A Single-arm, Open-label, Multi-center Phase 2 Study of Enfortumab Vedotin (ASG-22CE) in Chinese Subjects With Locally Advanced or Metastatic Urothelial Cancer Who Previously Received Platinum-containing Chemotherapy and PD 1/PD-L1 Inhibitor Therapy (EV-203)
Phase: PHASE2
Conditions: Metastatic Urothelial Cancer
Sponsor: Astellas Pharma China, Inc.

Sponsor: ACN 
ISN/Protocol 7465-CL-1104 
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Clinical Study Protocol 
 
29 Mar 2022 
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Amendment 2 
 
A Single-arm, Open-label, Multi-center Phase 2 Study of 
Enfortumab Vedotin (ASG-22CE) in Chinese Subjects with 
Locally Advanced or Metastatic Urothelial Cancer Who 
Previously Received Platinum-containing Chemotherapy and 
PD-1/PD-L1 Inhibitor Therapy (EV-203) 
 
ISN/Protocol 7465-CL-1104 
Amendment 2 [Substantial]  
29 Mar 2022 
 
Sponsor: 
Astellas Pharma China, Inc. 
No 3 Jia 6 Road 10 
Shenyang Economic and Technological Development Zone, 
Shenyang 110027 China 
 
 
 
Protocol History: 
Version 1.0 [31 Jul 2020] 
Version 2.0 [12 Feb 2021] 
 
 
 
 
 
 
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.   
 

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Amendment 2 
Table of Contents  
SIGNATURES ································
································
································
 8 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ································
·····  10 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ································
·······  11 
1 
PROTOCOL SUMMARY ································
································
·······  12 
1.1 
Synopsis ································
································
························
 12 
1.2 
Study Schema ································
································
··················
 16 
1.3 
Schedule of Assessments ································
································
·····  18 
1.3.1 
Sample Collection Schedule ································
···························
 21 
2 
INTRODUCTION ································
································
·················
 23 
2.1 
Study Rationale ································
································
················
 23 
2.2 
Background ································
································
····················
 24 
2.2.1 
Disease and Nectin-4 Antigen Target ································
·················
 24 
2.2.2 
Enfortumab Vedotin ································
································
····  25 
2.2.3 
Nonclinical Data ································
································
·········  25 
2.2.3.1 
ASG-22CE Nonclinical Pharmacology ································
·········  25 
2.2.3.2 
ASG-22CE Nonclinical Immunogenicity and Pharmacokinetics ············
 26 
2.2.3.3 
ASG-22CE Nonclinical Toxicology ································
·············
 26 
2.2.4 
Clinical Data ································
································
·············
 28 
2.3 
Risk/Benefit Assessment ································
································
·····  30 
2.3.1 
Risk Assessment ································
································
·········  30 
2.3.2 
Benefit Assessment ································
································
·····  31 
2.3.3 
Overall Risk-Benefit Conclusion ································
······················
 31 
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ································
·········  31 
4 
STUDY DESIGN AND DOSE RATIONALE ································
················
 33 
4.1 
Overall Study Design ································
································
·········  33 
4.2 
Scientific Rationale for Study Design ································
······················
 34 
4.3 
Dose Rationale ································
································
················
 35 
4.4 
End of Study Definition ································
································
······  35 
5 
STUDY POPULATION ································
································
··········
 35 
5.1 
Inclusion Criteria ································
································
··············
 35 
5.2 
Exclusion Criteria ································
································
·············
 37 

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5.3 
Lifestyle Considerations ································
································
······  39 
5.4 
Screen Failures ································
································
················
 39 
5.4.1 
Rescreening ································
································
··············
 39 
6 
INVESTIGATIONAL PRODUCT(S) ································
·························
 39 
6.1 
Investigational Product(s) Administered ································
···················
 39 
6.1.1 
Investigational Product Administration ································
···············
 40 
6.2 
Preparation/Handling/Storage/Accountability ································
·············
 41 
6.2.1 
Packaging and Labeling ································
································
 41 
6.2.2 
Handling, Storage and Accountability ································
················
 41 
6.3 
Randomization and Blinding ································
································
 41 
6.4 
Investigational Product Compliance ································
························
 41 
6.5 
Dose Modification ································
································
············
 41 
6.5.1 
Enfortumab Vedotin-Related Rash ································
····················
 44 
6.5.2 
Management of Hyperglycemia ································
·······················
 45 
6.5.3 
Management of Enfortumab Vedotin Infusion Related Reactions ················
 45 
6.6 
Continued Access to Investigational Product After the End of the Study ··············
 46 
6.7 
Treatment of Overdose ································
································
·······  46 
6.8 
Concomitant Therapy ································
································
·········  46 
6.8.1 
Allowed Concomitant Therapy ································
························
 46 
6.8.2 
Prohibited Concomitant Therapy ································
······················
 47 
7 
STUDY PROCEDURES AND ASSESSMENTS ································
············
 47 
7.1 
Efficacy Assessments ································
································
·········  48 
7.1.1 
Evaluation of Target Lesions ································
··························
 49 
7.1.1.1 
Complete Response ································
································
 49 
7.1.1.2 
Partial Response ································
································
···  49 
7.1.1.3 
Progressive Disease ································
·······························
 49 
7.1.1.4 
Stable Disease ································
································
······  49 
7.1.2 
Evaluation of Non-target Lesions ································
·····················
 49 
7.1.2.1 
Complete Response ································
································
 49 
7.1.2.2 
Non-CR/Non-PD ································
································
··  50 
7.1.2.3 
Progressive Disease ································
·······························
 50 
7.1.3 
New Lesions ································
································
·············
 50 
7.1.4 
Time Point for Response Evaluation ································
··················
 50 
7.2 
Safety Assessments ································
································
···········
 50 

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7.2.1 
Laboratory Assessments ································
································
 50 
7.2.2 
Vital Signs ································
································
················
 51 
7.2.3 
Physical Examination ································
································
···  51 
7.2.4 
Electrocardiogram ································
································
·······  51 
7.2.5 
ECOG Performance Status ································
·····························
 52 
7.2.6 
Ophthalmology Examination ································
··························
 52 
7.2.7 
Order of Assessments ································
································
···  52 
7.3 
Adverse Events and Other Safety Aspects ································
·················
 52 
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information································
·····························
 52 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ···············
 53 
7.3.3 
Follow-up of Adverse Events and Serious Adverse Events ························
 53 
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ·················
 53 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ································
··········
 54 
7.3.6 
Special Situations ································
································
········  54 
7.4 
Pharmacokinetics ································
································
··············
 54 
7.5 
Immunogenicity Assessments ································
·······························
 55 
7.6 
Total Amount of Blood ································
································
·······  55 
8 
PARTICIPANT DISCONTINUATION ································
······················
 55 
8.1 
Discontinuation of Individual Participant(s) from Study Treatment ····················
 56 
8.2 
Discontinuation of Individual Participant(s) from Study ································
· 56 
8.3 
Lost to Follow-up ································
································
·············
 56 
9 
STATISTICAL CONSIDERATIONS ································
·························
 57 
9.1 
Statistical Hypotheses ································
································
········  57 
9.2 
Sample Size Determination ································
································
··  57 
9.3 
Populations for Analyses ································
································
·····  57 
9.4 
Statistical Analyses ································
································
···········
 58 
9.4.1 
General Considerations ································
································
· 58 
9.4.2 
Analysis of Efficacy ································
································
·····  59 
9.4.2.1 
Analysis of Primary Endpoint ································
····················
 59 
9.4.2.2 
Analysis of Secondary Endpoints ································
················
 59 
9.4.2.2.1 
DOR per IRC ································
································
·······  59 
9.4.2.2.2 
DCR per IRC ································
································
·······  59 

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9.4.2.2.3 
PFS per IRC ································
································
········  60 
9.4.2.2.4 
Confirmed ORR per Investigator Assessment ································
· 60 
9.4.2.2.5 
DOR per Investigator Assessment ································
···············
 60 
9.4.2.2.6 
DCR per Investigator Assessment ································
···············
 60 
9.4.2.2.7 
PFS per Investigator Assessment ································
················
 60 
9.4.2.2.8 
Overall Survival ································
································
····  60 
9.4.2.2.9 
Tumor shrinkage ································
································
···  61 
9.4.3 
Analysis of Safety ································
································
·······  61 
9.4.3.1 
Adverse Events································
································
·····  61 
9.4.3.2 
Laboratory Assessments ································
··························
 61 
9.4.3.3 
Vital Signs ································
································
··········
 61 
9.4.3.4 
Electrocardiogram ································
································
· 62 
9.4.3.5 
ECOG Performance Status ································
·······················
 62 
9.4.3.6 
Ophthalmology Examination ································
·····················
 62 
9.4.4 
Analysis of Pharmacokinetics ································
··························
 62 
9.4.4.1 
Pharmacokinetic Concentrations ································
·················
 62 
9.4.4.2 
Estimation of Pharmacokinetic Parameters ································
·····  62 
9.4.5 
Analysis of Pharmacodynamics | Immunogenicity ································
··  63 
9.4.6 
Other Analyses ································
································
···········
 63 
9.5 
Interim Analysis ································
································
···············
 63 
9.6 
Additional Conventions ································
································
······  63 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ································
································
·············
 63 
10.1 
Appendix 1: Ethical, Regulatory and Study Oversight Considerations ·················
 63 
10.1.1 
Regulatory and Ethical Considerations ································
···············
 63 
10.1.2 
Financial Disclosure ································
································
····  64 
10.1.3 
Informed Consent of Participants································
······················
 64 
10.1.3.1 
Informed Consent Process ································
························
 64 
10.1.3.2 
Supply of New and Important Information Influencing the 
Participant’s Consent and Revision of the Written Information ·············
 64 
10.1.4 
Data Protection ································
································
··········
 65 
10.1.5 
Committee(s) Structure ································
································
· 65 
10.1.6 
Dissemination of Clinical Study Data································
·················
 65 
10.1.7 
Data Quality Assurance ································
································
· 65 
10.1.8 
Source Documents ································
································
······  66 

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10.1.9 
Study and Site Start and Closure ································
······················
 67 
10.1.10 
Arrangement for Use of Information and Publication of the Study ···············
 67 
10.1.11 
Quality Assurance ································
································
·······  68 
10.2 
Appendix 2: Contraception Requirements ································
·················
 69 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ································
······················
 71 
10.3.1 
Definition of Adverse Events ································
··························
 71 
10.3.1.1 
Abnormal Laboratory Findings ································
··················
 72 
10.3.1.2 
Potential Cases of Drug-induced Liver Injury (DILI) ·························
 72 
10.3.2 
Definition of Serious Adverse Events································
·················
 72 
10.3.3 
Assessment of Causality ································
································
 73 
10.3.4 
Assessment of Severity ································
································
· 75 
10.3.5 
Recording and Follow-Up of AEs and/or SAEs ································
·····  75 
10.3.6 
Reporting Procedures for Serious Adverse Events ································
··  76 
10.3.7 
Reporting Procedures for Special Situations ································
·········  77 
10.3.7.1 
Contraceptive Guidance and Collection of Pregnancy Information ·········  77 
10.3.7.2 
Lack of Efficacy ································
································
···  78 
10.3.7.3 
Medication Error, Overdose and “Off-label Use” ·····························
 78 
10.3.7.4 
Misuse/Abuse ································
································
······  78 
10.3.7.5 
Occupational Exposure ································
···························
 78 
10.3.7.6 
(Suspicion of) Transmission of Infectious Agent ······························
 78 
10.3.7.7 
Suspected Drug-drug Interaction ································
················
 79 
10.3.8 
Supply of New Information Affecting the Conduct of the Study ··················
 79 
10.3.9 
Urgent Safety Measures ································
································
 79 
10.3.10 
Reporting Urgent Safety Measures ································
····················
 79 
10.4 
Appendix 4: Liver Safety Monitoring and Assessment ································
···  79 
10.5 
Appendix 5: List of Excluded Concomitant Medications ································
 83 
10.6 
Appendix 6: Clinical Laboratory Assessments ································
············
 84 
10.7 
Appendix 7: ECOG Performance Status Scale ································
············
 85 
10.8 
Appendix 8: RECIST Version 1.1 ································
··························
 85 
10.9 
Appendix 9: Scanning and Contrast Guidelines ································
···········
 87 
10.10 
List of Abbreviations and Definition of Key Study Terms ·······························
 88 
11 
REFERENCES ································
································
····················
 93 
12 
SPONSOR SIGNATURE ································
································
········  95 

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Amendment 2 
 
List of In-text Tables 
Table 1 
Schedule of Assessments ································
································
·····  18 
Table 2 
Pharmacokinetic Sample Collection Time Points (PK Cohort)··························
 21 
Table 3 
Schedule and Acceptable Time Range for PK Sampling (Non-PK Cohort) ···········
 22 
Table 4 
Schedule for ATA Sampling ································
································
· 22 
Table 5 
Study Objectives and Endpoints ································
·····························
 31 
Table 6 
Investigational Product(s) ································
································
····  39 
Table 7 
Recommended Dose Modifications for Enfortumab Vedotin Associated 
Hematologic Toxicity* ································
································
·······  42 
Table 8 
Recommended Dose Modifications for Enfortumab Vedotin Associated Non-
hematologic Toxicity ································
································
·········  43 
Table 9 
Quality Tolerance Limits ································
································
·····  68 
Table 10 
Grading Scale Defining the Severity of an Adverse Event ·······························
 75 
Table 11 
Moderate and Severe Liver Abnormalities ································
·················
 80 
Table 12 
Clinical Laboratory Tests ································
································
····  84 
 
List of In-text Figures 
Figure 1 
Study Schema ································
································
··················
 16 
 

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SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 12 
Sponsor’s Signatures].  
 
 
 

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2.  INVESTIGATOR’S SIGNATURE 
A Single-arm, Open-label, Multi-center Phase 2 Study of Enfortumab Vedotin (ASG-
22CE) in Chinese Subjects with Locally Advanced or Metastatic Urothelial Cancer 
Who Previously Received Platinum-containing Chemotherapy and PD-1/PD-L1 
Inhibitor Therapy (EV-203)  
ISN/Protocol 7465-CL-1104  
Amendment 2 [Substantial] 
29 Mar 2022 
 
I have read all pages of this 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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations. I will also 
ensure that subinvestigator(s) and other relevant members of my personnel 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: 
 
 
 
 
Date (DD-MMM-YYYY) 
Printed 
Name: 
 
 
<Insert name and qualification of the investigator> 
Address of 
trial site: 
 
 
 
 
 
 
 
 
 

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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL 
 
24-hour Contact for 
Serious Adverse Events 
 
See [Section 10.3.6 
Reporting Procedures for 
Serious Adverse Events] 
 
, Development Medical 
Department - Oncology  
Astellas Pharma China, Inc.  
 
 
Please fax or email the serious adverse events/special 
situations worksheet to: 
 
Astellas Pharma Global Development Inc. 
Pharmacovigilance 
International fax number: +44-800-471-5263 
Alternate fax number: +1-888-396-3750 
Email: safety-us@astellas.com* 
*Please use email in general. 
Medical Monitor/Medical 
Expert: 
 
, Development Medical 
Department - Oncology  
Astellas Pharma China, Inc.  
 
 
PPD
PPD
PPD
PPD

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Amendment 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 1 [Substantial] 
12 Feb 2021 
Original Protocol 
31 Jul 2020 
Amendment 2 [Substantial] 29 Mar 2022 
This amendment is considered to be [substantial] based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union and EU Clinical Trial Regulation. 
Overall Rationale for the Amendment: 
To align the protocol with updated skin toxicity management guidance in the 
CHMP-approved EU Summary of Product Characteristics of EV  
Summary of Changes 
Substantial Changes 
Section Number 
Description of Change 
Brief Rationale 
6.5 (Table 8), 
6.5.1 
Additional information added for 
the recommended dose 
modifications for EV associated 
nonhematologic toxicities 
Guidance is added to clarify dose 
modifications recommendations for 
rashes and skin reactions. 
 
Nonsubstantial Changes 
Section Number 
Description of Change 
Brief Rationale 
Contact Details 
of Sponsor’s Key 
Personnel 
 is the current 
24-hour contact for SAEs and 
the medical monitor/medical 
expert 
To provide updated staffing 
information 
5.2 
Update exclusion criterion #9 
To clarify expected treatment of 
participants at baseline with positive 
hepatitis B surface antigens and/or 
anti-hepatitis B core antibodies 
10.3.4 
Correct NCI-CTCAE version to 
Version 4.03 
To correct an error 
Throughout 
Minor administrative-type 
changes, e.g., typos, format, 
numbering, consistency 
throughout the protocol.   
To provide clarifications to the 
protocol and to ensure complete 
understanding of study procedures. 
 
PPD

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title of Study:   
A Single-arm, Open-label, Multi-center Phase 2 Study of Enfortumab Vedotin (ASG-22CE) in 
Chinese Subjects with Locally Advanced or Metastatic Urothelial Cancer Who Previously 
Received Platinum-containing Chemotherapy and PD-1/PD-L1 Inhibitor Therapy (EV-203) 
Planned Study Period/Duration:  
From approximately 2Q2021 to 4Q2023 
Planned Total Number of Study Sites and Location(s):   
Approximately 5 study sites in China. 
One to 2 study centers will be designated as a “pharmacokinetic (PK) cohort site”. PK samples 
after single and repeated doses will be collected from approximately 12 participants enrolled at 
the PK cohort site(s). 
Study Objectives, Endpoints and Estimands: 
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of 
single-agent enfortumab vedotin (EV) as 
measured by confirmed objective response 
rate (ORR) per Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 as 
determined by independent review 
committee (IRC) 
• 
Confirmed ORR per RECIST V1.1 by IRC 
 
• 
To assess the PK of antibody-drug conjugate 
(ADC), total antibody (TAb) and 
monomethyl auristatin E (MMAE) in 
Chinese participants with locally advanced 
or metastatic urothelial cancer. 
• 
PK variables  
Selected PK parameters of ADC, TAb and 
MMAE are as follows: 
• 
Maximum observed concentrations 
(Cmax)  
• 
Trough concentration (Ctrough)  
• 
Time to maximum concentration (Tmax)  
• 
Area under concentration-time curve 
from 0 to day 7 (AUC0-7d) 
• 
Area under concentration-time curve 
from 0 to day 28 (AUC0-28d)  
• 
Accumulation ratio of Cmax (Rac[Cmax]) 
• 
Accumulation ratio of AUC0-7d 
(Rac[AUC0-7d]) 
• 
Terminal or apparent terminal half-life 
(t1/2) as appropriate 
• 
Systemic clearance (CL) and volume of 
distribution at steady state (Vss) as 
appropriate 
Table continued on next page 
 

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Secondary 
• 
To assess confirmed ORR per investigator 
assessment 
• 
Confirmed ORR per RECIST V1.1 per 
investigator assessment 
• 
To assess duration of response (DOR) 
• 
DOR per RECIST V1.1 per IRC and per 
investigator assessment  
• 
To assess disease control rate (DCR) 
• 
DCR per RECIST V1.1 per IRC and per 
investigator assessment 
• 
To assess progression-free survival (PFS) 
• 
PFS per RECIST V1.1 per IRC and per 
investigator assessment 
• 
To assess overall survival (OS) 
• 
OS 
• 
To assess the immunogenicity as defined by 
the incidence of antitherapeutic antibodies 
(ATA)  
• 
Incidence of ATA to ADC 
 
• 
To assess the safety and tolerability of 
enfortumab vedotin in Chinese participants 
with locally advanced or metastatic 
urothelial cancer. 
• 
Safety variables: 
• 
Adverse events (AEs) 
• 
Laboratory tests 
• 
Vital sign measurements 
• 
12-lead electrocardiogram (ECG) 
• 
Eastern Cooperative Oncology Group 
(ECOG) performance status 
ADC: antibody-drug conjugate; AE: adverse event; ATA: antitherapeutic antibodies; AUC4d: area under 
the concentration-time curve from time 0 to 4 days; AUC7d: area under the concentration-time curve 
from time 0 to 7 days; CL: clearance; Cmax: maximum concentration; Ctrough: trough concentration; DCR: 
disease control rate; DOR: duration of response; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EV: enfortumab vedotin; IRC: independent review committee; MMAE: monomethyl 
auristatin E; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PK: 
pharmacokinetic; Rac(AUC): accumulation ratio calculated using AUC; Rac(Cmax): accumulation ratio 
calculated using Cmax; t1/2: terminal half-life; TAb: total antibody; tmax: time of maximum concentration; 
Vss: volume of distribution at steady state. 
Estimands 
Not Applicable. 
Study Population:   
The population to be studied includes Chinese participants with locally advanced (LA) or 
metastatic urothelial cancer (mUC) who previously received therapy with platinum-containing 
chemotherapy and programmed cell death protein-1 (PD-1)/ programmed death ligand-1 (PD-
L1) inhibitor therapy, with baseline measurable disease according to Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1. Participants who received PD-1/PD-L1 
inhibitor therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease 
(PD) either during therapy or within 3 months of therapy completion are eligible. 
Participants who received prior treatment with platinum-containing chemotherapy defined as 
those who received platinum in the neoadjuvant/adjuvant setting and had recurrent or 
progressive disease within 12 months of completion or received treatment with platinum in the 
LA (defined as unresectable with curative intent) or metastatic setting.  
Number of Participants:  
Up to 40 Chinese participants will be enrolled in this study, of which approximately 12 
participants from 1 to 2 PK cohort site(s) will participate in intense PK sample collection. 

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Amendment 2 
Study Design Overview:   
This is a single-arm, open-label, multi-center, Phase 2 study to assess the safety, efficacy, and 
pharmacokinetics of enfortumab vedotin in Chinese participants with LA or mUC who have 
previously been treated with platinum-containing chemotherapy and PD-1/PD-L1 inhibitor 
therapy.  Up to 40 participants will be enrolled including approximately 12 PK participants in 
the PK Cohort. 
All participants will receive enfortumab vedotin at 1.25 mg/kg dose level administered as an 
intravenous (IV) infusion on Days 1, 8 and 15 of every 4-week (28 days) cycle. Participants 
will continue on study treatment until one or more of the following discontinuation criteria are 
met: 
• Participant requests to stop treatment.  
• Investigator decides it is in the participant’s best interest to discontinue. 
• Participant develops documented radiological disease progression per RECIST V1.1 by 
investigator assessment. 
• Participant starts a new anticancer therapy. 
• Participant develops unacceptable toxicity. 
• Female participant becomes pregnant. 
• Participant is noncompliant with the protocol based on the investigator or medical monitor 
assessment. 
• Participant did not receive study drug continuously for >2 cycles (i.e., > 6 consecutive 
doses not received). Medical Monitor consultation is required after the participant was 
unable to receive one full cycle of study drug administration (i.e., 3 consecutive doses).  
Dose delays for patients who are responding to treatment may be extended beyond 8 weeks 
in consultation with Medical Monitor, if the patient’s toxicity does not otherwise require 
permanent discontinuation. 
The participants who discontinue study treatment for reasons other than objective disease 
progression per RECIST V 1.1 will be followed every 8 weeks (± 1 week) for response 
assessments. After 1 year from the start of treatment, the frequency of response assessments 
will be reduced to every 12 weeks (± 1 week). The tumor assessments will continue until the 
participant has radiological disease progression per RECIST V1.1 as determined by the 
investigator assessment, initiates a new anticancer therapy, dies, withdraws study consent, lost 
to follow-up or the study closes, whichever comes first. All participants are to be followed for 
survival status and subsequent anticancer therapy until death, lost to follow-up, withdrawal of 
consent from study, or study closure, whichever occurs first. The study will be closed 
approximately 2 years after the last participant enrollment or no participants remain in long-
term follow-up, whichever occurs first. A provision of drug supply to the participants who are 
still benefiting from treatment will be prepared prior to study closure. Additionally, the sponsor 
may terminate the study at any time.  
One to 2 study centers will be designated as a “PK cohort site”. Approximately 12 participants 
enrolled at the PK cohort site(s) will have intense PK samples collected after single and 
repeated doses. The other participants enrolled at non-PK cohort sites will have sparse PK 
samples collected. Additional participants may be enrolled in PK cohort to compensate for 
participants who become unevaluable for the PK relevant primary endpoint (PK evaluable). 
Blood samples for pharmacokinetics and antitherapeutic antibodies (ATA) will be collected at 
protocol-specified time points. Validated assays will be used to measure the concentrations of 
antibody-drug conjugate (ADC), total antibody and monomethyl auristatin E (MMAE) in 
serum or plasma and to assess ATA.   
An ongoing review of participant safety and serious adverse events (SAEs) will also be 
conducted by the sponsor’s Drug Safety Department. 
After treatment discontinuation, participant will have an end of treatment (EOT) visit for a 30-
day Safety Follow-up.  
Safety data will be monitored closely throughout the study per the Sponsor relevant study 
monitoring plan. 

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Treatment Groups and Duration: 
Arm/IP 
Name 
Enfortumab vedotin 
Use 
test product 
Dose 
1.25 mg/kg 
Frequency 
Days 1, 8 and 15 of every 4-week (28 days) 
cycle 
Route 
IV infusion  
Duration 
8 months 
IP: investigational product; IV: intravenous infusion 
 
The anticipated treatment duration of the study for each participant, from first dose to disease 
progression per relevant publication in the same target population and treatment setting, is 
approximately 8 months.  
 
 

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1.2 
Study Schema 
Figure 1 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes appear on next page 
Screening 
Enrollment 
EV 1.25mg/kg IV on Days 1, 8, 15 
Response assessments every 8 weeksa 
(± 1 week), with confirmatory repeat 
scans at least 4 weeks after first 
documentation of response 
• 
Intensive PK sampling: ADC, 
TAb, serum concentrations and 
MMAE plasma concentrations and 
other PK parametersb 
• 
ATA 
Post 
treatment 
Follow-up 
 
 
Response 
assessments 
every 8 weeksa,c 
(± 1 week) 
Long-term 
Follow-up 
(LTFU) 
 
 
Survival and 
subsequent 
anticancer 
therapies 
End of Treatment 
(EOT) 
Pre-study 
Each 28-day cycle 
Until radiological 
progression or start 
of subsequent 
anticancer therapy 
Date of Last 
Dose+30 days 
Until death, study 
closure, withdrawal of 
consent from study, or 
lost to follow-up 
EV 1.25mg/kg IV on Days 1, 8, 15 
Response assessments every 8 weeksa 
(± 1 week), with confirmatory repeat 
scans at least 4 weeks after first 
documentation of response 
• 
Sparse PK sampling: ADC, TAb 
serum concentrations and MMAE 
plasma concentrations and other 
PK parameters 
• 
ATA 
PK 
Cohort 
Site(s)  
Non-PK 
Cohort 
Sites  

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ADC: antibody-drug conjugate; EOT: End of Treatment; EV: Enfortumab vedotin; FU: follow-up; MMAE: monomethyl auristatin E; PK: pharmacokinetic; TAb: total antibody; 
a. 
Participants will have disease response assessments every 8 weeks (± 1 week) for the first year on study treatment. After 1 year from the start of treatment, the frequency of response 
assessments will be reduced to every 12 weeks (± 1 week). The schedule of response assessments should not be adjusted after the confirmatory scan.  
b. 
One to 2 study sites will be designated as the PK cohort site(s). Approximately 12 participants will be enrolled in PK cohort. Additional participants may be enrolled in PK cohort to 
compensate for participants who become unevaluable for the PK relevant primary endpoint (PK evaluable).  
c. 
Only participants that have not met radiographic disease progression in the Treatment Period will go into Post-Treatment Period, while participants that have met radiographic disease 
progression within the Treatment Period will go into the Long-Term Follow-Up directly. 
 
 

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1.3 
Schedule of Assessments 
Table 1 
Schedule of Assessments 
 
 
Screening/ 
Baseline 
Enrollment 
Every 28-day Cycle 
EOTb 
(30-day Safety 
Follow-up) 
Post-Treatment 
Follow-up 
Long-term 
Follow-up 
 
Day 
Day -28 
to -1 
Day -7 
to -1 
Within 7 Days 
of 1st dose 
Day 1 
Day 8 
Day 15 
Every 8 
weeks 
Date of Last 
Dose +30 days 
Every 8 weeks 
Every 12 weeks 
 
Visit window 
 
 
 
± 3 daysa 
± 3 days 
± 3 days 
± 7 days 
+7 days 
± 7 days 
± 7 days 
Screening/baseline 
assessments  
 
Inclusion/exclusion 
X 
 
Submit confirmation of eligibility prior to treatment 
 
 
 
 
 
 
 
Medical history/Disease 
history/demographics 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Brain scanc 
X 
 
 
 
 
X 
 
X 
 
Bone scanc 
X 
 
 
 
 
X 
 
X 
 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
 
 
 
Urinalysis with 
microscopic analysis 
X 
 
 
 
 
 
 
 
 
HbA1cd 
 
X 
 
 
 
 
X 
 
 
Safety assessments 
Pregnancy teste 
 
X 
X 
 
 
 
X 
X 
X 
Full physical examination 
(including weight) 
 
X 
Xf 
 
 
 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Vital signs 
 
X 
X 
X 
X 
 
X 
 
 
Hematologyh,i 
 
X 
Xf  
Xg 
Xg 
 
X 
 
 
Biochemistryh,i 
 
X 
Xf 
X 
X 
 
X 
 
 
CrCl 
 
X 
 
 
 
 
 
 
 
ECOG performance status 
 
X 
X 
 
 
 
X 
 
 
12-lead ECGj 
 
X 
 
 
 
 
X 
 
 
Ophthalmological 
assessmentk 
X 
 
 
 
 
 
 
X 
 
 
Prior and Concomitant 
medicationsl 
Every Visit 
 
 
AEs assessmentm 
 
 
Table continued on next page 

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Amendment 2  
 
 
Screening/ 
Baseline 
Enrollment 
Every 28-day Cycle 
EOTb 
(30-day Safety 
Follow-up) 
Post-Treatment 
Follow-up 
Long-term 
Follow-up 
 
Day 
Day -28 
to -1 
Day -7 
to -1 
Within 7 Days 
of 1st dose 
Day 1 
Day 8 
Day 15 
Every 8 
weeks 
Date of Last 
Dose +30 days 
Every 8 weeks 
Every 12 weeks 
 
Visit window 
 
 
 
± 3 daysa 
± 3 days 
± 3 days 
± 7 days 
+7 days 
± 7 days 
± 7 days 
Treatment 
Study drug 
administrationn 
 
 
 
X 
X 
X 
 
 
 
 
PK/ATA  
Blood sample collection 
See PK and ATA Tables (Table 2, Table 3 and Table 4) for sample collection details. 
Response assessment 
CT scan with contrast of 
chest, abdomen, pelvis 
and any other region of 
known or suspected 
diseaseo  
X 
 
 
 
 
 
Xp,q 
 
X p,r 
 
OS 
Survival status 
 
 
 
 
 
 
 
X 
X 
Xs 
AE: adverse event; ATA: antitherapeutic antibodies; BCVA: best corrected visual acuity; CrCl: creatinine clearance; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOM: 
extra ocular movement; EOT: End of Treatment; HbA1c: hemoglobin A1c; HDL: high-density lipoprotein; IOP: inter ocular pressure; LDL: low-density lipoprotein; OS: overall survival; PK: 
pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; VA: visual acuity.  
a. 
This visit window is not applicable for Cycle 1 Day 1, could only be applied for the subsequent cycle.  
b. The EOT visit should be completed prior to the initiation of the next anticancer therapy. 
c. 
Brain scan and bone imaging will be performed at screening. Repeated at response assessment time points if metastases are identified at screening, or if metastasis is known or suspected, 
or as clinically indicated throughout the study. 
d. If HbA1c is elevated (≥ 6.5%), refer participant to appropriate provider during Cycle 1 for glucose management. HbA1c needs to be tested in EOT evaluation as safety assessment. 
e. 
For women of childbearing potential only. A 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 
study drug administration, at the EOT and post-treatment follow-up visit till 6 months after the last dose of study treatment administration. 
f. 
Not required for Cycle 1 if the assessments performed within 7 days, except for body weight, which should be measured on Day 1 of each cycle. 
g. Hematology tests should be collected at the following timepoints: Screening, Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15 and Day 1 of each subsequent cycle.  
h. Hematology and biochemistry tests may be collected or conducted locally up to 1 day prior to dosing. Local laboratory results must be reviewed prior to study drug administration in 
order to determine whether to proceed with dosing or whether dose modification is required. 
i. 
Clinical laboratory tests at screening and on Cycle 1 Day 8 are to be performed after the participant has been fasting in order to ensure accurate interpretation of lab values such as 
glucose values. Fasting status will be recorded in source documents. Fasting is not necessary for laboratory tests performed at all other visits. Lipid panel (total cholesterol, LDL, HDL, 
and triglyceride) is only required at Screening. 
j. 
Prior to performing 12-lead ECGs, participants should rest in supine position (or semi-recumbent, if supine is not tolerated) for 10 minutes. ECGs will be read and assessed locally. 
Footnotes continued on next page 

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Amendment 2  
k. Repeated as clinically indicated throughout the study. Complete eye exam is required at baseline. This consists of visual acuity (VA), best corrected visual acuity (BCVA), inter ocular 
pressure (IOP), extra ocular movement (EOM), pupils, external exam, slit lamp exam, and dilated fundoscopic exam. Eye exams performed during the study where clinically indicated 
will be at the ophthalmologist’s discretion. Eye exams at EOT are required for participants who experience ocular AEs during the study and this at minimum must include VA, BCVA, 
and slit lamp exam. 
l. 
Include all medications taken within 28 days prior to inform consent and up until the 30-day safety follow up visit will be collected. 
m. AEs will be collected from the time of informed consent through 30 days following the last dose of study treatment or until initiation of a new anticancer treatment, whichever occurs 
first.  
n. At least 7 days must elapse between doses of enfortumab vedotin. Participants should be observed during enfortumab vedotin administration and for at least 60 minutes following the 
infusion for the first 3 cycles. 
o. If contrast is contraindicated, see [Section 7.1 Efficacy Assessments] and [Section 10.9 Appendix 9: Scanning and Contrast Guidelines]. 
p. Responses will be confirmed with repeat scans at least 4 weeks after first documentation of response. Following confirmation scans, response assessments should continue with the 
previous scan schedule (i.e., the schedule should not be adjusted). Tumor imaging should also be performed whenever disease progression is suspected. 
q. Response assessment will be performed every 8 weeks (± 1 week). After 1 year from the start of treatment, response assessments will be reduced to every 12 weeks  
(± 1 week). The schedule of response assessments should not be adjusted for dose delays/interruptions or other reasons for changes in the timing of a participant’s study activities; 
timepoints for response assessments should be calculated from Cycle 1 Day 1 during treatment. 
r. 
Participants who discontinue study treatment for reasons other than objective disease progression by RECIST V 1.1 will continue to have response assessments every 8 weeks (± 1 week) 
following the previous visit thereafter. After 1 year from the start of treatment, the frequency of response assessments will be reduced to every 12 weeks (± 1 week). The tumor 
assessments will continue until the participant has radiological disease progression per RECIST V 1.1 as determined by investigator assessment, initiates a new anticancer therapy, death, 
lost to follow-up, study closure, or withdrawal of consent, whichever comes first.  
s. 
Contact participant for survival status and collection of subsequent anticancer treatment information every 12 weeks (± 1 week) (calculation from disease progression) until death, study 
closure, or withdrawal of consent from study, or participant is lost to follow-up, whichever occurs first. Phone contact with participant is sufficient. 
 

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1.3.1 
Sample Collection Schedule 
Table 2 
Pharmacokinetic Sample Collection Time Points (PK Cohort) 
Cycle 
Day 
Time Point 
Collection Window 
Cycle 1 
1 
Predose 
Predose 
EOI 
Within 15 min after EOI 
2 hr (Day 1)  
± 15 min 
4 hr (Day 1) 
± 15 min 
2 
24 hr (Day 1) 
± 4 hr 
3 
48 hr (Day 1) 
± 4 hr 
4 
72 hr (Day 1) 
± 4 hr 
8 
Predose  
Within 2 hr prior to dosing 
EOI 
Within 15 min after EOI 
15 
Predose 
Within 2 hr prior to dosing 
EOI 
Within 15 min after EOI 
2 hr (Day 15) 
± 15 min 
4 hr (Day 15) 
± 15 min 
16 
24 hr (Day 15) 
± 4 hr 
17 
48 hr (Day 15) 
± 4 hr 
18 
72 hr (Day 15) 
± 4 hr 
22 
168 hr (Day 15) 
± 4 hr 
Cycle 2 
1 
Predose 
Within 2 hr prior to dosing 
EOI  
Within 15 min after EOI 
Cycle 3 
1 
Predose 
Within 2 hr prior to dosing 
Cycle 4 
1 
Predose 
Within 2 hr prior to dosing 
Cycles 6, 8 and 10 
1 
Predose 
Within 2 hr prior to dosing 
End of Treatment 
within 30–37 days of last dose 
EOI: end of infusion. 
In general, the time points relative to the start of infusion, except for EOI relative to end of infusion in each corresponding cycle and day. 
 

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Table 3 
Schedule and Acceptable Time Range for PK Sampling (Non-PK Cohort) 
Visit 
Time 
Window 
Cycle 1 
Day 1 
EOI 
Within 15 min 
Day 8 
Pre-dose 
Within 24 hr 
EOI 
Within 15 min 
Day 15 
Pre-dose 
Within 24 hr 
EOI 
Within 15 min 
Cycles 2, 4, 6, 8 and 10 
Day 1 
Pre-dose 
Within 24 hr 
End of Treatment 
within 30–37 days of last dose 
EOI: end of infusion. 
In general, the time points relative to the start of infusion, except for EOI relative to end of infusion in each corresponding cycle and day. 
 
Table 4 
Schedule for ATA Sampling  
Visit 
Time 
Window 
Cycle 1 
Day 1 
Predose 
Within 24 hr 
Cycle 2 
Day 1 
Predose 
Within 24 hr 
Cycle 3 
Day 1 
Predose 
Within 24 hr 
Cycle 4 
Day 1 
Predose 
Within 24 hr 
Cycles 6, 8 and 10 
Day 1 
Predose 
Within 24 hr 
End of Treatment 
within 30–37 days of last dose 
ATA: antitherapeutic antibodies. 
In general, the time points relative to the start of infusion. 
 
 

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2 
INTRODUCTION 
Urothelial cancer (UC) kills approximately 200,000 patients annually and is the eleventh 
most common cancer overall worldwide [Ferlay et al, 2018]. Enfortumab vedotin targets 
the cell adhesion protein Nectin-4. Nectin-4 is a type I transmembrane protein and 
member of a family of related immunoglobulin-like adhesion molecules implicated in 
cell-to-cell adhesion. Nectin-facilitated adhesion supports several biological processes, 
such as immune modulation, host-pathogen interaction, and immune evasion [Sakisaka et 
al, 2007]. Nectin-4 is highly expressed in cancer cells, particularly in urothelial cancers, 
breast cancer, non-small cell lung cancer (NSCLC), and other epithelial tumors, with 
moderate expression observed in normal human skin [Deng et al, 2019; Zhang, Chen et al, 
2018; Takano et al, 2009; Fabre-Lafay et al, 2007].  
Enfortumab vedotin (previously known as ASG-22CE) is a novel, fully humanized, 
monoclonal antibody-drug conjugate (ADC) that delivers a microtubule-disrupting agent, 
monomethyl auristatin E (MMAE), to cells expressing Nectin-4 [Sakisaka et al, 2007]. 
Enfortumab vedotin selectively binds to Nectin-4-expressing cells, initiating 
internalization of the ADC-Nectin-4 complex and proteolytic cleavage of the conjugated 
MMAE, disrupting microtubule networks and resulting in apoptotic cell death. Targeting 
tumors with enfortumab vedotin, which targets Nectin-4, could provide a novel approach 
to the treatment of certain cancers such as urothelial, lung, breast, head and neck, gastric, 
and esophageal cancers [Challita-Eid et al, 2016; Zhang, Zhang et al, 2018].  
Enfortumab vedotin has shown activity and was approved by United States (US) Food 
and Drug Administration (FDA) for the treatment of adult patients with locally advanced 
(LA) or metastatic urothelial cancer (mUC) who have previously received a programmed 
cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, and a 
platinum-containing chemotherapy in the neoadjuvant/adjuvant, LA or metastatic setting 
in Dec 2019 [PADCEVTM Prescribing Information, Dec 2019]. 
2.1 
Study Rationale 
Enfortumab vedotin will be administered monotherapy at a dose of 1.25 mg/kg as an IV 
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 and 2 studies in 
patients with urothelial cancer (Studies AGS-22M6E-11-1, EV-101, EV-102, EV-201 and 
EV-103).  
This study is designed to assess the safety, tolerability, pharmacokinetics as well as the 
efficacy of enfortumab vedotin monotherapy in Chinese participants with LA or mUC. In 
addition, as a bridging study to global pivotal phase 2 and phase 3 studies EV-201 and 
EV-301, to demonstrate efficacy and safety in the Chinese population are consistent with 
non-Chinese population. As enfortumab vedotin has not previously been explored in the 
Chinese population, the other primary objective of the study is to demonstrate ethnic 
consistency of enfortumab vedotin monotherapy between the Chinese and non-Chinese 
populations through PK parameter analysis. No differences are anticipated for enfortumab 
vedotin based on ethnicity from the Phase 1 and 2 studies in enfortumab vedotin 
monotherapy up to date.  

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2.2 
Background 
A detailed description of the chemistry, pharmacology, efficacy and safety of enfortumab 
vedotin is provided in the Investigator’s Brochure. 
2.2.1 
Disease and Nectin-4 Antigen Target 
The International Agency for Research on Cancer has reported that urothelial cancer (UC) 
kills approximately 200,000 patients annually and is the 11th most common cancer 
worldwide [Ferlay et al, 2018]. In China, there were 82,270 new bladder cancer cases and 
38,208 deaths due to bladder cancer according to The International Agency for Research 
on Cancer database [Ferlay et al, 2018]. First-line (1L) therapy for LA or mUC consists of 
cisplatin-based combinations, such as methotrexate, vinblastine, doxorubicin and cisplatin 
(MVAC) and gemcitabine plus cisplatin in patients eligible for these therapies [Bellmunt 
et al, 2014]. In China, platinum-based first-line chemotherapies are recommended by 
Chinese guidelines for diagnosis and treatment of urothelial carcinoma of bladder 
[National Health Commission of the People’s Republic of China, 2019] and are 
commonly used in clinical practice, similar to global standards. The reported initial 
response rates chemotherapy regimen in first line were approximately 50% to 70%. 
However, few patients have durable responses, and patients become resistant to the initial 
treatment. In the US and Europe, 2 PD-1/PD-L1 inhibitors (atezolizumab and 
pembrolizumab) are approved for treatment of cisplatin-ineligible UC patients in the 
front-line setting. These approvals were based on open-label, single-arm studies that 
showed objective response rates (ORRs) of 24% and 29%, respectively [Keytruda® 
Prescribing Information 2020; Tecentriq® Prescribing Information 2020]. Of note, in 
2018, prescribing information for pembrolizumab and atezolizumab monotherapy in the 
front-line setting was revised to restrict usage to cisplatin-ineligible patients with high 
PD-L1 expression (present in approximately one-third of the 1L mUC population). In 
addition, these PD-1/PD-L1 inhibitors, both in combination regimens or monotherapy, are 
not currently approved in China for 1L mUC. 
For second-line (2L) therapy, several PD-1/PD-L1 inhibitors such as nivolumab (PD-1 
inhibitor), atezolizumab, durvalumab and avelumab (PD-L1 inhibitors) have been 
approved in different countries for the treatment of patients with LA or mUC that have 
progressed during or after platinum-containing chemotherapy. However, up-to-date there 
is current one PD-1 inhibitor tislelizumab approved in China, in patients with LA/mUC 
with PD-L1 high expression whose disease progressed during or following platinum-
containing chemotherapy. The National Medical Products Administration (NMPA) 
approval was based on a single-arm, multi-center pivotal trial of tislelizumab showing 
ORR 24.8% and complete response (CR) rate 9.9%. For UC patients previously treated 
with a platinum-based chemotherapy and no accepted standard of care exists, although 
single-agent taxanes such as paclitaxel are commonly used following platinum therapies. 
However, the single-agent chemotherapy response rates were around 10% in the second 
line setting and have not demonstrated a survival advantage [McCaffrey et al, 1997, 
Vaughn et al, 2002]. 
In conclusion, novel agents are needed to treat patients with LA or mUC, especially 
whose disease progressed during or following platinum-containing chemotherapy and 
PD-1/PD-L1 inhibitor in China. 

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Nectin-4 is a type I transmembrane protein and member of a family of related 
immunoglobulin-like adhesion molecules implicated in cell-to-cell adhesion. Nectin-4 is 
highly expressed in cancer cells, particularly in urothelial cancers, breast cancer, non-
small cell lung cancer (NSCLC), and other epithelial tumors, with moderate expression 
observed in normal human skin [Deng et al, 2019; Zhang, Chen et al, 2018; Takano et al, 
2009; Fabre-Lafay et al, 2007].  
The expression pattern and levels of Nectin-4 on tumors suggest that it would be an 
attractive target for ADC therapy in several solid tumors including UC. The aim of using 
ADCs in cancer therapy is to improve the therapeutic index of cytotoxic agents and 
minimize exposure to normal tissue.   
2.2.2 
Enfortumab Vedotin 
Enfortumab vedotin (previously known as ASG-22CE) targets the cell adhesion protein 
Nectin-4. Enfortumab vedotin is a novel, fully humanized, monoclonal ADC that delivers 
a microtubule-disrupting agent, MMAE, to cells expressing Nectin-4 [Sakisaka et al, 
2007]. Enfortumab vedotin selectively binds to Nectin-4-expressing cells, initiating 
internalization of the ADC-Nectin-4 complex and proteolytic cleavage of the conjugated 
MMAE, disrupting microtubule networks and resulting in apoptotic cell death.  
Data from preclinical studies of brentuximab vedotin (a CD30-directed ADC comprising 
the same linker and MMAE payload as enfortumab vedotin), shows potential to induce 
immunogenic cell death (ICD), antigen presentation, and tumor immune infiltration 
[Gardai et al, 2015]. These results suggest that the effects are due to MMAE. Treatment 
with brentuximab vedotin in vitro and in preclinical models has been shown to induce 
hallmarks of ICD. ICD is characterized by induction of the endoplasmic reticulum stress 
response and subsequent surface presentation of danger-associated molecular patterns 
immune stimulatory molecules. These danger-associated molecular patterns induce innate 
immune migration and activation into the tumor cell activation [Cao et al, 2018; Cao et al, 
2017]. 
Enfortumab vedotin has shown activity and was approved by FDA in Dec 2019 for the 
treatment of adult patients with LA or mUC who have previously received PD-1/PD-L1 
inhibitor therapy, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, 
LA or metastatic setting. 
2.2.3 
Nonclinical Data 
2.2.3.1 ASG-22CE Nonclinical Pharmacology 
ASG-22CE is the final product (enfortumab vedotin) used for clinical development and is 
derived from a Chinese hamster ovary (CHO) cell line, while AGS-22M6E is derived 
from a murine hybridoma cell line and was used in the pharmacology and toxicology 
studies, as well as in a completed Phase I study. These 2 molecules have identical amino 
acid sequences and 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).  
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). 

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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, as well as in a human breast carcinoma cell line 
endogenously positive for Nectin-4 (RD10-017). 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 
representing various cancer indications in which expression of Nectin-4 has been 
demonstrated. AGS-22M6E significantly inhibited the tumor growth in a xenograft model 
of human bladder cancer (RD10-009), as well as in xenograft models of other cancer 
indications such as breast, pancreatic and lung cancers (RD10-010, RD10-011, RD10-
019). 
2.2.3.2 ASG-22CE Nonclinical Immunogenicity and Pharmacokinetics 
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 (IV) infusion in cynomolgus monkeys with a 6-week 
recovery period (Charles River Laboratories [CRL] Study No. 20021751). 
Maximum serum concentrations of ADC and total antibody (TAb) for both ADCs were 
attained at the end of the IV infusion and showed a bi-exponential decline thereafter. 
There were no sex-related differences observed in the toxicokinetic characteristics for 
ADC, TAb and small molecule metabolite for both ADCs. 
Maximum concentration (Cmax) of MMAE metabolite for both ADCs was attained 
between 24 - 72 hours post dose injection. The elimination half-life (t1/2) for ADC, TAb 
and MMAE after administration of AGS-22M6E and AGS-22C3E (the CHO cell line- 
derived product) were calculated as follows; 1.70 and 1.53 days for ADC, 3.23 and 2.09 
days for TAb and 4.31 days and 3.54 days for MMAE, respectively. 
Overall incidences of seroconversion were 40% for both AGS-22M6E and AGS-22C3E 
dosed groups. 
Exposure of AGS-22M6E and AGS-22C3E based on area under the concentration-time 
curve from time 0 to 7 days (AUC0-7d) and Cmax after first dose of AGS-22M6E and 
AGS-22C3E were within the pre-specified comparability criteria, and therefore, the 
toxicokinetics of the two materials, AGS-22M6E and AGS-22C3E were considered to be 
comparable. 
2.2.3.3 ASG-22CE Nonclinical Toxicology 
In a 4-week Good Laboratory Practice (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 body weight, and was found dead on Day 27. AGS-22M6E-
related changes mainly included skin abrasion at 5 mg/kg and 10 mg/kg, decreased body 
weight gain and food consumption at 10 mg/kg. Decreased indicators of red cell mass (red 

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blood cell, 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 IV 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. 20005664), 
AGS-22M6E (1, 3 and 6 mg/kg) and AGS-22M6 (6 mg/kg) were administered by IV 
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 Days 11 to 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/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/week. Administration of AGS-22M6E and AGS-22C3E by IV 
infusion for 4 doses over 4 weeks was well tolerated. Test article-related effects included 
dry skin, reddened areas of skin, decreased erythrocyte mass, reticulocytes, neutrophils 
and eosinophil counts, microscopic findings in bone marrow, injection site, and skin. 
These findings were noted in both AGS-22M6E and AGS-22C3E-dosed animals. 
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 IV infusion once 
weekly for 4 weeks to cynomolgus monkeys.   
In genotoxic studies performed with other investigational compounds containing MMAE 
(Adcetris package insert [PI]) the MMAE was found to be genotoxic in the rat bone 
marrow micronucleus assay through an aneugenic mechanism. This effect is consistent 

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with the 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 PI]. Maleimide, which is a component of linker is reported to be 
mutagenic in Ames test and mouse lymphoma assay.  
2.2.4 
Clinical Data 
Enfortumab vedotin is currently being tested in multiple studies including Phase 1, 2, and 
3 studies, both as monotherapy and in combination with several anticancer therapies. 
Much of the safety and efficacy data summarized below are from monotherapy data and 
limited to Phase 1 and 2 studies. 
EV-101 is a phase 1 study evaluating the safety and pharmacokinetics of escalating doses 
of enfortumab vedotin that enrolled patients with Nectin-4-expressing solid tumors (e.g., 
mUC, NSCLC and ovarian cancer), who progressed on ≥1 prior chemotherapy regimen, 
including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. 
Patients received escalating doses of enfortumab vedotin up to 1.25 mg/kg on Days 1, 8 
and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability 
and pharmacokinetics; antitumor activity was a secondary objective. The maximum 
tolerated dose (MTD) was not established; however, the recommended phase 2 dose was 
identified as 1.25 mg/kg. Overall (data cutoff date: 27 Dec 2019), 17 of 18 (94.4%) 
participants with NSCLC who received at least 1 infusion of enfortumab vedotin reported 
at least 1 TEAE. Of these, 9 (50.0%) participants had serious TEAEs and 1 participant 
had a TEAE leading to death that was not considered to be drug-related. The most 
common TEAE in this population was nausea and the most common drug-related TEAE 
was alopecia. Six (33.3%) participants discontinued treatment due to one of the following 
TEAEs, occurring in 1 participant each: fatigue, acute respiratory failure, dyspnea, 
dyspnea exertional, hypoxia and rash maculopapular. 
All 16 participants with OC who received at least 1 infusion of enfortumab vedotin 
reported at least 1 TEAE. Of these, 5 (31.3%) participants had serious TEAEs and 2 
participants (12.5%) had a TEAE leading to death that was not considered to be drug-
related. The most common TEAE in this population was fatigue (68.8% of participants), 
which was also the most common drug-related TEAE (62.5% of participants). Four 
(25.0%) participants discontinued treatment due to one of the following TEAEs, occurring 
in 1 participant each: malignant bowel obstruction, swelling, delirium and pulmonary 
embolism. 
All 18 participants with metastatic UC and renal insufficiency who received at least 
1 infusion of enfortumab vedotin reported at least 1 TEAE. Of these, 10 (55.6%) 
participants had serious TEAEs. No participant had a TEAE leading to death. The most 
common TEAE in this population was fatigue (77.8% of participants), and the most 
common drug-related TEAEs were alopecia and fatigue (61.1% of participants each). 
Decreased appetite and cerebrovascular accident led to discontinuation of study drug in 
1 (5.6%) participant each.  
Single agent enfortumab vedotin was generally well tolerated and responses were 
observed at all does levels tested but were numerically higher at a dose of 1.25 mg/kg on 
Days 1, 8 and 15 of each 28-day cycle. Enfortumab vedotin provided durable responses 
and meaningful survival results in patients after anti-PD-(L)-1 therapy in a population 

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with a high unmet medical need. The confirmed ORR by central review was 45% in 
patients with urothelial cancer [Rosenberg et al, 2019]. The median OS of 12.3 months is 
encouraging given the historical median OS is ≤ 10.3 months [Bellmunt et al, 2017].  
EV-201 is an ongoing global, phase 2, single-arm, 2-cohort study of enfortumab vedotin 
(1.25 mg/kg intravenously on Days 1, 8, and 15 of every 28-day cycle) that enrolled 
patients with LA or mUC previously treated with anti-PD-1/L1 therapy. This study 
contains 2 cohorts. Cohort 1 consisted of 125 treated participants who had previously 
received a platinum-containing chemotherapy in the LA or metastatic setting, while 
Cohort 2 consisted of 27 treated participants who had not and were ineligible for 
cisplatin-containing therapy at the time of enrollment. Results were consistent with 
EV-101, for Cohort 1, enfortumab vedotin treatment led to a 44% ORR including a 12% 
CR rate and a 11.7-month median overall survival (OS) in addition to a 7.6-month 
duration of response (DOR) [Petrylak et al, 2019]. For Cohort 2, of those patients who 
have had a postbaseline assessment or discontinued from the study without undergoing a 
response assessment (i.e., Efficacy Evaluable Set), the ORR per independent review 
committee (IRC) assessment was 41% (9 of 22 patients) (95% CI: 20.7%, 63.6%), similar 
to the 44% ORR for Cohort 1.  Additional initial responses are pending confirmation.  
The data cutoff date for the Cohort 1 primary analysis does not provide sufficient follow-
up for the response duration in Cohort 2.  The range of response duration among the 
9 responders is 1.02 to 5.85+ months.  Five of the 9 responders (56%) were censored with 
ongoing response.  
Adverse events (AEs) in Cohort 1 (n = 125) were consistent with those previously 
reported in the enfortumab vedotin clinical development program. The most common 
TEAEs of any grade in Cohort 1 were fatigue, decreased appetite, alopecia, nausea, 
peripheral sensory neuropath, diarrhea and dysgeusia. The Grade 3 or higher TEAEs 
reported in > 5% of participants included anemia (14%), neutropenia (9%), 
hyperglycemia (7%), and fatigue and hyponatremia (6% each). The incidence of TEAEs 
leading to withdrawal of treatment was 16%, with peripheral sensory neuropathy as the 
most common reason for treatment withdrawal (6%). Seven participants (6%) died due to 
TEAEs; none of these deaths were considered treatment-related. 
One participant died of interstitial lung disease that was considered related to study 
treatment; the event did not meet the definition of a TEAE because it occurred > 30 days 
after the last dose of enfortumab vedotin. This case was confounded by high dose steroid 
use and suspected pneumocystis jiroveci pneumonia.  
In Cohort 2 (n = 27), AEs were consistent with those in Cohort 1 and as previously 
reported in the enfortumab vedotin clinical development program.  The most common 
TEAEs of any grade in Cohort 2 were alopecia, anemia and fatigue, dry eye and edema 
peripheral.  The incidence of Grade 3 or higher TEAEs was 67% and the most common 
≥ Grade 3 TEAE was neutropenia (15%). SAEs were reported for 8 participants (30%); 
the most common were acute kidney injury (AKI) and diarrhea in 2 participants each 
(7%).  The incidence of TEAEs leading to withdrawal of treatment was 19%; 2 
participants (7%) withdrew due to acute kidney disease.  There were no other AEs leading 
to withdrawal of treatment reported for more than 1 participant.  As of the data cutoff 
date, 2 participants (7%) had died due to TEAEs (1 event of sepsis and 1 event of AKI).  

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Neither event was considered treatment-related. Enfortumab vedotin was tolerable with a 
manageable safety profile that was similar in both cohorts. 
EV-102 is a phase 1 study evaluating safety and pharmacokinetics of enfortumab vedotin 
enrolling Japanese patients with LA/mUC treated with prior chemotherapy, or ineligible 
for cisplatin. Patients were randomized 1:1 to receive 1.0 mg/kg (arm A) or 1.25 mg/kg 
(arm B) enfortumab vedotin on days 1, 8 and 15 of each 28-day cycle. Seventeen patients 
(n = 9, arm A; n = 8, arm B) received treatment. Enfortumab vedotin was well tolerated 
across both doses. ORR was 35%, the antitumor activity, safety and pharmacokinetic 
profile were consistent with prior reports from non-Japanese patients [Takahashi et al, 
2019]. The most common TEAEs in total were anemia, dysgeusia and alopecia. The most 
common drug-related TEAEs were dysgeusia and alopecia. Overall, 7 of 17 (41.2%) 
participants experienced serious TEAEs and 1 participant on 1.25 mg/kg experienced a 
TEAE leading to death, which was considered unrelated to the study drug. Overall, 
8 (47.1%) participants had a grade 3 or above drug-related TEAE. No grade 3 or above 
study drug-related TEAEs were reported in more than 1 participant, with the exception of 
anemia and hypertension, which were reported in 2 (11.8%) participants each. Overall, 
the safety profile was consistent with what had been observed in other enfortumab vedotin 
studies and found to be manageable and tolerable. 
Pharmacokinetic analyses showed that the mean exposures of enfortumab vedotin after IV 
infusion generally increased with increasing dose levels.  In Study AGS-22M6E-11-1, a 
median terminal t1/2 estimate of 2.39 days for ADC was determined in participants who 
received enfortumab vedotin at the 1.2 mg/kg dose level. When comparing results from 
Study EV-101 to results from Study EV-102, no apparent differences in exposure were 
observed between Japanese and North American participants. 
The safety profile of enfortumab vedotin monotherapy consists of the identified risks of 
peripheral neuropathy, rash, extravasation site reactions, nausea, vomiting and diarrhea, 
considered also AE of interest (AEOI). Rash events are anticipated on-target events, as 
Nectin-4 is expressed in the skin. The safety and efficacy profile are consistent across all 
monotherapy studies (EV-101, EV-201, and EV-102), demonstrating that treatment with 
enfortumab vedotin as a single agent is manageable, tolerable and effective. 
In addition, EV-301 is an ongoing Phase 3, multinational, open-label, randomized study 
to evaluate the efficacy and safety of enfortumab vedotin compared to chemotherapy in 
participants with LA or mUC who have received a platinum-containing chemotherapy and 
have experienced disease progression or relapse during or following treatment with  
PD-1/PD-L1 inhibitor therapy. The study completed the enrollment in January 2020 and 
is under study follow-up duration. Given its primary endpoint of OS, EV-301 will 
demonstrate whether enfortumab vedotin has a life prolong superiority compared to single 
agent chemotherapy in late line LA/mUC participants, and in a position of supporting 
enfortumab vedotin global registration in late line LA/mUC setting. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Risk Assessment 
The safety profile of enfortumab vedotin monotherapy consists of the known risks of 
peripheral neuropathy, rash, extravasation site reactions, nausea, vomiting, diarrhea, 

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hyperglycemia, and ocular toxicities, which are considered AEOI. Rash events are 
anticipated on-target events, as Nectin-4 is expressed in the skin. 
Evidence of clinical activity in LA or metastatic UC has been observed in other single-
arm studies of enfortumab vedotin. This may translate into an improvement in outcome 
for the population setting selected for this trial in a same tumor type.  However, 
evaluation of clinical benefit is ongoing in the existing clinical studies. Final results are 
pending. 
2.3.2 
Benefit Assessment 
Participants with selected for this study have LA or mUC that at least recurred or 
progressed following standard of care therapy in first line and have limited treatment 
options, especially for Chinese patients as there is only one PD-1 inhibitor (tislelizumab) 
approved in China to date, for patients with PD-L1 highly expressing LA/mUC whose 
disease progressed following or during platinum-based chemotherapy, without more 
options of PD-1/PD-L1 inhibitors. Enfortumab vedotin has been approved in US in Dec 
2019 in LA or mUC patients who was heavily pretreated based on EV-201 study Cohort 1 
results.  
In addition, the safety and efficacy profiles are consistent across all monotherapy studies 
(EV-101, EV-201, and EV-102), demonstrating that treatment with enfortumab vedotin as 
a single agent is manageable, tolerable and effective in LA or mUC. 
2.3.3 
Overall Risk-Benefit Conclusion 
Based on comprehensive evaluation and analysis of cumulative safety data and review of 
safety risks reported with ADC medications or other medications in the same therapeutic 
category, the important potential/identified risks posed by enfortumab vedotin treatment 
may be gastrointestinal toxicity, skin toxicity, visual/ocular toxicity, anaphylaxis or 
anaphylactoid signs, hyperglycemia, peripheral neuropathy and infusion-related reactions. 
Strict adherence to the eligibility criteria and safety assessments and close monitoring are 
essential to assure the safety of participants in this study. 
The activity/efficacy data from the clinical studies for enfortumab vedotin, together with 
acceptable safety, support a favorable benefit-risk assessment for enfortumab vedotin 
monotherapy in treatment of patients with LA or mUC.  
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
The primary and secondary objectives and endpoints for this study are listed in [Table 5]. 
Table 5 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of 
single-agent enfortumab vedotin (EV) as 
measured by confirmed objective 
response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 as determined by 
independent review committee (IRC) 
• 
Confirmed ORR per RECIST V1.1 by IRC 
Table continued on next page 

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Objectives 
Endpoints 
• 
To assess the PK of antibody-drug 
conjugate (ADC), total antibody (TAb) 
and monomethyl auristatin E (MMAE) in 
Chinese participants with locally 
advanced or metastatic urothelial cancer. 
• 
PK variables:  
Selected PK parameters of ADC, TAb and 
MMAE are as follows: 
• 
Maximum observed concentrations (Cmax)  
• 
Trough concentration (Ctrough)  
• 
Time to maximum concentration (Tmax)  
• 
Area under concentration-time curve from 0 
to day 7 (AUC0-7d) 
• 
Area under concentration-time curve from 0 
to day 28 (AUC0-28d)  
• 
Accumulation ratio of Cmax (Rac[Cmax]) 
• 
Accumulation ratio of AUC0-7d (Rac[AUC0-
7d]) 
• 
Terminal or apparent terminal half-life (t1/2) 
as appropriate 
• 
Systemic clearance (CL) and volume of 
distribution at steady state (Vss) as 
appropriate 
Secondary 
• 
To assess confirmed ORR per 
investigator assessment 
• 
Confirmed ORR per RECIST V1.1 per investigator 
assessment 
• 
To assess duration of response (DOR) 
• 
DOR per RECIST V1.1 per IRC and per 
investigator assessment 
• 
To assess disease control rate (DCR) 
• 
DCR per RECIST V1.1 per IRC and per 
investigator assessment 
• 
To assess progression-free survival (PFS) 
• 
PFS per RECIST V1.1 per IRC and per 
investigator assessment 
• 
To assess overall survival (OS) 
• 
OS 
• 
To assess the immunogenicity as defined 
by the incidence of antitherapeutic 
antibodies (ATA)  
• 
Incidence of ATA to ADC 
• 
To assess the safety and tolerability of 
enfortumab vedotin in Chinese 
participants with locally advanced or 
metastatic urothelial cancer. 
 
• 
Safety variables: 
• 
Adverse events (AEs) 
• 
Laboratory tests 
• 
Vital sign measurements 
• 
12-lead electrocardiogram (ECG) 
• 
Eastern Cooperative Oncology Group 
(ECOG) performance status 
ADC: antibody-drug conjugate; AE: adverse event; ATA: antitherapeutic antibodies; AUC4d: area under the 
concentration-time curve from time 0 to 4 days; AUC7d: area under the concentration-time curve from time 
0 to 7 days; CL: clearance; Cmax: maximum concentration; Ctrough: trough concentration; DCR: disease 
control rate; DOR: duration of response; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology 
Group; EV: enfortumab vedotin; IRC: independent review committee; MMAE: monomethyl auristatin E; 
ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetic; 
Rac(AUC): accumulation ratio calculated using AUC; Rac(Cmax): accumulation ratio calculated using Cmax; 
t1/2: terminal half-life; TAb: total antibody; tmax: time of maximum concentration; Vss: volume of distribution 
at steady state. 
Estimands 
Not Applicable. 

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4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Overall Study Design 
This is a single-arm, open-label, multi-center, Phase 2 study to assess the safety, efficacy 
and pharmacokinetics of enfortumab vedotin in Chinese participants with LA or mUC 
who have previously been treated with platinum-containing chemotherapy and PD-1/PD-
L1 inhibitor therapy. Up to 40 participants will be enrolled including approximately 
12 PK Chinese participants in the PK Cohort. 
All participants will receive enfortumab vedotin at 1.25 mg/kg dose level administered as 
an IV infusion on Days 1, 8 and 15 of every 4-week (28 days) cycle. Participants will 
continue on study treatment until one or more of the following discontinuation criteria are 
met: 
• 
Participant requests to stop treatment.  
• 
Investigator decides it is in the participant’s best interest to discontinue. 
• 
Participant develops documented radiological disease progression per Response 
Evaluation Criteria in Solid Tumor (RECIST) V1.1 by investigator assessment. 
• 
Participant starts a new anticancer therapy. 
• 
Participant develops unacceptable toxicity. 
• 
Female participant becomes pregnant. 
• 
Participant is noncompliant with the protocol based on the investigator or medical 
monitor assessment. 
• 
Participant did not receive study drug continuously for > 2 cycles (i.e., 
> 6 consecutive doses not received). Medical Monitor consultation is required after 
the participant was unable to receive one full cycle of study drug administration (i.e., 
3 consecutive doses). Dose delays for patients who are responding to treatment may 
be extended beyond 8 weeks in consultation with Medical Monitor, if the patient’s 
toxicity does not otherwise require permanent discontinuation. 
The participants who discontinue study treatment for reasons other than objective disease 
progression per RECIST V1.1 will be followed every 8 weeks (± 1 week) for response 
assessments. After 1 year from the start of treatment, the frequency of response 
assessments will be reduced to every 12 weeks (± 1 week). The tumor assessments will 
continue until the participant has radiological disease progression per RECIST V 1.1 as 
determined by investigator assessment, initiates a new anticancer therapy, dies, withdraws 
study consent, or the study closes, whichever comes first. All participants are to be 
followed for survival status and subsequent anticancer therapy until death, lost to 
follow-up, withdrawal of consent from study, or study closure, whichever occurs first. 
The study will be closed approximately 2 years after last participant enrollment or no 
participants remain in long-term follow-up, whichever occurs first. A provision of drug 
supply to the participants who are still benefiting from treatment will be prepared prior to 
study closure. Additionally, the sponsor may terminate the study at any time.  
One to 2 study centers will be designated as a “pharmacokinetic cohort site”. 
Approximately 12 participants enrolled in the PK cohort will have intense PK samples 
collected after single and repeated doses. The other participants enrolled at non-PK cohort 
sites will have sparse PK samples collected. Additional participants may be enrolled in 
the PK cohort to compensate for participants who become unevaluable for the PK relevant 

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primary endpoint (PK evaluable). 
Blood samples for pharmacokinetics and antitherapeutic antibodies (ATA) will be 
collected at time points specified in the [Table 1 Schedule of Assessments]. Validated 
assays will be used to measure the concentrations of ADC, TAb and MMAE in serum or 
plasma and to assess ATA.   
After treatment discontinuation, participant will have an end of treatment (EOT) visit for 
a 30-day Safety Follow-up.  
Safety data will be monitored closely throughout the study per the Sponsor relevant study 
monitoring plan. 
The screening/baseline period will take place up to 28 days prior to the first dose of study 
treatment. In the treatment period, starting at cycle 1, participants will receive enfortumab 
vedotin on days 1, 8, and 15 every 28-day cycle until one of the treatment discontinuation 
criteria are met.  
4.2 
Scientific Rationale for Study Design 
This is an open label, single-arm study designed to assess the safety, efficacy and 
pharmacokinetics of enfortumab vedotin monotherapy in Chinese participants with LA or 
mUC.  
One of the primary endpoints is confirmed ORR (cORR) as an efficacy endpoint to 
explore enfortumab vedotin monotherapy’s efficacy in the Chinese population, and 
demonstrate the consistent efficacy trend between the Chinese population and non-
Chinese population. cORR is a surrogate endpoint accepted by health authorities in late 
line LA/mUC patients. In addition, as a primary endpoint in global pivotal Phase 2 
EV-201 study and according to the Cohort 1 data, enfortumab vedotin received 
accelerated approval by US FDA in Dec 2019 for the treatment of adult patients with LA 
or mUC who have previously received a PD-1 or PD-L1 inhibitor and a platinum-
containing chemotherapy in the neoadjuvant/adjuvant, LA or metastatic setting. In regard 
to a single-arm design in this study, cORR assessed by IRC is implemented, to minimize 
bias inter-investigators and is in accordance with the recommendation from health 
authorities.  
As enfortumab vedotin has not previously been explored in the Chinese population, the 
other primary objective of the study is to demonstrate ethnic consistency of enfortumab 
vedotin monotherapy between the Chinese and the non-Chinese populations through PK 
parameter analysis, even though no differences are anticipated for enfortumab vedotin 
based on ethnicity from the Phase 1 and 2 studies (Studies AGS-22M6E-11-1, EV-101, 
EV-102, EV-201) in enfortumab vedotin monotherapy to date. In Study EV-102, 
comparisons of Japanese and non-Japanese participants following enfortumab vedotin 
dosing indicate that there are no ethnic differences between Japanese and non-Japanese 
participants with respect to pharmacokinetics.  
Therefore, the PK cohort is set in the study to collect intensive PK samplings along with 
sparse PK samplings in non-PK cohort participants, to address PK parameters in Chinese 
LA/mUC population.  

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Population pharmacokinetic analysis included data from 369 participants based on 3 
Phase 1 studies (AGS-22M6E-11-1, EV-101 and EV-102), and 1 Phase 2 study (EV-201), 
demonstrated no clinically significant differences in the pharmacokinetics of enfortumab 
vedotin based on sex. Population pharmacokinetic analysis did not identify race 
(Caucasian vs. non-Caucasian) as a significant covariate on PK either. Therefore, the 
study is planned to enroll PK cohort participants who previously received platinum 
containing chemotherapy and PD-1/PD-L1 inhibitor therapy treatment regardless of sex.  
A single-arm study design, with cORR by IRC being one of the primary endpoints, along 
with global registrational pivotal Phase 3 study EV-302 data on non-Chinese population, 
will support the demonstration of enfortumab vedotin monotherapy efficacy in late line 
LA/mUC Chinese population. 
4.3 
Dose Rationale 
In the Phase 1 study of ASG-22CE in North America (EV-101), the Recommended Phase 
2 Dose (RP2D) were established to be 1.25 mg/kg once weekly for 3 weeks of every 
4-week cycle. The study tested a starting dose of 0.5 mg/kg and escalated up to a 
maximum dose of 1.25 mg/kg using a continual reassessment method (CRM) for dose 
escalation with subsequent expansion cohorts. The MTD was not reached for this study. 
In the dose escalation portion of this study, a total of 2 DLTs (proctalgia and blood uric 
acid increased) were reported in 2 participants receiving 1.0 mg/kg dose (n = 14). No 
DLTs were reported at 1.25 mg/kg dose (n = 6). The RP2D was determined to be 
1.25 mg/kg based on both safety and efficacy data.  
In this study, 1.25 mg/kg will be tested and enfortumab vedotin is dosed based on body 
weight. This should mitigate potential ethnic differences of ADC exposure in PK due to 
differences in body weight between US and Chinese participants. Thus, the dose of 
enfortumab vedotin as 1.25mg/kg to be tested in this study are both anticipated to be safe 
and active in Chinese mUC participants. 
4.4 
End of Study Definition  
The study start is defined as the date the first participant signs informed consent. End of 
the study is defined as the last visit or scheduled procedure shown in schedule of 
assessments for the last participant in the study. The study will be closed approximately 
2 years after last participant enrollment or no participants remain in long-term follow-up, 
whichever occurs first. 
5 
STUDY POPULATION 
All screening assessments must be completed and reviewed to confirm the potential 
participant meets all eligibility criteria. Prospective approval of protocol deviations to 
eligibility criteria (also known as protocol waivers or exemptions) is not permitted. 
5.1 
Inclusion Criteria 
Participant is eligible for participation in 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 must be 

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obtained from the participant prior to any study-related procedures (including 
withdrawal of prohibited medication, if applicable). 
2. Participant is legally 18 years or older or considered an adult according to local 
regulation at the time of signing the informed consent form (ICF). 
3. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1. 
4. Participant must have histologically or cytologically documented 
urothelial/transitional cell carcinoma of the bladder, renal pelvis, ureter or urethra. 
Other histologies including adenocarcinoma, squamous differentiation or mixed are 
eligible.  
5. Participant has locally advanced or metastatic disease that is not amenable to curative 
intent treatment. Participants must have measurable disease at baseline according to 
RECIST Version 1.1 (Eisenhauer 2009). Lesions in a prior radiation field must have 
progressed subsequent to radiotherapy to be considered measurable. 
6. Participant must have received prior treatment with PD-1/PD-L1 inhibitor therapy in 
the locally advanced or metastatic urothelial cancer setting. Participants who received 
PD-1/PD-L1 therapy in the neoadjuvant/adjuvant setting and had recurrent or 
progressive disease either during therapy or within 3 months of therapy completion 
are eligible.  
7. Participant who received prior treatment with platinum-containing chemotherapy 
defined as those who received platinum in the neoadjuvant/adjuvant setting and had 
recurrent or progressive disease within 12 months of completion or received 
treatment with platinum in the locally advanced (defined as unresectable with 
curative intent) or metastatic setting  
• Platinum based chemotherapy may include combination use with a PD-1 or 
PD-L1 inhibitor.  
8. Participant has the following baseline laboratory data. If a participant has received a 
recent blood transfusion or growth factor, the hematology tests must be obtained 
≥7 days after any growth factor and ≥ 28 days after any blood transfusion. 
a. absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
b. platelet count ≥ 100 × 109/L 
c. hemoglobin ≥ 9 g/dL 
d. serum total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN 
for participants with Gilbert’s disease 
e. 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). 
f. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 3 × ULN 

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9. Female participant is not pregnant (see [Section 10.2 Appendix 2 Contraception 
Requirements]) and at least one of the following conditions apply:  
a. Not a woman of childbearing potential (WOCBP) (see [Section 10.2 
Appendix 2 Contraception Requirements]) 
b. WOCBP who agrees to follow the contraceptive guidance (see [Section 10.2 
Appendix 2 Contraception Requirements]) from the time of informed consent 
through at least 6 months after the last dose of study treatment administration 
10. Female participant must agree not to breastfeed starting at screening and throughout 
the study period and for at least 6 months after the last dose of study treatment 
administration. 
11. Female participant must not donate ova starting at first dose of study treatment and 
throughout the study period and for 6 months after the last dose of study treatment 
administration. 
12. Male participant with female partner(s) of childbearing potential (including 
breastfeeding partner) must agree to use contraception (see [Section 10.2 Appendix 2 
Contraception Requirements]) throughout the treatment period and for 6 months after 
the last dose of study treatment administration. 
13. Male participant must not donate sperm during the treatment period and for 6 months 
after the last dose of study treatment administration. 
14. Male participant with pregnant partner(s) must agree to remain abstinent or use a 
condom for the duration of the pregnancy throughout the study period and for 6 
months after the last dose of study treatment administration. 
15. Participant agrees not to participate in another interventional study while receiving 
study treatment in the present study. 
16. Participant must have had progression or recurrence of urothelial cancer during or 
following receipt of most recent therapy. 
17. Participant must have an anticipated life expectancy of ≥ 3 months as assessed by the 
investigator. 
5.2 
Exclusion Criteria 
Participant will be excluded from participation in the study if any of the following apply: 
1. Participant has preexisting sensory or motor neuropathy Grade ≥ 2. 
2. Participant has active central nervous system (CNS) metastases. Participants with 
treated CNS metastases are permitted on study if all the following are true: 
a. CNS metastases have been clinically stable for ≥ 6 weeks prior to screening 
b. If requiring steroid treatment for CNS metastases, the participant is on a stable 
dose ≤ 20 mg/day of prednisone or equivalent for ≥ 2 weeks 
c. Baseline imaging scans show no evidence of new or enlarged brain metastasis 
d. Participant does not have leptomeningeal disease 

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3. Participant has ongoing clinically significant toxicity (Grade 2 or higher with the 
exception of alopecia) associated with prior treatment (including systemic therapy, 
radiotherapy or surgery). 
4. Participant with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or 
panhypopituitarism is excluded.  Participant with ongoing immunotherapy-related 
colitis, uveitis, myocarditis or pneumonitis, or participants with other 
immunotherapy-related AEs requiring high doses of steroids (> 20 mg/day of 
prednisone or equivalent), is excluded. Participant 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).   
5. Participant has a history of uncontrolled diabetes mellitus within 3 months before the 
first dose of study treatment.  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. 
6. Participant has prior treatment with enfortumab vedotin or other MMAE-based 
ADCs. 
7. Participant has a second malignancy diagnosed within 3 years before first dose of 
study drug, or any evidence of residual disease from a previously diagnosed 
malignancy.  Participants with non-melanoma 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. Participant is currently receiving systemic antimicrobial treatment for viral, bacterial 
or fungal infection at the time of first dose of study treatment.  Routine antimicrobial 
prophylaxis is permitted. 
9. Participants with a positive hepatitis B surface antigen and/or anti-hepatitis B core 
antibody and a negative polymerase chain reaction (PCR) assay at baseline should 
receive appropriate antiviral prophylaxis or regular surveillance monitoring as per 
local or institutional guidelines. 
10. Active hepatitis C infection or known human immunodeficiency virus (HIV) 
infection. Participant who have been treated for hepatitis C infection are permitted if 
they have documented sustained virologic response of ≥ 12 weeks. 
11. Participant 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-IV within 6 months prior to the first dose of study drug. 
12. Participant had major surgery within 2 weeks or radiotherapy, chemotherapy, 
biologics, investigational agents, and/or antitumor treatment with immunotherapy 
that is not completed 2 weeks prior to first dose of study drug. Toxicities from these 
therapies must have resolved or adequately stabilized before starting study treatment.  

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13. Participant has known hypersensitivity to enfortumab vedotin or to any excipient 
contained in the drug formulation of enfortumab vedotin (including histidine, 
trehalose dihydrate and polysorbate 20) or participant has known hypersensitivity to 
biopharmaceuticals produced in CHO cells. 
14. Participant has known active keratitis or corneal ulcerations.  Participant with 
superficial punctate keratitis is allowed if the disorder is being adequately treated in 
the opinion of the investigator. 
15. Participant has any condition, which, in the investigator’s opinion, makes the 
participant unsuitable for study participation. 
16. Uncontrolled tumor-related bone pain or impending spinal cord compression. 
Participant requiring pain medication must be on a stable regimen for at least 2 weeks 
at the time of first dose. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
A screen failure is defined as a potential participant who signed the ICF, but did not meet 
one or more criteria required for participation in the study and was not enrolled. 
For screen failures, the demographic data, date of signing the ICF, inclusion and 
exclusion criteria, AEs up to the time of screen failure and reason for screen failure will 
be collected in the electronic case report form (eCRF). 
5.4.1 
Rescreening 
Results of screening assessments that do not meet the parameters required by eligibility 
criteria (e.g., clinical laboratory tests, vital signs, physical examination, electrocardiogram 
[ECG], etc) may be repeated once within the 28-day screening period without the need to 
register the participant as a screen failure. If the participant meets exclusion criteria that 
cannot resolve during the screening period, or more than 28 days elapse from the date of 
signing the ICF, the participant must be documented as a screen failure. In order to re-
screen after prior screen failure, a new ICF must be signed and the participant will enter 
into screening with a new participant identification number. Rescreening is only allowed 
once for an individual participant after discussion with medical monitor. The 
Screening/baseline and safety assessments do not need to be repeated if they still within 
the acceptable procedure completed time frame and all results meet inclusion and no 
exclusion criteria.  
6 
INVESTIGATIONAL PRODUCT(S)  
6.1 
Investigational Product(s) Administered 
Table 6 
Investigational Product(s) 
Name 
Enfortumab vedotin 
Use 
test product  
Dosage Form 
lyophilized powder for reconstitution 
Physical Description 
white to off-white 

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Unit Dose Strength 
30 mg of enfortumab vedotin in a single-dose vial 
Packaging and Labeling 
clear single use vial 
Route of Administration 
intravenous infusion 
Administration  
Administered intravenously over 30 minutes. Refer to Section 6.1.1 for 
additional details. 
IMP or Non-IMP 
IMP 
Sourcing 
provided centrally by sponsor 
IMP: Investigational Medicinal Product. 
The investigational product, enfortumab vedotin (ASG-22CE), is a sterile, preservative-
free, white to off-white lyophilized powder to be reconstituted for IV administration. The 
investigational product is supplied by Astellas in single-use glass vials containing 30 mg 
enfortumab vedotin in each vial. The investigational product should be stored at 2°C to 
8°C. 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding preparation, handling and storage of the enfortumab vedotin. 
6.1.1 
Investigational Product Administration  
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered monotherapy as an IV 
infusion over approximately 30 minutes on Days 1, 8, and 15 of every 28-day cycle. In 
the absence of infusion related reactions (IRRs), the infusion rate for all participants 
should be calculated in order to achieve an approximate 30-minute infusion period. 
Enfortumab vedotin must not be administered as an IV push or bolus. Enfortumab vedotin 
should not be mixed with other medications. At least 7 days must elapse between doses of 
enfortumab vedotin.  
Participant weight must be measured during all relevant assessment time points as 
described in the [Table 1 Schedule of Assessments]. Weight-based dosing is calculated 
using the participant’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 unless it is 
required by institutional standards. An exception to weight-based dosing is made for 
participants weighing greater than 100.0 kg; doses will be based on 100 kg for these 
individuals. The maximum dose permitted on this study is 125.0 mg.   
Participants should be observed during enfortumab vedotin administration and for at least 
60 minutes following the infusion for the first 3 cycles. All supportive measures 
consistent with optimal participant 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. Participants should be advised to report 
redness or discomfort promptly at the time of administration or after infusion. Events of 
extravasation should be managed per institutional guidelines and precautions should be 
taken to prevent extravasation per institutional standards.  

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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
All study drug(s) used in this study will be prepared, packaged and labeled under the 
responsibility of qualified personnel at sponsor’s designee in accordance with sponsor’s 
designee standard operating procedures (SOPs), current Good Manufacturing Practice 
(GMP) guidelines, International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and 
applicable local laws/regulations. 
Each vial will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual for detailed information regarding packaging and labeling 
of the enfortumab vedotin. 
6.2.2 
Handling, Storage and Accountability 
• 
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all enfortumab vedotin received and any 
discrepancies are reported and resolved before use of the enfortumab vedotin. 
• 
Only participants enrolled in the study may receive enfortumab vedotin and only 
authorized study site personnel may administer enfortumab vedotin. Only study drug 
with appropriate expiry/retest dating may be dispensed. 
• 
All enfortumab vedotin must be stored in a secure, environmentally controlled and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions and access must be limited to the investigator and authorized study site 
personnel. 
• 
The investigator, institution or the head of the medical institution (where applicable) 
is responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).  
• 
Further guidance and instruction on final disposition of used and unused study drug is 
provided in the pharmacy manual.  
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the enfortumab vedotin. 
6.3 
Randomization and Blinding 
This is an open-label, single-arm study. Participant enrollment and dispensation of 
enfortumab vedotin will be performed via the interactive response technology (IRT) 
system. Specific IRT procedures will be described in the respective study manual.  
6.4 
Investigational Product Compliance 
The dose and schedule of enfortumab vedotin administered to each participant will be 
recorded on the eCRF for each dose. Reasons for dose delay, reduction or omission will 
be documented. 
6.5 
Dose Modification 
Intrapatient 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. Participants requiring a 

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dose reduction may be re-escalated by 1 dose level (e.g., participants 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. Participants with ≥ Grade 2 corneal AEs will not be 
permitted to dose re-escalate.  
Dose modification recommendations for enfortumab vedotin associated toxicity 
(hematologic and non-hematologic, by National Cancer Institute-common terminology 
criteria for adverse event [NCI-CTCAE] v4.03 grade) are presented in Table 7 and 
Table 8. 
If toxicities present on Day 1 of any cycle and require the enfortumab vedotin dose to be 
held, then the start of the cycle may be delayed. If toxicities present on Days 8 or 15 of 
any cycle and require the dose to be held > 2 days, then the dose(s) must be eliminated, 
rather than delayed. If a participant only receives enfortumab vedotin on Day 1 and needs 
to skip Days 8 and 15, the participant could resume the next cycle as early as Day 22 (new 
Day 1) if the toxicity has resolved by that time. 
Treatment break, dose reduction or delay for other enfortumab vedotin associated 
toxicities is permitted at the discretion of the investigator. Medical Monitor consultation is 
required after the participant was unable to receive one full cycle of study drug 
administration. (i.e., 3 consecutive doses) for toxicities or any other reasons. If participant 
was unable to receive study drug ≥ 2 cycles (i.e., ≥ 6 consecutive doses not received) for 
toxicity or for any other reasons, the participant will be discontinued.  Dose delays for 
participants who are responding to treatment may be extended beyond 8 weeks in 
consultation with Medical Monitor, if the participant’s toxicity does not otherwise require 
permanent discontinuation.  
Disease assessment must continue to be performed at the protocol specified frequency and 
will not be adjusted while participant is not receiving study treatment or any dose delay. It 
will continue to be timed from Cycle 1 Day 1 during treatment. 
The treatment could be continued until any of the study discontinuation criteria is met. 
Participants may not receive other investigational drugs and/or vaccines, radiotherapy 
(except palliative radiotherapy as described in Section 6.8.1), or systemic antineoplastic 
therapy during dose delays.  
Dose modification recommendations for enfortumab vedotin associated toxicity are 
presented in Table 7 below. 
Table 7 
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 
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. 
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 

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Grade 1 
Grade 2 
Grade 3 
Grade 4 
resume treatment at 
the same dose level. 
Transfusions or growth 
factors may be used as 
indicated per 
institutional guidelines. 
institutional guidelines. 
For anemia, treatment 
discontinuation should be 
strongly considered. 
*Hematologic toxicity refers to anemia, thrombocytopenia, neutropenia and febrile neutropenia. 
 
Table 8 
Recommended Dose Modifications for Enfortumab Vedotin Associated 
Non-hematologic Toxicity 
Any Grade 
For suspected SJS, suspected TEN or bullous lesions, immediately withhold enfortumab vedotin and 
refer the subject to a dermatologist/specialist for diagnosis and specialized care. 
For confirmed SJS or TEN, permanently discontinue treatment. 
If SJS or TEN is ruled out, see recommendations provided below for skin reactions. 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same dose 
level. 
For Grade 1 rash or skin 
reactions, the subject 
may continue at the same 
dose level. See also 
[Section 6.5.1] for 
recommended 
management of rash. 
If ocular symptoms 
and/or changes in 
vision are identified, 
the participant should 
be evaluated with an 
ophthalmologic 
exam.* 
Continue at same dose 
level, except in the event 
of Grade 2 neuropathy 
or corneal AEs. 
For worsening rash or 
skin reactions, or skin 
reactions with 
concomitant fever, 
withhold enfortumab 
vedotin until toxicity is 
≤ Grade 1 or has 
returned to baseline, and 
then resume treatment at 
the same dose level or  
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 rash or skin 
reactions, withhold 
enfortumab vedotin until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
and then resume 
treatment at the same 
For Grade 4 AEs, 
discontinue 
treatment.** 
For confirmed SJS or 
TEN, or Grade 4 rash 
or skin reactions, 
permanently 
discontinue treatment. 
Grade 4 vomiting 
and/or diarrhea that 
improves to ≤ Grade 2 
within 72 hours with 
supportive management 
does not require 
discontinuation. 
Table continued on next page 

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Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
consider dose reduction 
by 1 level. Consider 
referral of the subject to 
a 
dermatologist/specialist 
for diagnosis and 
specialized care.  
For Grade 2 neuropathy 
or corneal AEs, 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 
participant should be 
evaluated with an 
ophthalmologic exam.* 
dose level or consider 
dose reduction by 1 
level. Consider referral 
of the subject to a 
dermatologist/specialist 
for diagnosis and 
specialized care.  
Subjects who have 
confirmed SJS or 
recurrent ≥ Grade 3 rash 
events should have 
therapy permanently 
discontinued. 
For Grade 3 neuropathy 
or corneal AEs, 
discontinue treatment. 
For Grade 3 
hyperglycemia/elevated 
blood glucose, withhold 
study treatment.  
Resume treatment once 
hyperglycemia/elevated 
blood glucose has 
improved to ≤ Grade 2 
and participant is 
clinically and 
metabolically stable. 
If ocular symptoms 
and/or changes in vision 
are identified, the 
participant should be 
evaluated with an 
ophthalmologic exam.* 
For Grade 4 
hyperglycemia/elevated 
blood glucose, 
withhold enfortumab 
vedotin treatment and 
undertake a full 
evaluation of the 
hyperglycemia event. 
Once the blood glucose 
levels return to Grade 2 
drug dosing may be 
resumed with close 
monitoring after 
consultation with 
medical monitor. 
AEs: adverse events; SJS: Stevens-Johnson Syndrome; TEN: toxic epidermal necrolysis 
*  Ophthalmologic exam should be performed by an ophthalmologist.  If optometrists can perform 
exams and prescribe medications, an optometrist may be used instead. 
**  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 or 4 elevations of 
amylase or lipase, if asymptomatic do not require treatment delay or treatment discontinuation.   
6.5.1 
Enfortumab Vedotin-Related Rash 
Enfortumab vedotin is a Nectin-4 directed antibody drug conjugate. Nectin-4 is a cell 
adhesion molecule that is highly expressed in urothelial carcinoma. Low to moderate 
levels of Nectin-4 are also expressed on normal tissues, including skin keratinocytes, 
sweat glands and hair follicles; thus, skin reactions are anticipated events. As such, skin 
reactions are AEs of interest in all clinical studies with enfortumab vedotin.  
A cumulative review of post-marketing safety data from 18 Dec 2019 (the approval date 
of enfortumab vedotin in the US) through 22 Oct 2020 identified reports of severe 
cutaneous adverse reactions in 15 subjects receiving enfortumab vedotin, some of whom 
had fatal outcomes. These reactions occurred predominantly during the first cycle of 

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treatment. AEs reported in these cases included Stevens-Johnson Syndrome (SJS) (5 
cases), blister (3 cases), dermatitis bullous (3 cases), symmetrical drug-related 
intertriginous and flexural exanthema (SDRIFE; 2 cases), and 1 case each of dermatitis 
exfoliative, exfoliative rash, epidermal necrosis, oropharyngeal blistering, stomatitis and 
toxic epidermal necrolysis (TEN).  
In enfortumab vedotin monotherapy studies of urothelial carcinoma, SAEs of severe 
cutaneous adverse reactions were reported in 11 of 749 subjects (1.5%) and included 
dermatitis bullous (0.4%), drug eruption (0.4%), blister (0.1%), conjunctivitis (0.1%), SJS 
(0.1%), stomatitis (0.1%) and toxic skin eruption (0.1%).  
Subjects should be informed that rash and severe skin reactions have occurred after 
administration of EV, and to contact the Investigator immediately if they have signs and 
symptoms of skin reactions, oral mucosal and ocular abnormalities including mucositis or 
conjunctivitis. Starting in the first cycle and throughout treatment, closely monitor 
subjects for skin reactions. For mild to moderate skin reactions, consider appropriate 
treatment, such as topical corticosteroids and antihistamines as clinically indicated. For 
recommendations regarding dose modifications for skin reactions due to EV, refer to 
[Table 8]. 
6.5.2 
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, participants should be treated according to local standard of care and referral to 
endocrinology may be considered. 
Participants, especially those with a history of or ongoing diabetes mellitus or 
hyperglycemia, should be advised to immediately notify their physicians 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. Participants 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 participant’s blood glucose has improved to ≤ Grade 2 and participant is 
clinically and metabolically stable. Blood glucose > 500 mg/dL (27.8 mmol/L) (Grade 4) 
considered related to enfortumab vedotin requires treatment discontinuation. If a 
participant experiences new onset of diabetes mellitus, evaluate participants with a 
metabolic panel, urine ketones, HbA1c, and C-peptide to assess for new onset diabetes. 
6.5.3 
Management of Enfortumab Vedotin Infusion Related Reactions  
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 participant care should be given 
throughout the study according to institutional standards. Supportive measures may 
include administering medications for IRRs. 

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Participants who experience 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 to 60 minutes prior to each infusion or according to institutional 
standards. Should a participant experience IRRs in the setting of premedication, continued 
treatment with enfortumab 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. 
6.6 
Continued Access to Investigational Product After the End of the 
Study  
Options to provide enfortumab vedotin to participants who are continuing to receive 
treatment and are benefiting will be determined at the time of study closure. 
6.7 
Treatment of Overdose  
Neither the effects of overdose of enfortumab vedotin nor an antidote to overdose are 
known. In the case of an overdose, the participant should be closely monitored for adverse 
reactions and supportive treatment should be administered. 
Weight-based dosing for enfortumab vedotin is based on the participant’s actual body 
weight, with the exception of participants weighing greater than 100 kg; doses will be 
based on 100 kg for these individuals. The maximum dose calculated per cycle in this 
study is 125 mg. 
In the event of an overdose of enfortumab vedotin >10%, study personnel should: 
Care for and medically stabilize the participant until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of enfortumab vedotin. 
Notify the Medical Monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (e.g., exact amount of enfortumab vedotin administered, 
participant weight) and AEs, if any.  
Refer to [Section 10.3.7 Reporting Procedures for Special Situations] for reporting 
requirements for suspected overdose or other medication error.  
6.8 
Concomitant Therapy 
Medications taken within 28 days prior to inform consent and up to the first dose of study 
medication will be documented on the appropriate case report form (CRF) as a prior 
medication. 
Medications taken after the first dose of study medication up until the 30-day safety 
follow-up visit (EOT visit in [Table 1 Schedule of Assessments]) will be documented on 
the appropriate CRF as concomitant medication. 
6.8.1 
Allowed Concomitant Therapy 
Concomitant chronic prednisone (or equivalent) may be used at a dose of ≤20 mg/day. 
Higher doses of prednisone (or equivalent) are permitted for limited duration to treat acute 

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conditions that arise during the study as medically indicated. The use of anti-emetics is 
permitted. Premedications for IRRs per Section 6.5.3 are permitted. 
Therapies to manage enfortumab vedotin-associated toxicity as recommended in 
Section 6.5 are permitted, including growth factors, and transfusions. 
Participants who are receiving strong CYP3A4 inhibitors or P-glycoprotein (P-gp) 
inhibitors concomitantly with enfortumab vedotin should be closely monitored for 
adverse reactions. 
Routine prophylaxis with vaccines is permitted; it is recommended that vaccines used do 
not contain live micro-organisms. Antimicrobial prophylaxis or ongoing treatment of 
resolving and/or controlled infection is permitted during the study. 
Participants with a positive hepatitis B surface antigen and/or anti-hepatitis B core 
antibody and a negative PCR assay at baseline should receive appropriate antiviral 
prophylaxis or regular surveillance monitoring as per local or institutional guidelines. 
Participants with treated CNS metastases are permitted on study conditionally; participant 
with uncontrolled tumor-related bone pain or impending spinal cord compression 
requiring pain medication on a stable regimen is permitted as per Section 5.2. 
Palliative radiotherapy on a non-target bone lesion that is not progressing is allowed after 
3 cycles of treatment; must be administered after the initial response assessment and 
repeat scans described in Section 7.1. This will not be considered a subsequent anticancer 
therapy, but must not interfere with the assessment of tumor target lesions. Treatment 
with enfortumab vedotin should be interrupted during palliative radiotherapy. 
6.8.2 
Prohibited Concomitant Therapy 
If the investigator determines that any of the following medications are necessary to 
provide adequate medical support to the participant, the participant must be withdrawn 
from further administration of the study treatment: 
a. Other investigational drugs and/or vaccines 
b. Chemotherapy or other medications intended for antitumor activity. This does not 
apply to participants on endocrine therapy, or to participants on agents intended for the 
treatment of bone metastasis where participants should be on a stable dose of bone 
targeting agents for at least 2 weeks prior to first dose of study drug (e.g., 
bisphosphonates, or receptor activator of nuclear factor kappa-Β [RANK] ligand 
inhibitors). 
c. Radiation therapy except palliative radiation for non-target lesions (as described in 
Section 6.8.1) that is approved by the sponsor. Note: Radiation therapy to a 
preexisting symptomatic solitary lesion or to the bone may be considered on an 
exceptional case-by-case basis after consultation with the sponsor. 
7 
STUDY PROCEDURES AND ASSESSMENTS 
● 
Study procedures and their timing are summarized in the [Table 1 Schedule of 
Assessments]. Adherence to the study design requirements, including those specified 
in the schedule of assessments, is essential and required for study conduct. 
Prospective protocol waivers or exemptions are not allowed. 

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● 
Any change, divergence or departure from the study design or procedures identified 
in the protocol is considered a protocol deviation. All deviations from the protocol 
are to be recorded. 
● 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
● 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
● 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the schedule of assessments. 
7.1 
Efficacy Assessments  
Measures of anticancer activity will be assessed by computed tomography (CT) scans 
with contrast approximately every 8 weeks (± 1 week). After 1 year on study, response 
assessments will be reduced to every 12 weeks (± 1 week). The schedule of response 
assessments should not be adjusted for dose delays/interruptions or other reasons for 
changes in the timing of a participant’s study activities; timepoints for response 
assessments should be calculated from Cycle 1 Day 1. A CT scan with contrast (chest, 
abdomen, and pelvis) is the preferred modality for tumor assessment.  Magnetic 
resonance imaging (MRI) is acceptable if CT scans are contraindicated in a participant 
(e.g., participant is allergic to contrast media). Participants must be evaluated using the 
same imaging method throughout the study for efficacy assessments. Other regions 
should be scanned if the participant has known or suspected disease in that region. Brain 
and/or bone scans should also be repeated at response assessment timepoints if bone 
metastases were identified at baseline, or if metastasis is known or suspected. Responses 
(CR or partial response [PR]) will be confirmed with repeat scans at least 4 weeks after 
first documentation of response. The schedule for response assessments should not be 
adjusted after the confirmatory scan (e.g., CR at Week 8, confirmatory scans at Week 12, 
next assessment due at Week 16). Tumor imaging should also be performed whenever 
disease progression is suspected. The determination of antitumor activity will be based on 
confirmed objective response assessments by IRC as defined by RECIST V 1.1. The 
investigator could make treatment decisions based on site assessments of scans by 
RECIST V 1.1. 
Participants who discontinue study treatment for reasons other than objective disease 
progression by RECIST V 1.1 will continue to receive CT scans with contrast 8 weeks 
(±1 week) after the previous response assessment scan and every 8 weeks (±1 week) 
following the previous scan thereafter. After 1 year on study the frequency of response 
assessments will be reduced to every 12 weeks (±1 week). The tumor assessments will 
continue until the participant has radiological disease progression per RECIST V 1.1 as 
determined by investigator, initiates a new anticancer therapy, dies, withdraws study 
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antitumor activity will be based on confirmed objective response assessments as defined 
by RECIST V 1.1. Participants who do not have at least 2 (initial response and 
confirmation scan) post-baseline response assessments will be counted as non-responders. 
Clinical response of CR, PR, SD, or progressive disease (PD) will be determined at each 
assessment. Response and progression will also be assessed by IRC and investigator 
independently.  
Survival status will be updated every 12 weeks (±1 week) (calculated from disease 
progression) until death, study closure, lost to follow-up or withdrawal of consent from 
study, whichever occurs first.  
Participants’ clinical data must be available for CRF source verification. Tumor images 
will be submitted to a central imaging laboratory. 
7.1.1 
Evaluation of Target Lesions 
7.1.1.1 Complete Response 
CR is defined as disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm from baseline 
measurement. 
7.1.1.2 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.  
7.1.1.3 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 (Note: the appearance of 1 or more new lesions is also considered 
progression). 
7.1.1.4 Stable Disease 
SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters while on study drug. 
7.1.2 
Evaluation of Non-target Lesions 
To achieve unequivocal progression on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target 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 non-target lesions 
is usually not sufficient to qualify for unequivocal progression. 
7.1.2.1 Complete Response 
For CR of non-target lesions, participants must have disappearance of all non-target 
lesions and all lymph nodes must be nonpathological in size (< 10 mm short axis). 

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7.1.2.2 Non-CR/Non-PD 
Non-CR/Non-PD of non-target lesions is defined as persistence of 1 or more non-target 
lesions. 
7.1.2.3 Progressive Disease 
PD of non-target lesions is defined as unequivocal progression of existing non-target 
lesions or the appearance of 1 or more new lesions. 
7.1.3 
New Lesions 
New lesion is defined as the new finding in an anatomical location on the follow-up scan 
assessment, exclude the impact of differences of scan technique. Such lesion that was not 
scanned at baseline is also considered a new lesion. The appearance of 1 or more new 
lesions is also considered progression. 
7.1.4 
Time Point for Response Evaluation 
The overall response status at each time point for participants with measurable disease at 
baseline will be reported according to the [Table 1 Schedule of Assessments].   
7.2 
Safety Assessments 
7.2.1 
Laboratory Assessments 
● 
See [Section 10.6 Appendix 6: Laboratory Assessments] for the list of clinical 
laboratory tests (including hematology, biochemistry, urinalysis and HbA1c) to be 
performed and refer to [Table 1 Schedule of Assessments] for timing and frequency. 
● 
The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
● 
Clinical significance of out-of-range laboratory findings is to be determined and 
documented by the investigator or subinvestigator who is a qualified physician. 
Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
Laboratory tests will be sent to the local laboratory for analysis and entered into eCRF. 
Clinical laboratory tests will be performed locally prior to dosing. Tests will be obtained 
as indicated in the [Table 1 Schedule of Assessments]. If hematology and biochemistry 
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. Clinical laboratory tests at screening, at screening and on 
Cycle 1 Day 8 are to be performed after the participant has been fasting in order to ensure 
accurate interpretation of lab test values such as glucose values. Participant can take food 
after fasting blood samples are obtained. Fasting status will be recorded in source 
documents. Fasting is not necessary for laboratory tests performed at all other visits. 
HbA1c will be obtained at screening/baseline and EOT visits. If HbA1c is elevated  
(≥ 6.5%), refer participant to appropriate provider during cycle 1 for glucose 
management. Lipid panel, including total cholesterol, high-density lipoprotein cholesterol 
(HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride tests, will be only 
obtained at screening.  

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Additional assessments may be done to monitor AEs or as required by dose modification 
requirements. Additional laboratory tests should be performed according to institutional 
standard of care.  
For women of childbearing potential only, a 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 study drug administration at the EOT and follow-up visits till 6 months after the 
last dose of study treatment administration. Adequate contraception should be used by 
study participants during or after the last dose of study treatment administration per the 
requirement stated in [Section 10.2 Appendix 2 Contraception Requirements]. 
7.2.2 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate 
(beats/minute) and temperature will be obtained as indicated in the [Table 1 Schedule of 
Assessments]. All vital sign measures will be taken prior to dosing with the participant in 
the sitting or supine position. 
If clinically significant vital sign changes from screening/baseline 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.  
7.2.3 
Physical Examination  
Standard, full physical examinations will be performed to assess general appearance, skin, 
eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status, mental status, and lymphatic systems. Physical examinations will be 
conducted at visits as outlined in the [Table 1 Schedule of Assessments]. Height 
measurement is only required at screening/baseline. Weight measurement will also be 
performed as indicated in the [Table 1 Schedule of Assessments]. If physical examination 
except for weight was performed within 7 days prior to the first day of dosing, it does not 
need to be repeated on Cycle 1 Day 1. 
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, which has medical relevance that could result in an 
alteration in medical care. The investigator will continue to monitor the participant 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. 
7.2.4 
Electrocardiogram  
Routine 12-lead ECGs will be performed and assessed using local standard procedures as 
indicated in the [Table 1 Schedule of Assessments]. If clinically significant worsening of 
a finding from baseline is noted, the abnormality will be documented as AEs on the AE 
eCRF. Prior to performing 12-lead ECGs, participants should rest in supine position (or 
semi-recumbent, if supine is not tolerated) for 10 minutes. ECGs will be read and 
assessed locally.   

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7.2.5 
ECOG Performance Status 
ECOG performance status [Section 10.7 Appendix 7: ECOG Performance Status Scale] 
will be evaluated at protocol-specified timepoints. 
7.2.6 
Ophthalmology Examination 
Participants will have a complete eye examination at baseline performed by a qualified 
ophthalmologist or optometrist, including but not limited to: visual acuity (VA), best 
corrected visual acuity (BCVA), inter ocular pressure (IOP), extra ocular movement 
(EOM), pupils, external exam, slit lamp exam, and dilated fundoscopic exam. Eye exams 
performed during the study where clinically indicated will be at the ophthalmologist’s 
discretion. Eye exams at EOT are required for participants who experience ocular AEs 
during the study and this at minimum must include VA, BCVA, and slit lamp exam.  
7.2.7 
Order of Assessments  
Not applicable.  
7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in [Sections 10.3.1 and 10.3.2], 
respectively. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study drug, or that caused the 
participant to discontinue the study drug and/or study (see [Section 10.3 Appendix 3: 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up and 
Reporting]).  
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in [Section 10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting]. 
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All SAEs will be collected from the signing of the ICF until 30 days following the last 
dose of study treatment or until initiation of a new anticancer treatment, whichever occurs 
first, at the time points specified in the schedule of assessments [Section 1.3] and reported 
on the eCRF. 
All AEs will be collected from the signing of the ICF until the follow up visit at the time 
points specified in the schedule of assessments [Section 1.3] and reported on the eCRF.  
If the NCI-CTCAE grade of an SAE/AE changes, the event should be relisted on the 
eCRF with the new NCI-CTCAE grade and new onset date. 

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If the NCI-CTCAE grade decreases, the SAE/AE should be relisted on the eCRF with the 
new NCI-CTCAE grade and new onset date. The exception is ongoing pre-dose events 
that continue post-dose and improve post-dose. Such events should not be re-listed. 
If the NCI-CTCAE grade of an SAE reduces, the details of the AE should be provided on 
the SAE worksheet for the medical assessor to be able to assess the course of the event. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in [Section 10.3 Appendix 3: 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up and 
Reporting]. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study drug or study participation, the investigator must 
promptly notify the sponsor. 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrences.  
7.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in [Section 8.3]). Further information on follow-up procedures is provided in 
[Section 10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting]. 
If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period for 
Collecting Adverse Event and Serious Adverse Event Information]), an AE progresses to 
an SAE, or the investigator learns of any (S)AE (serious adverse event or adverse event) 
including death, where he/she considers there is reasonable possibility it is related to the 
study drug or study participation, the investigator must promptly notify the sponsor.  
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
● 
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study drug under clinical investigation are met. 
● 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC and investigators. 
● 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary. 

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● 
An investigator who receives an investigator safety report describing a SUSAR or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Under this protocol, the following event(s) will not be considered as an (S)AE: 
● 
Disease progression: events that are clearly consistent with the expected pattern of 
progression of the underlying disease are not to be recorded as (S)AEs. 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 up to 30 days after the final 
administration of study drug must be reported as an SAE, even if attributed to disease 
progression.   
7.3.6 
Special Situations  
Certain special situations observed in association with the study drug, such as incorrect 
administration (e.g., wrong dose of study drug or background therapy) are reported as 
protocol deviations and/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. 
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 an SAE, the SAE is to be reported as described in [Section 10.3.6 
Reporting Procedures for Serious Adverse Events] and the details of the associated 
special situation are to be included in the clinical description on the special situation 
worksheet or pregnancy reporting form. 
The special situations are: 
● 
Pregnancy 
● 
Lactation 
● 
Medication error, overdose and use outside protocol 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
(Suspicion of) Transmission of infectious agent  
● 
Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in [Section 10.3.7 
Reporting Procedures for Special Situations].  
7.4 
Pharmacokinetics 
Approximately 12 participants enrolled at the PK cohort site(s) will participate in the PK 
cohort. Additional participants may be enrolled in the PK cohort to compensate for 
participants who become unevaluable for the PK relevant primary endpoint (PK 
evaluable). Blood samples (7 mL/sample) for the analysis of ADC, TAb and MMAE will 
be collected as indicated in the [Table 1 Schedule of Assessments], [Table 2 

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Pharmacokinetic Sample Collection Time Points (PK Cohort)] and [Table 3 Schedule and 
Acceptable Time Range for PK Sampling (Non-PK Cohort)] for the evaluation of 
pharmacokinetics. Blood samples should be collected via a peripherally placed IV 
cannula or by direct venipuncture, which should always be performed on the opposite arm 
of the enfortumab vedotin infusion line. Only in the case where venous access cannot be 
gained from the opposite arm of the study drug infusion line, then the arm of the study 
drug infusion line should be used. In the event that blood cannot be drawn by 
venipuncture, the central line may be used. If blood is collected from central line, use the 
lumen that was not used to administer the study drug. 
Bioanalysis of ADC, TAb and MMAE in serum or plasma will be performed using 
validated methods at bioanalytical laboratories specified by the sponsor. The actual date 
and time of each blood sample collection will be documented. Blood sampling, 
processing, storage and shipment instructions will be provided in the Laboratory Manual. 
Samples will be shipped to and analyzed by a Sponsor designated analytical laboratory.  
7.5 
Immunogenicity Assessments 
Blood samples will be collected during the study treatment period till the EOT visit for 
determination of ATA concentrations [Table 4 Schedule for ATA Sampling]. Blood 
samples (4 mL/sample) will be collected at the time points indicated in [Table 1 Schedule 
of Assessments]. Blood samples should be collected via a peripherally placed IV cannula 
or by direct venipuncture, which should always be performed on the opposite arm of the 
enfortumab vedotin infusion line. Only in the case where venous access cannot be gained 
from the opposite arm of the study drug infusion line, then the arm of the study drug 
infusion line should be used. In the event that blood cannot be drawn by venipuncture, the 
central line may be used. If blood is collected from central line, use the lumen that was 
not used to administer the study drug. Bioanalysis of ATA in serum will be performed 
using validated methods at bioanalytical laboratories specified by the sponsor. 
Blood sampling, processing, storage and shipment instructions will be provided in the 
laboratory manual. Samples will be shipped to and analyzed by a sponsor designated 
analytical laboratory. 
7.6 
Total Amount of Blood 
The total amount of blood for each participant will vary depending on the course of their 
disease, duration on treatment and local laboratory requirements. At any time during the 
study, if any laboratory abnormalities are found for a participant, additional blood may be 
drawn for safety monitoring. 
The maximum amount of blood collected within 24 hours is approximately 70 mL for 
participant in the PK cohort and 40 mL for participant in Non-PK cohort on Cycle 1 
Day 1.  
8 
PARTICIPANT DISCONTINUATION 
Refer to [Section 10.1.9 Study and Site Start and Closure] regarding discontinuation of 
study sites or of the study as a whole.  

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8.1 
Discontinuation of Individual Participant(s) from Study 
Treatment  
A discontinuation from treatment is defined as a participant who enrolled in the study and 
for whom study treatment is permanently discontinued for any reason.  
The participant 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 participant from study treatment or to terminate 
a participant’s involvement in the study at any time if the participant’s clinical condition 
warrants it. 
The reason for discontinuation from study treatment must be documented in the 
participant’s medical records. 
A participant must discontinue study treatment for any of the following reasons: 
● 
Participant requests to stop treatment.  
● 
Investigator decides it is in the participant’s best interest to discontinue. 
● 
Participant develops documented radiological disease progression per RECIST V1.1 
by investigator assessment. 
● 
Participant starts a new anticancer therapy. 
● 
Participant develops unacceptable toxicity. 
● 
Female participant becomes pregnant. 
● 
Participant is noncompliant with the protocol based on the investigator or medical 
monitor assessment. 
● 
Participant did not receive study drug continuously for > 2 cycles (i.e., > 6 
consecutive doses not received). Medical Monitor consultation is required after the 
participant was unable to receive one full cycle of study drug administration. (i.e., 3 
consecutive doses).  Dose delays for participants who are responding to treatment 
may be extended beyond 8 weeks in consultation with medical monitor, if the 
participant’s toxicity does not otherwise require permanent discontinuation. 
8.2 
Discontinuation of Individual Participant(s) from Study 
All participants who discontinue study treatment will remain in the study and must 
continue to be followed for protocol-specific follow-up procedures as outlined in [Table 1 
Schedule of Assessments]. The only exception to this is when the participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized 
by the participant to provide this information. A participant may be discontinued from the 
study for any of the following reasons: 
• 
Lost to follow-up 
• 
Death 
• 
Participant withdrawal of consent 
• 
Participant termination by sponsor  
8.3 
Lost to Follow-up 
Every reasonable effort is to be made to contact any participant lost to follow-up during 
the course of the study to complete study-related assessments, record outstanding data and 

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retrieve study drug. These contact attempts should be documented in the participant’s 
medical record. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The statistical hypothesis is that ORR will be superior to 10% historical control.  
9.2 
Sample Size Determination 
Up to 40 participants will be enrolled to study of which approximately 12 participants will 
be enrolled to the PK cohort. Additional participants may be enrolled in the PK cohort to 
compensate for participants who become unevaluable for the PK relevant primary 
endpoint (PK evaluable). 
The study was designed to estimate the confirmed ORR in participants receiving 
enfortumab vedotin and to detect an improvement in the ORR compared with a historical 
10% response rate which was previously applied in the study EV-201(Cohort 1). The 
Study EV-201 (Cohort 1) was the pivotal study led to the US registration approval for the 
same patient population, of which the primary efficacy outcome was 44% ORR with 95% 
confidence interval (CI) of (35.1%, 53.2%).  
The study sample size was determined to detect the ORR improvement of 25% from 10% 
with sufficient statistical power. The power for various sample size were listed in 
following table: 
Sample Size 
Approximate Power Based on Exact Method to Detect a 25% Increase in ORR from 
10% 
N=30 
87% 
N=35 
95% 
N=40 
97% 
N=50 
99% 
 
Therefore, 35 – 40 sample size will be appropriate to have sufficient statistical power to 
detect the 25% improvement of ORR from 10%.  
Up to 40 participants will be enrolled in this study to ensure collection of sufficient 
efficacy and safety data. Using the estimate of up to 40 participants, the study will have 
over 97% power to detect a 25% increase in ORR from 10% to 35%, at one-sided 
significant level of 0.025, based on exact methods.  
9.3 
Populations for Analyses 
The number and percentage of participants will be characterized for all enrolled 
participants and by each population. 
The following populations are defined: 

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Population 
Description 
Enrolled  
All participants who signed the informed consent form, met the inclusion 
and exclusion criteria, and enrolled into the study. 
Full Analysis Set 
(FAS) 
All participants who are enrolled and receive any amount of study drug 
in the study. The FAS population will be used for primary analysis of 
efficacy endpoints.  
Safety Analysis Set 
All participants who are enrolled and take any amount of study drug. The 
safety analysis set will be used for all safety analyses. 
Pharmacokinetic 
analysis set 
(PKAS) 
All participants in the PK cohort who have received at least 3 of 4 doses 
up through Cycle 2 Day 1, and have at least 5 blood samples collected 
and assayed for measurement of ADC, TAb and MMAE serum/plasma 
concentrations to determine at least 1 PK parameter. Time of sampling 
and the time of dosing on the day of sampling must be known. For non-
PK Cohort, all participants who are administered study drug for which 
concentration data of any analyte is available.  Inclusion of participants 
in the pharmacokinetic analysis set with missing data or major protocol 
deviations will be considered by the pharmacokineticist on a 
case-by-case basis. 
 
9.4 
Statistical Analyses 
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. Changes from the 
planned analyses in the final SAP that impact the statistical analyses will be justified in 
the clinical study report (CSR). 
9.4.1 
General Considerations 
In general, data will be summarized with descriptive statistics for continuous endpoints, 
and frequency and percentage for categorical endpoints, unless otherwise specified. 
Percentages by categories will be based on the number of participants with no missing 
data (i.e., will add up to 100%). 
Baseline will be defined as the last non-missing observation prior to first administration of 
study drug, unless otherwise specified. 
Demographics and baseline characteristics will be summarized overall for all enrolled 
participants. 
The number and percentage of participants who completed and discontinued treatment 
and reasons for treatment discontinuation will be presented for all enrolled participants 
and for participants in the Safety Analysis Set (SAF) overall. Similar tables for 
investigational period disposition and follow-up disposition will also be presented for all 
enrolled participants overall. All disposition details and dates of first and last evaluations 
for each participant will be listed.  
Previous and concomitant treatment and medical history will be listed. Investigational 
product exposure will be summarized by descriptive statistics and will be listed. 

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9.4.2 
Analysis of Efficacy 
9.4.2.1 Analysis of Primary Endpoint  
9.4.2.1.1 
Primary Analysis 
Efficacy analysis will be conducted on the FAS. The interpretation of results from 
statistical tests and the study efficacy conclusion will be based on the FAS. 
The primary efficacy endpoint of this study is the confirmed ORR per IRC. The ORR is 
defined as the proportion of participants with confirmed CR or PR according to RECIST 
V 1.1. Participants who do not have at least 2 (initial response and confirmation scan) 
post-baseline response assessments will be counted as non-responders.  
The primary efficacy analysis will be performed by testing the null hypothesis of ORR 
being less than or equal to 10% against the alternative hypothesis that ORR is greater than 
10% at overall 1-sided 2.5% level of significance. The study will be considered successful 
if the lower bound of the 2-sided 95% exact Clopper-Pearson CI for ORR is greater than 
10%, so that the null hypothesis that the ORR is less than or equal to 10% can be rejected. 
The primary analysis will be done once confirmatory image scan results are available, or 
have discontinued from study, or had 30 days safety follow-up after PD, whichever comes 
first. 
9.4.2.1.2 
Sensitivity Analysis 
Sensitivity may be conducted for selected endpoints as deemed appropriate. Details will 
be specified in the SAP. 
9.4.2.1.3 
Subgroup Analysis 
Subgroup analyses may be conducted for selected endpoints as deemed appropriate. 
Details will be specified in the SAP.  
9.4.2.2 Analysis of Secondary Endpoints  
9.4.2.2.1 
DOR per IRC 
Duration of response per IRC is defined as the time from first documentation of objective 
response (CR or PR that is subsequently confirmed) to the first documentation of PD 
based on IRC assessment or to death due to any cause, whichever comes first. DOR will 
only be calculated for the participants achieving a confirmed CR or PR.  
The median DOR and DOR at 6 and 12 months will be estimated using the Kaplan-Meier 
method and reported along with the corresponding 95% CI. The DOR at 6 and 12 months 
is defined as the proportion of the responders who are still ongoing response after 6 and 
12 months from their first documented response. Details on the definition of censoring 
will be provided in the SAP. This analysis will be conducted using the FAS. 
9.4.2.2.2 
DCR per IRC 
Disease control rate (DCR) per IRC is defined as the proportion of participants whose 
best overall response is a CR, PR or SD according to RECIST V 1.1 based on IRC. 
Responses do not need to be confirmed to be scored as responders for the purpose of 
determining DCR. 
DCR will be summarized for the FAS, and the 2-sided 95% CI will be calculated.  

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9.4.2.2.3 
PFS per IRC 
Progression-free survival (PFS) per IRC is defined as the time from start of study 
treatment to first documentation of objective tumor progression (PD per RECIST V 1.1) 
based on IRC assessment, or to death due to any cause, whichever comes first.  
The median PFS and PFS at 6 and 12 months will be estimated using the Kaplan-Meier 
method and will be reported along with the corresponding 95% CI. Details on the 
definition of censoring will be provided in the SAP. This analysis will be conducted using 
the FAS. 
9.4.2.2.4 
Confirmed ORR per Investigator Assessment 
Confirmed ORR per investigator assessment is defined as the proportion of participants 
with confirmed CR or PR according to RECIST V 1.1 based on investigator’s assessment. 
Participants who do not have at least 2 (initial response and confirmation scan) post-
baseline response assessments will be counted as non-responders. 
Confirmed ORR per investigator will be summarized for the FAS. The exact 2-sided 95% 
CI will be calculated.  
9.4.2.2.5 
DOR per Investigator Assessment 
Duration of response (DOR) per investigator assessment is defined as the time from first 
documentation of objective response (CR or PR that is subsequently confirmed) to the 
first documentation of PD based on investigator assessment or to death due to any cause, 
whichever comes first. DOR will only be calculated for the participants achieving a 
confirmed CR or PR. 
The same analysis as described in [Section 9.4.2.2.1 DOR per IRC] will be conducted 
using the FAS. 
9.4.2.2.6 
DCR per Investigator Assessment 
Disease control rate (DCR) per investigator assessment is defined as the proportion of 
participants whose best overall response is a CR, PR or SD according to RECIST V 1.1 
based on investigator assessment. Responses do not need to be confirmed to be scored as 
responders for the purpose of determining DCR. 
The same analysis as described in [Section 9.4.2.2.2 DCR per IRC] will be conducted 
using the FAS.  
9.4.2.2.7 
PFS per Investigator Assessment  
Progression-free survival (PFS) per investigator assessment is defined as the time from 
start of study treatment to first documentation of objective tumor progression (PD per 
RECIST V 1.1) based on investigator assessment, or to death due to any cause, whichever 
comes first. 
The same analysis as described in [Section 9.4.2.2.3 PFS per IRC] will be conducted 
using the FAS. 
9.4.2.2.8 
Overall Survival 
Overall survival (OS) is defined as the time from start of study treatment to date of death 
due to any cause. 

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The median OS and OS at 6 and 12 months will be estimated using the Kaplan-Meier 
method and will be reported along with the corresponding 95% CI. Details on the 
definition of censoring will be provided in the SAP. This analysis will be conducted using 
the FAS. 
9.4.2.2.9 
Tumor shrinkage 
Best percent change from baseline in sum of diameters in target lesion(s) will be plotted 
as a waterfall plot for the participants with both baseline and at least 1 post-baseline 
measurements. 
9.4.3 
Analysis of Safety 
Safety analysis is secondary endpoint in this study. The SAF will be used for the safety 
analysis.  All participants who are enrolled and received study drug will be included in the 
SAF.  The frequency of AEs and the SAEs will be summarized by MedDRA system 
organ class (SOC) and preferred term.  In addition, summary statistics will be provided 
for the following safety parameters: 
• 
Laboratory values 
• 
Vital sign measurements 
• 
12-lead ECG 
• 
ECOG performance status 
9.4.3.1 Adverse Events  
AEs will be coded using MedDRA.  
An TEAE is defined as an AE observed after starting administration of the study drug and 
up to 30 days after the final administration of study drug. A study drug-related TEAE is 
defined as any TEAE with a causal relationship assessed as “yes” by the investigator. 
The number and percentage of participants with TEAEs, drug-related TEAEs, serious 
TEAEs, drug-related serious TEAEs, TEAEs leading to withdrawal of treatment and 
drug-related TEAEs leading to withdrawal of treatment, TEAEs excluding SAEs will be 
summarized as deemed appropriate.  The number and percentage of TEAEs by severity 
will also be summarized. The worst severity will be summarized if the same AE is 
recorded more than once for a participant.  
AE data will be listed. 
9.4.3.2 Laboratory Assessments  
For quantitative clinical laboratory measurements (hematology, biochemistry and 
urinalysis analysis), descriptive statistics will be used to summarize results and change 
from baseline by visit.  
Laboratory data will be listed. 
9.4.3.3 Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from 
baseline for participants in the SAF by visit and time point.  
Vital signs data will be listed. 

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9.4.3.4 Electrocardiogram 
12-lead ECG data interpretations will be listed. 
9.4.3.5 ECOG Performance Status 
ECOG status will be summarized for each visit. Shifts from baseline to the best and worst 
postbaseline score may be tabulated. 
9.4.3.6 Ophthalmology Examination 
The analysis for ophthalmological assessment will be described in SAP in details. 
9.4.4 
Analysis of Pharmacokinetics 
The Pharmacokinetic analysis set (PKAS) will be used for all summaries and analyses of 
the pharmacokinetic data.  
Descriptive statistics will include n, mean, standard deviation, minimum, median, 
maximum, coefficient of variation (CV), geometric mean and geometric CV. For the 
pharmacokinetic parameter tmax, only n, median, minimum and maximum will be 
calculated. 
9.4.4.1 Pharmacokinetic Concentrations 
Descriptive statistics will be used to summarize plasma or serum concentrations of ADC, 
TAb and MMAE by Cycle, Day and Time Point for the PK and Non-PK Cohorts 
separately.  Standard graphics including mean (standard deviation) plasma or serum 
concentration-time profiles (linear and semi-logarithmic scales) and overlay (spaghetti) 
plots will be produced for each analyte. 
9.4.4.2 Estimation of Pharmacokinetic Parameters 
Noncompartmental analysis will be used for the calculation of plasma and serum 
pharmacokinetic parameters using Phoenix WinNonlin software version 6.3 or higher 
(Certara LP, 100 Overlook Center, Suite 101, Princeton, NJ 08540, US).  
Participants in the PK cohort who are also part of PKAS will have pharmacokinetic 
parameter estimates for each of the 3 analytes (ADC, TAb and MMAE), the following PK 
parameters will be calculated if data permit: 
• Cmax after first dose and third dose 
• Ctrough after first dose and third dose.  
• Tmax after first dose and third dose  
• AUC0-7d after first dose and third dose  
• AUC0-28d in Cycle 1 
• Rac(Cmax) 
• Rac(AUC0-7d) 
• t1/2 as appropriate 
• CL and Vss as appropriate 

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Descriptive statistics will be used to summarize plasma or serum pharmacokinetic 
parameters of ADC, TAb and MMAE separately. 
9.4.5 
Analysis of Pharmacodynamics | Immunogenicity 
ATA to ADC will be listed, number and percentage of participants with positive ATA 
will be summarized. 
9.4.6 
Other Analyses 
Not applicable. 
9.5 
Interim Analysis  
No formal interim analysis is planned. 
9.6 
Additional Conventions 
As a general principle, no imputation of missing data will be done. Exceptions are the 
start and stop dates of AEs and concomitant medications, the detailed imputation rules 
will be specified in the SAP. The imputed dates will be used to assess if the AEs or 
concomitant medications are treatment emergent or concomitant, respectively. Listings of 
the AEs and concomitant medications will present the actual partial dates; imputed dates 
will not be shown.   
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Ethical, Regulatory and Study Oversight 
Considerations 
10.1.1 Regulatory and Ethical Considerations 
● 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
● 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
● 
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
● 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 

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536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3 Informed Consent of Participants 
10.1.3.1 Informed Consent Process 
● 
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
● 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center. 
● 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
● 
A copy of the ICF(s) must be provided to the participant. 
10.1.3.2 Supply of New and Important Information Influencing the Participant’s 
Consent and Revision of the Written Information 
● 
The investigator or his/her representative will immediately inform the participant 
verbally whenever new information becomes available that may be relevant to the 
participant’s consent or may influence the participant’s willingness to continue 
participating in the study (e.g., report of serious adverse drug reaction). The 
communication must be documented in the participant’s medical records and whether 
the participant is willing to remain in the study or not must be confirmed and 
documented.  
● 
The investigator must update the participant’s ICF and submit it for approval to the 
IRB/IEC. The investigator or his/her representative must obtain written informed 
consent from the participant on all updated ICFs throughout their participation in the 
study. The investigator or his/her designee must reconsent participants with the 
updated ICF even if relevant information was provided verbally. The investigator or 
his/her representative who obtained the written informed consent and the participant 
should sign and date the ICF. A copy of the signed ICF will be given to the 
participant and the original will be placed in the participant’s medical record. An 
entry must be made in the participant’s records documenting the reconsent process. 

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10.1.4 Data Protection 
Individual participant medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the participant provides 
written consent or approval. Additional medical information may be given only after 
approval of the participant to the investigator or to other appropriate medical personnel 
responsible for the participant's well-being. 
The sponsor shall not disclose any confidential information on participants obtained 
during the performance of their duties in the 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 a participant’s privacy due to direct access to 
source documents, or from other sources, they may not disclose the content to third 
parties.  
The sponsor affirms the participant's right to protection against invasion of privacy. Only 
a participant identification number will identify participant 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 the sponsor shall serve as 
the controller of such data, as defined by the EU Data Protection Directive (DPD), and 
investigator and/or third party shall act only under the instructions of the sponsor in 
regard to personal data. If the sponsor is not based in the EEA, the 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 DPD. 
10.1.5 Committee(s) Structure 
Sponsor will provide the imaging IRC charter including the organization, responsibility 
and procedure as an independent document before site initiation.  
10.1.6 Dissemination of Clinical Study Data 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final CSR 
that 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 the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database lock. 
10.1.7 Data Quality Assurance 
● 
All participant data relating to the study will be recorded on the eCRF unless 
transmitted to the sponsor or designee electronically in an external data file (e.g., 

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central laboratory data). The investigator is responsible for verifying that data entries 
on the eCRF are accurate and correct by physically or electronically signing the 
eCRF. 
● 
Guidance on completion of CRFs will be provided in a separate eCRF Completion 
Guideline. 
● 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
● 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
● 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations [CROs]). 
● 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator according to ICH or applicable local 
regulatory requirements, whichever is longer, after study completion. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the sponsor. 
10.1.8 Source Documents 
1. Source data must be available at the study site to document the existence of the 
participants 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 participant.  
2. The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
3. The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten 
on paper or entered electronically. If source data are created (first entered), modified, 
maintained, achieved, retrieved or transmitted electronically via computerized 
systems (and/or other kind of electronic devices) as part of regulated study activities, 
such systems must be compliant with all applicable laws and regulations governing 
use of electronic records and/or electronic signatures. Such systems may include, but 
are not limited to, electronic medical/health records, protocol-related assessments, 
AE tracking, electronic clinical outcome assessment (eCOA) and/or drug 
accountability.  
4. Paper records from electronic systems used in place of electronic format must be 
certified copies. A certified copy must be an exact copy and must have all the same 
attributes and information as the original. Certified copies must include signature and 
date of the individual completing the certification. Certified copies must be a 
complete and chronological set of study records (including notes, attachments, and 

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audit trail information, if applicable). All printed records must be kept in the 
participant file and be available for archiving.  
5. Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.9 Study and Site Start and Closure 
The study start date is the date the first participant signs the ICF for the study. 
The sponsor or designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study test product development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor or designee shall 
promptly inform the Investigators, the IECs/IRBs, the regulatory authorities, and any 
CRO(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.10 Arrangement for Use of Information and Publication of the Study 
Information concerning the test product, 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 study in connection with the 
development of the product 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 

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derived from this study, the investigator understands that he/she has an obligation to 
provide the sponsor with all data obtained during the study. 
Publication of the study results is discussed in the study agreement. 
10.1.11 Quality Assurance 
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) 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 QA and QC systems and 
written SOPs of the CRO will be applied. 
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites 
and facilities. The audit may include on-site review of regulatory documents, CRFs and 
source documents. Direct access to these documents will be required by the auditors. 
To support quality around participant safety and reliability of study results, quality 
tolerance limits (QTLs) are defined and monitored. QTLs represent the acceptable 
variation of study data, taking into consideration the current state of medical and 
statistical knowledge about the variables to be analyzed, as well as the statistical design of 
the study. It is a level, point, or value associated with a parameter that should trigger an 
evaluation if a deviation is detected to determine if there is a possible systematic issue 
(i.e., a trend has occurred). The QTLs defined for this study are provided below. 
Table 9 
Quality Tolerance Limits 
QTL #: Name and 
Parameter 
Definition 
Parameter Justification 
QTL1: Eligibility  
Proportion % of enrolled participants 
who do not meet critical inclusion/ 
exclusion criteria 
A high number of participants 
not meeting the entrance 
criteria can have a negative 
impact on interpretation of the 
primary endpoint and overall 
validity of the study results. 
QTL2: Tumor Scan 
Compliance  
 
Proportion (%) of enrolled 
participants who do not have all 
imaging scans collected per study 
protocol requirements. 
 
A high number of participants 
with missing tumor imaging 
data can have a negative impact 
on interpretation of the primary 
endpoint and overall validity of 
the study results. 
QTL3: Safety Data 
 
Proportion (%) of enrolled 
participants with outliers or trends in 
AE reporting rates. 
Possible over or under 
reporting of safety information 
can impact subject safety. 
QTL4: Pharmacokinetic Data 
Proportion (%) of enrolled 
participants with missing data in 
actual sampling times or dosing, 
major protocol deviations, or dose 
adjustment. 
A high number of participants 
with missing PK data/dose 
adjustment can have a negative 
impact on interpretation of the 
primary endpoint and overall 
study validity.  
AE: adverse event; QTL: quality tolerance limit. 
 

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QTL Management Activities: 
For control of risks associated with QTL 1: Eligibility, refer to [Section 5 Study 
Population, Section 7.1 Efficacy Assessments and Study Monitoring Plan].  
For control of risks associated with QTL2 Tumor Scan Compliance, refer to [Section 7.1 
Efficacy Assessments and Study Monitoring Plan]. 
For control of risks associated with QTL3 Safety Data, refer to [Section 7.2 Safety 
Assessments, Section 7.3 Adverse Events and Other Safety Aspects, Section 10.3 
Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting, and Study Monitoring Plan]. 
For control of risks associated with QTL4 Pharmacokinetic Data, refer to [Section 7.4 
Pharmacokinetics and Study Monitoring Plan]. 
10.2 
Appendix 2: Contraception Requirements 
WOCBP who are eligible for participation in the study, including those who choose 
complete abstinence, must have pregnancy tests as specified in the schedule of 
assessments. Pregnancy test results must confirm that the participant is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS 
OF CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.  
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with one of the following (i.e., permanently sterile): 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
● 
Postmenopausal 
A postmenopausal state is defined as at least 12 months after last menstrual bleeding 
without an alternative medical cause.  
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than one follicle-stimulating hormone (FSH) measurement of at least > 40 IU/L (or higher 
per local institutional guidelines) is required.  
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the nonestrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status by repeated 
FSH measurements before study enrollment. 
Documentation of any of these categories can come from the study site personnel’s 
review of the female participant’s medical records, medical examination or medical 
history interview. 

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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF 
CHILDBEARING POTENTIAL 
Female participants of childbearing potential are eligible for participation in the study if 
they agree to use a condom plus one of the highly effective methods of contraception 
listed below from the time of signing the ICF and until the end of relevant systemic 
exposure, defined as 6 months after the final study drug administration.a 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b: 
● 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o Oral 
o Intravaginal 
o Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral 
o Injectable 
o Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
o Vaginal ring 
o Injectable 
o Implantable 
o Intrauterine hormone-releasing system or intrauterine device 
o Bilateral tubal occlusion 
Male is sterile due to a bilateral orchiectomy or radical cystoprostatectomy/removal of 
seminal vesicles 
● 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used. 
● 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the test product. 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. It is not necessary to use any other method of contraception when 
complete abstinence is elected. 
a Local laws and regulations may require use of alternative and/or additional 
contraception methods. 
b Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants participating in clinical studies. 

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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH 
PARTNER(S) OF CHILDBEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible for 
participation in the study if they agree to the following during treatment and until the end 
of relevant systemic exposure defined as 6 months after final study drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the 
need to comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male participants who have not undergone a vasectomy with the 
absence of sperm confirmed or a bilateral orchiectomy should require use of one 
form of highly effective methods of contraception 
a Local laws and regulations may require use of alternative and/or additional 
contraception methods. 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
10.3.1 Definition of Adverse Events 
AE Definition: 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study drug, whether or not considered related to the 
study IP. 
“Adverse event” means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
NOTE: 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 study IP. This includes events related to the comparator and 
events related to the (study) procedures. 
Events Meeting the AE Definition 
● 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
● 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
● 
New conditions detected or diagnosed after study IP administration even though it 
may have been present before the start of the study. 
Events NOT Meeting the AE Definition 
● 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 

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● 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
● 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
● 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
● 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, biochemistry) or other safety 
assessment (e.g., vital signs, physical examination, ECGs or radiographic scans), 
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 
participant’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. 
10.3.1.2 Potential Cases of Drug-induced Liver Injury (DILI) 
Refer to [Section 10.4 Appendix 4: Liver Safety Monitoring and Assessment] for detailed 
instructions on drug induced liver injury. Abnormal values in AST and/or ALT concurrent 
or with abnormal elevations in TBL that meet the criteria outlined in [Section 10.4 
Appendix 4: Liver Safety Monitoring and Assessment], in the absence of other causes of 
liver injury, are considered potential cases of drug-induced Liver Injury (DILI) (potential 
Hy’s Law cases) and are always to be considered important medical events and reported 
per [Section 10.3.6 Reporting Procedures for Serious Adverse Events]. 
10.3.2 Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose: 
● 
Results in death 
● 
Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o 
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 

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hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
o 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
● 
Results in persistent or significant disability/incapacity 
o 
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
o 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle), which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
● 
Is a congenital anomaly/birth defect 
● 
Other situations: 
o 
Medical or scientific judgment should be exercised in deciding whether SAE 
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 participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
o 
Examples of such events include invasive or malignant cancers, 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. 
If an event is not an AE per definition in Section 10.3.1, then it cannot be an SAE even if 
serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under 
study, death due to progression of disease). 
10.3.3 Assessment of Causality 
● 
The investigator is obligated to assess the relationship between study IP and each 
occurrence of each AE/SAE. 
● 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
● 
The investigator will use clinical judgment to determine the relationship. 
● 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study IP administration 
will be considered and investigated. 
● 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
● 
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. 

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● 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
● 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?” 
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 IP (rather than a relationship 
cannot be ruled out) or if there is evidence to reasonably deny a causal relationship: 
● 
Has the participant been administered IP?  
● 
Plausibility (i.e., could the event been caused by the suspect IP? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, 
preclinical and study data, etc.) 
● 
Dechallenge/dose reduction/rechallenge:  
o Dechallenge: Did the (S)AE resolve or improve after only stopping the dose of 
the suspect drug without any treatment? 
o Dose reduction: Did the (S)AE resolve or improve after reducing the dose of the 
suspect drug? 
o Rechallenge: 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 IP (e.g., based on values pre-, during 
and post-treatment) 
● 
Available alternative explanations independent of IP 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  
● 
Temporal relationship between exposure to the IP and (S)AE onset and/or resolution. 
Did the (S)AE occur in a reasonable temporal relationship to the administration of the 
IP?  
● 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
will be provided.  
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. While it is very important that 
the investigator always assesses causality for every event before the initial transmission of 
the SAE data to the sponsor, the initial report should be submitted without delay (i.e., 
within 24 hours of awareness). With limited or insufficient information about the event to 
make an informed medical 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. 

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The medically qualified 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.  
10.3.4 Assessment of Severity  
AEs, including abnormal clinical laboratory values, will be graded using the National 
Cancer Institute-common terminology criteria for adverse event (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: 
Table 10 
Grading Scale Defining the Severity of an Adverse Event 
Grade 
Assessment Standard 
1 - Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
2 - Moderate 
Minimal local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL† 
3 - Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization indicated; disabling; limiting self-care ADL‡ 
4 - Life-threatening 
Life threatening consequences, urgent intervention indicated 
5 - Death 
Death related to AE 
ADL: activities of daily living; AE: adverse event 
†Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
‡Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications 
and not bedridden. 
10.3.5 Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the eCRF. 
• There may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Follow-Up of AEs and SAEs 
● 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 

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● 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post mortem 
findings including histopathology. 
● 
New or updated information will be recorded in the originally completed eCRF. 
● 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.3.6 Reporting Procedures for Serious Adverse Events 
The investigator must complete and submit an SAE worksheet containing all information 
that is required by local and/or regional regulations to the sponsor by fax or email 
immediately (within 24 hours of awareness).  
The investigator must complete and submit the reports as required by local regulation, 
containing all necessary information, to the competent authority. 
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log). Signature confirms accuracy and completeness of the SAE 
data, as well as the investigator causality assessment including the explanation for the 
causality assessment. 
For contact details, see [Contact Details of Sponsor's Key Personnel]. Fax or email the 
SAE/special situations/product defect worksheet to: 
Astellas Pharma Global Development Inc. 
Pharmacovigilance  
International Fax: +44-800-471-5263 
Alternative fax number: +1-888-396-3750 
Email: safety-us@astellas.com* 
*Please use email in general. 
If there are any questions, or if clarification is needed regarding the SAE, please contact 
the sponsor’s medical monitor/study physician or their designee [Contact Details of 
Sponsor’s Key Personnel].  
Follow-up information for the event should be sent promptly (as soon as available but no 
longer than 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 eCRF. 
The following minimum information is required: 
● 
International study number/study number  
● 
Participant number, sex and age 
● 
Date of report 
● 
Description of the SAE (event and seriousness criteria)  
● 
Causal relationship to the IP (including reason) 
● 
Drug provided (if any) 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 

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regulatory requirements. The sponsor or sponsor's designee will submit expedited safety 
reports to competent authorities and concerned ethics committee 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/IEC within timelines set 
by regional regulations where required. Documentation of the submission to and receipt 
by the IRB/IEC of expedited safety reports should be retained by the study site.  
The sponsor will notify all investigators responsible for ongoing clinical studies with the 
test product of all SUSARs and all SAE line listings, which require submission per local 
requirements IRB/IEC. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the participant. 
10.3.7 Reporting Procedures for Special Situations 
10.3.7.1 Contraceptive Guidance and Collection of Pregnancy Information 
If a female participant 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 10.3.6 Reporting Procedures for Serious 
Adverse Events] using the SAE worksheet as a special situation and in the eCRF.  
The investigator will attempt to collect pregnancy information on any female partner of a 
male participant 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 10.3.6 Reporting Procedures for Serious Adverse 
Events] using the special situation worksheet or pregnancy 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 participant as an AE in the eCRF or SAE per [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events]. Participant pregnancy outcomes listed below are 
to be reported as SAEs: 
● 
Spontaneous abortion/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 IP. 
● 
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator. 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
● 
Benign hydatidiform mole 
● 
Blighted ovum 

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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 or 
other means as appropriate. (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. 
10.3.7.2 Lack of Efficacy  
Not Applicable. 
10.3.7.3 Medication Error, Overdose and “Off-label Use” 
If a medication error (defined as an unintended failure in the treatment process that leads 
to, or has the potential to lead to, harm to the participant), overdose or “off-label use” 
(i.e., use outside of the target disease defined in the protocol) is suspected, refer to 
[Section 6.7 Treatment of Overdose]. Any associated (S)AEs are to be reported in the 
eCRF. If the AE meets the definition of an SAE, the SAE is also to be reported as 
described in [Section 10.3.6 Reporting Procedures for Serious Adverse Events] together 
with the details of the medication error, overdose and/or “off-label use.” 
10.3.7.4 Misuse/Abuse 
Definition of misuse: Situations where the IP is/are intentionally and inappropriately used 
not in accordance with the intended use as defined in the protocol. 
Definition of abuse: Persistent or sporadic, intentional excessive use of medicinal 
products which is accompanied by harmful physical or psychological effects. 
If misuse or abuse of the IP 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 an SAE, the SAE is also to be reported as described in [Section 10.3.6 
Reporting Procedures for Serious Adverse Events] together with details of the misuse or 
abuse of the IP. 
10.3.7.5 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the participant) to the IP 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. 
10.3.7.6 (Suspicion of) Transmission of Infectious Agent  
If transmission of an infectious agent associated with the IP is suspected, the investigator 
must forward the special situation worksheet to the sponsor by fax or email immediately 
(within 24 hours of awareness) and any associated (S)AEs are to be reported in the eCRF. 
If the AE meets the definition of an SAE, the SAE is also to be reported as described in 
[Section 10.3.6 Reporting Procedures for Serious Adverse Events] together with the 
details of the suspected transmission of infectious agent.  

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10.3.7.7 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP 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 an SAE, the SAE is also to be reported as described in 
[Section 10.3.6 Reporting Procedures for Serious Adverse Events] together with details of 
the suspected drug-drug interaction. 
10.3.8 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the study 
properly, the sponsor will inform all investigators involved in the study as well as the 
appropriate regulatory authorities. Investigators should inform the IRB/IEC of such 
information when needed.  
The investigator will also inform the participants, who will be required to sign an updated 
ICF in order to continue in the study. 
10.3.9 Urgent Safety Measures 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities (CA), IRB/IEC, where applicable, in order to 
protect participants from any immediate hazard to their health and/or safety. Either the 
investigator or the sponsor can initiate a USM. The cause of a USM can be safety-, 
product- or procedure-related.   
10.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness). Full details of the potential USM are to be recorded in the 
participant’s medical records. The sponsor may request additional information related to 
the event to support their evaluation.  
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure 
the safety and welfare of the participants. These actions may include but are not limited to 
a change in study procedures or study treatment, halting further enrollment in the study, 
or stopping the study in its entirety. The sponsor or sponsor's designee will notify the 
relevant competent authorities and concerned ethics committee within the timelines 
required per current local regulations, and will inform the investigators, as required. When 
required, investigators must notify their IRB/IEC within timelines set by regional 
regulations.  
10.4 
Appendix 4: Liver Safety Monitoring and Assessment  
The purpose of this appendix is to provide guidance for the monitoring of DILI during the 
course of the study. It should be noted that this section does not specify the end-of-study 
analyses of liver enzymes. The end-of-study liver enzymes analyses will be described in the 
SAP. Any participant enrolled in a study with active drug therapy and who reveals an 
increase of serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in participants with 
liver metastases) or TBL> 2 × ULN should undergo detailed testing for liver enzymes 
(including at least ALP, ALT, AST and TBL). Testing should be repeated within 72 hours of 

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notification of the test results. Participants 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 is as 
shown below. 
Table 11 
Moderate and Severe Liver Abnormalities  
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN (in participants without liver metastases), > 
5 × ULN (in participants with liver metastases) 
or 
> 2 × ULN 
Severe 
> 3 × ULN 
and† 
> 2 × ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal 
†Samples taken simultaneously or within maximum 24 hours. 
In addition, the participant 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† TBL > 2 × ULN or international normalized ratio 
(INR) > 1.5 (If INR testing is applicable/evaluated) 
● 
ALT or AST > 5 × ULN and† (TBL > 2 × ULN in participants 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%)  
† Samples taken simultaneously or within a maximum of 24 hours.  
The investigator may determine that abnormal liver function results, other than those 
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 clinical laboratory tests. The study site personnel are to complete 
the liver abnormality case report form (LA-CRF). Participants with confirmed abnormal 
liver function testing should be followed as described below.   
Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
participant is asymptomatic.  
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 an SAE. 
The sponsor should be contacted and informed of all participants for whom severe hepatic 
liver function abnormalities possibly attributable to IP are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 

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● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
Symptoms and new-onset diseases are to be recorded as AEs in the eCRF. 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 participants 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, are to be entered in the eCRF. 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 participant’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 clinical 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 Treatment Discontinuation 
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
preexisting or acute liver disease, presence of liver metastases, or exposure to other agents 
associated with liver injury, the participant may be discontinued from study treatment. 
The investigator may determine that it is not in the participant’s best interest to continue 
study treatment. Discontinuation of study treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in participants 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 participants 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%) 
† Samples taken simultaneously or within a maximum of 24 hours. 
In addition, if close monitoring for a participant with moderate or severe hepatic 
laboratory tests is not possible, study treatment should be discontinued. 
Hy’s Law Definition:  
• Evidence that a drug can cause hepatocellular-type injury, generally shown by a 
higher rate than control of people with 3 × AT elevations over the ULN (2 × 
elevations are too common in treated and untreated participants to be discriminating). 
• Cases of increased bilirubin (to at least 2 × ULN) in people with concomitant AT 
elevation to at least 3 × ULN (but it is almost invariably higher) and no evidence of 

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intra-or extra-hepatic bilirubin obstruction (elevated ALP) or Gilbert’s syndrome 
[Temple, 2006]. 
FDA Guidance for Industry titled “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
FDA Guidance for Industry: 
• 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.  
• Among participants showing such AT elevations, often with AT levels 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). 
• 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. 
 
 

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10.5 
Appendix 5: List of Excluded 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. Refer to Section 6.8 for concomitant therapies. 
P-gp Inhibitors 
Strong 
CYP3A 
Inhibitors 
Strong 
CYP3A4 
Inducers 
Strong 
CYP2C8 
Inhibitors 
Strong 
CYP2C8 
Inducers 
amiodarone 
boceprevir 
carbamazepine 
clopidogrel 
rifampin 
carvedilol 
cobicistat 
enzalutamide 
gemfibrozil 
clarithromycin 
conivaptan 
mitotane 
drenedarone 
danoprevir/ 
phenytoin 
itraconazole 
ritonavir 
rifampin 
lapatinib 
elvitegravir/ 
St John’s wort 
lopinavir/ritonavir 
ritonavir 
propafenone 
grapefruit juice 
quinidine 
indinavir/ ritonavir 
ranolazine 
itraconazole 
saquinavir/ritonavir 
ketoconazole 
telaprevir 
lopinavir/ritonavir 
tipranavir/ritonavir 
paritaprevir/ 
verapamil 
ritonavir/ 
(ombitasvir and/or 
dasabuvir) 
posaconazole 
ritonavir 
saquinavir/ 
ritonavir 
telaprevir 
tipranavir/ritonavir 
troleandomycin 
voriconazole 
Note: Any additional strong inhibitors/inducers of CYP3A, CYP2C8, and p-glycoprotein (P-gp) inhibitors 
that are identified or become commercially available while the clinical trial in ongoing are also applicable.  
P-gp: p-glycoprotein 
 
 

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10.6 
Appendix 6: Clinical Laboratory Assessments 
Laboratory tests will be performed according to the schedule of assessments. Except for 
PK and PD related testing, all the other laboratory tests will be sent to a local laboratory 
for analysis.  
Table 12 
Clinical Laboratory Tests 
Panel/Assessments 
Parameters to be Analyzed 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count 
White blood cell count differential 
Biochemistry 
Albumin  
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Hemoglobin A1c (HbA1c, screening and EOT only) 
High density lipoprotein (HDL) (Screening only) 
Glucosea 
Lactate dehydrogenase 
Low-density lipoprotein (LDL) (Screening only) 
Magnesium 
Phosphate 
Potassium 
Serum HCG for female participants 
Sodium  
Total and direct bilirubin  
Total cholesterol (Screening only) 
Total protein 
Triglyceride (Screening only) 
Urinalysis 
Specific gravity  
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic (epithelial cells, bacteria, casts, crystals, WBC 
and RBC) 
Serology 
Hepatitis B and C at screening 
EOT: end of treatment; HbA1c: hemoglobin A1c; HCG: human chorionic gonadotropin  
a. Glucose at screening and on Cycle 1 Day 8 are required to be tested in fasting status in order to ensure 
accurate interpretation of glucose values. Fasting is not necessary for biochemistry laboratory tests 
performed at all other visits.  

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10.7 
Appendix 7: ECOG Performance Status Scale 
 
*Reference 
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(6):649 
55. 
10.8 
Appendix 8: RECIST Version 1.1 
 

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Response Evaluation Criteria in Solid Tumors 
Term 
Definition 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to <10 mm. 
Partial response (PR) 
A ≥30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of 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 0.5 cm. The 
appearance of one or more new lesions is also considered progression. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Measurable lesion 
Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of 10 mm 
by CT scan (CT slice thickness no greater than 5 mm). 
A lymph node must be ≥15 mm in short axis when assessed by CT scan to be 
considered measurable. 
From RECIST Version 1.1 (Eisenhauer 2009) 
 
A response (CR or PR) will be considered confirmed if the following disease assessment 
(at least 4 weeks after the initial response) still shows response (CR or PR). In cases 
where the initial response is followed by SD, it will be considered as confirmed if the SD 
is later followed by PR or CR. For example, if a participant had PR in Week 8, SD in 
Week 12, and PR in Week 16, this PR will be considered as confirmed.  
 
 

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10.9 
Appendix 9: Scanning and Contrast Guidelines 
In decreasing order of preference 
 
Brain Scan 
Brain MRI with gadolinium 
If gadolinium is medically contraindicated: 
Brain MRI without gadolinium 
Brain CT with IV contrast 
Brain CT without IV contrast 
 
 
Chest-Abdomen-Pelvis Scans: 
Chest-Abdomen-Pelvis CT with IV contrast 
If iodine media is medically contraindicated: 
Chest CT without IV contrast and Abdomen-Pelvis MRI with gadolinium 
Chest-Abdomen-Pelvis CT without IV contrast (oral contrast is recommended) 
Chest-Abdomen-Pelvis MRI with gadolinium 
 
 
CT Oral Contrast 
Radio opaque agents (e.g., iodine and barium based agents) 
Radio-lucent agents (whole milk, VoLumen®, water) 
 
 
Important: Imaging modality, anatomical coverage and acquisition parameters 
should remain consistent across all imaging visits for each patient. 
 
 

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10.10 List of Abbreviations and Definition of Key Study Terms 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
1L 
first-line 
2L 
second-line 
ADC 
antibody-drug conjugate 
ADL 
activities of daily living 
AE 
adverse event 
AEOI 
AE of interest 
AKI 
acute kidney injury  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count  
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
AUC 
area under the concentration-time curve 
AUC4d 
area under the concentration-time curve from time 0 to 4 days 
AUC7d 
area under the concentration-time curve from time 0 to 7 days 
BCVA 
best corrected visual acuity 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CA  
competent authority 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CIOMS  
council for international organizations of medical sciences 
Cmax 
maximum concentration 
CNS 
central nervous system 
CrCl 
creatinine clearance 
CR 
complete response 
CRF 
case report form 
CRL 
Charles River Laboratories 
CRM 
continual reassessment method 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
Ctrough 
trough concentration 
CV  
coefficient of variation 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DOR 
duration of response 

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Abbreviations 
Description of abbreviations 
DPD 
Data Protection Directive 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EEA 
European Economic Area 
EOM 
extra ocular movement 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase  
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 
HbA1c  
hemoglobin A1c 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein cholesterol 
HRT 
hormone replacement therapy 
ICD 
immunogenic cell death 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IOP 
inter ocular pressure 
IRC 
independent review committee 
IRR 
infusion related reaction 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISN 
international study number 
LA 
locally advanced 
LA-CRF 
liver abnormality case report form 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
IV 
intravenous 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 

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Abbreviations 
Description of abbreviations 
MTD 
maximum tolerated dose 
mUC 
metastatic urothelial cancer 
NCI-CTCAE 
National Cancer Institute-common terminology criteria for adverse event 
NMPA 
National Medical Products Administration  
NOAEL 
no observed adverse effect level 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein  
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival 
PK 
Pharmacokinetic(s) 
PKAS 
pharmacokinetic analysis set 
PR 
partial response 
QA 
quality assurance 
QC 
quality control 
QTL 
quality tolerance limit 
Rac(AUC) 
accumulation ratio calculated using AUC 
Rac(Cmax) 
accumulation ratio calculated using Cmax 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumor (new guidelines to evaluate the 
response to treatment in solid tumors) 
RP2D  
Recommended Phase 2 Dose 
(S)AE 
serious adverse event or adverse event 
SAE 
serious adverse event 
SAF  
safety analysis set 
SAP 
statistical analysis plan 
SD 
stable disease 
SJS 
Stevens-Johnson Syndrome 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal elimination half-life 
TAb 
total antibody 
TEAE 
treatment-emergent adverse event 
TBL 
total bilirubin 
TEN 
toxic epidermal necrolysis 
tmax 
time of maximum concentration  

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Abbreviations 
Description of abbreviations 
ULN 
upper limit of normal 
UC 
urothelial cancer 
US 
United States 
USM 
urgent safety measure 
VA 
visual acuity 
Vss 
volume of distribution at steady state 
WOCBP 
woman of childbearing potential 

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Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline  
Assessments of participants as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Note: Not all endpoints are themselves assessments since certain 
endpoints might apply to populations or emerge from analysis of results. 
That is, endpoints might be facts about assessments (e.g., prolongation of 
survival). 
Enroll 
To register or enter a participant into a study. Note: Once a participant 
has received the study drug or placebo, the protocol applies to the 
participant.  
Investigational 
Product 
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics).  
Post 
investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening 
A process of active consideration of potential participants for enrollment 
in a study. 
Screen failure 
Potential participant who signed the ICF, but did not meet one or more 
criteria required for participation in the study and was not enrolled. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a participant signs the consent form until just before the test 
product or comparative drug (sometimes without randomization) is given 
to a participant.  
Study period 
Period of time from the first study site initiation date to the last study site 
completing the study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can 
have different qualitative or quantitative values. 

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11 
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SPONSOR SIGNATURE