An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
Phase: PHASE3
Conditions: Ureteral Cancer, Urothelial Cancer, Bladder Cancer
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD
ISN/Protocol 7465-CL-0301
EudraCT number 2017-003344-21
- CONFIDENTIAL -
14 Sep 2020
Astellas
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Version 4.0 Incorporating Substantial Amendment 3
An Open-Label, Randomized Phase 3 Study to Evaluate 
Enfortumab Vedotin vs Chemotherapy in Subjects with 
Previously Treated Locally Advanced or Metastatic 
Urothelial Cancer (EV-301)
ISN/Protocol 7465-CL-0301
Version 4.0
Incorporating Substantial Amendment 3 [See Section 13]
14 Sep 2020
IND 116360
EudraCT 2017-003344-21
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History: 
Version 1.0 Original [20Dec2017]
Version 2.0 Incorporating Substantial Amendment 1 [22Aug2018] 
Version 3.0 Incorporating Substantial Amendment 2 [11Dec2019]
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.  
NCT03474107

Sponsor: APGD
ISN/Protocol 7465-CL-0301
EudraCT number 2017-003344-21
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Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························12
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················13
IV.
SYNOPSIS··························································································17
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································31
1
INTRODUCTION·················································································38
1.1
Urothelial Cancer··············································································38
1.2
Nonclinical and Clinical Data ·······························································39
1.2.1
Enfortumab Vedotin Nonclinical Pharmacology ····································39
1.2.2
Enfortumab Vedotin ····································································39
1.2.3
Enfortumab Vedotin Nonclinical Toxicology········································39
1.2.4
Clinical Data ·············································································41
1.3
Summary of Key Safety Information for Enfortumab Vedotin··························42
1.4
Risk Benefit Assessment ·····································································42
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS···································43
2.1
Study Objective(s) ············································································43
2.1.1
Primary Objective ·······································································43
2.1.2
Secondary Objectives ···································································43
2.1.3
Exploratory Objectives ·································································43
2.2
Study Design and Dose Rationale···························································44
2.2.1
Study Design·············································································44
2.2.2
Dose Rationale···········································································46
2.3
Endpoints·······················································································47
2.3.1
Primary Endpoints·······································································47
2.3.2
Secondary Endpoints····································································47
2.3.3
Exploratory Endpoints ··································································47
3
STUDY POPULATION··········································································48
3.1
Selection of Study Population ·······························································48
3.2
Inclusion Criteria··············································································48
3.3
Exclusion Criteria ·············································································51
4
TREATMENT(S)··················································································53

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4.1
Identification of Investigational Product(s) ················································53
4.1.1
Study Drug(s) ············································································53
4.1.2
Comparative Drug(s)····································································53
4.2
Packaging and Labeling ······································································53
4.3
Study Drug Handling ·········································································54
4.4
Blinding ························································································54
4.5
Assignment and Allocation ··································································54
5
TREATMENTS AND EVALUATION························································55
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················55
5.1.1
Dose/Dose Regimen and Administration Period ····································55
5.1.1.1
Enfortumab Vedotin·······························································55
5.1.1.2
Comparative Drug(s)······························································55
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································57
5.1.2.1
Enfortumab Vedotin·······························································57
5.1.2.2
Dose Modification for treatment with Docetaxel, Paclitaxel or 
Vinflunine ··········································································60
5.1.2.3
Docetaxel Dose Modifications ···················································62
5.1.2.4
Vinflunine Dose Modifications ··················································63
5.1.2.5
Paclitaxel Dose Modifications ···················································64
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································65
5.1.4
Treatment Compliance··································································66
5.2
Demographics and Baseline Characteristics ···············································66
5.2.1
Demographics············································································66
5.2.2
Medical History··········································································66
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············66
5.2.4
Performance Status······································································67
5.3
Efficacy Assessments·········································································67
5.3.1
Evaluation of Target Lesions ··························································68
5.3.1.1
Complete Response································································68
5.3.1.2
Partial Response ···································································68
5.3.1.3
Stable Disease······································································68
5.3.1.4
Progressive Disease ·······························································68
5.3.2
Evaluation of Nontarget Lesions ······················································68
5.3.2.1
Complete Response································································68

Sponsor: APGD
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5.3.2.2
NonCR/NonPD ····································································68
5.3.2.3
Progressive Disease ·······························································69
5.3.3
Evaluation of Time Point Response···················································69
5.4
Pharmacokinetic Assessment ································································69
5.5
Safety Assessment ············································································69
5.5.1
Vital Signs················································································69
5.5.2
Adverse Events ··········································································69
5.5.2.1
Adverse Events of Possible Hepatic Origin ····································69
5.5.3
Laboratory Assessments································································70
5.5.4
Physical Examination···································································71
5.5.5
Ophthalmology Examination ··························································71
5.5.6
Electrocardiogram·······································································71
5.6
Adverse Events and Other Safety Aspects ·················································71
5.6.1
Definition of Adverse Events ··························································71
5.6.1.1
Abnormal Laboratory Findings ··················································72
5.6.1.2
Potential Cases of Drug-Induced Liver Injury ·································72
5.6.1.3
Disease Progression and Study Endpoints······································72
5.6.2
Definition of Serious Adverse Events (SAEs) ·······································73
5.6.3
Criteria for Causal Relationship to Study Drug······································73
5.6.4
Criteria for Defining the Severity of an Adverse Event ····························74
5.6.5
Reporting of Serious Adverse Events·················································75
5.6.6
Follow-up of Adverse Events··························································77
5.6.7
Monitoring of Common Serious Adverse Events ···································77
5.6.8
Special Situations········································································77
5.6.8.1
Pregnancy···········································································78
5.6.8.2
Medication Error, Overdose and “Off-Label Use” ····························79
5.6.8.3
Misuse/Abuse ······································································79
5.6.8.4
Occupational Exposure ···························································79
5.6.8.5
Suspected Drug-Drug Interaction················································79
5.6.9
Supply of New Information Affecting the Conduct of the Study··················80
5.6.10
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Unique to Japan)····································80
5.7
Test Drug Concentration ·····································································81
5.8
Other Measurements, Assessments or Methods ···········································81
5.8.1
Exploratory Biomarker ·································································81

Sponsor: APGD
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5.8.2
Biomarkers in Blood ····································································81
5.8.3
Biomarkers in Pre-Treatment Tumor Tissue·········································81
5.8.4
Blood Sample for Future Pharmacogenomic Analysis (Retrospective)···········81
5.8.5
EORTC Core Quality of Life Questionnaire, QLQ-C30 ···························82
5.8.6
EuroQOL-5 Dimensions································································82
5.8.7
Healthcare Resource Utilization (HRU)··············································82
5.9
Total Amount of Blood·······································································82
6
DISCONTINUATION············································································83
6.1
Discontinuation of Individual Subject(s)···················································83
6.2
Discontinuation of the Site···································································84
6.3
Discontinuation of the Study·································································84
7
STATISTICAL METHODOLOGY ···························································85
7.1
Sample Size····················································································85
7.2
Analysis Sets···················································································85
7.2.1
Full Analysis Set ········································································85
7.2.2
Safety Analysis Set······································································85
7.2.3
Response Evaluable Set ································································85
7.2.4
Pharmacokinetic Analysis Set ·························································86
7.3
Demographics and Baseline Characteristics ···············································86
7.3.1
Subject Disposition······································································86
7.3.2
Previous and Concomitant Medications ··············································86
7.3.3
Medical History··········································································86
7.4
Analysis of Efficacy ··········································································86
7.4.1
Analysis of Primary Endpoint ·························································87
7.4.1.1
Primary Analysis···································································87
7.4.1.2
Sensitivity Analysis ·······························································87
7.4.2
Analysis of Secondary Endpoints ·····················································87
7.4.2.1
Progression Free Survival ························································87
7.4.2.2
Overall Response Rate ····························································88
7.4.2.3
Duration of Response ·····························································88
7.4.2.4
Disease Control Rate (DCR) ·····················································88
7.4.2.5
QOL and PRO Parameters························································88
7.4.3
Subgroup Analysis ······································································88
7.4.4
Analysis of Exploratory Endpoints····················································89

Sponsor: APGD
ISN/Protocol 7465-CL-0301
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7.5
Analysis of Safety·············································································89
7.5.1
Adverse Events ··········································································89
7.5.2
Laboratory Assessments································································90
7.5.3
Vital Signs················································································90
7.5.4
Routine 12-lead Electrocardiograms ··················································90
7.5.5
ECOG Performance Status ·····························································90
7.5.6
Exposure-Response Relationship Analysis···········································90
7.6
Analysis of Pharmacokinetics ·······························································90
7.7
Major Protocol Deviations and Other Analyses···········································90
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················91
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········91
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················91
8.1
Procedure for Clinical Study Quality Control ·············································91
8.1.1
Data Collection ··········································································91
8.1.2
Specification of Source Documents···················································92
8.1.3
Clinical Study Monitoring······························································93
8.1.4
Direct Access to Source Data/Documents············································93
8.1.5
Data Management ·······································································93
8.1.6
Major Protocol Deviations ·····························································93
8.1.7
End of Trial in All Participating Countries···········································94
8.2
Ethics and Protection of Subject Confidentiality··········································94
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities················································································94
8.2.2
Ethical Conduct of the Study···························································95
8.2.3
Informed Consent of Subjects ·························································95
8.2.3.1
Subject Information and Consent················································95
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························95
8.2.4
Subject Confidentiality and Privacy···················································96
8.3
Administrative Matters ·······································································96
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····96
8.3.2
Documents and Records Related to the Clinical Study ·····························97
8.3.3
Protocol Amendment and/or Revision················································98
8.3.4
Insurance of Subjects and Others······················································99
8.3.5
Signatory Investigator for Clinical Study Report····································99

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9
QUALITY ASSURANCE······································································ 100
10
STUDY ORGANIZATION···································································· 100
10.1
Independent Data-Monitoring Committee ··············································· 100
11
REFERENCES ·················································································· 101
12
APPENDICES ··················································································· 103
12.1
List of Cautionary Concomitant Medications············································ 103
12.2
Liver Safety Monitoring and Assessment ················································ 104
12.3
Common Serious Adverse Events························································· 107
12.4
Retrospective PGx Sub-Study ····························································· 108
12.5
EORTC-QLQ-30············································································ 110
12.6
EQ-5D-5L···················································································· 112
12.7
Health Resource Utilization································································ 114
12.8
RECIST V1.1················································································ 116
12.9
ECOG Performance Status································································· 118
12.10
Crossover Extension ········································································ 119
12.10.1
Rationale················································································ 119
12.10.2
Inclusion Criteria ······································································ 119
12.10.3
Exclusion Criteria ····································································· 119
12.10.4
Schedule and Assessments ··························································· 120
12.10.5
Duration of Treatment and Discontinuation Criteria······························ 126
12.10.6
Statistical Methods ···································································· 127
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 3 ································ 128
14
COORDINATING INVESTIGATOR’S SIGNATURE·································· 142
15
SPONSOR’S SIGNATURES·································································· 143

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I.
SIGNATURES
1.
AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND 
THE INVESTIGATOR
This clinical study will be conducted in adherence to GCP, ICH Guidelines and applicable 
laws and regulatory requirements, as well as this study protocol. As the evidence of the 
agreement, the investigator (CHIKEN SEKININ ISHI) and responsible person of the Sponsor 
(CHIKEN IRAI SEKININSHA) inscribe in the bipartite agreement by signature or “printed 
name and seal”. 

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2.
SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 15
Sponsor’s Signatures], located at the end of this document.

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3.
COORDINATING INVESTIGATOR’S SIGNATURE
The Coordinating Investigator’s signature can be found in [Section 14 Coordinating 
Investigator’s Signature].

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4.
INVESTIGATOR’S SIGNATURE
An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs 
Chemotherapy in Subjects with Previously Treated Locally Advanced or 
Metastatic Urothelial Cancer (EV-301)
ISN/Protocol 7465-CL-0301
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I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set 
out therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations. I 
will also ensure that subinvestigator(s) and other relevant members of my staff have access to 
copies of this protocol and the ICH GCP guidelines to enable them to work in accordance with the 
provisions of these documents.
Principal Investigator:
Signature:
Printed Name:-----------------------------------------------------------------------
Date (DD MMM YYYY)
<Insert name and qualification of the Investigator>
Address:

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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ADC
Antibody drug conjugate
AE
adverse event
Alb
albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APEBV
Astellas Pharma Europe B.V.
APGD
Astellas Pharma Global Development
AST
aspartate aminotransferase
AT
aminotransferases
ATA
antitherapeutic antibodies
AUST
Astellas US Technologies 
BLOQ
below the lower limit of quantification
BUN
blood urea nitrogen
CA
competent authority
cfDNA
circulating free deoxyribonucleic acid
CFR
Code of Federal Regulations
CHO
Chinese Hamster Ovary
CIOMS
council for international organizations of medical sciences
CNS
central nervous system
CPI
checkpoint inhibitor
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation 
COE
crossover extension
CYP3A4
cytochrome P450 3A4
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data capture
EEA
European Economic Area 

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Abbreviations
Description of abbreviations
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
ePRO
electronic patient reported outcome
EQ-5D-5L
EuroQOL 5-dimensions
EV
enfortumab vedotin
FAS
full analysis set
FDA
Food and Drug Administration
GCP
good clinical practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GMP
good manufacturing practice
HbA1c
Hemoglobin A1c
HBsAg
hepatitis B surface antigen
Hct
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HIPAA
health insurance portability and accountability act
HIV
human immunodeficiency virus
HRU
healthcare resource utilization 
IARC
International Agency for Research on Cancer
IB
Investigator’s Brochure
ICF
informed consent form
ICH 
International Council for Harmonisation
IDAC
Independent data analysis center
IDMC
Independent data monitoring committee
IEC
independent ethics committee
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
ITT
Intent to treat
ISN
international study number
IUD
intrauterine device
IUS
intrauterine hormone releasing system 
LA-CRF
liver abnormality case report form
LFT
liver function test
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mUC
metastatic urothelial cancer
MVAC
methotrexate, vinblastine, doxorubicin, and cisplatin

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Abbreviations
Description of abbreviations
NCI-CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
NOAEL
no observed adverse effect level
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PDAS
pharmacodynamics analysis set
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PFS
progression free survival
P-gp
p-glycoprotein
PGx
pharmacogenomics analyses
PKAS
pharmacokinetic analysis set
PR
partial response
PRES
posterior reversible encephalopathy syndrome 
PRO
patient reported outcome
QLQ-C30
EORTC Quality of Life Questionnaire
QOL
quality of life
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RES
response evaluable set
ROW
rest of the world
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SD
stable disease
SmPC
Summary of product characteristics
SOP
standard operating Procedure
Tab
total antibody
TBL
total bilirubin
TEAE
treatment emergent adverse events
TMF
trial master file
TP
total protein
ULN
upper limit of normal
US
United States
WBC
white blood cell

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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Assessments of subjects as they enter a trial before they receive any 
treatment. 
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject. 
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for 
participation in a trial.
Screening period
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.

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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
14 Sep 2020, Version 4.0 
Study Sponsor:  
Astellas Pharma Global Development Inc. (APGD)
Study Collaborator: 
Seattle Genetics, Inc. 
Protocol Number: 
7465-CL-0301
Name of Study Drug: 
Enfortumab Vedotin (ASG-22CE)
Phase of Development: 
Phase 3
Title of Study:  
An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in
Subjects with Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
Planned Study Period:
2Q2018 to 2Q2021. The planned study enrollment is approximately 24 months from first subject 
enrolled with an additional 12 months anticipated for overall survival (OS) follow-up after the last 
subject enrolled. The total study duration will be approximately 36 months. 
Study Objective(s):
Primary 
To compare the OS of subjects with locally advanced or metastatic urothelial cancer treated 
with enfortumab vedotin (EV) to the OS of subjects treated with chemotherapy 
Secondary 
To compare progression-free survival on study therapy (PFS1) per Response Evaluation 
Criteria in Solid Tumors (RECIST) V1.1 of subjects treated with EV to subjects treated with 
chemotherapy
To compare the overall response rate (ORR) per RECIST V1.1 of EV to chemotherapy
To evaluate the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy
To compare the disease control rate (DCR) per RECIST V1.1 of EV to chemotherapy
To assess the safety and tolerability of EV
To assess quality of life (QOL) and Patient Reported Outcomes (PRO) parameters
Exploratory
Exploratory genomic and/or other biomarkers in tumor tissue and in peripheral blood that may 
correlate with treatment outcome, including Nectin-4 expression
To assess the pharmacokinetics of EV (total antibody [TAb], antibody-drug conjugate [ADC] 
and monomethyl auristatin E [MMAE])
To assess the incidence of antitherapeutic antibodies (ATA) 
To evaluate PFS as assessed by RECIST V1.1 by investigator review in the next line of 
therapy (PFS2) in subjects treated with EV compared to chemotherapy
Healthcare resources utilization (HRU)
Planned Total Number of Study Centers and Locations:  
Approximately 185 study centers in North America, Europe, Asia Pacific and Latin America
Study Population:  
Subjects with locally advanced or metastatic urothelial cancer previously treated with platinum-
based chemotherapy and an immune checkpoint inhibitor (CPI)

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Number of Subjects to be Enrolled / Randomized:  
Approximately 600 subjects
Study Design Overview:  
This is a global, open-label, randomized Phase 3 study in adult subjects with locally advanced or 
metastatic urothelial cancer who have received a platinum-containing chemotherapy and have 
experienced disease progression or relapse during or following treatment with an immune 
checkpoint inhibitor. Approximately 600 subjects will be randomized to EV (Arm A) or 
chemotherapy (Arm B) in a 1:1 ratio. Subjects will be stratified according to the following: 
Eastern Cooperative Oncology Group Performance Status (ECOG PS), regions of the world and 
liver metastasis.
OS is the primary endpoint. OS is defined as the time from randomization to the date of death. 
Secondary endpoints include PFS1, ORR, DOR, DCR, safety and QOL/PRO. 
Subjects in Arm A will receive EV on Days 1, 8 and 15 of each 28-day cycle. Subjects in arm B 
will receive docetaxel, paclitaxel or vinflunine (as decided by the investigator prior to 
randomization: vinflunine is a choice of comparator only in countries where it is approved for 
urothelial cancer) on Day 1 of every 21-day cycle. Within the control arm, the overall proportion 
of subjects receiving vinflunine will be capped at approximately 35%. Subjects will continue to 
receive study treatment until radiological disease progression as determined per investigator 
assessment or other discontinuation criteria are met or upon study termination, or study 
completion, whichever occurs first. No on-study crossover will be allowed other than as allowed 
in [Appendix 12.10]. This study will consist of 3 phases: screening, treatment and follow-up.
Screening will take place up to 28 days prior to randomization. Subjects will start with cycle 1 
and continue on to subsequent 21-day or 28-day cycles until one of the discontinuation criteria are 
met. A treatment cycle is defined as 28 days for Arm A and 21 days for Arm B. Subjects 
randomized to Arm A (EV) will receive treatment and evaluation on Days 1, 8 and 15 of all 
treatment cycles. Subjects randomized to Arm B (docetaxel, paclitaxel or vinflunine) will receive 
treatment and evaluation on Day 1 of all treatment cycles.
Subjects will be evaluated for response according to the RECIST V1.1. Imaging for both arms 
will be performed at baseline and every 56 days (± 7 days) from the first dose of study treatment 
throughout the study until PFS1 is documented by radiological disease progression or the subject 
is lost to follow-up, death, withdraws study consent or starts a subsequent anti-cancer therapy. 
Baseline imaging performed prior to informed consent as standard of care may be used so long as 
it is performed within 28 days prior to randomization. All subjects will have a bone scan 
(scintigraphy) performed at screening/baseline. Subjects with positive bone scans at baseline will 
have a bone scan performed every 56 days (± 7 days) throughout the study or more frequently if 
clinically indicated. Subjects should have a follow-up bone scan performed if clinically indicated 
regardless of baseline status. Brain scans (computed tomography with contrast/magnetic 
resonance imaging [MRI]) will only be performed if clinically indicated at screening/baseline and 
repeated as clinically indicated or per standard of care throughout the study. 
QOL assessments and PRO will be collected at protocol-specified time points from all 
randomized subjects. The following validated tools will be used: European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and 
EuroQOL 5-dimensions (EQ-5D-5L). Healthcare Resource Utilization (HRU) information will be 
collected at protocol-specified time points with particular focus on the number of subjects who 
have an unplanned use of healthcare resources related to clinical or AEs from subjects assigned to 
treatment arms A and B.

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Blood samples for pharmacokinetics and ATA will be collected throughout the study for subjects 
randomized into Arm A. Validated assays will be used to measure the concentrations of EV ADC 
and MMAE in serum or plasma and to assess ATA. Pharmacokinetic samples will not be collected 
from subjects randomized into Arm B. Samples for exploratory biomarkers will be collected at 
protocol-specified time points. Biomarker assessments will not be used for subject selection.  
Following discontinuation from study drug, subjects will have a follow-up visit 30 days (+ 7 days) 
after their last dose of drug for safety assessments. If a subject discontinues study drug prior to 
radiographic disease progression (i.e., PFS1), the subject should enter the post treatment follow-up 
period and continue to undergo imaging assessments every 56 days (± 7 days) until PFS1 is 
documented or the subject starts another anticancer treatment, whichever occurs earlier. 
Following PFS1, subjects will enter the long-term follow-up period and be followed per 
institutional guidelines, but not less than every 3 months from the date of the follow-up visit for 
survival status and progression status on subsequent therapy (i.e., PFS2). 
Subjects will be followed until PFS2 is documented or the subject starts another anticancer 
treatment, whichever occurs earlier. All subsequent anticancer therapy including date and site of 
progression for PFS2 will be recorded on the case report form. 
Following PFS2, subjects will enter the survival follow-up period and be followed every 3 months 
for survival status until death, lost to follow-up, withdrawal of study consent, or study termination 
by sponsor. This study is expected to end once final survival analysis is complete.
An Independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and the 
planned interim efficacy analysis, which will occur after at least 285 OS events (about 65% of the 
total planned events) are observed. The primary analysis will occur at 439 OS events. The IDMC 
may recommend to the sponsor whether the trial should be terminated, modified or continue 
unchanged based on ongoing reviews of safety data and interim efficacy analysis. Further details 
will be outlined in the IDMC charter.
Inclusion/Exclusion Criteria:
Inclusion:
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from 
the subject prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).
2.
Subject is legally an adult according to local regulation at the time of signing informed 
consent.
3.
Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the 
bladder, renal pelvis, ureter or urethra). Subjects with urothelial carcinoma (transitional cell) 
with squamous differentiation or mixed cell types are eligible.
4.
Subject must have experienced radiographic progression or relapse during or after a CPI (anti-
programmed cell death-1 [PD-1] or anti-programmed cell death-ligand 1 [PD-L1]) for locally 
advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are 
eligible provided that they have evidence of disease progression following discontinuation. The 
CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a 
non-CPI based regimen are eligible if they have progressed/relapsed during or after their most 
recent therapy. Locally advanced disease must not be amenable to resection with curative 
intent per the treating physician.

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Inclusion/Exclusion Criteria:
Inclusion continued:
5.
Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the 
metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in 
the adjuvant/neoadjuvant setting subject must have progressed within 12 months of 
completion.
6.
Subject has radiologically documented metastatic or locally advanced disease at baseline.
7.
An archival tumor tissue sample should be available for submission to central laboratory prior 
to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample 
should be provided. If a fresh tissue sample cannot be provided due to safety concerns, 
enrollment into the study must be discussed with the medical monitor. 
8.
Subject has ECOG PS of 0 or 1
9.
The subject has the following baseline laboratory data:
absolute neutrophil count (ANC) ≥ 1500/mm3
platelet count ≥100 × 109/L
hemoglobin ≥9 g/dL
serum total bilirubin ≤ 1.5 × upper limit of normal (ULN)* or ≤ 3 × ULN for subjects 
with Gilbert’s disease
creatinine clearance (CrCl) ≥30 mL/min as estimated per institutional standards or as 
measured by 24 hour urine collection (glomerular filtration rate [GFR] can also be used 
instead of CrCl)
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN or 
≤3 × ULN for subjects with liver metastases*
* Docetaxel should not be chosen as a comparator for subjects if total bilirubin > ULN, or 
if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. 
10. Female subject must either:
Be of nonchildbearing potential:
Postmenopausal (defined as at least 1 year without any menses for which there is no 
other obvious pathological or physiological cause) prior to screening, or 
Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy).
Note: Those who are amenorrheic due to an alternative medical cause are not considered 
postmenopausal and must follow the criteria for childbearing potential subjects.
Or, if of childbearing potential: 
Agree not to try to become pregnant during the study and for at least 6 months after 
the final study drug administration,
And have a negative urine or serum pregnancy test within 7 days prior to Day 1 
(Females with false positive results and documented verification of negative 
pregnancy status are eligible for participation),
And if heterosexually active, agree to consistently use a condom plus 1 form of 
highly effective birth control * per locally accepted standards starting at screening 
and throughout the study period and for at least 6 months after the final study drug 
administration.
11. Female subject must agree not to breastfeed or donate ova starting at screening and throughout 
the study period, and for at least 6 months after the final study drug administration.

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12. A sexually active male subject with female partner(s) who is of childbearing potential is 
eligible if:
Agrees to use a male condom starting at screening and continue throughout the study 
treatment and for at least 6 months after final study drug administration. If the male 
subject has not had a vasectomy or is not sterile as defined below their female partner(s) 
is utilizing 1 form of highly effective birth control* per locally accepted standards starting 
at screening and continue throughout study treatment and for at least 6 months after the 
male subject receives his final study drug administration.
*Highly effective forms of birth control include:
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,
Established intrauterine device (IUD) or intrauterine hormone releasing system (IUS).
Bilateral tubal occlusion
Vasectomy (A vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used)
Male is sterile due to a bilateral orchiectomy or radical cystoprostatectomy/removal of 
seminal vesicles
Sexual Abstinence is considered a highly effective method only if defined as refraining 
from heterosexual activity during the entire period of risk associated with the study 
drug. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
  Please note: Sexual abstinence is not sufficient as contraception method in Switzerland.
13. Male subject must not donate sperm starting at screening and throughout the study period, and 
for at least 6 months after the final study drug administration.
14. Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a 
condom for the duration of the pregnancy or time partner is breastfeeding throughout the study 
period and for at least 6 months after the final study drug administration.
15. Subject agrees not to participate in another interventional study while on treatment in present 
study.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion:
Subject will be excluded from participation if any of the following apply:
1.
Subject has preexisting sensory or motor neuropathy Grade ≥2.
2.
Subject has active central nervous system (CNS) metastases. Subjects with treated CNS 
metastases are permitted on study if all the following are true:
CNS metastases have been clinically stable for at least 6 weeks prior to screening 
If requiring steroid treatment for CNS metastases, the subject is on a stable dose 
≤20 mg/day of prednisone or equivalent for at least 2 weeks
Baseline scans show no evidence of new or enlarged brain metastasis
Subject does not have leptomeningeal disease

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3.
Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of 
alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). 
Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be 
enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if 
indicated). Patients with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or 
panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, 
myocarditis, or pneumonitis or subjects with other immunotherapy related AEs requiring high 
doses of steroids (> 20 mg/day of prednisone or equivalent) are excluded.
4.
Subject has prior treatment with EV or other MMAE-based ADCs.
5.
Subject has received prior chemotherapy for urothelial cancer with all available study therapies 
in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not 
an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine 
is an approved therapy).
Note:  After vinflunine cap is reached subjects who have received both docetaxel and 
paclitaxel will be excluded.
6. Subject has received more than 1 prior chemotherapy regimen for locally advanced or 
metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if 
recurrence occurred within 12 months of completing therapy. The substitution of carboplatin 
for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were 
added to the regimen.
7. Subject has history of another malignancy within 3 years before the first dose of study drug, or 
any evidence of residual disease from a previously diagnosed malignancy. Subjects with 
nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no 
evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate 
cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of 
any type (if complete resection was performed) are allowed.
8.
Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal 
infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted.
9.
Subject has known active Hepatitis B (e.g., HBsAg reactive) or active hepatitis C (e.g., HCV
RNA [qualitative] is detected). 
10. Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
11. Subject has documented history of a cerebral vascular event (stroke or transient ischemic 
attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive 
heart failure) consistent with New York Heart Association Class III to IV within 6 months prior 
to the first dose of study drug. 
12. Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug. 
13. Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment 
with immunotherapy that is not completed 2 weeks prior to first dose of study drug. 
14. Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation 
of EV (including histidine, trehalose dihydrate, and polysorbate 20); OR subject has known 
hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells. 

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15. Subject has known hypersensitivity to: 

docetaxel or to any of the other excipients listed in product label, including polysorbate 80;

paclitaxel or to any of the other excipients listed in product label, including 
macrogolglycerol ricinoleate 35 (Ph.Eur.); and 

vinflunine or to any of the other excipients listed in product label, including other vinca 
alkaloids (vinblastine, vincristine, vindesine, vinorelbine).
16. [Criterion removed]. 
17. Subject has known active keratitis or corneal ulcerations. Subject with superficial punctate 
keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
18. Subject has other underlying medical condition that, in the opinion of the investigator, would 
impair the ability of the subject to receive or tolerate the planned treatment and follow-up. 
19. History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. 
Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 
and < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise 
explained.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product: 
Enfortumab Vedotin 
Dose, Mode of Administration and Dose Modification:
EV 1.25 mg/kg will be administered on Days 1, 8, and 15 of every 28-day cycle. The 
investigational product will be administered intravenously over a 30-minute period. 
EV will be administered based on the subject’s actual body weight on Day 1 of every cycle except 
for subjects weighing greater than 100 kg; in such cases, the dose will be calculated based on a 
maximum weight of 100 kg. The dose does not need to be re-calculated based on actual weight on 
Day 8 and 15 of each cycle for Arm A unless it is required by institutional standards.
Dose reduction to 1 mg/kg (dose level - 1) and to 0.75 mg/kg (dose level - 2) will be allowed 
depending on the type and severity of toxicity. Subjects requiring a dose reduction may be re-
escalated by 1 dose level (i.e., subjects reduced to 0.75 mg/kg may only be re-escalated to 1 mg/kg) 
provided the toxicity does not require study drug discontinuation and has returned to baseline or 
≤Grade 1. If the toxicity recurs, re-escalation will not be permitted. Subjects with ≥Grade 2 
corneal AEs will not be permitted to dose re-escalate. EV should not be administered to subjects 
with CrCl < 30 mL/min. Dose modification recommendations for EV associated toxicity are 
presented in [Table A] and [Table B].
Dose interruptions for other EV associated toxicity is permitted at the discretion of the site 
investigator. Dose interruptions may last up to 8 weeks (2 cycles). Dose interruptions for subjects 
who are deriving clinical benefit from treatment may be extended beyond 8 weeks, if the subject’s 
toxicity does not otherwise require permanent discontinuation. If there is a dose interruption, the 
schedule for response assessments will not be adjusted.

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Table A
Recommended dose modifications for enfortumab vedotin associated hematologic 
toxicity*
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose 
level.
Continue at same dose 
level.
For Grade 2
thrombocytopenia, 
withhold
dose until toxicity is
≤ Grade 1 or has returned 
to baseline, then resume
treatment at the same dose
level.
Withhold dose until 
toxicity is ≤ Grade 1 or has 
returned to baseline, then 
resume treatment at the 
same dose level or consider 
dose reduction by 1 dose 
level.
Transfusions or growth
factors may be used as
indicated per institutional
guidelines.
Withhold dose until 
toxicity is ≤ Grade 1 or has 
returned to baseline, then 
reduce dose by 1 dose level 
and resume treatment, or 
discontinue at the 
discretion of the
investigator. 
Transfusions or growth
factors may be used as
indicated per institutional
guidelines.
For anemia, treatment 
discontinuation should be 
strongly considered.
*Note: hematological toxicity refers to anemia, thrombocytopenia, neutropenia and febrile neutropenia.
Table B
Recommended dose modifications for enfortumab vedotin associated 
nonhematologic toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose 
level.
If ocular symptoms and/or 
changes in vision are 
identified, the subject 
should be evaluated with an 
ophthalmologic exam.**
Continue at same dose 
level, except in the event 
of Grade 2 neuropathy or 
corneal AEs.
For Grade 2 neuropathy or 
corneal AE’s, withhold 
dose until toxicity is 
≤Grade 1 or has returned 
to baseline, and then 
resume treatment at the 
same dose level. For the 
second occurrence of 
Grade 2 neuropathy or 
corneal AE’s withhold 
dose until toxicity is ≤ 
Grade 1, and then reduce 
the dose by 1 dose level 
and resume treatment.
If ocular symptoms and/or 
changes in vision are 
identified, the subject 
should be evaluated with an 
ophthalmologic exam.**
Withhold dose until 
toxicity is ≤ Grade 1 or has 
returned to baseline, then 
resume treatment at the 
same dose level or 
consider dose reduction by 
1 dose level.*
For Grade 3 neuropathy or 
corneal AEs, discontinue 
treatment 
For Grade 3 
hyperglycemia/elevated 
blood glucose, withhold 
EV treatment. Resume 
treatment once 
hyperglycemia/elevated 
blood glucose has 
improved to ≤ Grade 2 and 
subject is clinically and 
metabolically stable. 
If ocular symptoms and/or 
changes in vision are 
identified, the subject 
should be evaluated with an 
ophthalmologic exam.**
For Grade 4 AEs, 
discontinue treatment.*
Grade 4 vomiting and/or 
diarrhea that improves to 
≤Grade 2 within 72 hours 
with supportive 
management does not 
require discontinuation.
AE: adverse events; EV: enfortumab vedotin
* Grade 3/4 electrolyte imbalances/laboratory abnormalities that are not associated with clinical sequelae and/or are 
corrected with supplementation/appropriate management within 72 hours of their onset do not require discontinuation 
(e.g., Grade 4 hyperuricemia). Grade 3 rash that is not limiting self-care activities of daily living or associated with 
infection requiring systemic antibiotics does not require treatment interruption, provided symptoms are not severe and 
can be managed with supportive treatment.
**Ophthalmologic exam should be performed by an ophthalmologist. In countries where optometrists can perform exams 
and prescribe medications, an optometrist may be used instead.

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Comparative Drug(s):  
In general, treatment with the chemotherapy comparators (docetaxel, paclitaxel or vinflunine) 
should be withheld for drug related Grade 4 hematologic toxicities and for non-hematologic 
toxicities ≥Grade 3, and subsequent doses modified as per Table 6. Recommended dose 
modification guidelines specific for subjects receiving docetaxel, paclitaxel or vinflunine are 
detailed below. Dose modifications should also be considered according to local product labels or 
summary of product characteristics (SmPC) and institutional guidelines. For docetaxel, paclitaxel
or vinflunine associated hematologic toxicities ≥ Grade 3, transfusions or growth factors may be 
used as indicated per institutional guidelines.
Docetaxel
Dose, Mode of Administration and Dose Modification: 
Docetaxel will be administered intravenously on Day 1 of every 21-day cycle. The starting dose of 
docetaxel 75 mg/m2 will be administered over 60-minute period or per local requirement. Refer to 
local product label or SmPC and institution guidelines for docetaxel for further guidance on 
docetaxel dosing.
Docetaxel should not be given to subjects with total bilirubin > ULN, or to subjects with AST 
and/or ALT > 1.5 × ULN with concomitant alkaline phosphatase > 2.5 × ULN. Subjects with 
elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at 
increased risk for the development of Grade 4 neutropenia, febrile neutropenia, infections, severe 
thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Docetaxel should also 
not be given to subjects with a neutrophil count of < 1500 cells/mm3. Severe fluid retention has 
been reported following docetaxel therapy.
Subjects should be premedicated with corticosteroids per institutional guidelines prior to each 
docetaxel administration. Subjects with pre-existing effusions should be closely monitored from 
the first dose for the possible exacerbation of the effusions. Subjects developing peripheral edema 
may be treated with standard measures, e.g., salt restriction, oral diuretic(s). Dose interruptions 
may last up to 6 weeks (2 cycles). Dose interruptions for subjects who are deriving clinical benefit 
from treatment may be extended beyond 6 weeks, if the subject’s toxicity does not otherwise 
require permanent discontinuation.
Dose modifications not specified in Table C (e.g., severe or cumulative cutaneous reactions) 
should also be considered according to local product label or SmPC and institutional guidelines.
Table C
Recommended dose modifications for subjects receiving docetaxel
Toxicity
Grade 
Occurrence
Hold Treatment 
Dose Modification
Discontinue 
Treatment 
Peripheral
Neuropathy
Grade 1, 
2
No
60 mg/m2
N/A
Grade 3, 
4
Yes
N/A
Discontinue 
upon onset
Neutropenic
fever (defined as
T ≥100.5°F (38.1°C) 
and
ANC ≤ 1,000/L)
1
Hold treatment 
until ANC
≥1,500/L
60 mg/m2
2
Hold treatment 
until ANC
≥1,500/L
50 mg/m2
3
Yes
N/A
Yes
ANC: absolute neutrophil count; N/A: not applicable; T: temperature

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Vinflunine
Dose, Mode of Administration and Dose Modification: 
Vinflunine will be administered intravenously on Day 1 of every 21-day cycle. The starting dose of 
vinflunine 320 mg/m2 will be administered over a 20-minute period (or per local requirement) 
unless otherwise specified below. In case of WHO/ECOG PS of ≥1 or ECOG PS of 0 and prior 
pelvic irradiation, vinflunine treatment should be started at the dose of 280 mg/m². In the absence 
of any hematological toxicity during the first cycle causing treatment delay or dose reduction, the 
dose may be increased to 320 mg/m² every 21-days for the subsequent cycles.
In subjects with moderate renal impairment (40 mL/min ≤CrCl ≤60 mL/min), the recommended 
dose is 280 mg/m² given once every 21-day cycle. In subjects with renal impairment 
(30 mL/min ≤CrCl < 40 mL/min), the recommended dose is 250 mg/m² given once every 21-day 
cycle. The recommended dose of vinflunine is 250 mg/m² given once every 21-day cycle in 
subjects with mild liver impairment (Child-Pugh grade A). 
The doses recommended in subjects ≥75 years old are as follows:

in subjects at least 75 years old but less than 80 years, the dose of vinflunine to be given is 
280 mg/m² every 21-day cycle.

in subjects 80 years old and beyond, the dose of vinflunine to be given is 250 mg/m² every 
21-day cycle.
Refer to local product label or SmPC and institution guidelines for vinflunine for further guidance 
on vinflunine dosing.
Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for subjects who are 
deriving clinical benefit from treatment may be extended beyond 6 weeks, if the subject’s toxicity 
does not otherwise require permanent discontinuation. Please refer to the approved product label 
for specific dose modifications for subjects receiving vinflunine.
Paclitaxel
Dose, Mode of Administration and Dose Modification: 
Study treatment of paclitaxel should be administered intravenously on Day 1 of every 21-day cycle 
after all procedures/assessments have been completed. The starting dose of paclitaxel 175 mg/m2
will be administered as an intravenous infusion administered over 3 hours or per local requirement 
See guidelines on adjustment of initial dose. Refer to local product label or SmPC and institution 
guidelines for paclitaxel for further guidance on paclitaxel dosing.
All subjects should be premedicated prior to paclitaxel administration per institutional guidelines in 
order to prevent severe hypersensitivity reactions. Such premedication may consist of 
dexamethasone 20 mg orally administered approximately 12 and 6 hours before paclitaxel, 
diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine 
(300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel. The appropriate 
premedication regimen may be determined by the investigator.
Paclitaxel should not be administered to subjects with baseline neutrophil counts of less 
than 1500 cells/mm3. Subjects should not be re-treated with subsequent cycles of 
paclitaxel until neutrophils recover to a level > 1500 cells/mm3 and platelets recover to a 
level > 100000/mm3. Severe conduction abnormalities have been documented in < 1% of 
subjects during paclitaxel therapy and in some cases requiring pacemaker placement. If 
subjects develop significant conduction abnormalities during paclitaxel infusion, 
appropriate therapy should be administered and continuous cardiac monitoring should be 
performed during subsequent therapy with paclitaxel.

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In case of mild hepatic impairment (total bilirubin ≥1.25 ULN), paclitaxel should be started at a 
dose of 135 mg/m2. 
Recommended dose modification guidelines specific for subjects receiving paclitaxel are detailed 
in Table D below. Dose modifications should also be considered according to local product label or 
SmPC and institutional guidelines. 
Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for subjects who are 
deriving clinical benefit from treatment may be extended beyond 6 weeks, if the subject’s toxicity 
does not otherwise require permanent discontinuation.
Table D
Recommended dose modifications for subjects receiving paclitaxel
Toxicity 
Grade 
Occurrence 
Hold
Treatment
Dose
Modification
Treatment
Discontinuation
Peripheral
Neuropathy
Grade 1, 2 
No
135 mg/m2
N/A
Grade 3, 4 
Yes
N/A
Discontinue upon 
onset
Neutropenic
fever (defined as
T ≥100.5°F 
(38.1°C) and
ANC ≤1,000/L)
1
Hold until 
ANC 
≥1,500/L
135 mg/m2
2
Hold until 
ANC 
≥1,500/L
100 mg/m2
3
yes
N/A
Yes
N/A: not applicable; T: temperature
Discontinuation Criteria:
A discontinuation from treatment applies to a subject who enrolled in the study and for whom 
study treatment is permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice. The investigator is also 
free to discontinue the subject from study treatment or to terminate a subject's involvement in the 
study at any time if the subject's clinical condition warrants it. If a subject is discontinued from the 
study with an ongoing adverse event (AE) or an unresolved laboratory result that is significantly 
outside of the reference range, the investigator will attempt to provide follow-up until the condition 
stabilizes or no longer is clinically significant. 
The following are discontinuation criteria from treatment for individual subjects:
Subject develops radiological disease progression.  
Subject is required to receive another systemic anti-cancer treatment for underlying or new 
cancer.
Subject develops unacceptable toxicity.
Female subject becomes pregnant.
Investigator decides it is in the subject’s best interest to discontinue. 
Subject declines further treatment.
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment.

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Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject.
Death.
Subjects who discontinue treatment prior to radiological disease progression will enter the post
treatment follow-up period and continue to undergo imaging assessments every 56 days (± 7 days) 
until PFS1 is documented by radiological disease progression or the subject starts another 
anticancer treatment, whichever occurs earlier.
Following PFS1, subjects will enter the long-term follow up period and be followed per 
institutional guidelines but not less than every 3 months from the date of the follow-up visit for 
survival status and progression on next line therapy until PFS2 is documented or the subject starts 
another anticancer treatment, whichever occurs earlier.
Subjects will then enter the survival follow-up period. Subjects will be followed every 3 months 
for survival status until any of the discontinuation criteria for OS are met. The subject will be 
discontinued from the OS post treatment follow-up period if any of the following occur:
Subject declines further study participation (i.e., withdraws consent).
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject.
Death.
Study termination.
Concomitant Medication Restrictions or Requirements: 
If the investigator determines that any of the following medications are deemed necessary to 
provide adequate medical support to the subject, the subject must be withdrawn from further 
administration of the study treatment:
Other investigational drugs
Chemotherapy or other medications intended for antitumor activity. This does not apply to 
subjects with a history of breast cancer on adjuvant endocrine therapy, or to subjects on agents 
intended for the treatment of bone metastasis (e.g., bisphosphonates, or RANK ligand 
inhibitors).
Radiation therapy
Note:  Radiation therapy to a symptomatic solitary lesion or to the bone may be considered on 
an exceptional case-by-case basis after consultation with Sponsor. The radiated lesion must be 
a non-target lesion per RECIST V1.1 and the subject must have clear measurable disease 
outside the radiated field. 
Arm A (Enfortumab vedotin)
Subjects who are receiving strong cytochrome P450 (CYP)3A4 inhibitors or P-pg inhibitors 
concomitantly with EV should be closely monitored for adverse reactions.
Arm B (Docetaxel)
Concomitant use of drugs that strongly inhibit or induce CYP3A4 may affect exposure to 
docetaxel and should be avoided.
Arm B (Vinflunine)
Strong inhibitors or inducers of the CYP3A4 enzymes for subjects receiving vinflunine should 
be avoided.
QT/QTc interval prolonging medicinal products should be avoided. 
Arm B (Paclitaxel)
Caution should be exercised when paclitaxel is administered with strong inhibitors or inducers 
of CYP3A4 and CYP2C8.

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Please refer to the local package insert for concomitant medication restrictions or requirements for 
docetaxel, paclitaxel and vinflunine.
Duration of Treatment:  
Subjects will be allowed to receive EV or comparator until discontinuation criteria are met or upon 
study termination, or study completion, whichever occurs first.  
Endpoints for Evaluation:  
Primary
OS 
Secondary 
PFS1 per RECIST V1.1
ORR (complete response [CR] + PR) per RECIST V1.1
DCR (CR + PR + stable disease [SD]) per RECIST V1.1
DOR per RECIST V1.1
Safety variables (e.g., AEs, laboratory tests, vital sign measurements, 12-lead 
electrocardiogram and ECOG PS)
QOL and PRO parameters (QLQ-C30 and EQ-5D-5L)
Exploratory 
Exploratory genomic and/or other biomarkers in tumor tissue and in peripheral blood that may
correlate with treatment outcome, including Nectin-4 expression
Selected plasma or serum concentrations of TAb, ADC and MMAE
Incidence of ATA to EV
PFS2 per RECIST V1.1 
HRU
Statistical Methods:
Approximately 600 subjects will be randomized in a 1:1 ratio to 2 treatment arms: Arm A (EV) and 
Arm B (docetaxel, paclitaxel or vinflunine). Randomization will be stratified by:
Liver Metastasis (yes/no)
ECOG PS (0 vs 1)
Regions of the world (US, Western Europe and Rest of World)
Sample Size Justification: 
Approximately 600 subjects (with 10% dropout rate and 1 interim analysis) will be randomized in 
a 1:1 ratio to receive EV or chemotherapy. 
Primary endpoint:  OS
One-sided 2.5% Type I error; 85% Power
OS Assumption: hazard ratio (HR) = 0.75 (median OS of 10.7m vs 8m, for EV vs 
Chemotherapy arm)
A formal interim efficacy analysis will be done when approximately 65% of deaths have 
occurred. 
Primary analysis will occur at about 439 OS events
For planned interim efficacy analysis, a group sequential design using the O’Brien-Fleming 
boundaries as implemented by Lan-DeMets method will be used to control the overall 1-sided 
0.025 type I error. If the interim analysis demonstrates a statistically significant outcome for EV in 
efficacy, the study may be stopped and concluded due to efficacy.

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The Full Analysis Set (FAS) will be used for the efficacy analysis on OS and PFS1. All subjects 
who are randomized will be included in the FAS. For time to event endpoints including OS and 
PFS1 log-rank test stratified by randomization stratification factors including liver metastasis, 
baseline ECOG PS and regions of the world at baseline will be used to compare the 2 treatment 
arms. The hazard ratio and corresponding 95% confidence interval from the stratified Cox 
proportional hazards regression model will also be presented. The median OS, PFS1 and DOR will 
be estimated using the Kaplan-Meier method and will be reported along with the corresponding 
95% confidence interval by treatment arm.
ORR and DCR will be compared between treatment arms using Cochran-Mantel-Haenszel test, 
stratified by the same stratification factors used in time to event analyses. The difference in 
response rates between the treatment arms will be estimated along with the corresponding 95% 
confidence interval.
Safety:
The Safety Analysis Set (SAF) will be used for the safety analysis. All subjects who are 
randomized and received study drug will be included in the SAF. The frequency of AEs and the 
serious AEs will be summarized by MedDRA system organ class and preferred term. In addition, 
summary statistics will be provided for the following safety parameters:
Laboratory values
Vital sign measurements
ECOG PS
Pharmacokinetics:
Descriptive statistics (e.g., number, mean, standard deviation, minimum, median, maximum, 
coefficient of variation and geometric mean) will be provided for plasma or serum concentrations 
of TAb, ADC and MMAE. The incidence of ATA to EV will be summarized by cycle and overall, 
and possible relationship to pharmacokinetics explored. Additional model-based analyses and 
exposure response may be performed and reported separately.

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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Figure 1
Study Schema
OS: overall survival; PD: progressive disease; PFS: progression free survival; PFS1: progression free survival on study therapy; PFS2: progression free survival on subsequent therapy
*Imaging for both Arms will be performed at baseline and every 56 days (± 7 days) from the first dose of study treatment throughout the study until radiological 
disease progression, lost to follow-up, withdrawal of study consent, or start of a subsequent anti-cancer therapy. If a subject discontinues study drug prior to 
radiographic disease progression (i.e., PFS1), the subject should continue to undergo imaging assessment (including brain/bone imaging when indicated and 
collection of tumor measurements) every 56 days (± 7 days) in the post treatment follow-up period until PFS1 is documented per the investigator or the subject starts 
another cancer treatment, whichever occurs earlier. After PFS1, subjects will be followed in the long-term follow-up period per institutional guidelines, but not less 
frequently than every 3 months to confirm survival status and collect subsequent anticancer treatment details and progression status until PFS2 is documented or the 
subject starts another cancer treatment, whichever occurs earlier. Phone contact with subject is sufficient for follow-up. Additional follow-up contacts may be 
required per sponsor request for analysis purposes.

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Table 1
Schedule of Assessments for Arms A and B
Visit
Screening/Baseline1
Every Cycle
End of 
Treatment21
Follow-up18 
Post treatment 
Follow-Up
Long Term 
Treatment 
Follow-up
Survival 
Follow-up
Base Date
Day -28 
to -1
Day -7 
to -1
Day 1
Day 8
Arm A 
(only)
Day 15
Arm A 
(only)
Every
56 Days
Date of Last 
Dose
Date of last
Dose +30 
days
Every 56 days
Every 3 
months
Every 3 
months
Visit Window
NA
NA
± 3 
days
± 3 day
± 3 days
± 7 days
+ 7 days
+ 7 days
± 7 days
± 7 days
± 7 days
Informed Consent
X
Medical and Disease History
X
Confirmation of Eligibility
X
Tumor Tissue Sample2
X
Brain Scan3
X
X
X
Bone Scan4
X
X
X
PGx blood sample (optional)
X
Serum/Urine Pregnancy Test5
X
X
X
X
X5
X5
X5
Physical Examination 6 
X
X
X
Weight 
X
X
X6
X6
X
Vital Signs
X
X
X6
X6
X
X
Biochemistry7
X
X
X7
X7
X
X
Hemoglobin A1C8
X
X
Hematology9
X
X
X9
X9
X
X
ECOG PS
X
X
X
X
12-lead ECG10
X
X
Ophthalmology Assessment11
X
X
Randomization12
X
Arm A: EV Administration – 28 
Day Cycle13
X
X
X
Arm B: Docetaxel/Paclitaxel/ 
Vinflunine Administration – 21 
Day Cycle14
X
Table continued on next page

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Visit
Screening/Baseline
1
Every Cycle
End of 
Treatment21
Follow-up18 
Post treatment 
Follow-Up
Long Term 
Treatment 
Follow-up
Survival 
Follow-up
Base Date
Day -28 
to -1
Day -7 
to -1
Day 1
Day 8
Arm A 
(only)
Day 15
Arm A 
(only)
Every
56 Days
Date of Last 
Dose
Date of last
Dose +30 
days
Every 56 days
Every 3 months
Every 3 
months
Visit Window
NA
NA
± 3 
days
± 3 day
± 3 
days
± 7 days
+ 7 days
+ 7 days
± 7 days
± 7 days
± 7 days
Image Assessment15
X
X15
X 19
Subsequent Therapy Assessment20
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
AE
X
X
X
X
X
X
X
X
QOL16
X
X
X
X
HRU22
X 22
X
X
Overall Survival17
X
X
X
X
AE: adverse event; ALT: alanine transaminase; AST: aspartate transaminase; CR: complete response; CT: computed tomography; ECG: electrocardiogram; ECOG PS: Eastern 
Cooperative Oncology Group Performance Status; EORTC-QLQ-C30: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EOT: end of 
treatment; EQ-5D-5L: EuroQOL 5-Dimension 5-Level Questionnaire; EV: enfortumab vedotin; HRU: health resource utilization; MRI: magnetic resonance imaging; NA: Not 
Applicable; PD: progressive disease; PFS1: progression free survival on study therapy; PFS2: progression free survival on subsequent therapy; PGx: Pharmacogenetic analyses; PR: 
partial response; QOL: quality of life; RECIST: Response Evaluation Criteria in Solid Tumors
1. Screening period is 28 days. Subjects may have screening assessments repeated once. If more than 1 assessment is taken during the screening, the assessment closest to 
enrollment date should be used for eligibility. 
2. Archival tumor tissue (from primary or metastatic site) for biomarker studies should be available for submission to the Sponsor prior to study treatment. If an archival tumor 
tissue sample is not available, a fresh tissue sample should be provided. A tissue block or a minimum of 10 and up to 15 freshly sectioned, unstained charged slides should be 
provided.  
3. Only if clinically indicated at baseline. Repeat as clinically indicated or per standard of care throughout the study. 
4. All subjects will have a baseline bone scan (scintigraphy) performed at screening. Subjects with positive bone scans at baseline will have a bone scan performed every 56 days 
(± 7 days) throughout the study or more frequently if clinically indicated. Subjects should have a follow-up bone scan performed if clinically indicated regardless of baseline 
status.    
5. For all female subjects of child bearing potential only, a urine or serum pregnancy test will be performed at baseline. A urine or serum pregnancy test will then be repeated on 
day 1 of each cycle prior to EV or chemotherapy administration, at EOT and Follow-up visits. After EOT, a monthly (± 7 days) pregnancy test will be maintained until 
6 months after the last dose of study treatment.
Footnotes continued on next page

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6. Full Physical examination and other evaluations including height (at screening only); weight, ECOG PS and vital signs (pulse, temperature and blood pressure) will be 
performed at screening. The physical examination will also be performed on day 1 of each cycle and EOT visit. Physical examination is only repeated on Cycle 1 Day 1 if 
clinically significant changes from Screening (in the opinion of the investigator) are observed. For subsequent and EOT visits physical examinations maybe more directed but 
should include examination of lungs, abdomen, skin and cardiovascular systems. Vital signs and weight will be completed on days 1, 8 and 15 of each cycle for Arm A and on 
day 1 of each cycle for Arm B, and at EOT visit. Vital signs will also be performed at follow up visit. 
7. Biochemistry: See [Section 5.5.3 Laboratory Assessments]. Amylase and lipase will only be collected at screening and Day 1 of each Cycle. All biochemistry laboratory tests 
should be collected at the start of the following time points:  Screening, Cycle 1 Day 1, Cycle 1 Day 8 (Arm A only), Cycle 1 Day 15 (Arm A only) and Day 1 of each 
subsequent cycle. If all biochemistry laboratory tests were performed within 7 days prior to the first day of dosing, they do not need to be repeated on Cycle 1 Day 1. 
Biochemistry tests will be sent to a central laboratory for analysis. Local laboratory results may be used to determine eligibility if the screening results from the central 
laboratory are not available in time for planned randomization. In the event that the central laboratory results received after randomization are not within eligibility parameters, 
the subject will still be considered eligible, if local labs met the eligibility criteria, and will not be considered a protocol deviation. Local laboratory results that support 
eligibility and dosing decisions must be entered into the clinical database. If local laboratory is to be used to support dosing decisions, local laboratory tests will include 
complete blood count (CBC) with differential, glucose, serum creatinine, ALT and AST. Additional assessments may be done centrally or locally to monitor AEs or as 
required by dose modification requirements.
8. If HbA1c is elevated (≥ 6.5%), refer subject to appropriate provider during Cycle 1 for glucose management.
9. Hematology: See [Section 5.5.3 Laboratory Assessments]. Hematology tests should be collected at the following time points: Screening, Cycle 1 Day 1, Cycle 1 Day 8 (Arm 
A only), Cycle 1 Day 15 (Arm A only) and Day 1 of each subsequent cycle. If hematology tests were performed within 7 days prior to the first day of dosing, they do not need
to be repeated on Cycle 1 Day 1. Hematology tests will be sent to a central laboratory for analysis. Local laboratory results may be used to determine eligibility if the screening 
results from the central laboratory are not available in time for planned randomization. In the event that the central laboratory results received after randomization are not 
within eligibility parameters, the subject will still be considered eligible if local laboratory results met the eligibility criteria; such evens will not be considered protocol 
deviations. Local laboratory results that support eligibility and dosing decisions must be entered into the clinical database. If local laboratory is to be used to support dosing 
decisions, local laboratory tests will include CBC with differential, glucose, serum creatinine, ALT and AST. Additional assessments may be done centrally or locally to 
monitor AEs or as required by dose modification requirements.
10.ECGs will be read locally.
11.Ophthalmologic assessment for subjects with recent ocular complaints (within 3 months of screening) are required. Assessments should include the following: visual acuity, 
slit lamp, tonometry examination and dilated fundus examination. Prior ophthalmologic exam done within 3 months of screening is acceptable provided symptoms are not new 
since the exam. Ophthalmology assessments should be performed per standard of care or if clinically indicated (e.g., subject develops new or worsening ocular symptoms). 
EOT slit lamp examinations are required for subjects who experience corneal adverse events during the study. EOT slit lamp examinations must be performed ≥4 weeks from 
last dose. Additional eye examinations are to be conducted as clinically indicated. 
12.Randomization will be allowed starting at Day -3 to allow for premedication in Arm B. Cycle 1 Day 1 treatment should occur within 3 days of randomization.  
13.EV will be administered on Days 1, 8 and 15 of every 28-day cycle. Weight-based dosing is calculated using the subject’s actual body weight on Day 1 of each cycle. The 
dose does not need to be recalculated based on actual weight on Day 8 and 15 of each cycle for Arm A unless it is required by institutional standards. At least 1 week must 
elapse between doses of EV. Subjects receiving EV should be observed during EV administration and for at least 60 minutes following the infusion for the first 3 cycles.
14.Docetaxel, paclitaxel or vinflunine will be administered on Day 1 of every 21-day cycle. Subjects receiving docetaxel, paclitaxel or vinflunine should be observed during study 
drug administration and for at least 30 minutes following the infusion during the first 3 cycles.
Footnotes continued on next page.

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15.Imaging for Arms A & B will be evaluated at Baseline and every 56 days (± 7 days) throughout the study. CT scan with contrast (chest, abdomen and pelvis) is the preferred 
modality for tumor assessment.  MRI is acceptable if local standard practice or if CT scans are contraindicated in a subject (e.g., subject is allergic to contrast media). All other 
RECIST approved scanning methods such as x-ray are optional.  To ensure comparability, the screening and subsequent assessment of response should be performed using 
identical techniques. The same method should be employed and assessed by the same individual on each occasion if possible. Imaging assessments methods used at Baseline 
are to be used throughout the study.  
16.QOL questionnaires (EORTC-QLQ-C30 and EQ-5D-5L) will be completed at Baseline (Day -7 to -1) and on Day 1 of each week (+7 days) for the first 12 weeks and then 
every 12 weeks afterward, EOT visit and at the follow-up visit. QOL questionnaire completion timing should be calculated based on Cycle 1 Day 1dosing. If a visit occurs out 
of the assessment window, QOL questionnaires should still be completed. QOL questionnaires will be completed by the subject at home on hand-held devices prior to coming 
to the clinic visit with the exception of Baseline Day 1 of the first week. The EOT and the follow-up visits at which the QOL questionnaires will be completed by the subject at 
the clinic.  
17.Contact subjects in the survival follow-up period approximately every 3 months to collect survival status until subject death or study closure. Additional follow-up contacts may 
be required per sponsor request for analysis purposes.
18.Follow up assessments should be completed prior to the initiation of the next therapy.
19.If a subject discontinues study drug prior to radiographic disease progression (i.e., PFS1), the subject should continue to undergo imaging assessment (including brain/bone 
imaging when indicated and collection of tumor measurements) every 56 days (± 7 days) in the post-treatment follow-up period until PFS1 is documented per the investigator, 
or the subject starts another cancer treatment, whichever occurs earlier.
20.After PFS1, subjects will be followed in the long-term follow-up period per institutional guidelines, but not less frequently than every 3 months to confirm survival status and 
collect subsequent anticancer treatment details and progression status until PFS2 is documented or the subject starts another cancer treatment, whichever occurs earlier. Phone 
contact with subject is sufficient for follow-up. Additional follow-up contacts may be required per sponsor request for analysis purposes.
21.EOT visit will occur within 7 days after the last dose or when the decision is made by the investigator to discontinue subject from treatment.
22.HRU questionnaires will be completed monthly (Day 1 of every 4 weeks [+7 days]), starting on Week 5 Day 1 (timing calculated based on Cycle 1 Day 1dosing), and at the 
EOT and follow-up visit. HRU questionnaires will be completed by the subject at home on hand-held devices prior to coming to the clinic visit with the exception of the EOT 
and the follow-up visits at which the HRU questionnaires will be completed by the subject at the clinic.

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Table 2
Pharmacokinetic, ATA and Biomarker Blood Sample Collection Time Points - Arm A
Study Day
Time
Window
Relative Time
Blood
Pharmacokinetics
ATA
Biomarkers
Plasma
PBMC
  Cytokines
  cf DNA
  Immuno-
phenotyping
Cycles 1 
Day 1
Pre-dose
within 24 hr
START of infusion
X
X
X
X
X
End of infusion
Within 15 min
END of infusion
X
Day 8
Pre-dose
Within 24 hrs
START of infusion
X
X
X
Day 15
Pre-dose
Within 24 hrs
START of infusion
X
X
X
End of infusion 
Within 15 min
END of infusion 
X
Cycle 2 
Day 1
Pre-dose
Within 24 hrs
START of infusion
X
X
X
X
X
Cycles 3, 4 , 6, 8 and 10
Day 1
Pre-dose
Within 24 hrs
START of infusion
XA
XA
XB
XC
XB
End of Treatment (Date of last dose + 7 days )
X
X
X
X
X
Follow-up (Date of last dose +30 days)
X
X
ATA: antitherapeutic antibodies; PBMC: peripheral blood mononuclear cells; cfDNA: circulating free deoxyribonucleic acid
A. Pharmacokinetics and ATA: Pre-dose of cycle 3, 4, 6, 8 and 10
B. Cytokines and Immuno-phenotyping: Pre-dose cycles 3 and 4 only
C. cfDNA: Pre-dose every even numbered cycle up to 10 cycles (e.g., cycle 4, 6, 8, 10)

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Table 3
Biomarker Blood Sample Collection Time Points - Arm B
Study Day
Time
Window
Relative Time
Biomarkers
Plasma
PBMC
  Cytokines
  cf DNA
  Immuno-
phenotyping
Cycle 1 
Day 1
Pre-dose
Within 24 hr
START of infusion
X
X
X
Cycle 2 
Day 1 
Pre-dose
Within 24 hr
START of infusion
X
X
X
Subsequent Dosing Cycles
Day 1
Pre-dose
Within 24 hr
START of infusion
XB
XA
XB
End of Treatment (Date of last dose + 7 days)
X
X
X
cfDNA: circulating free deoxyribonucleic acid; PBMC: peripheral blood mononuclear cells
A. cfDNA: Pre-dose every even numbered cycle up to 10 cycles (e.g., cycle 4, 6, 8, 10) 
B. Cytokines and immune-phenotyping: pre-dose cycles 3 and 4 only

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1
INTRODUCTION
1.1
Urothelial Cancer
According to the International Agency for Research on Cancer (IARC), urothelial cancer kills 
more than 165000 patients annually and is the ninth most common cancer overall worldwide. 
Approximately 151000 new cases of urothelial cancer are diagnosed annually in Europe, with 
52000 deaths per year. Over 22000 new cases are diagnosed annually in Japan, with 
7600 deaths per year [Cancer Fact Sheets, 2017]. According to National Cancer Institute 
estimates, over 79000 new cases of urothelial cancer were diagnosed in 2017, and more than 
16000 people died from the disease in the United States (US) [SEER Cancer Stat Facts, 2017]. 
First-line therapy for metastatic urothelial cancer in patients with sufficient renal function 
consists of cisplatin-based combinations, like methotrexate, vinblastine, doxorubicin, and 
cisplatin (MVAC) or gemcitabine plus cisplatin, which demonstrate overall response rates up 
to 50%, including approximately 10 – 15% complete responses (CRs) [Bellmunt et al, 2011]. 
Despite initial chemosensitivity, patients are not cured and the outcome of metastatic 
urothelial cancer after these regimens is poor: median time to progression is only 7 months 
and median overall survival (OS) is 14 months. Approximately 15% of patients survive at 
least 5 years and the prognosis is particularly poor among patients with visceral metastases 
for whom the 5-year OS rate is 7% [von der Maase, 2005].
For second line treatment, the small-molecule tubulin inhibitor vinflunine (Javlor®) is 
approved only in Europe. The median OS is 6.9 months compared to a median OS of 
4.6 months for best supportive care [Bellmunt et al, 2009]. For decades, there were no major 
changes to the treatment landscape with only cytotoxic chemotherapies available, until the 
recent approvals of immune check point inhibitors (CPI) targeting the programmed death 
1/programmed death-ligand 1 (PD-1/PD-L1). As of May 2016, starting with the PD-L1 
inhibitor atezolizumab, several CPIs have received FDA approval for urothelial cancer for 
platinum-pretreated patients in the United States. Most approvals have been based on single 
arm phase II data [Tecentriq Prescribing Information, Genentech, Apr 2017], [Opdivo 
Prescribing Information, Bristol-Myers Squibb, September 2017], [Imfinzi Prescribing 
Information, AstraZeneca, May 2017] and [Bavencio Prescribing Information, EMD Serono, 
Mar 2017]. However, in 2017, results from the phase III trial KEYNOTE-045 demonstrated 
that patients treated with pembrolizumab had significantly longer survival when compared 
with the standard second-line chemotherapy [Bellmunt et al, 2017]. This led to the regular 
approval of pembrolizumab as second line treatment for patients with locally advanced or 
metastatic urothelial cancer (mUC; [Keytruda Prescribing Information, Merck, Sep 2017]). 
The approval was based on a median OS of 10.3 months for pembrolizumab compared with 
7.4 months with taxane chemotherapy or vinflunine [Bellmunt et al, 2017]. Marketing 
approval of CPIs in Europe have followed and approvals in Asia are expected. Other PD-1 
and PD-L1 inhibitors are currently being evaluated in clinical trials for urothelial cancer, as 
first and second line therapy [Mullane & Bellmunt, 2016].

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Currently, no therapies are approved for patients with locally advanced or mUC previously 
treated with a CPI. 
1.2
Nonclinical and Clinical Data
1.2.1
Enfortumab Vedotin Nonclinical Pharmacology 
AGS-22M6E is an antibody drug conjugate (ADC) derived from a murine hybridoma cell 
line that was used in pharmacology and toxicology studies, as well as in a completed phase I 
study. The amino acid sequence of this antibody is identical to that of enfortumab vedotin 
(EV), the final product used for clinical development that is derived from a Chinese Hamster 
Ovary (CHO) cell line. In addition to having identical amino acid sequences, these 2 
antibodies also have comparable pharmacological characteristics, such as binding affinity to 
Nectin-4, in vitro cytotoxicity, and in vivo antitumor activity [RD12-001, RD12-002, 
RD12-003, RD12-004]. Both AGS-22M6E and EV are ADCs comprised of a fully human 
IgG1Κ antibody conjugated to the microtubule-disrupting agent MMAE, which targets human 
Nectin-4, a member of the Nectin family of adhesion molecules. Nectin-4 has been identified 
as one of the genes markedly upregulated in bladder cancer tissue [ES10-005, ES10-007]. 
AGS-22M6E specifically binds to human Nectin-4 with high affinity and cross-reacts with 
cynomolgus monkey and rat orthologs of Nectin-4 [RD10-013, RD10-018]. AGS-22M6E 
does not cross-react with other Nectin family members, such as Nectin-1, -2, and -3 
[RD10-015]. 
In in vitro pharmacology studies, AGS-22M6E inhibited cell survival in a cell line 
engineered to express human Nectin-4. It was observed that AGS-22M6E was internalized 
after binding to Nectin-4 on the surface of cells [ES10-006]. Intracellular release of MMAE 
by proteolytic cleavage induced cell death. Antitumor activity of AGS-22M6E was evaluated 
in a panel of tumor xenograft models and significantly inhibited the tumor growth in a 
xenograft model of human bladder cancer [RD10-009]. 
1.2.2 Enfortumab Vedotin 
Toxicokinetics, immunogenicity and comparability of AGS-22M6E and AGS-22C3E bulk 
drug substance were evaluated in a 4-week study comparing AGS-22M6E and AGS-22C3E 
administered by intravenous infusion in cynomolgus monkeys with a 6-week recovery period 
[CRL Study No. 20021751]. 
The toxicokinetics of the 2 materials, AGS-22M6E and AGS-22C3E were considered to be 
comparable. Please refer to the Investigator’s Brochure for further details.
1.2.3 Enfortumab Vedotin Nonclinical Toxicology 
In a 4-week GLP toxicity study in rats [CRL Study No. 20005662], AGS-22M6E (ADC: 2, 
5 and 10 mg/kg) and AGS-22M6 (unconjugated antibody: 10 mg/kg) were intravenously 
administered once every week for a total of 4 doses. One animal administered AGS-22M6E at 
10 mg/kg was noted with severe abrasions and had loss of bodyweight, and was found dead on 
Day 27. AGS-22M6E-related changes mainly included skin abrasion at 5 mg/kg and 10 mg/kg, 

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decreased body weight and food consumption at 10 mg/kg. Decreased indicators of red cell 
mass (red blood cell [RBC], hemoglobin concentration and hematocrit) and increased 
reticulocyte count at 5 and 10 mg/kg, were also observed. Increased alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl 
transferase (GGT) levels at 5 and 10 mg/kg, decreased testis weight with histopathological 
changes (tubular epithelial degeneration), and epididymides (hypospermia/abnormal 
spermatids in the ducts) were observed at all dose levels. Femur bone marrow hypocellularity, 
and skin ulceration and/or epidermal inflammation were seen at 5 and 10 mg/kg dosing. After 
the 6-week recovery period, the testicular and epididymal findings were more severe. Bone 
marrow hypocellularity and skin ulcers/inflammation resolved in the recovery animals. There 
were no adverse AGS-22M6-related findings. A no observed adverse effect level (NOAEL) 
following administration of AGS-22M6E for four weekly intravenous injections in rats was not 
established due to the findings noted in the testis. 
In a 4-week GLP toxicity study in cynomolgus monkeys [CRL Study No. 200056640, 
AGS-22M6E (1, 3 and 6 mg/kg) and AGS-22M6 (6 mg/kg) were administered by intravenous 
infusion once weekly for a total of 4 doses. Administration of AGS-22M6E at 1 and 3 mg/kg 
was generally well tolerated, however doses of 6 mg/kg led to the unscheduled euthanasia of 
3 animals on Day 11-13 due to severe dry skin/reddened skin and abrasions. These findings are
considered a target-related effect based on the known expression of Nectin-4 in the epidermis 
of the skin. AGS-22M6E-related findings mainly included dry/reddened areas on the skin at all 
dose groups with ulceration, inflammation and hyperkeratosis in the skin at doses 3 mg/kg or 
more. Bone marrow suppression associated with MMAE toxicity included decreased 
reticulocyte count and red cell parameters, increased platelet counts, decreased neutrophils, 
eosinophils, and leukocyte counts at doses 3 mg/kg or more. All changes noted showed 
reversibility after a 6-week non-treatment period. There were no adverse AGS-22M6-related 
findings. 
The NOAEL for once weekly administration of AGS-22M6E in cynomolgus monkeys was 
considered to be 3 mg/kg per day. 
A 4-week GLP bridging study in cynomolgus monkeys [CRL Study No. 20021751] was 
conducted to evaluate comparability of the hybridoma cell line-derived product (AGS-22M6E) 
and the CHO cell line- derived product (AGS-22C3E) when given at the same dose of 3 mg/kg 
per week. 
All test article-related effects identified in both AGS-22M6E and AGS-22C3E-dosed animals 
were at similar incidence and severity. After a 6-week non-treatment period, all test 
article-related effects returned to normal. The data support the conclusion that AGS-22M6E 
and AGS-22C3E demonstrate comparable toxicity profiles and toxicokinetic characteristics, 
when given at the same 3 mg/kg dose by intravenous infusion once weekly for 4 weeks to 
cynomolgus monkeys. 
In genotoxic studies performed with other investigational compounds containing MMAE 
[ADCETRIS package insert] the MMAE was found to be genotoxic in the rat bone marrow 
micronucleus assay through an aneugenic mechanism. This effect is consistent with the 

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pharmacological effect of MMAE as a microtubule disrupting agent. MMAE was not 
mutagenic in the bacterial reverse mutation assay (Ames test) or mouse lymphoma assay 
[ADCETRIS package insert]. Maleimide, which is a component of the linker, is reported to 
be mutagenic in Ames test and mouse lymphoma assay.
1.2.4 Clinical Data
A phase 1 dose escalation and expansion study with EV monotherapy in patients with 
metastatic urothelial cancer and other malignant solid tumors is ongoing [Study ASG-22CE-
13-2]. In this study, patients received doses of EV ranging from 0.5 to 1.25 mg/kg on Days 1, 
8, and 15 of each 28-day cycle. As of the data cut-off date of 02 Oct 2017, 140 metastatic 
urothelial cancer patients had been enrolled in the phase 1 study. Interim data suggest that EV 
is generally well tolerated at doses up to 1.25 mg/kg. 
Among metastatic urothelial cancer patients, 137 (98%) experienced a treatment-emergent 
adverse event (TEAE), and 122 (87%) of these patients’ TEAEs were deemed possibly or 
probably related to study drug by the investigator. The most common TEAEs among 
metastatic urothelial cancer patients were fatigue (49%), nausea (45%), decreased appetite 
(39%), alopecia (37%), diarrhea (36%), dysgeusia (31%), pruritus (29%), anemia (26%), 
abdominal pain (24%), constipation (24%), vomiting (24%) and weight decreased (20%). 
Drug doses were reduced in 18 out of 140 metastatic urothelial cancer patients (13%) due to 
adverse events (AEs), including 16 out of 97 patients (17%) in the 1.25 mg/kg dose group.
Drug was withdrawn in 26 out of 140 (19%) metastatic urothelial cancer patients due to AEs, 
including 13 out of 97 (13%) from the 1.25 mg/kg dose group. Across all dose levels, drug 
was withdrawn from 12 out of 140 (8.6%) metastatic urothelial cancer patients due to AEs 
deemed possibly or probably related to EV. In the 1.25 mg/kg dose group, drug was 
withdrawn from 6 out of 97 (6%) metastatic urothelial cancer patients due to AEs deemed as 
possibly or probably related to EV. TEAEs leading to study drug discontinuation in more 
than 1 urothelial cancer patient included urosepsis, AST increased, blood creatinine 
increased, neuropathy peripheral and acute kidney injury (all events occurred in 2 subjects).
Fifty-five out of 140 (39%) metastatic urothelial cancer patients experienced at least one 
treatment emergent serious adverse event (SAE). Sixteen out of 140 (11%) patients had SAEs 
that were deemed by the investigator to be possibly or probably related to treatment. At the 
1.25 mg/kg dose level, 31 out of 97 patients (32%) had at least one treatment emergent SAE.
Nine patients (9%) at the 1.25 mg/kg dose level had SAEs that were deemed by the 
investigator to be possibly or probably related to treatment. As of the 02 Oct 2017 data cut-
off date, there were 6 fatal TEAEs in 6 out of 140 (4%) metastatic urothelial cancer patients 
during this study, and 2 events were deemed to be drug-related (1 event of urinary tract 
obstruction and 1 event of respiratory failure). One patient experienced a serious adverse 
event of hyperglycemia in conjunction with a drug-related fatal event.
Following the data cut-off date, 2 additional treatment-related fatal events were reported in 
metastatic urothelial patients; 1 patient died of diabetic ketoacidosis and hyperglycemia and 
the other patient died of multi-organ failure in conjunction with a serious adverse event of 

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hyperglycemia. All active EV study protocols (including the current study) were amended to 
address this new safety information.
Preliminary EV data show encouraging antitumor activity in patients with metastatic 
urothelial cancer with either post-baseline imaging or who had discontinued treatment before 
imaging. As of the data cut-off date of 02 Oct 2017, there were 4 CRs and 29 partial 
responses (PRs) (ORR=27.3%, 33 of 121 patients) across dose levels. The ORR at 
1.25 mg/kg (the dose level for the present study) was 32.1% (25 out of 78 patients). 
EV also shows promising antitumor activity in metastatic urothelial cancer patients 
previously treated with CPIs who had either post-baseline imaging or had discontinued 
treatment before imaging. At the 1.25 mg/kg dose level, the ORR was 31% (17 of 55 
patients).
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human subjects is provided in the EV Investigator’s Brochure.
1.3
Summary of Key Safety Information for Enfortumab Vedotin
Overall (data cutoff date 02 Oct 2017), 198 patients received at least 1 dose of EV across all 
studies (Study AGS-22M6E-11-1, Study ASG-22CE-13-2, Study 7465-CL-0101). AEs of 
interest for EV are based on current safety data from clinical studies and known risks with 
similar ADCs. Among them, the risks identified for EV are extravasation site reactions 
(important identified risk); rash, peripheral neuropathy, diarrhea, nausea and vomiting 
(identified risks); antitherapeutic antibodies (ATAs), infusion-related reactions (IRRs) other 
than extravasation, anemia and neutropenia, gastrointestinal disorders other than diarrhea, 
nausea and vomiting, ocular toxicity (corneal disorders), and hyperglycemia (potential risks). 
Please refer to the Investigator’s Brochure for further details. 
1.4
Risk Benefit Assessment
Subjects with locally advanced or metastatic urothelial cancer that has recurred or progressed 
following platinum-based chemotherapy present a challenge. While CPIs offer a new 
approach to treatment of metastatic urothelial cancer, tumor responses have occurred in a 
minority of patients and the improvement in long-term survival is only a few months. Most 
patients with locally advanced or metastatic urothelial cancer do not respond to CPIs and 
many who do respond ultimately develop disease progression [Rosenberg, 2016]. Currently, 
no therapies are approved for patients previously treated with a CPI. Although taxanes are 
not approved in this setting; they are a common choice for third line treatment (and were a 
standard second line treatment before atezolizumab was approved). Taxanes have response 
rates of approximately 10% as second line therapy, with progression-free survival (PFS) and 
OS of only 3.3 months and 7.4 months, respectively [Bellmunt et al, 2017]. Vinflunine is 
approved only in Europe and has an equally low response rate of 9% and a trend toward 
survival benefit when compared with best supportive care [Bellmunt et al, 2009]. No data are 
currently available regarding the clinical activity of taxanes or vinflunine in the third line 
setting after CPI therapy. The lack of approved therapies for patients with mUC after 

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treatment with a CPI and the limited activity observed with second line chemotherapy 
underscores the need for more treatment options in this patient population.  
The potential risks associated with EV are outlined in [Sections 1.2.3, 1.2.4, and 1.3], and in 
the Investigator’s Brochure. The potential risks associated with the chemotherapy comparators 
are well characterized and are outlined in [Section 5.1 Dosing and Administration of Study 
Drug(s) and Other Medication(s)], for more detailed information, please refer to their 
respective local product label. 
Clinical data to date support a favorable benefit-risk ratio for EV in patients with locally 
advanced or metastatic urothelial carcinoma who previously received CPI therapy. Evidence 
of clinical activity has been observed in other single arm studies of EV (described in [Section 
1.2.4 Clinical Data]) and this may translate into an improvement in effectiveness over the 
control arm. However, there may still be no direct benefit to subjects participating in the 
current clinical trial. To assure an ongoing favorable risk/benefit assessment for subjects 
enrolled into the study, an Independent Data Monitoring Committee (IDMC) will be utilized 
to monitor safety data and interim efficacy analysis.
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objective(s)
2.1.1
Primary Objective
To compare the OS of subjects with locally advanced or metastatic urothelial cancer treated 
with EV to the OS of patients treated with chemotherapy. 
2.1.2
Secondary Objectives
●
To compare progression free survival on study therapy (PFS1) per Response Evaluation 
Criteria in Solid Tumors (RECIST) V1.1 of subjects treated with EV to patients treated 
with chemotherapy 
●
To compare the overall response rate (ORR) per RECIST V1.1 of EV to chemotherapy
●
To evaluate the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy 
●
To compare the disease control rate (DCR) per RECIST V1.1 of EV to chemotherapy 
●
To assess the safety and tolerability of EV 
●
To assess quality of life (QOL) and Patient Reported Outcomes (PRO) parameters
2.1.3
Exploratory Objectives
●
Exploratory genomic and/or other biomarkers in tumor tissue and in peripheral blood that 
may correlate with treatment outcome, including Nectin-4 expression
●
To assess the pharmacokinetics of EV (TAb, ADC and MMAE)
●
To assess the incidence of ATA 
●
To evaluate PFS as assessed by RECIST V1.1 by investigator review in the next line of 
therapy (PFS2) in subjects treated with EV compared to docetaxel, paclitaxel or vinflunine.
●
Healthcare resources utilization (HRU)

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2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a global, open-label, randomized Phase 3 study in adult subjects with locally advanced 
or metastatic urothelial cancer who have received a platinum-containing chemotherapy and 
have experienced disease progression or relapse during or following treatment with an immune 
checkpoint inhibitor. Subjects who discontinued CPI treatment due to toxicity are eligible 
provided that they have evidence of disease progression following discontinuation. 
Approximately 600 subjects will be randomized to EV (Arm A) or chemotherapy (Arm B) in a 
1:1 ratio. Subjects will be stratified according to the following:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS), regions of the world and liver metastasis.
OS is the primary endpoint. OS is defined as the time from randomization to the date of 
death. Secondary endpoints include PFS1, ORR, DOR, DCR, safety and QOL/PRO. 
Subjects in Arm A will receive EV on Days 1, 8 and 15 of each 28-day cycle. Subjects in arm 
B will receive docetaxel, paclitaxel or vinflunine as decided by the investigator prior to 
randomization, (vinflunine is a choice of comparator only in countries where it is approved 
for urothelial cancer) on Day 1 of every 21-day cycle. Within the control arm, the overall 
proportion of subjects receiving vinflunine will be capped at approximately 35%. Subjects 
will continue to receive study treatment until radiological disease progression as determined 
per investigator assessment or other discontinuation criteria are met or upon study 
termination, or study completion, whichever occurs first. No on-study crossover will be 
allowed other than as allowed in [Appendix 12.10]. Subjects assigned to the chemotherapy 
arm will not be allowed to switch to a different chemotherapy treatment during study 
treatment. This study will consist of three phases: screening, treatment and follow-up.
Screening will take place up to 28 days prior to randomization. Screening assessments may 
be repeated within the 28-day screening period. 
Subjects do not need to be “screen failed” in IRT and re-entered in screening with a new 
subject ID as long as the subject is enrolled within the 28-day window from signing of the 
informed consent. If more than 28 days elapses from the date of signing the informed 
consent, the subject must be screen failed in IRT. A new consent must be signed and the 
subject entered into screening with a new subject ID. Subjects may only be rescreened once.
Subjects will start with cycle 1 and continue on to subsequent 21-day or 28-day cycles until 
one of the discontinuation criteria are met or upon study termination, or study completion, 
whichever occurs first. A treatment cycle is defined as 28 days for Arm A and 21 days for 
Arm B. 
Subjects will be evaluated for response according to RECIST V1.1. Imaging for both arms 
will be performed at baseline and every 56 days (± 7 days) from the first dose of study 
treatment throughout the study until PFS1 is documented by radiological disease progression 
or the subject is lost to follow-up, death, withdraws study consent or starts a subsequent anti-
cancer therapy. Baseline imaging performed prior to informed consent as standard of care 

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may be used so long as it is performed within 28 days prior to randomization. All subjects 
will have a bone scan (scintigraphy) performed at screening/baseline. Subjects with positive 
bone scans at baseline will have a bone scan performed every 56 days (± 7 days) throughout 
the study or more frequently if clinically indicated. Subjects should have a follow-up bone 
scan performed if clinically indicated regardless of baseline status. Brain scans (computed 
tomography [CT] with contrast/magnetic resonance imaging [MRI]) will only be performed 
if clinically indicated at screening/baseline and repeated as clinically indicated or per 
standard of care throughout the study. 
QOL assessments and PRO will be collected at protocol-specified time points from all 
randomized subjects. The following validated tools will be used: European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and 
EuroQOL 5-dimension 5-Level Questionnaire (EQ-5D-5L). HRU information will be 
collected at protocol-specified time points with particular focus on the number of subjects 
who have an unplanned use of healthcare resources related to clinical or AEs from subjects 
assigned to treatment arms A and B.
Blood samples for pharmacokinetics and ATA will be collected throughout the study for 
subjects randomized into Arm A. Validated assays will be used to measure the concentrations 
of EV ADC and monomethylauristatin E (MMAE) in serum or plasma and to assess ATA. 
Pharmacokinetic samples will not be collected from subjects randomized into Arm B. 
Samples for exploratory biomarkers will be collected at protocol-specified time points. 
Biomarker assessments will not be used for subject selection.  
Following discontinuation from study drug, subjects will have a follow-up visit 30 days 
(+ 7 days) after their last dose of drug for safety assessments. If a subject discontinues study 
drug prior to radiographic disease progression (i.e., PFS1), the subject should enter the post-
treatment follow-up period and continue to undergo imaging assessments every 56 days 
(± 7 days) until PFS1 is documented, or the subject starts another anticancer treatment, 
whichever occurs earlier. 
Following PFS1, subjects will enter the long-term follow-up period and be followed per 
institutional guidelines but not less than every 3 months from the date of the follow-up visit 
for survival status and progression status on subsequent therapy (i.e., PFS2). 
Subjects will be followed until PFS2 is documented or the subject starts another anticancer 
treatment, whichever occurs earlier. All subsequent anticancer therapy including date and site 
of progression for PFS2 will be recorded on the case report form. 
Following PFS2, subjects will enter the survival follow-up period and be followed every 
3 months for survival status until death, lost to follow-up, withdrawal of study consent, or 
study termination by sponsor. This study is expected to end once final survival analysis is 
complete. Subjects will be eligible to continue receiving treatment in this study until they 
meet a discontinuation criterion as outlined in [Section 6 Discontinuation] or upon study 
termination, or study completion, whichever occurs first.  

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An IDMC will be chartered to oversee safety and the planned interim efficacy analysis, 
which will occur after at least 285 OS events (about 65% of the total planned events) are 
observed. The primary analysis will occur at 439 OS events. The IDMC may recommend to 
the sponsor whether the trial should be terminated, modified or continue unchanged based on 
ongoing reviews of safety data and interim efficacy analysis. Further details will be outlined 
in the IDMC charter. 
2.2.2 Dose Rationale
Enfortumab Vedotin
EV will be administered at a dose of 1.25 mg/kg as an intravenous infusion over 
approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle. This dose and regimen 
has demonstrated an acceptable safety profile and encouraging clinical activity in the phase 1 
study [Study ASG-22CE-13-2], which evaluated escalating dose levels of 0.5, 0.75, 1 and 
1.25 mg/kg, with expansion cohorts at the 0.75, 1, and 1.25 mg/kg dose levels. A maximum 
tolerated dose (MTD) was not reached in this study. At the 1 mg/kg dose level, 2 dose-
limiting toxicities (DLTs) were observed: Grade 3 proctalgia (later changed to grade 2 by the 
investigator) thought related to radiation recall and Grade 4 hyperuricemia without clinical 
sequelae. No DLT was observed at 1.25 mg/kg and doses above 1.25 mg/kg were not tested.
Incidence of some of the most frequent drug-related AEs, such as diarrhea and rash, although 
primarily Grades 1–2 and clinically manageable, increased with increasing dose levels. 
Moreover, dose reductions due to AEs were more frequent for the 1.25 mg/kg vs lower dose 
levels. Safety assessments of both metastatic urothelial cancer patients and non-metastatic 
urothelial cancer patients showed that frequency of all TEAEs, AEs leading to withdrawal, 
and Grade 3–4 TEAEs were comparable across all dose levels.
While all doses of EV demonstrated activity, the 1.25 mg/kg dose was associated with the 
highest activity and had an acceptable safety profile. 
Based on pharmacokinetic data from the phase 1 study [Study ASG-22CE-13-2], the half-life 
of EV is ~ 1 – 2 days. No notable (< 30%) intra-cycle accumulation of ADC was observed 
with the current dosing regimen (on Days 1, 8 and 15 of every 28-day cycle) at any dose 
level. Minimal (< 50%) intra-cycle accumulation of MMAE was observed. It is anticipated 
that the dosing schedule in the study will maintain ADC exposures over each 28-day cycle, 
contributing to a favorable balance of activity and safety, as observed in the phase 1 trial 
[Study ASG-22CE-13-2].
In summary, the dose regimen of 1.25 mg/kg on Days 1, 8 and 15 of each 28-day cycle 
proposed for this study has demonstrated an acceptable safety profile and encouraging 
clinical activity that was higher than at lower dose levels.
Comparators
There is no accepted standard of care following CPI treatment for locally advanced or mUC; 
however, prior to CPI approvals, taxanes were commonly used following platinum-based 
therapy as recommended in the treatment guidelines [NCCN, 2017; ESMO, 2017]. In 

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addition, vinflunine is approved in Europe for treatment of mUC after failure of a prior 
platinum-based regimen [Bellmunt et al, 2011]. 
KEYNOTE-045, a multicenter, randomized, active-controlled trial in patients with locally 
advanced or mUC with disease progression on or after platinum-containing chemotherapy, 
compared pembrolizumab to investigator’s choice of paclitaxel, docetaxel, or vinflunine 
every 3 weeks [Bellmunt et al, 2017].
Although no labeled dosing guidelines for taxanes are available in this setting, this is the only 
large randomized trial that has reported combined survival data for these agents, as such the 
current phase 3 study of enfortumab vs chemotherapy will use the same choice of comparators 
and their corresponding doses. Patients randomized to the chemotherapy arm in the 
KEYNOTE-045 study were treated with paclitaxel (175 mg/m2), docetaxel (75 mg/m2) or 
vinflunine (320 mg/m2), administered intravenously every 3 weeks. The overall proportion of 
subjects receiving vinflunine in the control arm was capped at approximately 35% (KEYNOTE 
protocol).
2.3
Endpoints 
2.3.1
Primary Endpoints
●
OS 
2.3.2
Secondary Endpoints 
●
PFS1 by RECIST V1.1
●
ORR (CR + PR) by RECIST V1.1
●
DCR (CR + PR + SD) by RECIST V1.1
●
DOR by RECIST V1.1
●
Safety variables (e.g., AEs, laboratory tests, vital sign measurements, 12-lead ECG and 
ECOG PS)
●
QOL and PRO parameters (QLQ-C30 and EQ-5D-5L)
2.3.3
Exploratory Endpoints
●
Exploratory genomic and/or other biomarkers in tumor tissue and in peripheral blood 
that may correlate with treatment outcome, including Nectin-4 expression
●
Plasma or serum concentrations of TAb, ADC and MMAE
●
Incidence of ATA to EV
●
PFS2 
●
HRU

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3
STUDY POPULATION
3.1
Selection of Study Population 
Patients with locally advanced or metastatic urothelial cancer previously treated with 
platinum-based chemotherapy and an immune checkpoint inhibitor (CPI). 
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must 
be obtained from the subject prior to any study-related procedures (including withdrawal 
of prohibited medication, if applicable).
Subject is legally an adult according to local regulation at the time of signing informed 
consent.
Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of 
the bladder, renal pelvis, ureter, or urethra). Subjects with urothelial carcinoma 
(transitional cell) with squamous differentiation or mixed cell types are eligible.
Subject must have experienced radiographic progression or relapse during or after a CPI 
(anti-programmed cell death protein-1 [PD-1] or anti-programmed cell death-ligand 1 
[PD-L1]) for locally advanced or metastatic disease. Subjects who discontinued CPI 
treatment due to toxicity are eligible provided that they have evidence of disease 
progression following discontinuation. The CPI need not be the most recent therapy. 
Subjects for whom the most recent therapy has been a non-CPI based regimen are 
eligible if they have progressed/relapsed during or after their most recent therapy. 
Locally advanced disease must not be amenable to resection with curative intent per the 
treating physician. 
Subject must have received a platinum containing regimen (cisplatin or carboplatin) in 
the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was 
administered in the adjuvant/neoadjuvant setting subject must have progressed within 
12 months of completion.
Subject has radiologically documented metastatic or locally advanced disease at 
baseline.
An archival tumor tissue sample should be available for submission to central laboratory 
prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue 
sample should be provided. If a fresh tissue sample cannot be provided due to safety 
concerns, enrollment into the study must be discussed with the medical monitor. 
Subject has ECOG PS of 0 or 1.

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The subject has the following baseline laboratory data:
●
absolute neutrophil count (ANC) ≥ 1500/mm3
●
platelet count ≥100 × 109/L
●
hemoglobin ≥9 g/dL
●
serum total bilirubin ≤ 1.5 × upper limit of normal (ULN)* or ≤ 3 × ULN for 
subjects with Gilbert’s disease
●
creatinine clearance (CrCl) ≥30 mL/min as estimated per institutional standards 
or as measured by 24 hour urine collection (glomerular filtration rate [GFR] can 
also be used instead of CrCl)
●
ALT and AST ≤2.5 × ULN or ≤ 3 × ULN for subjects with liver metastases*
*Docetaxel should not be chosen as a comparator for subjects if total bilirubin > ULN, or 
if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. 
Female subject must either:
●
Be of nonchildbearing potential:
o
Postmenopausal (defined as at least 1 year without any menses for which 
there is no other obvious pathological or physiological cause) prior to 
screening, or 
o
Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy).
Note: Those who are amenorrheic due to an alternative medical cause are not 
considered postmenopausal and must follow the criteria for childbearing 
potential subjects.
●
Or, if of childbearing potential: 
o
Agree not to try to become pregnant during the study and for at least 
6 months after the final study drug administration,
o
And have a negative urine or serum pregnancy test within 7 days prior to 
Day 1 (Females with false positive results and documented verification of 
negative pregnancy status are eligible for participation),
o
And if heterosexually active, agree to consistently use a condom plus 1 form 
of highly effective birth control * per locally accepted standards starting at 
screening and throughout the study period and for at least 6 months after the 
final study drug administration.
Female subject must agree not to breastfeed or donate ova starting at screening and 
throughout the study period, and for at least 6 months after the final study drug 
administration.

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A sexually active male subject with female partner(s) who is of childbearing potential is 
eligible if:
●
Agrees to use a male condom starting at screening and continue throughout the 
study treatment and for at least 6 months after final study drug administration. If 
the male subject has not had a vasectomy or is not sterile as defined below his 
female partner(s) is utilizing 1 form of highly effective birth control* per locally 
accepted standards starting at screening and continue throughout study treatment 
and for at least 6 months after the male subject receives his final study drug 
administration.
*Highly effective forms of birth control include:

Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,

Established intrauterine device (IUD) or intrauterine hormone releasing system 
(IUS).

Bilateral tubal occlusion

Vasectomy (A vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used)

Male is sterile due to a bilateral orchiectomy or radical cystoprostatectomy/removal 
of seminal vesicles

Sexual Abstinence is considered a highly effective method only if defined as 
refraining from heterosexual activity during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant
Please note: Sexual abstinence is not sufficient as contraception method in Switzerland
Male subject must not donate sperm starting at screening and throughout the study 
period, and for at least 6 months after the final study drug administration.
Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use 
a condom for the duration of the pregnancy or time partner is breastfeeding throughout 
the study period and for at least 6 months after the final study drug administration.
Subject agrees not to participate in another interventional study while on treatment in 
present study.
Waivers to the inclusion criteria will NOT be allowed.

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3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
Subject has preexisting sensory or motor neuropathy Grade ≥2.
Subject has active central nervous system (CNS) metastases. Subjects with treated CNS 
metastases are permitted on study if all the following are true:
●
CNS metastases have been clinically stable for at least 6 weeks prior to screening 
●
If requiring steroid treatment for CNS metastases, the subject is on a stable dose 
≤20 mg/day of prednisone or equivalent for at least 2 weeks
●
Baseline scans show no evidence of new or enlarged brain metastasis
●
Subject does not have leptomeningeal disease
Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception 
of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or 
surgery). Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or 
panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of 
hormone replacement therapy (if indicated). Patients with ongoing ≥Grade 3 
immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects 
with ongoing immunotherapy related colitis, uveitis, myocarditis, or pneumonitis or 
subjects with other immunotherapy related AEs requiring high doses of steroids 
(> 20 mg/day of prednisone or equivalent) are excluded.
Subject has prior treatment with EV or other MMAE-based ADCs.
Subject has received prior chemotherapy for urothelial cancer with all available study 
therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where 
vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in 
regions where vinflunine is an approved therapy).
Note: After vinflunine cap is reached, subjects who have received both docetaxel and 
paclitaxel will be excluded.
Subject has received more than 1 prior chemotherapy regimen for locally advanced or 
metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant 
disease if recurrence occurred within 12 months of completing therapy. The substitution 
of carboplatin for cisplatin does not constitute a new regimen provided no new 
chemotherapeutic agents were added to the regimen.
Subject has history of another malignancy within 3 years before the first dose of study 
drug, or any evidence of residual disease from a previously diagnosed malignancy. 
Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative 
intent with no evidence of progression, low-risk or very low-risk (per standard 
guidelines) localized prostate cancer under active surveillance/watchful waiting without 
intent to treat, or carcinoma in situ of any type (if complete resection was performed) are 
allowed.   

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Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or 
fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is 
permitted.
Subject has known active Hepatitis B (e.g., HBsAg reactive) or active hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 
or 2).
Subject has documented history of a cerebral vascular event (stroke or transient ischemic 
attack), unstable angina, myocardial infarction, or cardiac symptoms (including 
congestive heart failure) consistent with New York Heart Association Class III to IV 
within 6 months prior to the first dose of study drug. 
Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study 
drug. 
Subject has had chemotherapy, biologics, investigational agents, and/or antitumor 
treatment with immunotherapy that is not completed 2 weeks prior to first dose of study 
drug. 
Subject has known hypersensitivity to EV or to any excipient contained in the drug 
formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20); OR 
subject has known hypersensitivity to biopharmaceuticals produced in CHO cells. 
Subject has known hypersensitivity to the following: 
●
docetaxel or to any of the other excipients listed in product label, including 
polysorbate 80; 
●
paclitaxel or to any of the other excipients listed in product label, including 
macrogolglycerol ricinoleate 35 (Ph.Eur.); and 
●
vinflunine or to any of the other excipient listed in product label, including other 
vinca alkaloids (vinblastine, vincristine, vindesine, vinorelbine).
[Criterion removed]. 
Subject has known active keratitis or corneal ulcerations. Subject with superficial 
punctate keratitis is allowed if the disorder is being adequately treated in the opinion of 
the investigator.
Subject has other underlying medical condition that, in the opinion of the investigator, 
would impair the ability of the subject to receive or tolerate the planned treatment and 
follow-up. 
History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. 
Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 
7 and < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not 
otherwise explained.
Waivers to the exclusion criteria will NOT be allowed.

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4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug(s)
The investigational product, EV (ASG-22CE), is a sterile, preservative-free, white to off-
white lyophilized powder to be reconstituted for intravenous administration. The 
investigational product is supplied by Astellas in single-use glass vials containing 30 mg EV 
(ASG-22CE) in each vial. The investigational product should be stored at 2-8°C. Details of 
investigational product receipt, labeling, storage and preparation are provided in a 
supplemental pharmacy guide.
4.1.2 Comparative Drug(s) 
Comparative drugs will be supplied by the responsible site pharmacy of each investigational 
site. If the site is unable to procure or utilize local supplies for the comparative drug, supplies 
may be provided centrally by the sponsor as applicable. Sites are permitted to utilize generic 
docetaxel and paclitaxel that is approved by the respective regulatory authority. Refer to 
product labels for docetaxel, paclitaxel and vinflunine for storage & handling conditions and 
caution statements. 
Please refer to [Section 5.1 Dosing and Administration of Study Drug(s) and Other 
Medication(s)] for specific dosing instructions. 
For sponsor supplied comparative drug, details of product receipt, labeling, storage and 
preparation are provided in a supplemental pharmacy guide.  
4.2
Packaging and Labeling
EV (ASG-22CE) used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at APGD-Astellas US Technologies (AUST) or sponsor’s 
designee in accordance with APGD-AUST or sponsor’s designee Standard Operating 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, 
and applicable local laws/regulations.
Each carton and vial will bear a label conforming to regulatory guidelines, GMP and local 
laws and regulations that identifies the contents as investigational drug.
Where supplied by the Sponsor, the comparative drug(s) used in this study will be labeled 
under the responsibility of APGD-AUST or sponsor’s designee in accordance with APGD-
AUST or sponsor’s designee SOPs, GMP guidelines, ICH GCP guidelines, and applicable 
local laws/regulations.
A qualified person of Astellas Pharma Europe B.V. (APEBV) or sponsor’s designee will 
perform the final release of the medication according to the requirements of the EU Directive 
2003/94/EC annex 13.

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4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and that:
●
such deliveries are recorded,
●
study drug is handled and stored according to labeled storage conditions,
●
study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
any unused study drug is returned to the sponsor or standard procedures (reviewed and 
approved by Astellas) for the alternative disposition of unused study drug are followed.
The head of the study site or the study drug storage manager should take accountability of the 
study drugs as follows:
●
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the sponsor.
●
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study site, the use by each subject, and the return to the 
sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique 
code numbers assigned to the study drugs and subjects.
●
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol, and 
reconcile all the study drugs supplied from the sponsor.
4.4
Blinding
This is an open label study. 
Although the study is an open label study, to maintain trial integrity, analyses or summaries 
by randomized treatment assignment or actual treatment assignment will be limited and 
documented while the study is ongoing and before the primary hard lock. Interim analysis 
will be conducted externally by independent data analysis center (IDAC). Details will be 
included in SAP. 
4.5
Assignment and Allocation
Subjects will be randomized in a 1:1 ratio to a treatment arm according to the randomization 
schedules through Interactive Response Technology (IRT). All subjects who meet the 
eligibility criteria will be randomized. The site personnel will dispense the treatment 
according to the IRT system’s assignment. Specific procedures for randomization through the 
IRT are contained in the study procedures manual. Investigators must select one treatment 
among the Arm B options before randomization occurs to be used in the event that the 
subject is randomized to the Arm B. Within the control arm, the overall proportion of 
subjects receiving vinflunine will be capped at approximately 35%.

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5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
5.1.1.1 Enfortumab Vedotin
EV at a dose of 1.25 mg/kg will be administered as an intravenous infusion over 
approximately 30 minutes on Days 1, 8, and 15 of every 28-day cycle. In the absence of 
IRRs, the infusion rate for all subjects should be calculated in order to achieve an 
approximate 30-minute infusion period. EV must not be administered as an intravenous push 
or bolus. EV should not be mixed with other medications. At least 1 week must elapse 
between doses of EV.
Weight-based dosing is calculated using the subject’s actual body weight on Day 1 of each 
cycle. The dose does not need to be re-calculated based on actual weight on Day 8 and 15 of 
each cycle for Arm A unless it is required by institutional standards. An exception to 
weight-based dosing is made for subjects weighing greater than 100 kg; doses will be based 
on 100 kg for these individuals. The maximum dose permitted on this study is 125 mg. 
Subject weight must be measured during all relevant assessment time points as described in 
the schedule of events. 
The subject should be observed during EV administration and for at least 60 minutes 
following the infusion during the first 3 cycles. All supportive measures consistent with 
optimal patient care should be given throughout the study according to institutional 
standards.
The injection site should be monitored closely for redness, swelling, pain, and infection 
during and at any time after administration. Subjects should be advised to report redness or 
discomfort promptly at the time of administration or after infusion. 
5.1.1.2 Comparative Drug(s)
Local product labels or summary of product characteristics (SmPC) and institutional 
guidelines will be followed for the administration of chemotherapy agents and precautions 
taken to prevent extravasation per institutional standards and as described in “Chemotherapy 
and Biotherapy Guidelines and Recommendations for Practice” [Polovich et al, 2014] and 
“Management of Chemotherapy Extravasation: ESMO-EONS Clinical Practice Guidelines” 
[Fidalgo et al, 2012].
Male subjects randomized to receive docetaxel, vinflunine or paclitaxel should seek medical 
advice regarding cryopreservation of sperm prior to receiving treatment due to the possibility 
of infertility.  

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5.1.1.2.1
Docetaxel
Study treatment of docetaxel should be administered as an intravenous infusion on Day 1 of 
every 21-day cycle after all procedures/assessments have been completed, including the 
required premedication per local standard of care prior to Day 1. Docetaxel will be 
administered at 75 mg/m2 unless specified otherwise in [Sections 5.1.2.2 and 5.1.2.3]. Refer 
to local product label or SmPC where supplied centrally and institution guidelines for 
docetaxel for further guidance on docetaxel dosing.
Docetaxel will be administered over 1 hour or per local guidelines. The subject should be 
observed during docetaxel administration and for at least 30 minutes following the infusion 
during the first 3 cycles. All supportive measures consistent with optimal patient care should 
be given throughout the study according to institutional standards. 
All subjects should be premedicated per local standard of care with corticosteroids, such as 
dexamethasone 16 mg/day orally (e.g., 8 mg twice daily) for 3 days starting 1 day prior to 
docetaxel administration in order to reduce the incidence and severity of fluid retention as 
well as the severity of hypersensitivity reactions. The appropriate premedication regimen 
may be determined by the investigator.
5.1.1.2.2
Vinflunine
Study treatment of vinflunine should be administered as an intravenous infusion on Day 1 of 
every 21-day cycle after all procedures/assessments have been completed. Vinflunine will be 
administered at 320 mg/m2 unless otherwise specified in [Section 5.1.2.4 Vinflunine Dose 
Modifications]. See [Section 5.1.2.4 Vinflunine Dose Modifications] for guidelines on 
adjustment of initial dose. The subject should be observed during vinflunine administration 
and for at least 30 minutes following the infusion during the first 3 cycles. All supportive 
measures consistent with optimal patient care should be given throughout the study according 
to institutional standards. Refer to local product label or SmPC and institution guidelines for 
vinflunine for further guidance on vinflunine dosing.
5.1.1.2.3
Paclitaxel
Study treatment of paclitaxel should be administered as an intravenous infusion on Day 1 of 
every 21-day cycle after all procedures/assessments have been completed. Paclitaxel will be 
administered at 175 mg/m2 unless specified otherwise in [Section 5.1.2.5 Paclitaxel Dose 
Modifications]. See [Section 5.1.2.5 Paclitaxel Dose Modifications] for guidelines on 
adjustment of initial dose. Paclitaxel should be administered over 3 hours or per local 
guidelines. The subject should be observed during paclitaxel administration and for at least 
30 minutes following the infusion during the first 3 cycles. All supportive measures 
consistent with optimal patient care should be given throughout the study according to 
institutional standards. Refer to local product label or SmPC and institution guidelines for 
paclitaxel for further guidance on paclitaxel dosing.
All subjects should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg 

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orally administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg intravenous 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) 
or ranitidine (50 mg) intravenous 30 to 60 minutes before paclitaxel. The appropriate 
premedication regimen may be determined by the investigator.
5.1.2 Increase or Reduction in Dose of the Study Drug(s)
5.1.2.1 Enfortumab Vedotin
Dose reduction to 1 mg/kg (dose level - 1) and to 0.75 mg/kg (dose level - 2) will be allowed 
depending on the type and severity of toxicity. Subjects requiring a dose reduction may be 
re-escalated by 1 dose level (i.e., subjects reduced to 0.75 mg/kg may only be re-escalated to 
1 mg/kg) provided the toxicity does not require study drug discontinuation and has returned 
to baseline or ≤Grade 1. If the toxicity recurs, re-escalation will not be permitted. Subjects 
with ≥ Grade 2 corneal AEs will not be permitted to dose re-escalate.
EV should not be administered to subjects with CrCl < 30 mL/min. Dose modification 
recommendations for EV associated toxicity are presented in Table 4 and Table 5. Dose 
interruptions for other EV associated toxicity is permitted at the discretion of the site 
investigator. Dose interruptions may last up to 8 weeks (2 cycles). Dose interruptions for 
subjects who are deriving clinical benefit from treatment may be extended beyond 8 weeks, if 
the subject’s toxicity does not otherwise require permanent discontinuation. If there is a dose 
interruption, the schedule for response assessments will not be adjusted.
Table 4
Recommended dose modifications for enfortumab vedotin associated 
hematologic toxicity*
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same 
dose level.
Continue at same 
dose level.
For Grade 2 
thrombocytopenia, 
withhold dose until 
toxicity is 
≤Grade 1 or has 
returned to baseline, 
then resume 
treatment at the 
same dose level.
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then resume treatment at 
the same dose level or 
consider dose reduction 
by 1 dose level. 
Transfusions or growth 
factors may be used as 
indicated per institutional 
guidelines.
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then reduce dose by 1 
dose level and resume 
treatment, or discontinue 
at the discretion of the 
investigator. Transfusions 
or growth factors may be 
used as indicated per 
institutional guidelines. 
For anemia, treatment 
discontinuation should be 
strongly considered. 
*Note: hematological toxicity refers to anemia, thrombocytopenia, neutropenia and febrile neutropenia.

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Table 5
Recommended dose modifications for enfortumab vedotin associated 
nonhematologic toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose 
level.
If ocular symptoms 
and/or changes in 
vision are identified, 
the subject should be 
evaluated with an 
ophthalmologic 
exam.** 
Continue at same dose 
level, except in the 
event of Grade 2 
neuropathy or corneal 
AEs.
For Grade 2 
neuropathy or corneal 
AE’s, withhold dose 
until toxicity is 
≤Grade 1 or has 
returned to baseline, 
and then resume 
treatment at the same 
dose level. For the 
second occurrence of 
Grade 2 neuropathy or 
corneal AE’s, 
withhold dose until 
toxicity is ≤ Grade 1, 
and then reduce the 
dose by 1 dose level 
and resume treatment.
If ocular symptoms 
and/or changes in 
vision are identified, 
the subject should be 
evaluated with an 
ophthalmologic 
exam.**
Withhold dose until 
toxicity is ≤ Grade 1 
or has returned to 
baseline, then resume 
treatment at the same 
dose level or consider 
dose reduction by 1 
dose level.*
For Grade 3 
neuropathy or corneal 
AEs, discontinue 
treatment. 
For Grade 3 
hyperglycemia/ 
elevated blood 
glucose, withhold EV 
treatment. Resume 
treatment once 
hyperglycemia/ 
elevated blood glucose 
has improved to 
≤Grade 2 and subject 
is clinically and 
metabolically stable.  
If ocular symptoms 
and/or changes in 
vision are identified, 
the subject should be 
evaluated with an 
ophthalmologic 
exam.** 
For Grade 4 AEs, 
discontinue 
treatment.*
Grade 4 vomiting 
and/or diarrhea that 
improves to ≤Grade 2 
or less within 72 hours 
with supportive 
management does not 
require 
discontinuation.
.
AE: adverse event; EV: enfortumab vedotin
* Grade 3/4 electrolyte imbalances/laboratory abnormalities, except hyperglycemia, that are not associated with 
clinical sequelae and/or are corrected with supplementation/appropriate management within 72 hours of their 
onset do not require discontinuation (e.g., Grade 4 hyperuricemia). Grade 3 rash that is not limiting self-care 
activities of daily living or associated with infection requiring systemic antibiotics does not require treatment 
interruption, provided symptoms are not severe and can be managed with supportive treatment. 
**Ophthalmologic exam should be performed by an ophthalmologist. In countries where optometrists can 
perform exams and prescribe medications, an optometrist may be used instead.

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Enfortumab Vedotin Related Rash
In the phase 1 study [Study ASG-22CE-13-2], rash and similar dermatologic AE’s were 
common among patients treated with EV, and were seen more frequently at the highest dose. 
Although the exact etiology of dermatologic toxicities associated with EV is unclear at this 
time, due to the expression of nectin-4 in the skin, rash maybe an on target toxicity. The most 
common type of dermatological AE reported in ASG-22CE-13-2 was maculo-papular rash, 
rash, skin exfoliation, and skin pigmentation disorder. Most occurred early on (during 
cycle 1), and some were associated with pruritus. Mild rash due to EV should be treated 
using local supportive care as needed. Topical corticosteroids have been used along with 
antihistamines for pruritus as needed. Grade 3 rash that is not limiting self-care activities of 
daily living or associated with infection requiring systemic antibiotics does not require 
treatment interruption, provided symptoms are not severe and can be managed with 
supportive treatment.
Management of Hyperglycemia 
Investigators should monitor blood glucose levels and are advised to perform additional 
assessments if any symptoms of hyperglycemia are observed, including a thorough 
evaluation for infection. In addition, if steroids are used to treat any other condition, blood 
glucose levels may require additional monitoring. If elevated blood glucose levels are 
observed, subjects should be treated according to local standard of care and referral to 
endocrinology may be considered.
Subjects, especially those with a history of or ongoing diabetes mellitus or hyperglycemia, 
should be advised to immediately notify their physician if their glucose level becomes 
difficult to control or if they experience symptoms suggestive of hyperglycemia such as 
frequent urination, increased thirst, blurred vision, fatigue, and headache.
Subjects who enter the study with an elevated HbA1c (≥6.5%) at baseline should be referred 
to an appropriate provider during Cycle 1 for glucose management. Blood glucose should be 
checked prior to each dosing and dose should be withheld for blood glucose > 250 mg/dL 
(13.9 mmol/L) (Grade 3 or higher). Dosing may continue once the subject’s blood glucose 
has improved to ≤Grade 2 and subject is clinically and metabolically stable. Blood glucose 
> 500 mg/dL (27.8 mmol/L) (Grade 4) considered related to EV requires treatment 
discontinuation. If a subject experiences new onset diabetes mellitus, evaluate subjects with a 
metabolic panel, urine ketones, glycosylated hemoglobin, and C-peptide to assess for new 
onset type 1 diabetes in the setting of prior CPI.
Management of Enfortumab Vedotin Infusion Related Reactions (IRR)
An IRR may occur during the infusion of study treatment. The infusion should be 
administered at a site properly equipped and staffed to manage anaphylaxis should it occur. 
All supportive measures consistent with optimal patient care should be given throughout the 
study according to institutional standards. Supportive measures may include administering 
medications for IRRs.

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Subjects who have experienced an IRR may be premedicated for subsequent infusions. 
Premedication may include pain medication (e.g., acetaminophen or equivalent), an 
antihistamine (e.g., diphenhydramine hydrochloride), and a corticosteroid administered 
approximately 30–60 minutes prior to each infusion or according to institutional standards. 
Should a subject experience IRRs in the setting of premedication, continued treatment with 
enformtumab vedotin must be discussed with the medical monitor prior to the next planned dose.
If anaphylaxis occurs, study treatment administration should be immediately and 
permanently discontinued. 
5.1.2.2 Dose Modification for treatment with Docetaxel, Paclitaxel or Vinflunine
In general, treatment with the chemotherapy comparators (docetaxel, paclitaxel or vinflunine) 
should be withheld for drug-related Grade 4 hematologic toxicities and for non-hematologic 
toxicity Grade 3, and subsequent doses modified as per Table 6 below. Dose modifications 
will be applied for all subsequent doses. Specific dose modification guidance for docetaxel, 
paclitaxel, and vinflunine is found below in [Sections 5.1.2.3, 5.1.2.4 and 5.1.2.5]. Dose 
modifications should also be considered according to local product labels or SmPC and 
institutional guidelines. For docetaxel, paclitaxel or vinflunine associated hematologic 
toxicities ≥3, transfusions or growth factors may be used as indicated per institutional 
guidelines.
Table 6
Dose Modification Guidelines for Drug-Related Adverse Events on the 
Active Comparator Arm
Toxicity*
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Neutropenia
Grade 1, 2,
3 or Grade 4
lasting ≤7 days
All
Hold treatment
until neutrophils
recover to 
> 1500 cells/mm3
NA
NA
Grade 4
lasting > 7 days
1st
Hold treatment
until neutrophils 
recover to 
> 1500 cells/mm3
Restart treatment 
at:
Paclitaxel: 
135 mg/m2 
Docetaxel: 
60 mg/m2
Vinflunine: 
280 mg/m2
Treatment
Discontinuation 
should be 
considered
2nd
Hold treatment
until neutrophils 
recover to 
> 1500 cells/mm3
Restart treatment 
at:
Paclitaxel: 
100 mg/m2
Docetaxel: 
50 mg/m2
Vinflunine: 
250 mg/m2
Treatment
Discontinuation 
should be 
considered
3rd
Yes 
NA
Yes
Table continued on next page

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Toxicity*
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Thrombocytopenia
Grade 1,2, 3
All
Hold treatment
until platelets
recover to
> 100000 cells/mm3
NA
NA
Grade 4 
1st
Hold treatment
until platelets
recover to
> 100000 cells/mm3
Restart treatment 
at:
Paclitaxel: 
135 mg/m2
Docetaxel: 
60 mg/m2
Vinflunine: 
280 mg/m2
Treatment
discontinuation
should be 
considered
2nd
Hold treatment
until platelets
recover to
> 100000 cells/mm3
Restart treatment 
at:
Paclitaxel: 
100 mg/m2
Docetaxel: 
50 mg/m2
Vinflunine: 
250 mg/m2
Treatment
Discontinuation 
should be 
considered
3rd
Yes
NA
Yes
Anemia
Grade 1,2, 3
All
Until anemia
resolves to Grade 1
or baseline
NA
NA
Grade 4 
1st
Until anemia resolves 
to Grade 1 or baseline
Restart treatment 
at:
Paclitaxel: 
135 mg/m2
Docetaxel: 
60 mg/m2
Vinflunine: 
280 mg/m2
Treatment
discontinuation
should be 
considered
2nd
Until anemia resolves 
to Grade 1 or baseline
Restart treatment 
at:
Paclitaxel: 
100 mg/m2
Docetaxel: 
50 mg/m2
Vinflunine: 
250 mg/m2
Treatment
Discontinuation 
should be 
considered
3rd
Yes
NA
Yes
Table continued on next page

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Toxicity*
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Nonhematological
toxicity and other
hematological
toxicity not
described 
above.**
Grade 1, 2
All
No
None
NA
Grade 3, 4 
1st
Yes, until toxicity
resolves to Grade 0-1 
or baseline
Restart treatment 
at:
Paclitaxel: 
135 mg/m2
Docetaxel: 
60 mg/m2
Vinflunine: 
280 mg/m2
Treatment
Discontinuation
should be 
considered
2nd
Yes, until toxicity 
resolves to Grade 0-1 
or baseline
Restart treatment 
at:
Paclitaxel: 
100 mg/m2
Docetaxel: 
50 mg/m2
Vinflunine: 
250 mg/m2
Treatment 
Discontinuation 
should be 
considered
3rd
Yes
NA
Yes
*See Table 7, Table 8 and Table 9 for additional dose modifications for drug-related adverse events specific to docetaxel, 
vinflunine and paclitaxel, respectively.
**Subjects who experience suspected severe hypersensitivity reaction to paclitaxel or vinflunine (e.g., generalized
rash/erythema, hypotension and/or bronchospasm, angioedema or anaphylaxis) should be discontinued from trial 
treatment.
*** For docetaxel, paclitaxel or vinflunine associated hematologic toxicities ≥ Grade 3, transfusions or growth factors 
may be used as indicated per institutional guidelines.
See Table 7 and Table 9 for guidelines on management of peripheral neuropathy specific to docetaxel and paclitaxel, 
respectively.
NA: not applicable
5.1.2.3 Docetaxel Dose Modifications
Docetaxel should not be given to subjects with total bilirubin > ULN, or to subjects with AST 
and/or ALT > 1.5 × ULN with concomitant alkaline phosphatase > 2.5 × ULN. Subjects with 
elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase 
are at increased risk for the development of Grade 4 neutropenia, febrile neutropenia, 
infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. 
Docetaxel should also not be given to subjects with a neutrophil count of < 1500 cells/mm3.
Severe fluid retention has been reported following docetaxel therapy. Subjects should be 
premedicated with corticosteroids prior to each docetaxel injection administration to reduce 
the incidence and severity of fluid retention. Subjects with pre-existing effusions should be 
closely monitored from the first dose for the possible exacerbation of the effusions. Subjects 
developing peripheral edema may be treated with standard measures, e.g., salt restriction, 
oral diuretic(s). Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for 
subjects who are responding to treatment may be extended beyond 6 weeks, if the subject’s 
toxicity does not otherwise require permanent discontinuation. Recommended dose 
modification guidelines for subjects receiving docetaxel are detailed below in Table 7. Dose 

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modifications not specified below (e.g., severe or cumulative cutaneous reactions) and 
starting doses should also consider local product label or SmPC and institutional guidelines. 
Table 7
Recommended Docetaxel Dose Modification Guidelines
Toxicity
Grade
Occurrence
Hold Treatment
Dose 
Modification
Discontinue 
Treatment
Peripheral
Neuropathy
Grade 1, 2
No
60 mg/m2
N/A
Grade 3, 4
Yes
N/A
Discontinue 
upon onset
Neutropenic fever 
(defined as T 
≥100.5°F 
(38.1°C) and 
ANC ≤1000/L)
1
Hold treatment 
until 
ANC ≥1500/L
60 mg/m2
2
Hold treatment 
until ANC 
≥1500/L
50 mg/m2
3
Yes
N/A
Yes
ANC: absolute neutrophil count; N/A: not applicable; T: temperature
5.1.2.4 Vinflunine Dose Modifications
In case of WHO/ECOG PS of 1 or ECOG PS of 0 and prior pelvic irradiation, vinflunine 
treatment should be started at the dose of 280 mg/m². In the absence of any hematological 
toxicity during the first cycle causing treatment delay or dose reduction, the dose may be 
increased to 320 mg/m² every 21 days for the subsequent cycles. In subjects with moderate 
renal impairment (40 mL/min ≤CrCl ≤60 mL/min), the recommended dose is 280 mg/m² given 
once every 21 day cycle. In subjects with renal impairment (30 mL/min ≤CrCl < 40 mL/min), 
the recommended dose is 250 mg/m² given once every 21 day cycle.
The recommended dose of vinflunine is 250 mg/m² given once every 21-day cycle in subjects 
with mild liver impairment (Child-Pugh grade A). Please refer to local product label or 
SmPC and institutional guidelines for further dose modifications.
The doses recommended in subjects ≥75 years old are as follows:
●
in subjects at least 75 years old but less than 80 years, the dose of vinflunine to be given 
is 280 mg/m² every 21 day cycle.
●
in subjects 80 years old and beyond, the dose of vinflunine to be given is 250 mg/m² 
every 21 day cycle.
In subjects who initiate vinflunine at 280 mg/m2 and who experience an AE requiring dose 
modification, the dose should be reduced to 250 mg/m2 following the 1st occurrence and 
resolution, and discontinued following a 2nd occurrence. In subjects who initiate vinflunine 
at 250 mg/m2 and who experience an AE requiring dose modification, vinflunine should be 
discontinued.
Cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been observed after 
administration of vinflunine. The typical clinical symptoms are, with various degrees: 
neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and 

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gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the 
posterior regions of the brain. Vinflunine must be discontinued in subjects who develop 
neurological signs of PRES. Dose modifications for subjects receiving vinflunine are detailed 
below in Table 8. Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for 
subjects who are deriving clinical benefit from treatment may be extended beyond 6 weeks, if 
the subject’s toxicity does not otherwise require permanent discontinuation. Please refer to 
the vineflunine (Javlor®) SmPC for additional information.  
Table 8
Vinflunine Dose Modifications
Toxicity
Dose Adjustments
Initial Dose: Vinflunine 320 mg/m2
Initial Dose: Vinflunine 280 mg/m2
1st Event 
2nd 
Consecutive
Event
3rd 
Consecutive
Event
1st Event 
2nd Consecutive
Event
Neutropenic fever 
(defined as 
T ≥100.5°F 
(38.1°C) and ANC 
≤ 1000/L)
Vinflunine
280 mg/m2
Vinflunine
250 mg/m2
Discontinue
treatment
Vinflunine
250 mg/m2
Discontinue 
treatment
Mucositis or 
Constipation Grade 
2 ≥5 days or 
Grade 3 ≥ any 
duration1
Cardiac ischemia 
in patients with 
prior history of 
myocardial 
infarction or 
angina pectoris
Discontinue 
treatment
N/A
N/A
Discontinue 
treatment
N/A
ANC: absolute neutrophil count; N/A: not applicable; T: temperature
1 National Cancer Institute Common Terminology Criteria for Adverse Events Grade 2 constipation is 
defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 4 as 
an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate,” Grade 3 as “severe” and 
Grade 4 as “life-threatening.”
5.1.2.5 Paclitaxel Dose Modifications
Paclitaxel should not be administered to subjects with baseline neutrophil counts of less than 
1500 cells/mm3. Subjects should not be re-treated with subsequent cycles of paclitaxel until 
neutrophils recover to a level > 1500 cells/mm3 and platelets recover to a level 
> 100000/mm3. Severe conduction abnormalities have been documented in < 1% of subjects 
during paclitaxel therapy and in some cases requiring pacemaker placement. If subjects 
develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy 
should be administered and continuous cardiac monitoring should be performed during 
subsequent therapy with paclitaxel provided the subject does not require discontinuation.

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In case of mild hepatic impairment (total bilirubin ≥ 1.25 ULN), paclitaxel should be started 
at a dose of 135 mg/m2. Dose modifications for subjects receiving paclitaxel are detailed 
below. Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for subjects 
who are responding to treatment may be extended beyond 6 weeks if the subject’s toxicity 
does not otherwise require permanent discontinuation. Recommended dose modification 
guidelines for subjects receiving paclitaxel are detailed below in Table 9. Please refer to local 
product label or SmPC and institutional guidelines for further dose modifications.
Table 9
Recommended Dose Modification Guidelines Paclitaxel 
Toxicity 
Grade
Occurrence
Hold
Treatment
Dose
Modification
Treatment
Discontinuation
Peripheral
Neuropathy
Grade 1, 2
No
135 mg/m2
N/A
Grade 3, 4
Yes
N/A
Discontinue upon 
onset
Neutropenic
fever (defined as
T ≥100.5°F 
(38.1°C) and
ANC ≤ 1,000/L)
1
Hold until 
ANC 
≥1,500/L
135 mg/m2
2
Hold until 
ANC 
≥1,500/L
100 mg/m2
3
yes
N/A
Yes
ANC: absolute neutrophil count; N/A: not applicable; T: temperature
5.1.3 Previous and Concomitant Treatment (Medication and Nonmedication Therapy)
If the investigator determines that any of the following medications are deemed necessary to 
provide adequate medical support to the subject, the subject must be withdrawn from further 
administration of the study treatment:
●
Other investigational drugs
●
Chemotherapy or other medications intended for antitumor activity. This does not apply 
to subjects with a history of breast cancer on adjuvant endocrine therapy, or for subjects 
on agents intended for the treatment of bone metastasis (e.g., bisphosphonates, or RANK 
ligand inhibitors).
●
Radiation therapy
Note:  Radiation therapy to a symptomatic solitary lesion or to the bone may be 
considered on an exceptional case-by-case basis after consultation with Sponsor. The 
radiated lesion must be a non-target lesion per RECIST V1.1 and the subject must 
have clear measurable disease outside the radiated field. 
Arm A (enfortumab vedotin)
●
Subjects who are receiving strong cytochrome P450 (CYP)3A4 inhibitors or P-pg 
inhibitors concomitantly with EV should be closely monitored for adverse reactions.

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Arm B (Docetaxel)
●
Concomitant use of drugs that strongly inhibit or induce CYP3A4 may affect exposure to 
docetaxel and should be avoided.
Arm B (Vinflunine)
●
Strong inhibitors of the CYP3A4 enzymes for subjects receiving vinflunine should be 
avoided.
●
QT/QTc interval prolonging medicinal products should be avoided. 
Arm B (Paclitaxel)
●
Caution should be exercised when paclitaxel is administered with strong inhibitors or 
inducers of CYP3A4 and CYP2C8.
Please refer to the local package inserts for concomitant medication restrictions or 
requirements for docetaxel, paclitaxel and vinflunine. All concomitant treatments will be 
recorded in the eCRF or electronic data source unless otherwise specified.
5.1.4
Treatment Compliance
The dose and schedule of EV, paclitaxel, docetaxel and vinflunine administered to each 
subject will be recorded on the appropriate electronic case report form (eCRF) at every cycle. 
Reasons for dose delay, reduction or omission will also be recorded. 
If toxicities or adverse events occur on Day 1 of any cycle and EV cannot be administered, 
then the start of the cycle may be delayed. If toxicities occur on Days 8 or 15 of any cycle 
and require the dose to be held > 3 days, then the dose(s) must be eliminated, rather than 
delayed. If a subject only receives day 1 and needs to skip days 8 and 15, the subject could 
resume the next cycle as early as day 22 (new day 1), if the toxicity has resolved by then.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information will be collected for all subjects as allowed per local regulation 
and will include date of birth, sex, race, ethnicity and tobacco use history (pack years).
5.2.2
Medical History
Medical history will include all significant medical conditions other than urothelial cancer 
that have resolved prior to informed consent or are ongoing at the time of consent. Details 
that will be collected include the onset date and recovery date and Common Terminology 
Criteria for Adverse Events (CTCAE) grade, if applicable for ongoing conditions.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
For urothelial carcinoma, the following information including but not limited to will be 
collected during the screening period, and be entered in the eCRF: 
●
Date of initial diagnosis of the primary carcinoma, histological type, date of 
histopathological or cytopathological diagnosis 

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●
Date of diagnosis for the locally advanced or metastatic or recurrent disease 
●
TNM classification and disease stage at screening 
●
Sampling method and the type of the tumor tissues for Nectin-4 mutation analysis
●
Previous treatment (including medication, radiotherapy and surgery) for underlying disease 
5.2.4
Performance Status
The ECOG PS Scale [Oken et al, 1982] will be used to assess performance status. Refer to 
[Appendix 12.8].
5.3
Efficacy Assessments
Response and progression will be evaluated using RECIST v1.1 [Appendix 12.7].  
Imaging for both Arms will be performed at screening/baseline and every 56 days (± 7 days) 
from the first dose of study treatment throughout the study. Baseline imaging performed prior 
to informed consent as standard of care may be used so long as it is performed within 28 days 
prior to randomization. All subjects will have a bone scan (scintigraphy) performed at 
screening/baseline. Subjects with positive bone scans at baseline will have a bone scan 
performed every 56 days (± 7 days) throughout the study or more frequently if clinically 
indicated. Subjects with negative bone scans at baseline should have a bone scan performed 
if clinically indicated throughout the study even if not positive at baseline. Brain scans 
(CT with contrast/MRI) will only be performed if clinically indicated at screening/baseline and 
repeated as clinically indicated or per standard of care throughout the study. If a subject 
discontinues study drug prior to radiological disease progression, the subject should continue 
to undergo imaging assessments every 56 days (± 7 days) until disease progression is 
documented, or the subject starts another anticancer treatment whichever occurs earlier.
A CT scan with contrast (chest and abdomen) is the preferred modality for tumor assessment.  
Magnetic resonance imaging is acceptable if local standard practice or if CT scans are 
contraindicated in a subject (e.g., subject is allergic to contrast media). All other RECIST-
approved scanning methods such as x-ray are optional. Additional instructions for imaging 
assessments can be found in the study procedures manual.
The assessment will include tumor measurements for target lesions, nontarget lesions and any 
new lesions. An overall assessment will be characterized for a given time point evaluation. At 
the end of study for that subject, the best overall response to the study regimen will be 
characterized. To ensure comparability, the screening and subsequent assessment of response 
should be performed using identical techniques. The same individual should assess images 
for any 1 subject for the duration of the study if possible. For subjects with known brain 
metastases at study entry, it is recommended that repeat imaging also include the brain and 
the same methods used to detect brain lesions at Baseline are to be used to follow the lesions 
throughout the study. 
The site of disease progression including target, non-target and/or new lesions should be 
documented in the eCRF. Additional imaging may be performed at any time to confirm 
suspected progression of disease.

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This study will be analyzed based on the results of local (investigator site) radiologic 
assessments, including dates of progression and death. Since imaging scans may be needed 
for future regulatory purposes or an independent review of all or a representative sample of 
scans may be considered following the completion of PFS1 analysis, copies of all scans will 
be collected throughout the study and stored centrally by a coordinating vendor. Images from 
all randomized subjects will be sent to the imaging vendor according to the frequency of 
Table 1. 
5.3.1
Evaluation of Target Lesions
5.3.1.1 Complete Response
CR is defined as disappearance of all target and nontarget lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from 
baseline measurement.
5.3.1.2 Partial Response
PR is defined as at least a 30% decrease in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum 
of diameters.
5.3.1.3 Stable Disease
SD is defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify 
for progressive disease taking as reference the smallest sum of diameters while on study 
drug.
5.3.1.4 Progressive Disease
PD is defined as at least a 20% increase in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of the target lesions taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. The appearance of 1 or more new lesions is also considered progression.
5.3.2
Evaluation of Nontarget Lesions
To achieve unequivocal progression on the basis of nontarget lesions, there must be an 
overall level of substantial worsening in nontarget disease such that, even in presence of SD 
or PR of target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of 1 or more nontarget lesions is 
usually not sufficient to qualify for unequivocal progression.
5.3.2.1 Complete Response
For CR of nontarget lesions, subjects must have disappearance of all nontarget lesions and all 
lymph nodes must be nonpathological in size (< 10 mm short axis).
5.3.2.2 NonCR/NonPD
NonCR/NonPD of nontarget lesions is defined as persistence of 1 or more nontarget lesions.

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5.3.2.3 Progressive Disease
PD of nontarget lesions is defined as unequivocal progression of existing nontarget lesions or 
the appearance of 1 or more new lesions.
5.3.3
Evaluation of Time Point Response
The overall response status at each time point for subjects with measurable disease at 
baseline will be reported according to the table in [Appendix 12.7].
5.4
Pharmacokinetic Assessment
PK samples will be collected during the treatment period and at the post-treatment follow-up 
visit for subjects who receive EV for determination of ADC and MMAE concentrations. If a 
subject presents to clinic but does not get dosed, a predose PK sample collection should be 
performed.
Blood samples (7 mL/sample) for pharmacokinetic analyses should be collected at the time 
points indicated in the Schedule of Assessments (Table 1). Blood samples should be collected 
via a peripherally placed intravenous cannula or by direct venipuncture.
Blood should not be drawn from the arm or port used for study drug infusion.
Bioanalysis of TAb, ADC and MMAE in serum or plasma will be performed using validated 
methods at bioanalytical laboratories specified by the sponsor.
5.5
Safety Assessment
5.5.1
Vital Signs
Vital signs, including systolic and diastolic blood pressures (mmHg), radial pulse rate 
(beats/minute) and temperature will be obtained according to the Schedule of Assessments 
(Table 1) and recorded. All vital sign measures will be obtained with the subject in the sitting 
or supine position.
If clinically significant vital sign changes from Baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance will be defined 
as a variation in vital signs that has medical relevance as deemed by the investigator that could 
result in an alteration in medical care. The investigator will continue to monitor the subject 
until the parameter returns to Grade ≤ 1, or to the Baseline (pretreatment) value, or until the 
investigator determines that follow up is no longer medically necessary.
5.5.2 Adverse Events
See [Section 5.6 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling. 
5.5.2.1 Adverse Events of Possible Hepatic Origin
See [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study 

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and receiving study drug is accompanied by increases in Liver Function Tests value ([LFT], 
e.g., AST, ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.
5.5.3 Laboratory Assessments
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See Schedule of Assessments for study visit collection dates. 
Biochemistry
Sodium (Na), Magnesium (Mg), Potassium (K), Calcium (Ca), Chloride (Cl), 
Phosphate (P), Serum Creatinine, Glucose (Gl), Blood Urea Nitrogen (BUN), 
ALP, AST, ALT, Lactate Dehydrogenase (LDH), Bilirubin (total and direct), 
Total Protein (TP), Albumin (Alb), Bicarbonate (HCO3), Amylase, Lipase, 
Uric Acid, Hemoglobin A1c (screening only), Serum HCG for female subjects 
of childbearing potential
Hematology
Red Blood Cell Count (RBC), Hematocrit (Hct), Hemoglobin (Hgb), Platelets, 
white blood cell count (WBC)/differential (Neutrophils, Eosinophils, 
Basophils, Lymphocytes, Monocytes), 
Urinalysis 
Pregnancy
HbA1c
Laboratory tests will be performed predose according to the Schedule of Assessments and 
sent to a central laboratory for analysis. All screening labs must be sent to the central 
laboratory, but local laboratory results may be used to determine eligibility if the screening 
results from the central laboratory are not available in time for planned randomization. In the 
event that the central laboratory results received after randomization are not within eligibility 
parameters, the subject will still be considered eligible if local labs met the eligibility criteria 
and will not be considered a protocol deviation. Local laboratory results that support 
eligibility and dosing decisions must be entered into the clinical database. If local laboratory 
is to be used to support dosing decisions, local laboratory tests will include complete blood 
count with differential, glucose, serum creatinine, ALT and AST. In case of multiple 
laboratory data within this period, the most recent data should be used. Laboratory 
assessments collected outside of -7 days of randomization should be repeated. Additional 
assessments may be done centrally or locally to monitor AEs or as required by dose 
modification requirements. 
Assessment of creatinine clearance or estimation of GFR per institutional guidelines should 
be performed prior to administration of vinflunine and EV as recommended in [Section 5.1.2
Increase or Reduction in Dose of the Study Drug(s)]. 
Additional laboratory tests should be performed according to institutional standard of care. 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician. 

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5.5.4 Physical Examination 
Standard, full physical examinations will be performed at screening to assess general 
appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, 
musculoskeletal, neurologic status, mental status and lymphatic systems. For subsequent and 
end of treatment (EOT) visits, physical examinations maybe more directed but should include 
examination of lungs, abdomen, skin, and cardiovascular system. Physical examinations will 
be conducted at visits as outlined in the Schedule of Assessments (Table 1). Each physical 
examination will include weight; height is only required at Screening. If clinically significant 
worsening of findings from Baseline is noted at any study visit, the changes will be 
documented as AEs on the AE eCRF. Clinical significance is defined as any variation in 
physical findings that has medical relevance that could result in an alteration in medical care. 
The investigator will continue to monitor the subject until the parameter returns to Grade ≤1, 
or to the Baseline condition, or until the investigator determines that follow up is no longer 
medically necessary.
5.5.5 Ophthalmology Examination
Ophthalmologic assessment for subjects with recent ocular complaints (within 3 months of 
screening) are required. Assessments should include the following: visual acuity, slit lamp, 
tonometry examination, and dilated fundus examination. Prior ophthalmologic exam done 
within 3 months of screening is acceptable provided symptoms are not new since the exam. 
Ophthalmology assessments during treatment should be performed per standard of care or if 
clinically indicated (e.g., subject develops new or worsening ocular symptoms). EOT slit 
lamp examinations are required for subjects who experience corneal adverse events during 
the study. EOT slit lamp examinations must be performed ≥4 weeks from last dose. 
Additional eye examinations are to be conducted as clinically indicated.
5.5.6
Electrocardiogram 
A standard 12-lead ECG will be performed and assessed using local standard procedures 
according to the schedule of assessments in Table 1. Clinically significant abnormal findings 
at screening should be recorded as medical history.
5.6
Adverse Events and Other Safety Aspects
5.6.1
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject, temporally associated with the use
of a medicinal product, whether or not considered related to the medicinal product. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product.
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the informed consent 
and will be collected until 30 days after the last dose of study drug.

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5.6.1.1 Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, clinical chemistry, or urinalysis) or 
other safety assessment (e.g., ECGs, radiographic scans, vital signs measurements, physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as an (S)AE.
Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition.
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE.
5.6.1.2 Potential Cases of Drug-Induced Liver Injury
Refer to [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed 
instructions on Drug Induced Liver Injury (DILI). Abnormal values in AST and/or ALT 
concurrent or with abnormal elevations in total bilirubin that meet the criteria outlined in 
[Appendix 12.2 Liver Safety Monitoring and Assessment], in the absence of other causes 
of liver injury, are considered potential cases of drug-induced liver injury (potential Hy’s 
Law cases) and are always to be considered important medical events and reported per 
[Section 5.6.5 Reporting of Serious Adverse Events].
5.6.1.3 Disease Progression and Study Endpoints
Under this protocol, the following event(s) will not be considered as an(S)AE:
●
Disease Progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs unless resulting in death. These data will be captured as efficacy assessment data 
as outlined in [Section 5.3 Efficacy Assessments]. If there is any uncertainty as to 
whether an event is due to anticipated disease progression and/or if there is evidence 
suggesting a causal relationship between the study drug and the event, it should be 
reported as an (S)AE. All deaths within 30 days of the last dose of study drug must be 
reported as SAEs.  
●
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic, or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical trial. These procedures are collected per the eCRFs Completion Guidelines.

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5.6.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious.) 
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.6.3 Criteria for Causal Relationship to Study Drug
The investigator is obligated to assess the relationship between the study drug and each 
occurrence of each (S)AE. The investigator will use clinical judgment to determine the 
relationship. The investigator should also use the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products. The investigator is requested to provide an explanation 
for the causality assessment for each SAE and must document this on the SAE worksheet. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the eCRF 
with the new information and updated causality assessment.
Following a review of the relevant data, the causal relationship between the study drug and 
each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider 

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that there is a reasonable possibility that the event may have been caused by the study 
drug”.
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship:
●
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug? 
●
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc.
●
Dechallenge/Dose reduction/Rechallenge: 
○Did the (S)AE resolve or improve after stopping or reducing the dose of the suspect 
drug? Also consider the impact of treatment for the event when evaluating a 
dechallenge experience. 
○Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?  
●
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study drug (e.g., based on values pre-, during 
and post-treatment)
●
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor. With limited or insufficient information about 
the event to make an informed judgment and in absence of any indication or evidence to 
establish a causal relationship, a causality assessment of ‘no’ is to be considered. In such 
instance, the investigator is expected to obtain additional information regarding the event as 
soon as possible and to re-evaluate the causality upon receipt of additional information. 
5.6.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the NCI-CTCAE 
guidelines (Version 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 
will be assessed according to the criteria below and entered into the eCRF.

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Grade
Assessment Standard
1-Mild
Asymptomatic or mild symptoms, clinical or diagnostic 
observations noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
The investigator will use the following definitions to rate the severity of each adverse event
●
Mild: 
No disruption of normal daily activities
●
Moderate:Affect normal daily activities
●
Severe: 
Inability to perform daily activities
5.6.5 Reporting of Serious Adverse Events
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to 30 days after last administration of study drug. 
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
The investigator must complete and submit a SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not 
possible within 24 hours, the local drug safety contact should be informed by phone.
For sites located in Japan:
In the case of a serious adverse event (SAE), the investigator or sub-investigator must report 
to the head of the study site and must contact the sponsor (directly or via the delegated CRO) 
by telephone or fax immediately (within 24 hours of awareness). 
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU HOUKOKUSHO 
containing all information that is required by the Regulatory Authorities to the sponsor (directly 
or via the delegated CRO) by fax immediately (within 24 hours of awareness) and to the head of 
the hospital. If the faxing of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible 
or is not possible within 24 hours, the sponsor should be informed by phone.
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. 

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Please Fax or email the SAE Worksheet for Japan (JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO) to:
PAREXEL International
Clinical Development
Fax number +81-(0)3-6888-1654
or
Astellas Pharma Inc. – Japan
JP Clinical Development,
Fax number +81-(0)3-3243-5737
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's Medical Monitor/Study Physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel]. 
Follow-up information for the event should be sent promptly (within 2 days of the initial 
notification.  
For sites located in all other countries:
Please fax or email the SAE worksheet for all other country sites to:
Astellas Pharma Global Development, Inc.
Pharmacovigilance
North America Fax number 1-888-396-3750
Alternate North America Fax number 1-847-317-1241
International Fax number +44-800-471-5263
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's Medical Monitor/Study Physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel].
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.  
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the (e)CRF. 
The following minimum information is required:
●
International Study Number (ISN)/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness criteria), 
●
Causal relationship to the study drug (including reason), and
●
The drug provided (if any) 
The sponsor or sponsor's designee will submit expedited safety reports (e.g., Investigational 
New Drug [IND] Safety Reports, Council for International Organizations of Medical 

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Sciences [CIOMS-I]) to Competent Authorities (CA) and concerned Ethics Committee (cEC) 
per current local regulations, and will inform the investigators of such regulatory reports as 
required. Investigators must submit safety reports as required by their IRB/local IEC within 
timelines set by regional regulations (e.g., EU, (e)CTD, FDA) where required. 
Documentation of the submission to and receipt by the IRB/local IEC of expedited safety 
reports should be retained by the site.
The sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all Suspected Unexpected Serious Adverse Reactions, which require 
submission per local requirements of the IRB/IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor.
5.6.6 Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator. 
If after the protocol defined AE collection period [see Section 5.6.1 Definition of Adverse 
Event], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor.
5.6.7 Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in [Appendix 12.3 Common 
Serious Adverse Events] for reference. The list does NOT change the investigator’s reporting 
obligations, nor his obligations to perform a causality assessment, or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to
alert the investigator that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common SAEs” as specified in 
[Appendix 12.3 Common Serious Adverse Events]. The sponsor will monitor these events 
throughout the course of the study for any change in frequency. Any changes to this list will 
be communicated to the participating investigational sites. Investigators must report 
individual occurrences of these events as stated in [Section 5.6.5 Reporting of Serious 
Adverse Events]. 
5.6.8 Special Situations 
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug, comparator, or background therapy) are 
collected in the eCRF, as Protocol Deviation per [Section 8.1.6 Protocol Deviations] or may 
require special reporting, as described below. These Special Situations are not considered 
AEs, but do require to be communicated to Astellas as per the timelines defined below.

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If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.6.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet.
The Special Situations are:
●
Pregnancy
●
Medication Error and Overdose 
●
Misuse/abuse
●
Occupational exposure
●
Suspected Drug-Drug interaction
5.6.8.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 6 months from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 5.6.5 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form and in the eCRF.
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 6 months from 
the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 5.6.5 Reporting of Serious Adverse Events] using the Pregnancy 
Reporting Form. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.6.5 Reporting of Serious Adverse 
Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form. 
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion.
●
Death of a newborn or infant within 1 month after birth is to be reported as an SAE
regardless of its relationship with the study drug.
●
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator.
●
Congenital anomaly (including anomaly in miscarried fetus)

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Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.
5.6.8.2 Medication Error, Overdose and “Off-Label Use”
If a Medication Error, Overdose or “Off label Use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to [Section 8.1.6 Protocol Deviations]. Any associated (S)AEs 
are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be 
reported as described in [Section 5.6.5 Reporting of Serious Adverse Events] together with 
the details of the medication error, overdose or “Off-Label Use”.
In the event of suspected EV overdose or accidental infusion as a bolus, the subject should 
receive supportive care and monitoring. The Medical Monitor/Expert should be contacted as 
applicable.
No specific procedures are available to treat overdose of EV or accidental infusion as a bolus, 
and only supportive treatment can be given. If EV is accidentally overdosed or accidentally 
infused as a bolus, the investigator/sub-investigator will provide emergency procedures 
and/or general maintenance therapy according to the symptoms to assure the subject’s safety. 
In the event of suspected overdose of paclitaxel, docetaxel or vinflunine, refer to the 
approved Package Insert, SmPC, or local product information supplied by the manufacturer 
for each agent. 
Events of overdose should be recorded in the eCRF with the dosages actually administered. 
5.6.8.3 Misuse/Abuse
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.6.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s).
5.6.8.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the patient) to the study drug(s) occurs, the investigator 
must forward the Special Situation worksheet to the sponsor by fax or email immediately 
(within 24 hours of awareness). Any associated (S)AEs occurring to the individual associated 
with or resulting from the Special Situation are to be reported on the Special Situations 
worksheet.
5.6.8.5 Suspected Drug-Drug Interaction
If a drug-drug interaction associated with the study drug(s) is suspected, the investigator must 
forward the Special Situation worksheet to the sponsor by fax or email immediately (within 

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24 hours of awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE 
meets the definition of a SAE, the SAE is also to be reported as described in [Section 5.6.5
Reporting of Serious Adverse Events] together with details of the suspected drug-drug 
interaction.
5.6.9
Supply of New Information Affecting the Conduct of the Study
When new information necessary for conducting the clinical study properly becomes 
available, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
The investigator will also inform the subjects, who will be required to sign an updated 
informed consent form in order to continue in the clinical study.
For sites located in Japan:
When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, in compliance with Article 80-2 
Paragraph 6 of the Pharmaceutical Affairs Law, the sponsor should inform all the 
investigators involved in the clinical study, the head of the study site, and the regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the clinical study should be continued after hearing the opinions of 
the IRB. The investigator will supply the new information to the subjects, in compliance 
with [Section 8.2.3.2 Supply of New and Important Information Influencing the 
Subject’s Consent and Revision of the Written Information.]
In addition to the above item (1), when the head of the study site receives the revisions of 
the Investigator’s Brochure, protocol, or written information, information on the matters 
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly, or documents to be examined by the IRB these 
documents should be sent to the IRB.
5.6.10
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Unique to Japan)
The investigator must not deviate from the protocol, excluding an emergency case for 
avoiding risks to the subjects. When the investigator does not follow the protocol in order to 
avoid urgent risks for subjects, the investigator should take the following actions. 
Describe the contents of the deviation and the reasons for it in a written notice, and 
immediately send the document stating the deviation or amendment and the reasons to 
the sponsor and the head of the study site. Keep a copy of the notice.
Consult with the sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the sponsor.

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5.7
Test Drug Concentration
Blood samples for PK and ATA will be collected throughout the study per the sample 
collection schedule provided in Table 2. Validated assays will be used to measure the 
concentrations of ADC, total antibody (TAb) and MMAE in serum or plasma. PK samples 
will be collected and archived for possible analysis of other EV-related species. A validated 
assay will also be used to determine the levels of ATA in serum.
Refer to the Laboratory Manual for information on collection, processing, storage, and 
shipment of sample.
5.8
Other Measurements, Assessments or Methods
5.8.1
Exploratory Biomarker 
The procedures for the collection, handling, and shipping of samples will be specified in the 
laboratory manual.
The samples described in [Section 5.8.2 Biomarkers in Blood] and [Section 5.8.3 Biomarkers 
in Pre-Treatment Tumor Tissue] may be analyzed for other biomarkers including DNA, RNA 
and protein, to investigate possible associations with mechanisms of resistance or sensitivity 
to study treatment, dynamic changes associated with study treatment and method 
development or validation of diagnostic assays related to study treatment. 
The samples may be stored at the study Sponsor’s facility or a contract laboratory facility for 
up to 15 years after database closure, at which time the samples will be destroyed.
5.8.2
Biomarkers in Blood
The plasma and peripheral blood mononuclear cells (PBMC) samples collected at baseline 
and post-baseline time points may be analyzed for markers of immune function, immune cell 
subsets and cytokines. The plasma and PBMC sample may be used for additional exploratory 
analyses as described in [Section 5.8.1 Exploratory Biomarker].
5.8.3
Biomarkers in Pre-Treatment Tumor Tissue
Submission of a FFPE tumor block or freshly sectioned unstained charged slides (at least 
10 and up to 15 slides) at screening should be provided (unless prior approval is obtained 
from the sponsor). Either archival tissue or pretreatment fresh tumor tissue (obtained from a 
fresh biopsy) is acceptable. See the Laboratory Manual for details. The tumor tissue samples 
may be analyzed for Nectin-4 expression, markers of disease subtype and markers related to 
the tumor immune microenvironment. The tumor tissue sample may be used for additional 
exploratory analyses as described in [Section 5.8.1 Exploratory Biomarker].
5.8.4
Blood Sample for Future Pharmacogenomic Analysis (Retrospective)
Pharmacogenomics (PGx) research may be conducted in the future to analyze or determine
genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. After 
randomization (see schedule of assessments), a 4 mL sample of whole blood for possible 

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retrospective PGx analysis will be collected. Samples will be shipped to a sponsor designated 
banking CRO.
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See [Appendix 12.4, Retrospective PGx Sub-study] for further details on the banking 
procedures.
5.8.5
EORTC Core Quality of Life Questionnaire, QLQ-C30
The QLQ-C30 was developed to measure aspects of QOL pertinent to patients with a broad 
range of cancers who are participating in clinical trials [Sneeuw 1998; Aaronson 1993]. The 
current version of the core instrument (QLQ-C30, Version 3) is a 30-item questionnaire 
consisting of the following:
●functional domains (physical, role, cognitive, emotional, social);
●3 symptom scales (fatigue, pain, nausea & vomiting);
●Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease; and
●2 global items (health, overall QOL).
5.8.6
EuroQOL-5 Dimensions
The EQ-5D-5L is a standardized instrument developed by the EuroQOL Group for use as a 
generic, preference-based measure of health outcomes. It is applicable to a wide range of 
health conditions and treatments and provides a simple descriptive profile and a single index 
value for health status. The EQ-5D-5L is a 5-item self-reported measure of functioning and 
well-being, which assesses 5 dimensions of health, including mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no 
problems, slight problems, moderate problems, severe problems, extreme problems). A 
unique EQ-5D-5L health state is defined by combining 1 level from each of the 
5 dimensions. This questionnaire also records the respondent’s self-rated health status on a 
vertical graduated (0 to 100) visual analogue scale. Responses to the 5 items will also be 
converted to a weighted health state index (utility score) based on values derived from 
general population samples [Herdman, 2011]. 
5.8.7
Healthcare Resource Utilization (HRU)
HRU information will be collected with particular focus on the number of subjects who have 
an unplanned use of healthcare resources related to clinical events or AEs from all subjects 
[Appendix 12.7].  
5.9
Total Amount of Blood
The total amount of blood collected for study assessments for each subject will vary depending 
on how long the subject stays on treatment.  
At any time during the study, if any laboratory abnormalities are found for a subject or for 
disease assessment, additional blood may be drawn for monitoring.

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Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment; hematology and chemistry evaluations at specific study 
defined time points; pharmacokinetics; and bioanalytical sampling.
The maximum amount of blood collected is approximately 130.0 mL in Cycle 1 for subjects 
randomized to Arm A and 37.0 mL in Cycle 1 for subjects randomized to Arm B. The 
maximum amount of blood collected for subjects that participate from Cycle 2 up to Cycle 6 
and complete the EOT visit is 219.0 mL for subjects randomized to Arm A and 164.0 mL for 
subjects randomized to Arm B.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason.  
The subject is free to discontinue from study treatment and/or withdraw from the study for 
any reason and at any time without giving reason for doing so and without penalty or 
prejudice. The investigator is also free to discontinue the subject from study treatment or to 
terminate a subject's involvement in the study at any time if the subject's clinical condition 
warrants it.
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol specific follow up procedures as outlined in the Schedule of 
Assessments (Table 1) until the subject specifically withdraws consent for any further contact 
with him/her or persons previously authorized by the participant to provide this information.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
The following are discontinuation criteria from treatment for individual subjects:
●
Subject develops radiological disease progression.  
●
Subject is required to receive another systemic anti-cancer treatment for underlying or 
new cancer.
●
Subject develops unacceptable toxicity.
●
Female subject becomes pregnant.
●
Investigator decides it is in the subject’s best interest to discontinue. 
●
Subject declines further treatment. 
●
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject.
●
Death.

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Subjects who discontinue study drug prior to reaching PFS1 and enter the post treatment 
follow-up period will be discontinued from the post treatment period if any of the following 
occur:
●
Subject develops radiological progressive disease (i.e., PFS1) based on investigator
assessment
●
Subject initiates a new systemic anticancer treatment (first line of anticancer therapy 
after discontinuation of study drug) 
●
Death
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow up despite reasonable efforts by the investigator to locate the 
subject
The subject will be discontinued from the long-term follow-up period (for PFS2) if any of the 
following occur:
●
Subject initiates a new systemic anticancer treatment (second line of anticancer therapy 
after discontinuation of study drug) 
●
Subject exhibits evidence of PD based on investigator assessment
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the
subject
●
Death
●
Sponsor ends long-term follow-up collection period
The subject will be discontinued from the survival follow-up period if any of the following 
occur:
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the
subject
●
Death
●
Sponsor ends survival follow-up collection period
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor (Japan only) and the head of the Study site.
6.3
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.

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7
STATISTICAL METHODOLOGY
A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the first subject is enrolled. Any changes from the analyses planned in SAP will be justified 
in the Clinical Study Report.
In general, continuous data will be summarized with descriptive statistics (number of subjects, 
mean, SD, minimum, median and maximum), and frequency and percentage for categorical data.
7.1
Sample Size
Approximately 600 subjects will be randomized in a 1:1 ratio to 2 treatment arms: EV 
(Arm A) and chemotherapy (Arm B). Randomization will be stratified by baseline ECOG PS 
(0 vs 1), regions of the world (Western EU, US or the rest of world) and liver metastasis (yes 
or no). Assuming HR = 0.75 (median OS in Arm A and Arm B are 10.7 months and 
8 months, respectively) drop-out rate of 10%, the final analysis at the planned 439 death 
events and 1 interim analysis at 65% of the total planned events (285 death events), this 
sample size will provide 85% power to detect a statistically significant difference at overall 
type I error rate of 1-sided 0.025.
Sample size is determined by primary endpoint OS; the 600 subjects will provide more than 
90% power to detect statistically significant differences on selected secondary endpoints: 
PFS1(assuming median PFS1 in Arm A and Arm B are 6 months and 4 months, 
respectively), ORR and DCR (assuming 15% treatment difference between Arm A and Arm 
B for both ORR and DCR).
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in SAP or Classification Specifications and 
the allocation of subjects to analysis sets will be determined prior to database hard-lock. 
7.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized. This analysis set 
is in compliance with the intent to treat (ITT) principle that includes all randomized subjects, 
the FAS is equivalent to the ITT population. This will be the primary analysis set for efficacy 
analyses except for response related efficacy endpoints.
7.2.2
Safety Analysis Set
The safety analysis set (SAF), which consists of all subjects who received any amount of 
study drug, will be used for safety analyses.
7.2.3
Response Evaluable Set
The response evaluable set (RES) is defined as all subjects in FAS and with measurable 
disease (per RECIST V1.1) at baseline. RES will be used for primary efficacy analysis of 
response related endpoints, e.g., ORR and DCR. 

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7.2.4
Pharmacokinetic Analysis Set
Pharmacokinetics Analysis Set (PKAS) includes subjects who received active drug for whom 
at least one blood sample was collected and assayed for measurement of the TAb, ADC and 
MMAE serum/plasma concentrations and for whom the time of sampling and the time of 
dosing on the day of sampling is known.
7.3
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and 
overall. Ethnic origin will only be summarized in demographic table. Descriptive statistics 
will include number of subjects, mean, standard deviation, minimum, median and maximum 
for continuous endpoints, and frequency and percentage for categorical endpoints. 
7.3.1
Subject Disposition
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all randomized subjects and for 
subjects in the SAF by treatment group and overall. Similar tables for screening disposition, 
investigational period disposition and follow-up disposition will also be presented for all 
randomized subjects by treatment group and overall. All disposition details and dates of first 
and last evaluations for each subject will be listed.
7.3.2
Previous and Concomitant Medications 
All previous and concomitant medications will be presented in a listing. The frequency of 
concomitant medications (prescription, over-the-counter and nutritional supplements) will be 
summarized by treatment group and preferred term (PT) for SAF. Medications will be coded 
using the WHO drug dictionary. Medications will be counted by the number of subjects who 
took each medication. A subject taking the same medication multiple times will only be 
counted once for that medication. Medications will be presented in decreasing order of 
frequency based on the total number of subjects who took each medication.
7.3.3
Medical History 
Medical history for each subject will be presented in a listing. A detailed medical history for 
each subject will be obtained during screening period and will be summarized by treatment 
group and overall.
7.4
Analysis of Efficacy 
Efficacy analysis for OS and PFS will be conducted on the FAS. The interpretation of results 
from statistical tests will be based on the FAS. Efficacy analysis for response related 
endpoints, e.g., ORR and DCR will be conducted on RES. 
The family-wise type I error rate for this study is strongly controlled at 2.5% (one-sided) that 
allows the study to declare positive on primary endpoint OS on the FAS population. OS will 
be formally tested at both interim analysis and final analysis. Formal hypothesis tests on the 
selected secondary endpoints including PFS1, ORR and DCR, will be performed 
hierarchically (per the order of PFS1-> ORR->DCR) only when the OS analysis is rejected. 

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PFS1 is planned to test at either the interim analysis or final analysis when OS is rejected. 
ORR and DCR will be tested only once after both OS and PFS1 are rejected (at either interim 
analysis or final analysis) and the test statistics will be computed from the interim data. DCR 
will be tested after ORR is rejected. The details about the significance levels at interim 
analysis and final analysis for each efficacy endpoints (OS, PFS1, ORR and DCR) are
specified in SAP.
7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The primary efficacy endpoint of OS will be analyzed using the log-rank test stratified by 
ECOG PS (0 vs 1), regions of the world (Western EU, US or the rest of world) and liver 
metastasis (yes or no). Randomized treatment and the strata used for randomization will be 
used for the analysis. In addition, the stratified Cox proportional hazard model will be used to 
estimate the hazard ratio and the corresponding 95% confidence interval. The median OS will 
be estimated using the Kaplan-Meier method and will be reported along with the 
corresponding 95% confidence interval by treatment arm.
The primary analysis will be performed using the FAS.
7.4.1.2 Sensitivity Analysis
Additional analyses such as unstratified log-rank test and OS analyses adjusting the crossover 
effect may be conducted, if appropriate. Details will be specified in the SAP.
7.4.2
Analysis of Secondary Endpoints 
7.4.2.1 Progression Free Survival
For each subject, PFS1 is defined as the time from the date of randomization until the date of 
radiological disease progression (per RECIST V1.1), or until death due to any cause. If a 
subject has neither progressed nor died, the subject will be censored at the date of last 
radiological assessment. Subjects who receive any further anticancer therapy for the disease 
before radiological progression will be censored at the date of the last radiological 
assessment before the anticancer therapy started. In addition, subjects who have PD or death 
after 2 or more missed disease assessments will be censored at the last disease assessment 
prior to the 2 or more missed disease assessments.
The efficacy endpoint of PFS1 will be analyzed using the log-rank test stratified by ECOG 
PS (0 vs 1), regions of the world (Western EU, US or the rest of world) and liver metastasis 
(yes or no). Randomized treatment and the strata used for randomization will be used for the 
analysis. In addition, stratified Cox proportional hazard model will be used to estimate the 
hazard ratio and the corresponding 95% confidence interval. The median PFS1 will be 
estimated using the Kaplan-Meier method and will be reported along with the corresponding 
95% confidence interval by treatment arm.
The primary analysis will be performed using the FAS. Additional sensitivity analyses for 
PFS1 will also be performed. Details will in specified in the SAP.

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7.4.2.2 Overall Response Rate
The overall response rate (ORR) is defined as the proportion of subjects with complete or 
partial objective response based on the RECIST V1.1. The comparison of ORR between Arm 
A and Arm B will be performed using a stratified CMH test. Same stratification factors used 
in time to event analyses will be used for the stratified CMH test. The difference in response 
rates between the treatment arms will be estimated along with the corresponding 95% 
confidence interval. In addition, ORR for each arm will be estimated and corresponding 95% 
confidence interval will be constructed. The primary analysis will be performed using the 
RES.
7.4.2.3 Duration of Response
Duration of Response (DOR) is defined as the time from the date of the first response CR/PR 
per RECIST V1.1 (whichever is first recorded) that is subsequently confirmed as assessed by 
investigator to the date of radiological progression or date of death for subjects who achieved 
CR or PR. If a subject has not progressed or died, the subject will be censored at the date of 
last radiological assessment or at the date of first CR/PR if no other post-baseline radiological 
assessment is available after the first CR/PR. Subjects who receive any further anti-cancer 
therapy for the disease before radiological progression will be censored at the date of the last 
radiological assessment before the anticancer therapy started. In addition, subjects who have 
PD or death after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the 2 or more missed disease assessments.
The median DOR will be estimated using the Kaplan-Meier method and will be reported 
along with the corresponding 95% confidence interval by treatment arm.
7.4.2.4 Disease Control Rate (DCR)
The DCR is defined as the proportion of subjects with a complete or partial objective 
response or a stable disease based on RECIST V1.1. The comparison of DCR between Arm 
A and Arm B will be performed using a stratified CMH test. Same stratification factors used 
in time to event analyses will be used for the stratified CMH test. The difference in response 
rates between the treatment arms will be estimated along with the corresponding 95% 
confidence interval. In addition, DCR for each arm will be estimated and corresponding 95% 
confidence interval will be constructed. The primary analysis will be performed using the 
RES.
7.4.2.5 QOL and PRO Parameters
Descriptive QOL and PRO analyses will be performed on the FAS. Completion rate for each 
questionnaire will be summarized. Additional analyses will be discussed in detail in the 
statistical analysis plan.
7.4.3
Subgroup Analysis 
Using FAS, the analysis for OS, PFS1 and ORR will be repeated by ECOG PS (0 vs 1),
regions of the world, and liver metastasis respectively.

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In addition, subgroup analyses may be conducted for selected endpoints to determine whether 
the treatment effect is consistent. Subgroups may include but are not limited to the following:
●
Age category (< 65 vs ≥65 years; < 75 vs ≥75 years)
●
Sex (female vs male)
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Prior platinum (cisplatin vs carboplatin vs both)
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Prior lines of systemic therapy in locally advanced or metastatic setting (1 to 2 vs ≥3)
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Best response to most recent CPI (responder vs non-responder) CPI most recent 
treatment (yes vs no)
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Baseline hemoglobin (≥10 vs < 10 g/dL)
●
Histology (Urothelial Carcinoma/transitional cell vs Urothelial Carcinoma mixed vs 
other)
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Primary site of tumor (upper tract vs bladder/other)
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Smoking status (never vs former vs current)
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Brain metastasis status (prior brain metastasis vs no prior brain metastasis)
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Investigators’ choice of paclitaxel/docetaxel or vinflunine
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Baseline Nectin-4 IHC score (<150 vs 150 - 225 vs >225) 
●
Prior taxane (yes vs no) 
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PD-L1 CPS (<10 vs ≥10) 
7.4.4
Analysis of Exploratory Endpoints 
Exploratory analysis for efficacy endpoints will be discussed in the statistical analysis plan. 
Serum or plasma TAb, ADC and MMAE concentrations will be summarized with descriptive 
statistics at each PK sampling time point using the PK analysis set. These data may be 
combined with data from previous studies for population PK and PK/PD analyses. The 
relationship between TAb, ADC, MMAE and PD endpoints, safety, or efficacy may be 
explored.
The incidence of ATA will be summarized by visit and overall using the safety analyses set.
7.5
Analysis of Safety
SAF will be used to perform all safety analysis. All treated subjects will be analyzed 
according to the treatment they received.
7.5.1
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
A TEAE is defined as an AE observed or worsened after starting administration of the study 
drug.
The number and percentage of subjects with treatment-emergent AEs, SAEs, AEs leading to 
withdrawal of treatment, and AEs related to study drug will be summarized by system organ 
class, preferred term and treatment group. The number and percentage of AEs by severity 
will also be summarized. All AEs will be listed.

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A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. AEs of interest as classified by customized MedDRA queries and/or standard 
MedDRA queries will also be summarized.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by treatment group and time point. 
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated. Laboratory data will be displayed in listings.
7.5.3
Vital Signs 
Vital sign results and changes from baseline at scheduled visits will be summarized with 
descriptive statistics for subjects in the SAF by treatment group. Vital signs data will be 
displayed in listings. 
7.5.4
Routine 12-lead Electrocardiograms
The 12-lead ECG results will be summarized by treatment group and time point.
7.5.5
ECOG Performance Status
Summary statistics (number and percent of subjects) for each category of the ECOG PS at 
each assessment will be provided. The change from baseline to final visit or early termination 
will also be summarized. Negative change scores indicate an improvement. Positive scores 
indicate a decline in performance.
7.5.6
Exposure-Response Relationship Analysis 
Relationships between TAb, ADC and MMAE concentrations and certain efficacy or safety 
endpoints may be analyzed in an exploratory manner. Further details of these analyses will be 
described in an exposure-response analysis plan.
7.6
Analysis of Pharmacokinetics
Individual and summary tables of serum TAb and ADC and plasma MMAE concentrations 
and a listing of blood collection times and concentrations will be provided.
Summary statistics will be provided including n, mean, SD, geometric mean, minimum, 
median, maximum, and %CV. Values below the lower limit of quantification (BLOQ) will be 
set to not be calculated if all values are BLOQ. In cases where more than half of the 
individual data in a group are BLOQ, the geometric mean will not be calculated. Additional 
model-based analyses may be performed and will be described in a separate population PK 
analysis plan.  
7.7
Major Protocol Deviations and Other Analyses
Major protocol deviations as defined in [Section 8.1.6 Major Protocol Deviations] will be 
summarized for all randomized subjects by treatment group and total as well as by site. A 
data listing will be provided by site and subject.

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The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim efficacy analysis is planned to occur after approximately 285 OS events (about 
65% of the total planned events) are observed. OS will be tested at 1-sided 0.00541 
significance level for efficacy according to the O’Brien-Fleming boundary as implemented 
by Lan-DeMets alpha spending function [Lan-DeMets, 1983]. The IDMC may recommend 
terminating the trial at the interim analysis based on statistically significant OS results 
favoring EV. When total deaths reach 439, the final OS analysis will be conducted at the 
1-sided 0.02332 significance level. If the exact numbers of events at interim and final 
analyses are different than planned, the significance level will be adjusted accordingly, based 
on the O’Brien-Fleming method with a Lan-DeMets alpha spending function.
The interim analysis will be conducted by IDAC and reviewed by the IDMC. In addition, 
safety data reviews during the trial will be conducted by the IDMC on a periodic basis. For 
example, the IDMC will review safety data after the first 50 subjects have been randomized 
and on study drug for approximately 3 months. The full procedures for IDMC safety review 
and interim analysis will be described in a separate IDMC charter and Interim Analysis Plan.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses will be outlined in the SAP. 
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within 5 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.

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The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at the central laboratory. Central laboratory data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The central laboratory will provide the sponsor or designee with a complete and clean copy 
of the data. 
For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
For sites located in Japan:
For screen failures, the minimum demographic data (sex, birth date or age, race and informed 
consent date), AEs and reason for screen failure will be collected in screen failure log (SFL), 
if applicable. This information will be entered into the study database.
Electronic Patient Reported Outcome (ePRO):
Questionnaires will be completed by the subject on an electronic device. Subjects will be 
provided with digital support (e.g., instruction) to fill in the questionnaires at home. The 
information completed by the subject on the electronic device will be automatically uploaded 
into a central website. The investigator or site designee should review the diaries and 
questionnaire data on the website for correct completion while the subject is at the site. The 
diary and questionnaire data will be transferred electronically to sponsor or designee at 
predefined intervals during the study. The vendor will provide sponsor or designee with a 
complete and clean copy of the data.
For subjects who are unable to read a language in a country for which ePRO translation is 
available or who is illiterate will not be required to complete the ePRO part of the study.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy, pharmacokinetic and safety data, if applicable
●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)

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●
Details of dispensing and return of study drug 
●
Reason for premature discontinuation (if applicable)
●
Randomization number
●
Pharmacokinetic sample processing and storage history, including date/time each sample 
is transferred to the freezer, freezer identification and the temperature log for the freezer 
8.1.3
Clinical Study Monitoring
The sponsor is responsible for monitoring the clinical study to ensure that subject's human 
rights, safety, and well-being are protected, that the study is properly conducted in adherence 
to the current protocol and GCP, and study data reported by the investigator/sub-investigator 
are accurate and complete and that they are verifiable with study-related records such as 
source documents. The sponsor is responsible for assigning study monitor(s) to this study for 
proper monitoring. They will monitor the study in accordance with planned monitoring 
procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
[refer to Section 8.1.2 Specification of Source Documents] when they are requested by the
sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science of the sponsor in accordance with 
the SOPs for data management. All study-specific processes and definitions will be 
documented by Data Management. eCRF completion will be described in the eCRF
instructions. Coding of medical terms and medications will be performed using MedDRA 
and WHO Drug Dictionary, respectively.
8.1.6
Major Protocol Deviations
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited. 
The major protocol deviation criteria are as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 

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PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow-up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy of the subject to determine subject continuation in the study. 
If a major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately. 
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file (TMF).  
8.1.7
End of Trial in All Participating Countries
Study completion is defined as the conclusion of data collection for the defined study 
endpoints. The end of study in all participating countries is therefore defined as the last 
subject’s last visit, or last contact. The study may be closed within a participating country per 
local regulations once the study has completed, if all subjects enrolled in the country are no 
longer receiving study treatment and once final survival analysis is completed.  
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible ethics committees and regulatory agencies, as required. During the conduct 
of the study, the investigator should promptly provide written reports (e.g., ICH Expedited 
Reports, and any additional reports required by local regulations) to the IEC/IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IEC/IRB should also be provided to sponsor.

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If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed (place a personal seal, if applicable) and dated 
by the subject or his/her guardian or legal representative, the person who administered the 
informed consent and any other signatories according to local requirements. A copy of the 
signed or sealed informed consent form will be given to the subject and the original will be 
placed in the subject’s medical record. An entry must also be made in the subject’s dated 
source documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the 
study (e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to 
remain in the study or not must be confirmed and documented.
2. The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The 
investigator or his/her designee must reconsent subjects with the updated ICF even if 
relevant information was provided orally. The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the 
informed consent form (place a personal seal, if applicable). A copy of the signed or 
sealed informed consent form will be given to the subject and the original will be 

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placed in the subject’s medical record. An entry must be made in the subject’s records 
documenting the re-consent process.
8.2.4
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties. 
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
sponsor. However, the sponsor requires the investigator to permit the sponsor, sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the EU Data Protection Directive, and Investigator and/or third party shall 
act only under the instructions of the sponsor in regard to personal data. If sponsor is not 
based in the EEA, sponsor must appoint a third party to act as its local data protection 
representative or arrange for a co-controller established in the EU for data protection 
purposes in order to comply with the Directive.
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study.

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Publication of the study results is discussed in the clinical study agreement.
After agreement between investigator(s) and sponsor, the manuscript can be submitted for 
publication.
8.3.2
Documents and Records Related to the Clinical Study
The sponsor will provide the investigator and/or institution with the following:
●
Study protocol (and amendments, where applicable)
●
Investigator’s Brochure (and amendments, where applicable)
●
eCRFs and JUTOKUNA YUUGAIJISHOU HOUKOKUSHO
●
Study drug with all necessary documentation
●
Study contract
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the sponsor: 
●
Financial disclosure in compliance with federal regulation 21 Code of Federal 
Regulations Part 54
●
Signed and dated FDA form 1572
●
Signed Investigator's Statement in this protocol and eCRF 
●
Current Curricula Vitae of all investigators
●
List of sub-investigators and collaborators 
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY)
●
Instruction and decision of the head of the study site
●
Study contract
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs, and investigator's file) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation (for US sites, two years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued. The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records. The sponsor will archive and 
retain all documents pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.
Data will be collected for each subject for the clinical study database via electronic data 
source.

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For sites located in Japan:
The following are the major documents to be retained at the study site.
Source documents (clinical data, documents, and records for preparing the CRF):
hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, administration records, data recorded by automatic measuring 
instruments, reproductions or transcripts verified as precise copies, microfiche, negative 
films, microfilms/magnetic media, X-ray films, subject files and study-related records 
kept at either a pharmacy, a laboratory, or medical technical office, as well as subject 
registration forms, laboratory test slips including central measurement, worksheets 
specified by the sponsor, records of clinical coordinators, and records related to the 
clinical study selected from those verified in other departments or hospitals. 
Contracts, written informed consent forms, written information, and other documents or 
their copies prepared by the study personnel. A letter of request for clinical study 
(including a request for continuation/amendment), letter of request for review, notice of 
clinical study contract, clinical study contract, notification of discontinuation or 
completion of clinical study, written information for informed consent (including 
revisions), signed and dated written informed consent (including revisions), CVs of 
investigators, list of sub-investigators, list of signatures and print of seals (copy), and 
case report forms (copy), etc. 
The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study by the head of the study sites (Article 32-1, MHW Ordinance No. 28), 
documents obtained from the IRB related to the adequacy of conducting a clinical study 
whose period exceeds 1 year or the adequacy of continuously conducting the clinical 
study from which information on adverse drug reactions is obtained, and other 
documents obtained. An agreed-upon protocol (including revisions), Investigator's 
Brochure (including revisions), operational procedures for the investigator, materials and 
information supplied by the sponsor (e.g., AE report), matters reported by the 
investigator (revisions of the protocol, AE reports, etc.), operational procedures for the 
IRB, the list of names of the IRB members, materials for IRB review (including 
continuous deliberation), IRB review records (including continuous deliberation), and 
the review result report of the IRB (including continuous deliberation), etc. 
Records of control for study drugs and other duties related to the clinical study. 
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).

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Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor. An approved copy of the new informed consent must also be 
forwarded to the sponsor.
8.3.4
Insurance of Subjects and Others
The sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
investigator's file. 
If a subject suffers any study-related injury, the sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study site, the sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the study-
related injury is provided by the following procedures:
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures. The sponsor should be 
notified of the injury. 
When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the sponsor. Both parties should work together towards
compensation settlement.
The sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.
The sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above.
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock.

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9
QUALITY ASSURANCE
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied.
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee
An IDMC will be chartered to oversee safety and the planned interim efficacy analysis, 
which will occur after at least 285 events (about 65% of the total planned events) are 
observed. The primary analysis will occur at 439 OS events. The interim analysis will be 
conducted by the IDMC. In addition, safety data reviews during the trial will be conducted by 
the IDMC on a periodic basis. For example, the IDMC will review safety data after the first 
50 subjects have been randomized and on study drug for approximately 3 months. The IDMC 
may recommend to the sponsor whether the trial should be terminated, modified or continue 
unchanged based on ongoing reviews of safety data and interim efficacy analysis. Further 
details will be outlined in the IDMC charter. 

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11
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. European Organization 
for Research and Treatment of Cancer Study Group on Quality of Life. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-76.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. KEYNOTE-045 Investigators. 
Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 
2017;376:1015-26. DOI: 10.1056/NEJMoa1613683.
Bellmunt J, Orsola A, Wiegel T, Guix M, De Santis M, Kataja V, et al. ESMO Guidelines Working 
Group. Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2011;22(S6):45-9.
Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of 
vinflunine plus best supportive care compared with best supportive care alone after a platinum-
containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. 
J Clin Oncol. 2009;27:4454-61.
Cancer Fact Sheets: All cancers excluding Non-Melanoma Skin. International Agency for Research 
on Cancer 2017. Retrieved from http://gco.iarc.fr/today/fact-sheets-
cancers?cancer=29&type=0&sex=0. Accessed 19 Dec 2017.
Docetaxel summary of product characteristics. Jul 2014.
Fidalgo JA, Garcia Fabregat L, Cervantes A, Margulies A, Vidall C, Roila F. Management of 
chemotherapy extravasation: ESMO clinical practice guidelines. Ann Oncol. 2012;23(7):167-73.
Herdman M, Godex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development an preliminary 
testing of the new-five level version of EQ-5D (EQ-5D-5L). Qual LifeRes. 2011;20(10):1727-36.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659-
63.
Mullane SA & Bellmunt J. Cancer immunotherapy: new applications in urologic oncology. Curr Opin 
Urol. 2016;26:556-63.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.
Paclitaxel Amneal summary of product characteristics. Nov 2016.
Polovich M, Olsen M, LeFebvre K. Chemotherapy and biotherapy guidelines and recommendations 
for practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014. 473 p.
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;387:1909-20.

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SEER Cancer Stat Facts: Bladder Cancer. National Cancer Institute. Bethesda, MD, 
http://seer.cancer.govstatfacts/html/urinb.html. Accessed 19 Dec 2017.
Sneeuw KC, Aaronson NK, Sprangers MA, Detmar SB, Wever LD, Schornagel JH. Comparison of 
patient and proxy EORTC QLQ-C30 ratings in assessing the quality of life of cancer patients. J 
Clin Epidemiol. 1998;51:617-31.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival 
results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, 
vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 
2005;23:4602-8.
Vinflunine (Javlor) summary of product characteristics.

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12
APPENDICES
12.1
List of Cautionary Concomitant Medications
The following list describes medications and foods that are common strong inhibitors/inducers 
of CYP3A, CYP2C8 and p-glycoprotein (P-gp) inhibitors that should be avoided, used with 
caution, or closely monitored. This list should not be considered all inclusive; consult 
individual drug labels for specific information. If there are concerns or questions about 
concomitant use of any drugs listed below, discussion with the sponsor is encouraged.
P-gp Inhibitors
Strong CYP3A 
Inhibitors
Strong CYP3A4 
Inducers
Strong CYP2C8 
Inhibitors
Strong CYP2C8 
Inducers
amiodarone 
carvedilol 
clarithromycin 
drenedarone
itraconazole
lapatinib 
lopinavir/ritonavir
propafenone
quinidine
ranolazine 
saquinavir/ritonavir 
telaprevir 
tipranavir/ritonavir
verapamil
boceprevir
cobicistat
conivaptan
danoprevir/ 
ritonavir
elvitegravir/ 
ritonavir 
grapefruit juice
indinavir/ ritonavir
itraconazole
ketoconazole
lopinavir/ritonavir
paritaprevir/ 
ritonavir/ 
(ombitasvir and/or 
dasabuvir) 
posaconazole
ritonavir
saquinavir/ 
ritonavir
telaprevir
tipranavir/ritonavir
troleandomycin
voriconazole
carbamazepine
enzalutamide
mitotane
phenytoin
rifampin
St John’s wort
clopidogrel
gemfibrozil
rifampin
Note: Any additional strong inhibitors/inducers of CYP3A, CYP2C8, and P-gp inhibitors that are identified or become 
commercially available while the clinical trial in ongoing are also applicable. P-gp: p-glycoprotein
Table 10
Summary of Potential Drug Reactions
Arm A: EV
Arm B: Docetaxel
Arm B: 
Vinflunine
Arm B: Paclitaxel
Strong CYP3A4 
inhibitor
Closely monitor
Should avoid
Should avoid
Exercise caution
Strong CYP3A4 
inducer
Should avoid
Should avoid
Exercise caution
P-gp inhibitor
Closely monitor
Strong CYP2C8 
inhibitor/inducer
Exercise caution 
EV: enfortumab vedotin; P-gp: p-glycoprotein
Additional information for inhibitors/inducers can be found in FDA’s guidance (Drug 
Interaction and Labeling). 
https://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664 ht
m#table5-2

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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases) or 
bilirubin > 2 × ULN should undergo detailed testing for liver enzymes (including at least ALT, 
AST, ALP, and TBL). Testing should be repeated within 72 hours of notification of the test 
results. For studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 × ULN (in patients without liver 
metastases), > 5 × ULN (in patients with 
liver metastases)
or
> 2 × ULN
Severe
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases).
●
ALT or AST > 3 × ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the liver abnormality case report 
form (LA-CRF) that has been developed globally and can be activated for any study or 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  

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Severe hepatic liver function abnormalities as defined above, in the absence of another etiology 
may be considered an important medical event and may be reported as a SAE. The sponsor 
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” in the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic, and/or diabetic patients and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, including dose, is to be entered in the (e)CRF. Information on 
alcohol, other substance use and diet should be entered on the LA-CRF or an appropriate 
document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
o Acute viral hepatitis (A, B, C, D, E or other infectious agents), 
o Ultrasound or other imaging to assess biliary tract disease,
o Other laboratory tests including INR, direct bilirubin.
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases).
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated).
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 

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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
*Hy’s Law Definition: 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by a higher rate 
than control of people with 3 × and greater transaminase elevations over the upper limit of 
normal (2 × elevations are too common in treated and untreated patients to be 
discriminating).
2. Cases of increased bilirubin (to at least 2 × ULN) in people with concomitant transaminase 
elevation to at least 3 × ULN (but it is almost invariably higher) and no evidence of intra-or 
extra-hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome.
[Temple, 2006]
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or 
placebo.
2. Among trial subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP).
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury [Guidance for Industry, 2009].
References
Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(S4):241-3.
Guidance for Industry. “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.

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12.3
Common Serious Adverse Events
The following is a list of SAE that the sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in [Section 5.6.2 Definition of 
Serious Adverse Events]. The purpose of this list is to alert the investigator that some events 
reported as SAEs may not require expedited reporting to the regulatory authorities based on 
the classification of “common SAEs”. The investigator is required to follow the requirements 
detailed in [Section 5.6.5 Reporting of Serious Adverse Events].
●
Urinary tract pain
●
Bladder disorder
●
Dysuria
●
Hemorrhage urinary tract (hematuria)
●
Urinary tract obstruction

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12.4
Retrospective PGx Sub-Study 
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood. As many diseases may be influenced by 1 or more genetic variations, PGx 
research may identify which genes are involved in determining the way a subject may or may 
not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx sub-
study. As part of this sub-study, subjects must provide written consent prior to providing any 
blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide one approximately 4-6 mL 
tube of whole blood per Astellas’ instructions. Each sample will be identified by the unique 
subject number (first code). Samples will be shipped frozen to a designated banking CRO 
either directly from site or via a central laboratory as directed by Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety. 
DISPOSAL OF PGx SAMPLES / DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.

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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas and its collaborator. 

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12.5
EORTC-QLQ-30

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12.6
EQ-5D-5L

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12.7
Health Resource Utilization
Since your last study visit, have you had any visits to the emergency room (ER)?

No (if no, go to 4)

Yes (if yes, go to 2)
Since your last visit, how many emergency room visits have you had?  ___________
For each emergency room visit please complete the following:
Result in a Hospital 
Admission (more 
than a 24-hour stay)?
Length of stay in hospital 
(number of days)
ER Visit 1
Yes/No
ER Visit 2
Yes/No
ER Visit 3
Yes/No
Since your last study visit, have you had any hospital admissions (more than a 24 hour 
stay) that occurred without first going to the emergency room (ER)?

No (if no, go to 7)

Yes (if yes, go to 5)
How many hospital admissions (more than 24-hour stay; without previous ER 
transferal)?  
For each hospital admission (more than 24 hour stay; without previous ER transferal) 
visit please complete the following:
Length of stay in hospital (number of 
days)
Hospital Visit 1
Hospital Visit 2
Hospital Visit 3
Since your last study visit, have you had any visits to a general practitioner (primary care 
physician)?

No (if no, go to 9)

Yes (if yes, go to 8)
How many visits have you had to a general practitioner (primary care physician)?  

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Since your last study visit, did you have any visits to a specialist physician (e.g., 
oncologist, rheumatologist, endocrinologist, orthopedic surgeon, etc.)?

No 

Yes (if yes, go to 10)
How many visits have you had to a specialist physician (e.g., oncologist, rheumatologist, 
endocrinologist, orthopedic surgeon, etc.)? 

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12.8
RECIST V1.1

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Reproduced from:  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;45:228-47.

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12.10 Crossover Extension
Note: The crossover extension study described below and outlined in the Crossover
Extension (COE) schematic [Figure 2] will be conducted if the EV-301 Interim Analysis
results in a positive outcome. With the exception of those procedures and processes indicated 
below, this extension study will be performed using the same general approach as described 
in the protocol. Refer to the main protocol for any study details not contained in the 
supplemental COE appendix.
12.10.1 Rationale 
Upon decision to stop the study for efficacy based on statistically significant OS result 
favoring EV, all eligible Arm B subjects can be evaluated for eligibility for COE EV 
treatment at the discretion of the subject and investigator. Day 1 of the COE will occur after 
COE informed consent form is signed and eligibility is confirmed. Treatment with EV will be 
stopped upon disease progression and/or when discontinuation criteria are met [Section 
12.10.5 Duration of Treatment and Criteria for Discontinuation]. Arm B Subjects who do not 
participate in the COE will continue to follow Arm B protocol procedures.
12.10.2 Inclusion Criteria
Subject is eligible for the COE if they continue to meet all inclusion criteria from the main 
protocol in addition to the following when the patient is evaluated for eligibility to participate 
in the COE portion of the study:
1. IRB/IEC approved written COE informed consent and privacy language as per national 
regulations (e.g., HIPAA Authorization for US sites) must be obtained from the subject 
prior to any study-related procedures (including withdrawal of prohibited medication, if 
applicable).
2. Subject was randomized to Arm B and is either currently on study treatment or has 
discontinued study treatment due to intolerance, AE or progression of disease, has not 
started a new systemic anticancer treatment and is still participating in the follow up 
phase of the study.
Waivers to the COE inclusion criteria will NOT be provided.
12.10.3 Exclusion Criteria
Subject will be excluded from participation in the COE if they meet any of the exclusion 
criteria listed in the main protocol or if any of the following apply when the patient is 
evaluated for eligibility to participate in the COE portion of the study:
Subject has been diagnosed with a new malignancy while on Arm B in the EV-301 
study. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with 
curative intent with no evidence of progression, low-risk or very low-risk (per standard 
guidelines) localized prostate cancer under active surveillance/watchful waiting without
intent to treat, or carcinoma in situ of any type (if complete resection was performed) are
allowed.

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Waivers to the COE exclusion criteria will NOT be allowed.
12.10.4 Schedule and Assessments
Arm B subjects meeting criteria as indicated in [Section 12.10.3] will sign informed consent 
prior to COE Day 1 dosing. The COE subjects will follow the COE Schematic and COE
Schedule of Assessments [Table 11].

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Figure 2
Crossover Extension Schema
COE: crossover extension; OS: overall survival; PFS2: progression free survival on subsequent therapy

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Table 11
Schedule of Assessments for Crossover Extension
Visit
Every Cycle
End of 
Treatment1
Follow-up2
Long Term PFS2 
Treatment 
Follow-up
Survival 
Follow-up
Base Date
Day 1
Day 8
Day 15
Every
56 Days
Date of Last 
Dose
Date of last
Dose + 30 
days
Every 3 months
Every 3 months
Visit Window
± 3 days
± 3 day
± 3 days
± 7 days
+ 7 days
+ 7 days
± 7 days
± 7 days
Informed Consent 
X3,4
Confirmation of Eligibility 
for COE
X3,4
Brain Scan5
X3,5
X5
Bone Scan6
X6
X6
Serum/Urine Pregnancy 
Test7
X
X
X
X7
X7
Physical Examination8
X
X
Weight8
X
X
X
X
Vital Signs8
X
X
X
X
X
Biochemistry9
X
X
X
X
X
Hemoglobin A1C10
X
X
Hematology11
X
X
X
X
X
ECOG PS
X
X
X
12-lead ECG12
X3,12
X12
Ophthalmology 
Assessment13
X
X
COE Enrollment via IRT
X4
EV Administration
X
X
X
Image Assessment14
X
X14
Concomitant Medication
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
QOL15
X
X
X
HRU16
X16
X
X
Table continued on next page

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Visit
Every Cycle
End of 
Treatment1
Follow-up2
Long Term PFS2 
Treatment 
Follow-up
Survival 
Follow-up
Base Date
Day 1
Day 8
Day 15
Every
56 Days
Date of Last 
Dose
Date of last
Dose + 30 
days
Every 3 months
Every 3 months
Visit Window
± 3 days
± 3 day
± 3 days
± 7 days
+ 7 days
+ 7 days
± 7 days
± 7 days
ATA19
X
X
X
Subsequent Therapy 
assessment17
X
X
Overall Survival18
X
X
X
AE: adverse event; ALT: alanine transaminase; AST: aspartate transaminase; ATA: antitherapeutic antibody; C: cycle; COE: crossover extension; CR: complete 
response; CT: computed tomography; D: day; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EORTC-QLQ-
C30: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EOT: end of treatment; EQ-5D-5L: EuroQOL 5-
Dimension 5-Level Questionnaire; EV: enfortumab vedotin; HRU: health resource utilization; MRI: magnetic resonance imaging; NA: Not Applicable; PD: 
progressive disease; PFS1: progression free survival on study therapy; PFS2: progression free survival on subsequent therapy; PGx: Pharmacogenetic analyses; 
PR: partial response; QOL: quality of life; RECIST: Response Evaluation Criteria in Solid Tumors
1.
EOT visit will occur within 7 days after the last dose or when the decision is made by the investigator to discontinue subject from treatment.
2.
Follow up assessments should be completed prior to the initiation of the next therapy.
3.
May be completed within 28 days prior to COE C1D1 visit.  
4.
COE Cycle 1 only.
5.
Only if clinically indicated at time of COE eligibility assessment. Repeat as clinically indicated or per standard of care throughout the study.
6.
All subjects will have a bone scan (scintigraphy) within 28 days prior to COE C1D1 dosing. Subjects with positive bone scans at time of COE eligibility 
assessment will have a bone scan performed every 56 days (± 7 days) throughout the study or more frequently if clinically indicated. Subjects should 
have a follow-up bone scan performed if clinically indicated regardless of status at time of COE eligibility assessment.  
7.
For all female subjects of child bearing potential only, a urine or serum pregnancy test will be performed within -7 days of COE C1D1 visit. A urine or 
serum pregnancy test will be performed at COE Day 1 prior to dosing, on day 1 of each cycle prior to EV administration, at EOT and Follow-up visits. 
After EOT, a monthly (± 7 days) pregnancy test will be maintained until 6 months after the last dose of study treatment.
8.
Full Physical examination, weight, ECOG PS and vital signs (pulse, temperature and blood pressure) will be performed at COE C1D1 prior to dosing. 
The physical examination will also be performed on day 1 of each cycle and EOT visit. For subsequent and EOT visits, physical examinations maybe 
more directed but should include examination of lungs, abdomen, skin and cardiovascular systems. Vital signs and weight will be completed on days 1, 8 
and 15 of each cycle and at EOT visit. Vital signs will also be performed at follow up visit.
Footnotes continued on next page

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9.
Biochemistry: See [Section 5.5.3 Laboratory Assessments]. Amylase and lipase will only be collected at COE Day 1 of each Cycle. All biochemistry 
laboratory tests should be collected at the start of the following COE time points: C1D1, C1D8, C1D15 and D1 of each subsequent cycle. If all 
biochemistry laboratory tests were performed within 7 days prior to the first day of dosing, they do not need to be repeated at C1D1. Biochemistry tests 
will be sent to a central laboratory for analysis. Local laboratory results may be used to determine eligibility if the C1D1 results from the central 
laboratory are not available in time for planned C1D1 dosing. In the event that the central laboratory results received after C1D1 dosing are not within 
eligibility parameters, the subject will still be considered eligible, if local labs met the eligibility criteria, and will not be considered a protocol deviation.
Local laboratory results that support eligibility and dosing decisions must be entered into the clinical database. If local laboratory is to be used to support 
dosing decisions, local laboratory tests will include complete blood count (CBC) with differential, glucose, serum creatinine, ALT and AST. Additional 
assessments may be done centrally or locally to monitor AEs or as required by dose modification requirements.
10.   If HbA1c was performed within 7 days prior to the first day of COE C1D1 dosing, it does not need to be repeated at COE C1D1. If HbA1c is elevated (≥ 
6.5%), refer subject to appropriate provider during Cycle 1 for glucose management.
11. Hematology: See [Section 5.5.3 Laboratory Assessments]. Hematology tests should be collected at the following COE time points: C1D1, C1D8, C1D15 
and Day 1 of each subsequent cycle. If hematology tests were performed within 7 days prior to the first day of dosing, they do not need to be repeated on 
C1D1. Hematology tests will be sent to a central laboratory for analysis. Local laboratory results may be used to determine eligibility if the C1D1 results
from the central laboratory are not available in time for planned dosing. In the event that the central laboratory results received after C1D1 dosing are not 
within eligibility parameters, the subject will still be considered eligible if local laboratory results met the eligibility criteria; such events will not be 
considered protocol deviations. Local laboratory results that support eligibility and dosing decisions must be entered into the clinical database. If local 
laboratory is to be used to support dosing decisions, local laboratory tests will include CBC with differential, glucose, serum creatinine, ALT and AST. 
Additional assessments may be done centrally or locally to monitor AEs or as required by dose modification requirements.
12. ECGs will be read locally. If there is no reason to suspect cardiac issues, ECG will not be required.
13. Ophthalmologic assessments for subjects with recent ocular complaints (within 3 months of COE consent) are required. Assessments should include the 
following: visual acuity, slit lamp, tonometry examination and dilated fundus examination. Prior ophthalmologic exam done within 3 months of COE 
consent is acceptable provided symptoms are not new since the exam. Ophthalmology assessments should be performed per standard of care or if 
clinically indicated (e.g., subject develops new or worsening ocular symptoms). EOT slit lamp examinations are required for subjects who experience 
corneal adverse events during the study. EOT slit lamp examinations must be performed ≥4 weeks from last dose. Additional eye examinations are to be 
conducted as clinically indicated.
14. Imaging will be evaluated within 28 days prior to COE C1D1 dosing and every 56 days (± 7 days) throughout the study. CT scan with contrast (chest, 
abdomen and pelvis) is the preferred modality for tumor assessment. MRI is acceptable if local standard practice or if CT scans are contraindicated in a 
subject (e.g., subject is allergic to contrast media). All other RECIST approved scanning methods such as x-ray are optional. To ensure comparability, 
the COE eligibility scan and subsequent assessment of response should be performed using identical techniques as were performed during Arm B 
participation. The same method should be employed and assessed by the same individual on each occasion if possible. Imaging assessments methods 
used at Baseline of the main study are to continue to be used throughout the study. 
Footnotes continued on next page

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15. QOL will be collected pre-dose on COE C1D1, every 12 weeks during treatment period, EOT visit and at the 30-day follow-up visit. QOL questionnaire 
completion timing should be calculated based on COE C1D1 dosing. If a visit occurs out of the assessment window, QOL questionnaires should still be 
completed. QOL questionnaires will be completed by the subject at home on hand-held devices prior to coming to the clinic visit with the exception of 
COE Day 1 of the first week, the EOT and the follow-up visits at which the QOL questionnaires will be completed by the subject at the clinic.
16. HRU will be collected pre-dose on COE C1D1. Subsequent questionnaires will be completed monthly (COE Day 1 of every 4 weeks [+7 days]), starting 
on COE Week 5 Day 1 (timing calculated based on COE C1D1 dosing), and at the EOT and follow-up visit. HRU questionnaires will be completed by the 
subject at home on hand-held devices prior to coming to the clinic visit with the exception of the COE C1D1, EOT and the follow-up visits at which the 
HRU questionnaires will be completed by the subject at the clinic.
17. Subjects that discontinue EV for reasons other than progressive disease will be followed in the long term follow up period per institutional guidelines, but not 
less frequently than every 3 months to confirm survival status until PFS2 is documented or the subject starts another cancer treatment, whichever is earlier.
Phone contact is sufficient for follow up. Additional follow up contacts may be required per sponsor request for analysis purposes.  
18. Contact subjects in the survival follow-up period approximately every 3 months to collect survival status until subject death or study closure. Additional 
follow-up contacts may be required per sponsor request for analysis purposes.
19. ATA will be collected at COE Cycles 1, 2, 3, 4, 6, 8 and 10 predose within 24 hrs of the start of the infusion EOT (Date of last dose + 7 days) and follow-up 
(Date of last dose +30 days).

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12.10.5 Duration of Treatment and Discontinuation Criteria
A discontinuation from treatment is a subject who enrolled in the COE and for whom study 
treatment is permanently discontinued for any reason. 
The subject is free to discontinue from study treatment and/or withdraw from the COE study 
for any reason and at any time without giving reason for doing so and without penalty or 
prejudice. The investigator is also free to discontinue the subject from COE study treatment 
or to terminate a subject's involvement in the study at any time if the subject's clinical 
condition warrants it.
All subjects who discontinue COE study treatment will remain in the study and must 
continue to be followed for protocol specific follow up procedures as outlined in the COE 
Schedule of Assessments [Table 11] until the subject specifically withdraws consent for any 
further contact with him/her or persons previously authorized by the participant to provide 
this information.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
The following are discontinuation criteria from treatment for individual subjects:
●
Subject develops radiological disease progression relative to scan performed within 28 
days of COE C1D1 dose.
●
Subject is required to receive another systemic anti-cancer treatment for underlying or 
new cancer
●
Subject develops unacceptable toxicity
●
Female subject becomes pregnant
●
Investigator decides it is in the subject’s best interest to discontinue.
●
Subject declines further treatment
●
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject.
●
Death.
The subject will be discontinued from the long-term PFS2 follow-up period if any of the 
following occur:
●
Subject initiates a new systemic anticancer treatment 
●
Subject exhibits evidence of PD based on investigator assessment
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Death
●
Sponsor ends long-term follow-up collection period

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The subject will be discontinued from the survival follow-up period if any of the following 
occur:
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Death
●
Sponsor ends survival follow-up collection period
12.10.6 Statistical Methods 
All eligible Arm B subjects who cross to COE EV treatment will be the analysis population, 
and analyzed in the same way as described in [Section 7 Statistical Methodology] for all 
applicable safety endpoints with data collected in COE period unless otherwise specified in 
SAP. The following analysis will be provided:
●
Study population in COE period:
o
Disposition at EOT, 30-day follow-up, long-term follow-up and survival follow-up
o
Days in the study and previous study treatment outcomes at the time initiating the 
EV treatment
o
Major protocol deviations in COE period
o
Demographics and other characteristics at original study enrollment
o
Concomitant medications in COE period.
●
Study drug exposure in COE period
●
Analysis of safety in COE period:
o
Adverse events
o
Lab assessments
o
Vital signs
o
12-lead ECG
o
ECOG performance status
Details will be specified in the SAP.

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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 3
I.  The purpose of this amendment is:
Substantial Changes
Add a Crossover Extension (COE) to Study Design
DESCRIPTION OF CHANGE:
A COE is added to the study design. Details of this extension amendment are added as 
Appendix 12.10 and include a rationale, enrollment criteria, schedule of assessments, 
duration of treatment and discontinuation criteria.
RATIONALE:
A COE is added for when the enfortumab vedotin (EV)-301 interim analysis results in a 
positive outcome.
Nonsubstantial Changes
Update Clinical Research Contact
DESCRIPTION OF CHANGE: 
Contact details for the clinical research contact are revised.
RATIONALE:
This change is made due to changes to study personnel.
Update Schedule of Assessments
DESCRIPTION OF CHANGE: 
In Table 2, the row for Subsequent Dosing Cycles is revised to specify cycles 3, 4, 6, 8 and 
10 and footnotes A and C are updated with cycle numbers. 
In Table 3, footnote A is updated to include cycles 8 and 10.
RATIONALE:
This change is made because the pharmacokinetics of EV (antibody drug conjugate, total 
antibody and monomethyl auristatin E) reaches steady-state by end of cycle 1 and 
immunogenicity of EV is low based on previous studies, sufficient pharmacokinetic and 
antitherapeutic antibodies data are collected by cycle 10 and most patients are off the study 
by cycle 10.
Update Response Evaluable Set (RES)
DESCRIPTION OF CHANGE: 

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The definition of the RES is updated to remove the requirement that subjects had at least 6 
months of follow-up since randomization.
RATIONALE:
This revision is made based on regulatory agency feedback.
Add Clarification to Efficacy Analysis
DESCRIPTION OF CHANGE: 
Additional text is added to clarify when progression-free survival on study therapy (PFS1), 
overall response rate (ORR) and disease control rate (DCR) can be tested.
RATIONALE:
This revision is made due to enrollment completion earlier. The multiplicity strategy was 
updated accordingly.
Update Duration of Response
DESCRIPTION OF CHANGE: 
Additional text is added to clarify when radiological progression will be censored.
RATIONALE:
This revision is made to update the censor rules for PFS1 and duration of response (DOR) 
to also censor the progressive disease (PD) or death after 2 or more missed disease 
assessments based on regulatory agency feedback.
Clarify Progression Free Survival
DESCRIPTION OF CHANGE: 
Additional text is added to clarify the requirements for progression free survival.
RATIONALE:
This revision is made to update the censor rules for PFS1 and DOR to also censor the PD 
or death after 2 or more missed disease assessments based on regulatory agency feedback.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol), add COE to the list of abbreviations and update an exploratory 
endpoint in the synopsis to match the same endpoint in the body of the protocol.
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.

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II.  Amendment Summary of Changes:
IIA. Substantial Changes
12 Appendices
ADDED:
12.10 Crossover Extension
Note: The crossover extension study described below and outlined in the Crossover 
Extension (COE) schematic [Figure 2] will be conducted if the EV-301 Interim 
Analysis results in a positive outcome. With the exception of those procedures and 
processes indicated below, this extension study will be performed using the same 
general approach as described in the protocol. Refer to the main protocol for any 
study details not contained in the supplemental COE appendix.
12.10.1 Rationale 
Upon decision to stop the study for efficacy based on statistically significant OS result 
favoring EV, all eligible Arm B subjects can be evaluated for eligibility for COE EV 
treatment at the discretion of the subject and investigator. Day 1 of the COE will 
occur after COE informed consent form is signed and eligibility is confirmed. 
Treatment with EV will be stopped upon disease progression and/or when 
discontinuation criteria are met [Section 12.10.5 Duration of Treatment and Criteria 
for Discontinuation]. Arm B Subjects who do not participate in the COE will 
continue to follow Arm B protocol procedures.
12.10.2 Inclusion Criteria
Subject is eligible for the COE if they continue to meet all inclusion criteria from the 
main protocol in addition to the following when the patient is evaluated for eligibility 
to participate in the COE portion of the study:
1. IRB/IEC approved written COE informed consent and privacy language as per 
national regulations (e.g., HIPAA Authorization for US sites) must be obtained 
from the subject prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2. Subject was randomized to Arm B and is either currently on study treatment or 
has discontinued study treatment due to intolerance, AE or progression of disease, 
has not started a new systemic anticancer treatment and is still participating in 
the follow up phase of the study.
Waivers to the COE inclusion criteria will NOT be provided. 
12.10.3 Exclusion Criteria
Subject will be excluded from participation in the COE if they meet any of the 
exclusion criteria listed in the main protocol or if any of the following apply when the 
patient is evaluated for eligibility to participate in the COE portion of the study:
1. Subject has been diagnosed with a new malignancy while on Arm B in the EV-301 
study. Subjects with nonmelanoma skin cancer, localized prostate cancer treated 
with curative intent with no evidence of progression, low-risk or very low-risk 
(per standard guidelines) localized prostate cancer under active 

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surveillance/watchful waiting without intent to treat, or carcinoma in situ of any 
type (if complete resection was performed) are allowed.
Waivers to the COE exclusion criteria will NOT be allowed.
12.10.4 Schedule and Assessments
Arm B subjects meeting criteria as indicated in [Section 12.10.3] will sign informed 
consent prior to COE Day 1 dosing. The COE subjects will follow the COE Schematic 
and COE Schedule of Assessments [Table 11].

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Figure 2
Crossover Extension Schema
COE: crossover extension; OS: overall survival; PFS2: progression free survival on subsequent therapy
Table 11
Schedule of Assessments for Crossover Extension
Visit
Every Cycle
End of 
Treatment1
Follow-up2
Long Term PFS2 
Treatment 
Follow-up
Survival 
Follow-up
Base Date
Day 1
Day 8
Day 15
Every
56 Days
Date of Last 
Dose
Date of last
Dose + 30 
days
Every 3 months
Every 3 months
Visit Window
± 3 days
± 3 day
± 3 days
± 7 days
+ 7 days
+ 7 days
± 7 days
± 7 days
Informed Consent 
X3,4
Confirmation of 
Eligibility for COE
X3,4
Brain Scan5
X3,5
X5
Bone Scan6
X6
X6
Serum/Urine 
Pregnancy Test7
X
X
X
X7
X7
Physical Examination8
X
X
Weight8
X
X
X
X
Vital Signs8
X
X
X
X
X
Biochemistry9
X
X
X
X
X
Hemoglobin A1C10
X
X
Hematology11
X
X
X
X
X
ECOG PS
X
X
X
12-lead ECG12
X3,12
X12

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Ophthalmology 
Assessment13
X
X
COE Enrollment via 
IRT
X4
EV Administration
X
X
X
Image Assessment14
X
X14
Concomitant 
Medication
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
QOL15
X
X
X
HRU16
X16
X
X
ATA19
X
X
X
Subsequent Therapy 
Assessment17
X
X
Overall Survival18
X
X
X
AE: adverse event; ALT: alanine transaminase; AST: aspartate transaminase; ATA: antitherapeutic antibody; C: cycle; COE: crossover extension; 
CR: complete response; CT: computed tomography; D: day; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group 
Performance Status; EORTC-QLQ-C30: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EOT: 
end of treatment; EQ-5D-5L: EuroQOL 5-Dimension 5-Level Questionnaire; EV: enfortumab vedotin; HRU: health resource utilization; MRI: 
magnetic resonance imaging; NA: Not Applicable; PD: progressive disease; PFS1: progression free survival on study therapy; PFS2: progression free 
survival on subsequent therapy; PGx: Pharmacogenetic analyses; PR: partial response; QOL: quality of life; RECIST: Response Evaluation Criteria 
in Solid Tumors
1.
EOT visit will occur within 7 days after the last dose or when the decision is made by the investigator to discontinue subject from treatment.
2.
Follow up assessments should be completed prior to the initiation of the next therapy.
3.
May be completed within 28 days prior to COE C1D1 visit.  
4.
COE Cycle 1 only.
5.
Only if clinically indicated at time of COE eligibility assessment. Repeat as clinically indicated or per standard of care throughout the study.
6.
All subjects will have a bone scan (scintigraphy) within 28 days prior to COE C1D1 dosing. Subjects with positive bone scans at time of COE 
eligibility assessment will have a bone scan performed every 56 days (± 7 days) throughout the study or more frequently if clinically 
indicated. Subjects should have a follow-up bone scan performed if clinically indicated regardless of status at time of COE eligibility 
assessment.  
7.
For all female subjects of child bearing potential only, a urine or serum pregnancy test will be performed within -7 days of COE C1D1 visit. 
A urine or serum pregnancy test will be performed at COE Day 1 prior to dosing, on day 1 of each cycle prior to EV administration, at EOT 
and Follow-up visits. After EOT, a monthly (± 7 days) pregnancy test will be maintained until 6 months after the last dose of study treatment.
8.
Full Physical examination, weight, ECOG PS and vital signs (pulse, temperature and blood pressure) will be performed at COE C1D1 prior 
to dosing. The physical examination will also be performed on day 1 of each cycle and EOT visit. For subsequent and EOT visits, physical 

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examinations maybe more directed but should include examination of lungs, abdomen, skin and cardiovascular systems. Vital signs and 
weight will be completed on days 1, 8 and 15 of each cycle and at EOT visit. Vital signs will also be performed at follow up visit.
9.
Biochemistry: See [Section 5.5.3 Laboratory Assessments]. Amylase and lipase will only be collected at COE Day 1 of each Cycle. All 
biochemistry laboratory tests should be collected at the start of the following COE time points: C1D1, C1D8, C1D15 and D1 of each 
subsequent cycle. If all biochemistry laboratory tests were performed within 7 days prior to the first day of dosing, they do not need to be 
repeated at C1D1. Biochemistry tests will be sent to a central laboratory for analysis. Local laboratory results may be used to determine 
eligibility if the C1D1 results from the central laboratory are not available in time for planned C1D1 dosing. In the event that the central 
laboratory results received after C1D1 dosing are not within eligibility parameters, the subject will still be considered eligible, if local labs 
met the eligibility criteria, and will not be considered a protocol deviation. 
Local laboratory results that support eligibility and dosing decisions must be entered into the clinical database. If local laboratory is to be 
used to support dosing decisions, local laboratory tests will include complete blood count (CBC) with differential, glucose, serum creatinine, 
ALT and AST. Additional assessments may be done centrally or locally to monitor AEs or as required by dose modification requirements.
10.   If HbA1c was performed within 7 days prior to the first day of COE C1D1 dosing, it does not need to be repeated at COE C1D1. If HbA1c is 
elevated (≥ 6.5%), refer subject to appropriate provider during Cycle 1 for glucose management.
11. Hematology: See [Section 5.5.3 Laboratory Assessments]. Hematology tests should be collected at the following COE time points: C1D1, 
C1D8, C1D15 and Day 1 of each subsequent cycle. If hematology tests were performed within 7 days prior to the first day of dosing, they do 
not need to be repeated on C1D1. Hematology tests will be sent to a central laboratory for analysis. Local laboratory results may be used to
determine eligibility if the C1D1 results from the central laboratory are not available in time for planned dosing. In the event that the central 
laboratory results received after C1D1 dosing are not within eligibility parameters, the subject will still be considered eligible if local 
laboratory results met the eligibility criteria; such events will not be considered protocol deviations. Local laboratory results that support 
eligibility and dosing decisions must be entered into the clinical database. If local laboratory is to be used to support dosing decisions, local 
laboratory tests will include CBC with differential, glucose, serum creatinine, ALT and AST. Additional assessments may be done centrally 
or locally to monitor AEs or as required by dose modification requirements.
12. ECGs will be read locally. If there is no reason to suspect cardiac issues, ECG will not be required.
13. Ophthalmologic assessments for subjects with recent ocular complaints (within 3 months of COE consent) are required. Assessments should 
include the following: visual acuity, slit lamp, tonometry examination and dilated fundus examination. Prior ophthalmologic exam done 
within 3 months of COE consent is acceptable provided symptoms are not new since the exam. Ophthalmology assessments should be 
performed per standard of care or if clinically indicated (e.g., subject develops new or worsening ocular symptoms). EOT slit lamp 
examinations are required for subjects who experience corneal adverse events during the study. EOT slit lamp examinations must be 
performed ≥4 weeks from last dose. Additional eye examinations are to be conducted as clinically indicated.
14. Imaging will be evaluated within 28 days prior to COE C1D1 dosing and every 56 days (± 7 days) throughout the study. CT scan with contrast 
(chest, abdomen and pelvis) is the preferred modality for tumor assessment. MRI is acceptable if local standard practice or if CT scans are 
contraindicated in a subject (e.g., subject is allergic to contrast media). All other RECIST approved scanning methods such as x-ray are 
optional. To ensure comparability, the COE eligibility scan and subsequent assessment of response should be performed using identical 
techniques as were performed during Arm B participation. The same method should be employed and assessed by the same individual on each 
occasion if possible. Imaging assessments methods used at Baseline of the main study are to continue to be used throughout the study. 

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15. QOL will be collected pre-dose on COE C1D1, every 12 weeks during treatment period, EOT visit and at the 30-day follow-up visit. QOL 
questionnaire completion timing should be calculated based on COE C1D1 dosing. If a visit occurs out of the assessment window, QOL 
questionnaires should still be completed. QOL questionnaires will be completed by the subject at home on hand-held devices prior to coming 
to the clinic visit with the exception of COE Day 1 of the first week, the EOT and the follow-up visits at which the QOL questionnaires will be 
completed by the subject at the clinic.
16. HRU will be collected pre-dose on COE C1D1. Subsequent questionnaires will be completed monthly (COE Day 1 of every 4 weeks [+7 days]), 
starting on COE Week 5 Day 1 (timing calculated based on COE C1D1 dosing), and at the EOT and follow-up visit. HRU questionnaires will 
be completed by the subject at home on hand-held devices prior to coming to the clinic visit with the exception of the COE C1D1, EOT and the 
follow-up visits at which the HRU questionnaires will be completed by the subject at the clinic.
17. Subjects that discontinue EV for reasons other than progressive disease will be followed in the long term follow up period per institutional 
guidelines, but not less frequently than every 3 months to confirm survival status until PFS2 is documented or the subject starts another cancer 
treatment, whichever is earlier. Phone contact is sufficient for follow up. Additional follow up contacts may be required per sponsor request for 
analysis purposes.  
18. Contact subjects in the survival follow-up period approximately every 3 months to collect survival status until subject death or study closure. 
Additional follow-up contacts may be required per sponsor request for analysis purposes.
19. ATA will be collected at COE Cycles 1, 2, 3, 4, 6, 8 and 10 predose within 24 hrs of the start of the infusion EOT (Date of last dose + 7 days) and 
follow-up (Date of last dose +30 days).

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12.10.5 Duration of Treatment and Discontinuation Criteria
A discontinuation from treatment is a subject who enrolled in the COE and for whom 
study treatment is permanently discontinued for any reason. 
The subject is free to discontinue from study treatment and/or withdraw from the 
COE study for any reason and at any time without giving reason for doing so and 
without penalty or prejudice. The investigator is also free to discontinue the subject 
from COE study treatment or to terminate a subject's involvement in the study at 
any time if the subject's clinical condition warrants it.
All subjects who discontinue COE study treatment will remain in the study and must 
continue to be followed for protocol specific follow up procedures as outlined in the 
COE Schedule of Assessments [Table 11] until the subject specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the 
participant to provide this information.
If a subject is discontinued from the study with an ongoing AE or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator 
will attempt to provide follow-up until the condition stabilizes or no longer is 
clinically significant. 
The following are discontinuation criteria from treatment for individual subjects:
●
Subject develops radiological disease progression relative to scan performed 
within 28 days of COE C1D1 dose.
●
Subject is required to receive another systemic anti-cancer treatment for
underlying or new cancer
●
Subject develops unacceptable toxicity
●
Female subject becomes pregnant
●
Investigator decides it is in the subject’s best interest to discontinue.
●
Subject declines further treatment
●
Subject is noncompliant with the protocol based on the investigator or medical 
monitor assessment.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate 
the subject.
●
Death.
The subject will be discontinued from the long-term PFS2 follow-up period if any of 
the following occur:
●
Subject initiates a new systemic anticancer treatment 
●
Subject exhibits evidence of PD based on investigator assessment
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate 
the subject
●
Death
●
Sponsor ends long-term follow-up collection period
The subject will be discontinued from the survival follow-up period if any of the 
following occur:
●
Subject declines further study participation (i.e., withdraws consent)

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V Flow Chart and Schedule of Assessments
Table 2 Pharmacokinetic, ATA, and biomarker blood sample collection timepoints - Arm A
WAS:
Study Day
Time
Window
Relative Time
Blood
Ph
ar
ma
ATA
Biomarkers
Subsequent Dosing Cycles
Day 1
Pre-dose
Within 24 hrs
START of infusion
XA
XA
XB
XC
XB
A.
Pharmacokinetics and ATA: Pre-dose of cycle 3, 4 and every even numbered cycle there after 
B.
Cytokines and Immuno-phenotyping: Pre-dose cycles 3 and 4 only
C.
cfDNA: Pre-dose every even numbered cycle (e.g., cycle 4, 6, etc.) only
IS AMENDED TO:
Cycles 3, 4 , 6, 8 and 10
Subsequent Dosing Cycles
Day 1
Pre-dose
Within 24 hrs
START of infusion
XA
XA
XB
XC
XB
A.
Pharmacokinetics and ATA: Pre-dose of cycle 3, 4, 6, 8 and 10 and every even numbered cycle there after 
B.
Cytokines and Immuno-phenotyping: Pre-dose cycles 3 and 4 only
C.
cfDNA: Pre-dose every even numbered cycle up to 10 cycles  (e.g., cycle 4, 6, 8, 10etc.) only
V Flow Chart and Schedule of Assessments
Biomarker blood sample collection timepoints - Arm B
WAS:
A. cfDNA: Pre-dose every even numbered cycle (e.g., cycle 4, 6, etc.) only
IS AMENDED TO:
A. cfDNA: Pre-dose every even numbered cycle up to 10 cycles (e.g., cycle 4, 6, etc 8, 10.) only

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IV Synopsis, Study Design Overview and 2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
WAS:
Subjects in Arm A will receive EV on Days 1, 8 and 15 of each 28-day cycle. Subjects in 
arm B will receive either docetaxel, paclitaxel or vinflunine (as decided by the investigator 
prior to randomization: vinflunine is a choice of comparator only in countries where it is 
approved for urothelial cancer) on Day 1 of every 21 day cycle.
No on-study crossover will be allowed. This study will consist of 3 phases: screening, 
treatment and follow-up.
IS AMENDED TO:
Subjects in Arm A will receive EV on Days 1, 8 and 15 of each 28-day cycle. Subjects in 
arm B will receive either docetaxel, paclitaxel or vinflunine (as decided by the investigator 
prior to randomization: vinflunine is a choice of comparator only in countries where it is 
approved for urothelial cancer) on Day 1 of every 21 day cycle.
No on-study crossover will be allowed other than as allowed in Appendix 12.10. This 
study will consist of 3 phases: screening, treatment and follow-up.
7 Statistical Methodology
7.2.3 Response Evaluable Set
WAS:
The response evaluable set (RES) is defined as all subjects in FAS and with measurable 
disease at baseline and had at least 6 months follow up since randomization. RES will be 
used for primary efficacy analysis of response related endpoints, e.g., ORR and DCR.
IS AMENDED TO:
The response evaluable set (RES) is defined as all subjects in FAS and with measurable 
disease (per RECIST V1.1) at baseline and had at least 6 months follow up since 
randomization. RES will be used for primary efficacy analysis of response related 
endpoints, e.g., ORR and DCR.
7 Statistical Methodology
7.4 Analysis of Efficacy
WAS:
family-wise type I error rate for this study is strongly controlled at 2.5% (one-sided) that 
allows the study to declare positive on primary endpoint OS on the FAS population. OS 
will be formally tested at both interim analysis and final analysis. At either interim or final 
analysis, the formal hypothesis tests on the selected secondary endpoints including PFS1, 
ORR and DCR, will be performed hierarchically (per the order of PFS1-> ORR->DCR) 
only when the OS analysis is rejected. The details about the significance levels at interim 
analysis and final analysis for each efficacy endpoints (OS, PFS1, ORR and DCR) is 
specified in SAP.

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IS AMENDED TO:
The family-wise type I error rate for this study is strongly controlled at 2.5% (one-sided) 
that allows the study to declare positive on primary endpoint OS on the FAS population. 
OS will be formally tested at both interim analysis and final analysis. At either interim or 
final analysis, the fFormal hypothesis tests on the selected secondary endpoints including 
PFS1, ORR and DCR, will be performed hierarchically (per the order of PFS1-> ORR-
>DCR) only when the OS analysis is rejected. PFS1 is planned to test at either the 
interim analysis or final analysis when OS is rejected. ORR and DCR will be tested 
only once after both OS and PFS1 are rejected (at either interim analysis or final 
analysis) and the test statistics will be computed from the interim data. DCR will be 
tested after ORR is rejected.  The details about the significance levels at interim analysis 
and final analysis for each efficacy endpoints (OS, PFS1, ORR and DCR) is are specified 
in SAP.
7 Statistical Methodology
7.4.2.1 Progression Free Survival
ADDED:
In addition, subjects who have PD or death after 2 or more missed disease 
assessments will be censored at the last disease assessment prior to the 2 or more 
missed disease assessments.
7 Statistical Methodology
7.4.2.3 Duration of Response
ADDED:
Subjects who receive any further anti-cancer therapy for the disease before 
radiological progression will be censored at the date of the last radiological 
assessment before the anticancer therapy started. In addition, subjects who have PD 
or death after 2 or more missed disease assessments will be censored at the last 
disease assessment prior to the 2 or more missed disease assessments.

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14
COORDINATING INVESTIGATOR’S SIGNATURE
An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs 
Chemotherapy in Subjects with Previously Treated Locally Advanced or 
Metastatic Urothelial Cancer (EV-301)
ISN/Protocol 7465-CL-0301
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I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD MMM YYYY)
Printed Name:
Address:

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15
SPONSOR’S SIGNATURES