and 8.8.2, the following samples will be 
collected from patients that consent to the OPTIONAL sub-study:

SCREENING: An additional FFPE tissue block (or unstained slides) will be collected 
from the initial sample confirming MIBC (ie, non-MIBC samples will not be acceptable). 
Tissue can be collected from newly acquired or archival specimens (≤ 3 months olds).

CYSTECTOMY: An additional FFPE tissue block (or unstained slides) will be collected 
from samples taken at the time of cystectomy (including for patients undergoing a partial 
cystectomy). 
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.
Tumor Marker Analyses 
Samples intended for analysis as part of the German sub-study will initially be received by the 
central laboratory and will be subsequently processed, in accordance with the instructions in the 
Laboratory Manual, and sent to testing laboratory for analysis. 

Clinical Study Protocol – 7.0
AstraZeneca
Durvalumab - D933RC00001
CONFIDENTIAL AND PROPRIETARY
233 (233)
If sufficient tissue is available (after prioritization has been given to the biomarker analyses 
required for the parent NIAGARA study), the following analyses will be performed for tumor 
tissue samples obtained from patients that consented to the sub-study:
1) Intrinsic MIBC subtyping (screening samples only)

Immunohistochemical subtyping via consensus-IHC panel derived by the consensus-
working group: CK5, CK14, CK20, GATA3, FOXA1, CD44

Gene expression-based subtyping according to the TCGA-II, consensus-working-
group approach or other molecular subtyping algorithms using RNA-sequencing or 
similar technologies (e.g. Nanostring-Technology).
2) Spatial and quantitative characterization of the tumor immune microenvironment 
(screening and cystectomy samples) 

Spatial and quantitative immunoscoring of key immune cell populations (CD3, CD4, 
CD8, FOXP3, CD68, CD163, Granzyme B and MHC1) detected by 
immunohistochemistry.

Gene expression profiling of tumor and immune biomarkers using RNA-sequencing 
or similar technologies (e.g. Nanostring-Technology).

Assessment of PD-L1 status by SP263-CDA (Ventana) in post-treatment tissues and 
correlation with PD-L1 status analysis of pre-treatment tissues as implemented in 
NIAGARA-main study based on exploratory digital PD-L1- assessment

Stromal tumor infiltrating lymphocyte assessment on HE-slide.
3) Mutational profiling of tumors (screening and cystectomy samples)

Mutational next-generation sequencing (NGS)-based profiling of all tumor samples 
before treatment (TMB, mutational signatures, key genetic alterations e.g. fibroblast 
growth-factor receptor [FGFR]-alterations).

Mutational NGS-based profiling of tumors in patients without pCR (TMB, mutational 
signatures, key genetic alterations e.g. fibroblast growth-factor receptor [FGFR]-
alterations).
Specific biomarker analyses may be adjusted based on biomarker assay availability and/or 
emerging data.
Once the sub-study analyses are complete, all sub-study samples will be returned to the central 
laboratory or AZ-assigned biobank for storage. Samples will be stored for a maximum of 15 
years from the end of study, after which they will be destroyed or repatriated. Analysis of the 
exploratory biomarker data within this sub-study will be analyzed and reported independently 
from the NIAGARA study in cooperation with the BRIDGE-Consortium.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d933rc00001-csp-v7
Document Title:
D933RC00001 Clinical Study Protocol version 7
Document ID:
Doc ID-003835423
Version Label:
8.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
31-Jan-2024 11:47 UTC
Content Approval
31-Jan-2024 10:10 UTC
Qualified Person Approval
31-Jan-2024 14:54 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD