An Open-label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202)
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Malignant Solid Tumors
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 1 of 160 
Amendment 6 
An Open-label, Multicenter, Multicohort, Phase 2 Study to 
Evaluate Enfortumab Vedotin in Subjects with Locally Advanced 
or Metastatic Malignant Solid Tumors 
(EV-202) 
 
 
ISN/Protocol 7465-CL-202 
Amendment 6 [Nonsubstantial] 
05 Feb 2024 
 
 
IND 116360 
 
 
 
Sponsor: 
Astellas Pharma Global Development Inc. 
Northbrook, IL 60062, US 
 
 
Protocol History: 
Version 1.0 [25 Nov 2019] 
Amendment 1 [17 Feb 2021] 
Amendment 2 [21 Oct 2021] 
Amendment 3 [31 Mar 2022] 
Amendment 4 [14 Feb 2023] 
Amendment 5 [13 Apr 2023] 
 
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 subject; 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. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 2 of 160 
Amendment 6 
Table of Contents 
SIGNATURES ································································································· 9 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ······································ 11 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ········································ 12 
1 
PROTOCOL SUMMARY ········································································ 15 
1.1 
Synopsis ························································································· 15 
1.2 
Study Schema ··················································································· 24 
1.3 
Schedules of Assessments ···································································· 26 
1.3.1 
Sample Collection Schedule ···························································· 33 
2 
INTRODUCTION ·················································································· 35 
2.1 
Background ····················································································· 36 
2.1.1 
Breast Cancer ············································································· 36 
2.1.1.1 
Hormone Receptor Positive, Human Epidermal Growth Factor 
Receptor 2 Negative Breast Cancer ·············································· 36 
2.1.1.2 
Triple Negative Breast Cancer ···················································· 37 
2.1.2 
Non-small Cell Lung Cancer ··························································· 37 
2.1.2.1 
Squamous Non-small Cell Lung Cancer ········································ 38 
2.1.2.2 
Non-squamous Non-small Cell Lung Cancer ··································· 38 
2.1.3 
Head and Neck Cancer ·································································· 38 
2.1.4 
Gastric, Gastroesophageal Junction and Esophageal Cancer ······················· 40 
2.2 
Enfortumab Vedotin ··········································································· 41 
2.2.1 
Nonclinical and Clinical Data ·························································· 42 
2.2.1.1 
Pharmacology ······································································· 42 
2.2.1.2 
Toxicology ··········································································· 43 
2.2.1.3 
Clinical Data ········································································ 43 
2.2.2 
Summary of Key Safety Information for Enfortumab Vedotin ···················· 46 
2.3 
Pembrolizumab ················································································· 46 
2.3.1 
Pharmaceutical and Therapeutic Background ········································ 46 
2.4 
Study Rationale ················································································· 48 
2.4.1 
Rationale for Cohort 9 – Enfortumab Vedotin and Pembrolizumab in 
Combination··············································································· 49 
2.5 
Risk/Benefit Assessment ······································································ 50 
2.5.1 
Risk/Benefit Assessment for Combination of Enfortumab Vedotin and 
Pembrolizumab ··········································································· 51 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 3 of 160 
Amendment 6 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ·············································· 54 
4 
STUDY DESIGN AND DOSE RATIONALE ················································ 56 
4.1 
Study Design ···················································································· 56 
4.2 
Dose Rationale ·················································································· 58 
4.2.1 
Enfortumab Vedotin ····································································· 58 
4.2.2 
Pembrolizumab ··········································································· 59 
4.3 
End of Study Definition ······································································· 61 
5 
STUDY POPULATION ··········································································· 61 
5.1 
Inclusion Criteria ··············································································· 61 
5.2 
Exclusion Criteria ·············································································· 67 
5.3 
Restrictions During the Study ································································ 69 
5.4 
Screen Failures ················································································· 69 
5.4.1 
Rescreening ··············································································· 69 
6 
INVESTIGATIONAL PRODUCT(S) ·························································· 70 
6.1 
Investigational Product(s) Administered ···················································· 70 
6.1.1 
Enfortumab Vedotin ····································································· 70 
6.1.1.1 
Dosing and Administration of Enfortumab Vedotin ··························· 70 
6.1.2 
Pembrolizumab (Cohort 9 Only) ······················································· 71 
6.2 
Preparation/Handling/Storage/Accountability ············································· 71 
6.2.1 
Packaging and Labeling ································································· 71 
6.2.2 
Handling, Storage and Accountability ················································· 71 
6.3 
Randomization and Blinding ································································· 72 
6.4 
Investigational Product Compliance ························································· 72 
6.5 
Previous and Concomitant Treatment (Medication and Nonmedication Therapy) ··· 72 
6.6 
Dose Modification ············································································· 73 
6.6.1 
Enfortumab Vedotin ····································································· 73 
6.6.1.1 
Enfortumab Vedotin-Related Skin Reactions (Rash and SCAR) ············ 78 
6.6.1.2 
Management of Pneumonitis/Interstitial Lung Disease related to 
Enfortumab Vedotin ································································ 79 
6.6.1.3 
Management of Hyperglycemia ·················································· 79 
6.6.1.4 
Management of Enfortumab Vedotin Infusion Related Reactions ··········· 80 
6.6.2 
Pembrolizumab ··········································································· 80 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 4 of 160 
Amendment 6 
6.6.2.1 
Dose Modification and Toxicity Management for Immune-mediated 
AEs Associated with Pembrolizumab ··········································· 80 
6.6.2.2 
Dose modification and toxicity management of infusion reactions 
related to pembrolizumab ························································· 84 
6.6.2.3 
Other allowed dose interruption for pembrolizumab ·························· 85 
6.7 
Overlapping Adverse Reactions ······························································ 85 
6.8 
Criteria for Continuation of Treatment ······················································ 86 
6.9 
Treatment of Overdose ········································································ 86 
7 
STUDY PROCEDURES AND ASSESSMENTS ············································· 86 
7.1 
Efficacy Assessments ·········································································· 86 
7.1.1 
Imaging for Disease Assessment (Computed Tomography/Magnetic 
Resonance Imaging) ····································································· 86 
7.1.2 
RECIST Version 1.1 Assessment ······················································ 88 
7.1.2.1 
Evaluation of Target Lesions ····················································· 88 
7.1.2.2 
Evaluation of Nontarget Lesions ················································· 89 
7.1.3 
iRECIST Assessment ···································································· 89 
7.1.4 
Evaluation of Time Point Response ··················································· 90 
7.1.5 
Survival Status ············································································ 90 
7.2 
Safety Assessments ············································································ 90 
7.2.1 
Adverse Events ··········································································· 90 
7.2.2 
Laboratory Assessments ································································· 90 
7.2.3 
Vital Signs ················································································· 91 
7.2.4 
Physical Examination ···································································· 91 
7.2.5 
Electrocardiogram ········································································ 92 
7.2.6 
Complete Eye Examination ····························································· 92 
7.2.7 
Cohort 9 Follow-Up Assessments ······················································ 92 
7.2.8 
Order of Assessments ···································································· 92 
7.3 
Adverse Events and Other Safety Aspects ·················································· 93 
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information ················································································ 93 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ··············· 93 
7.3.3 
Follow-up of Adverse Events ··························································· 93 
7.3.4 
Reporting of Serious Adverse Events ················································· 93 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ··········································· 94 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 5 of 160 
Amendment 6 
7.3.6 
Events of Clinical Interest Requiring Immediate Reporting (Cohort 9 only) ···· 94 
7.3.7 
Special Situations ········································································· 95 
7.3.8 
Supply of New Information Affecting the Conduct of the Study ·················· 95 
7.3.9 
Urgent Safety Measures ································································· 96 
7.3.10 
Reporting Urgent Safety Measures ···················································· 96 
7.4 
Pharmacokinetics ··············································································· 96 
7.5 
Pharmacodynamics | Immunogenicity ······················································ 97 
7.6 
Other Assessments ············································································· 97 
7.6.1 
Banked Pharmacogenomic Sample (Optional) ······································· 97 
7.6.2 
Exploratory Biomarker(s) ······························································· 98 
7.6.2.1 
Blood Sample for Biomarker Analysis ·········································· 98 
7.6.2.2 
Tumor Tissue Samples for Biomarker Analysis ································ 98 
7.6.3 
Quality of Life and Patient Reported Outcome Assessment ······················· 99 
7.6.3.1 
Cohorts 1 to 8: ······································································ 99 
7.6.3.2 
Cohort 9 ············································································ 100 
7.6.3.3 
FACT-G ············································································ 100 
7.7 
Total Amount of Blood ······································································ 100 
8 
DISCONTINUATION ··········································································· 101 
8.1 
Discontinuation of Individual Subject(s) From Study Treatment ····················· 101 
8.2 
Discontinuation of Individual Subject(s) From Study ·································· 101 
8.2.1 
Lost to Follow-up ······································································ 102 
8.3 
Discontinuation of the Study Site ·························································· 102 
8.4 
Discontinuation of the Study ······························································· 102 
9 
STATISTICAL METHODOLOGY ·························································· 102 
9.1 
Sample Size ··················································································· 102 
9.2 
Analysis Sets ·················································································· 103 
9.2.1 
Full Analysis Set ······································································· 103 
9.2.2 
Response Evaluable Set ······························································· 103 
9.2.3 
Safety Analysis Set ····································································· 103 
9.2.4 
Pharmacokinetic Analysis Set ························································ 103 
9.3 
Demographics and Baseline Characteristics ·············································· 103 
9.3.1 
Demographics ··········································································· 103 
9.3.2 
Subject Disposition ····································································· 103 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 6 of 160 
Amendment 6 
9.3.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ················································································· 103 
9.3.4 
Medical History ········································································· 103 
9.3.5 
Investigational Product Exposure ···················································· 104 
9.4 
Analysis of Efficacy ········································································· 104 
9.4.1 
Analysis of Primary Endpoint ························································ 104 
9.4.1.1 
Primary Analysis ································································· 104 
9.4.2 
Analysis of Secondary Endpoints ···················································· 104 
9.4.2.1 
Duration of Response ···························································· 104 
9.4.2.2 
Disease Control Rate ····························································· 104 
9.4.2.3 
Progression-free Survival ························································ 104 
9.4.2.4 
Overall Survival ·································································· 105 
9.4.3 
Analysis of Other Efficacy Endpoints ··············································· 105 
9.4.3.1 
Best Overall Response ··························································· 105 
9.4.3.2 
Sum of Diameters································································· 105 
9.4.3.3 
Time to Response ································································· 105 
9.4.3.4 
iRECIST Efficacy Endpoints ··················································· 105 
9.4.4 
Analysis of the Central Imaging Data ··············································· 106 
9.5 
Analysis of Safety ············································································ 106 
9.5.1 
Adverse Events ········································································· 106 
9.5.2 
Laboratory Assessments ······························································· 107 
9.5.3 
Vital Signs ··············································································· 107 
9.5.4 
Physical Examination ·································································· 107 
9.5.5 
Electrocardiogram ······································································ 107 
9.5.5.1 
Routine 12-lead Electrocardiogram ············································ 107 
9.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores ··········· 107 
9.6 
Analysis of Pharmacokinetics ······························································ 107 
9.7 
Analysis of Pharmacodynamics | Immunogenicity ······································ 107 
9.8 
Analyses of Exploratory Biomarker(s) ···················································· 107 
9.9 
Analysis of Quality of Life and Patient Reported Outcome Parameters ·············· 108 
9.10 
Major Protocol Deviations ·································································· 108 
9.11 
Interim Analysis (and Early Discontinuation of the Study) ···························· 108 
9.12 
Additional Conventions ····································································· 109 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 7 of 160 
Amendment 6 
10 
OPERATIONAL CONSIDERATIONS ····················································· 109 
10.1 
Data Collection ··············································································· 109 
10.2 
Demographics and Baseline Characteristics ·············································· 110 
10.2.1 
Demographics ··········································································· 110 
10.2.2 
Medical History ········································································· 110 
10.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ············ 110 
10.2.4 
Performance Status ····································································· 110 
10.3 
Major Protocol Deviations ·································································· 111 
10.4 
STUDY ORGANIZATION ································································ 111 
10.4.1 
Safety Monitoring Committee ························································ 111 
11 
REFERENCES ···················································································· 112 
12 
APPENDICES ····················································································· 119 
12.1 
Ethical, Regulatory and Study Oversight Considerations ······························ 119 
12.1.1 
Ethical Conduct of the Study ························································· 119 
12.1.2 
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities ··············································································· 119 
12.1.3 
Protocol Amendment and/or Revision ··············································· 119 
12.1.4 
Informed Consent of Subjects ························································ 120 
12.1.4.1 
Subject Information and Consent ··············································· 120 
12.1.4.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ··························· 120 
12.1.5 
Source Documents ····································································· 120 
12.1.6 
Record Retention ······································································· 121 
12.1.7 
Subject Confidentiality and Privacy ················································· 122 
12.1.8 
Arrangement for Use of Information and Publication of the Study ············· 123 
12.1.9 
Insurance of Subjects and Others ···················································· 123 
12.1.10 
Signatory Investigator for Clinical Study Report ·································· 123 
12.2 
Procedure for Study Quality Control ······················································ 124 
12.2.1 
Study Monitoring ······································································· 124 
12.2.2 
Direct Access to Source Data/Documents ·········································· 124 
12.2.3 
Data Management ······································································ 124 
12.2.4 
Quality Assurance ······································································ 124 
12.3 
Contraception Requirements ································································ 125 
12.4 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ············································································· 128 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 8 of 160 
Amendment 6 
12.4.1 
Definition of Adverse Events ························································· 128 
12.4.1.1 
Abnormal Laboratory Findings ················································· 128 
12.4.1.2 
Potential Cases of Drug-induced Liver Injury ································ 128 
12.4.2 
Definition of Serious Adverse Events ··············································· 128 
12.4.3 
Criteria for Causal Relationship to Investigational Product ······················ 129 
12.4.4 
Criteria for Defining the Severity of an Adverse Event ··························· 130 
12.4.5 
Reporting Procedures for Serious Adverse Events ································ 131 
12.4.6 
Reporting Procedures for Special Situations ······································· 132 
12.4.6.1 
Pregnancy ·········································································· 132 
12.4.6.2 
Medication Error, Overdose and “Off-label Use” ···························· 133 
12.4.6.3 
Misuse/Abuse ····································································· 133 
12.4.6.4 
Occupational Exposure ·························································· 134 
12.4.6.5 
(Suspicion of) Transmission of Infectious Agent ···························· 134 
12.4.6.6 
Suspected Drug-drug Interaction ··············································· 134 
12.5 
Liver Safety Monitoring and Assessment ················································· 135 
12.6 
List of Cautionary Concomitant Medications ············································ 138 
12.7 
Laboratory Assessments ····································································· 139 
12.8 
Pharmacogenomic Analysis with Banked Sample (Optional) ························· 141 
12.9 
RECIST Version 1.1 ········································································· 143 
12.10 
Eastern Cooperative Oncology Group Performance Status ···························· 145 
12.11 
Global Pain Assessment ····································································· 146 
12.12 
EQ-5D-5L ····················································································· 147 
12.13 
EORTC QLQ H&N43 ······································································· 149 
12.14 
PRO-CTCAE Questions ····································································· 151 
12.15 
FACT-G ······················································································· 153 
12.16 
List of Abbreviations and Definition of Key Study Terms ····························· 154 
13 
SPONSOR SIGNATURE ······································································· 160 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 9 of 160 
Amendment 6 
SIGNATURES 
1.  AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND 
THE INVESTIGATOR 
This study will be conducted in adherence to International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable laws and regulatory requirements, as well as this protocol.  
As the evidence of the agreement, the investigator (CHIKEN SEKININ ISHI) and 
responsible person of the sponsor (CHIKEN IRAI SEKININSHA) inscribe in the bipartite 
agreement by signature or “printed name and seal.” 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 13 
Sponsor’s Signatures].  
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 10 of 160 
Amendment 6 
3.  INVESTIGATOR’S SIGNATURE 
An Open-label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab 
Vedotin in Subjects with Locally Advanced or Metastatic Malignant Solid Tumors  
(EV-202) 
ISN/Protocol 7465-CL-202  
Amendment 6 
05 Feb 2024 
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:  
  
 
Address: 
 
 
 
 
 
 
 
 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 12 of 160 
Amendment 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 5/Version 6 [Substantial] 
13 Apr 2023 
Amendment 4/Version 5 [Substantial] 
14 Feb 2023 
Amendment 3/Version 4 [Substantial] 
31 Mar 2022 
Amendment 2/Version 3 [Substantial] 
21 Oct 2021 
Amendment 1/Version 2 [Substantial] 
17 Feb 2021 
Original Protocol/Version 1 
25 Nov 2019 
Amendment 6/Version 7 [Nonsubstantial] 05 Feb 2024 
This amendment is considered to be nonsubstantial 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 because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment: 
Global update for management of pneumonitis/interstitial lung disease (ILD) related to 
enfortumab vedotin and additional clarifications related to Cohort 9. 
Summary of Changes 
Nonsubstantial Changes 
Section 
Number 
Description of Change 
Brief Rationale 
CONTACT 
DETAILS OF 
SPONSOR’S 
KEY 
PERSONNEL 
Update Clinical Research Contacts. 
Update contact details of 
sponsors key personnel. 
1.1, 6.5 
Change second level bullet under cohort 9 to 
delete “Other glucocorticoid use except when 
used for the following purposes:” and “Note: 
Inhaled steroids are allowed for management of 
asthma.”, while retaining and revising third level 
bullets to second level bullets. 
Clarification of 
glucocorticoid use in 
Cohort 9. 
1.1, 4.1 
Add “(both enfortumab vedotin and 
pembrolizumab)” to “Subjects in cohort 9 who 
discontinue study treatment …).” 
Clarify that study treatment 
is considered to be both 
enfortumab vedotin and 
pembrolizumab. 
1.2 (Figure 2) 
Remove pre-screening consent/prescreening 
process for Cohort 9. 
Pre-screening and main 
informed consent form 
(ICF) language was 
combined into one consent 
form; therefore, the 
schedule of assessments 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 13 of 160 
Amendment 6 
Section 
Number 
Description of Change 
Brief Rationale 
was updated to remove pre-
screening 
consent/pre-screening 
process. 
1.2 (Figure 2) 
Update Cohort 9 schema to remove upper 
Pre-screening box.  
Replace "No local PD L1 result" and "Local PD
L1 result available" with “PD-L1 Testing (Local 
or Central)” in the Screening/Baseline Period. 
Update to align with 
removal of the 
Pre-screening 
consent/pre-screening 
process. 
1.3 (Table 1, 
Table 2) 
Merge Pregnancy Test at Follow-up (30-day 
Safety Follow-up, Post Treatment Follow-up, 
and Long-term Follow-up) and replace “X” with 
“Pregnancy test monthly until 6 mo after last 
dose of study treatment.” 
Clarify timing of Pregnancy 
Test. 
1.3 (Table 1, 
Table 2) 
Remove footnotes (Table 1: 12,13; Table 2: 
14,15) for 12-lead ECG at Screening/Baseline 
cycle Day -7 to -1. 
Updated to remove 
footnotes for clinical 
laboratory assessments from 
the 12-lead ECG 
assessment. 
1.3 (Table 2) 
Change Treatment Subsequent Every Cycle at 
Cycle 1 from a Visit Window of ±2 to ±3. 
Update timing of Visit 
Window to align with 
cohorts 1-8. 
1.3 (Table 2) 
Update Prior/Concomitant Medication and AE 
Assessments at Follow-up to extend to 30-day 
Safety Follow-up. 
Update to align with 
cohorts 1-8 as originally 
intended.   
1.3 (Table 2) 
Remove footnote 15 from Hemoglobin A1c. 
Removed duplicate 
information.  
1.3 (Table 2) 
Move the assessments of Informed Consent, 
Tumor Tissue Sample, and PD-L1 Test Result 
from Pre-Screening to Screening. 
Update to align with 
removal of the 
Pre-screening consent/pre-
screening process. 
1.3 (Table 2) 
Merge adverse events (AE) and Prior ConMed 
rows so that “Every visit” starts at 
Screening/Baseline. 
Correct formatting in the 
schedule of assessment. 
1.3 (Table 2, 
footnote 10), 
7.1.1 
Remove bone imaging as a requirement at 
screening assessment for Cohort 9. 
Bone imaging is not routine 
standard of care in HNSCC, 
and the CT scan can assess 
for metastasis to some 
extent. 
1.3 (Table 2, 
footnote 11), 
4.1, 7.1.1 
Revise 36 days to 42 days in the disease 
assessment “every 6 weeks (3642 days ±7 days) 
throughout the study.”  
Correction of Cohort 9 scan 
window from 36 to 42 days. 
1.3 (Table 2, 
footnote 12) 
Add “iRECIST should be assessed in parallel 
with all RECIST 1.1 assessments at every 
timepoint.” 
Clarify that iRECIST will 
be assessed in parallel with 
RECIST at every timepoint. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 14 of 160 
Amendment 6 
Section 
Number 
Description of Change 
Brief Rationale 
1.3 (Table 2, 
footnote 17) 
Add “cycle 2” to the required thyroid function 
tests treatment period. 
Correct omission of Cycle 2 
from footnote. 
6.4 
Add overdose definition for pembrolizumab. 
Clarification of dosing 
noncompliance for 
enfortumab vedotin and 
pembrolizumab. 
7.3.6, 12.5 
Add Japan country specific applicable 
assessment forms for collection of non-serious 
and SAEs. 
Update based on Japan 
specific amendment. 
6.6.1 
Add “Participants who experience an 
unacceptable AE that is clearly attributable 
only to pembrolizumab may continue on 
enfortumab vedotin monotherapy until a 
discontinuation criterion is met.” 
Clarify dose interruptions 
vs discontinuation 
guidance, 
interrupting/discontinuing 
one drug vs both drugs. 
6.6.1.2 
Add further guidance on the management of 
pneumonitis/ILD related to enfortumab vedotin. 
Update management of 
pneumonitis/ILD related to 
enfortumab vedotin. 
6.6.2.1 
Add “Participants who experience 
unacceptable toxicity that is clearly 
attributable only to enfortumab vedotin may 
continue on pembrolizumab monotherapy up 
to a maximum of 35 cycles.” 
Clarify dose interruptions 
vs discontinuation 
guidance, 
interrupting/discontinuing 
one drug vs both drugs. 
7.7 
Add maximum amount of blood collection for 
cohorts 1-8 and cohort 9. 
Clarify maximum volume 
of blood collection for each 
cohort. 
8.1 
Update dose discontinuation guidance to 
“clearly” attributable to either pembrolizumab or 
enfortumab vedotin treatment.  
Clarify dose discontinuation 
guidance for discontinuing 
one drug vs both drugs. 
10.1 
Update monitoring to indicate the study does not 
perform 100% source data validation 
Clarify monitoring source 
data validation. 
Throughout 
Minor administrative-type changes were made, 
e.g., typos, formatting, section and footnote 
numbering and other continuity throughout the 
protocol.  
To provide clarification and 
proper interpretation of the 
protocol.  
 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 15 of 160 
Amendment 6 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Date and Version of Protocol Synopsis: 
Amendment 6 
Sponsor: 
Astellas Pharma Global Development Inc. (APGD) 
Collaborator: 
Seagen, Inc. 
Protocol Number:  
7465-CL-202 
Compound Name: 
Enfortumab vedotin (ASG-22CE) 
Phase of Development: 
Phase 2 
Title of Study: 
An Open-label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab Vedotin in 
Subjects with Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) 
Planned Study Period: 
From approximately 1Q2020 to 1Q2026 
Study Objective(s) and Endpoint(s): 
Cohorts 1 to 8:  
Objective(s) 
Endpoint(s) 
Primary 
 
To determine the antitumor activity of 
enfortumab vedotin as measured by 
confirmed objective response rate 
(ORR) per investigator assessment 
 
Confirmed ORR (complete response [CR] + partial 
response [PR]) per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 as determined 
by investigator 
Secondary 
 
To assess other measures of antitumor 
activity of enfortumab vedotin per 
investigator assessment 
 
 
 
 
 
 
To assess the overall survival (OS) 
 
 
To assess the safety and tolerability of 
enfortumab vedotin 
 
Duration of response (DOR) per RECIST Version 
1.1 per investigator assessment 
 
Disease control rate (DCR) (CR + PR + stable 
disease [SD]) per RECIST Version 1.1 per 
investigator assessment 
 
Progression-free survival (PFS) per investigator 
assessment 
 
 
OS 
 
 
Safety variables  
o Adverse events (AEs) 
o Laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiogram 
o Eastern Cooperative Oncology Group (ECOG) 
performance status 
 
 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 16 of 160 
Amendment 6 
 
Exploratory 
 
To evaluate potential genomic and/or other 
biomarkers that may correlate with treatment 
outcome, including Nectin-4 expression 
 
To assess the pharmacokinetics of 
enfortumab vedotin and monomethyl 
auristatin E (MMAE) 
 
To assess the immunogenicity of enfortumab 
vedotin 
 
To evaluate the treatment effect of 
enfortumab vedotin on quality of life (QOL) 
 
To assess measures of antitumor activity of 
enfortumab vedotin per blinded independent 
central review (BICR) 
 
Exploratory genomic and/or other 
biomarkers that may correlate with treatment 
outcome, including Nectin-4 expression 
 
Selected pharmacokinetic parameters of 
enfortumab vedotin and MMAE 
 
Incidence of antitherapeutic antibodies 
(ATA) to enfortumab vedotin 
 
Patient reported outcome (PRO) per 
EuroQOL 5-dimensions (EQ-5D-5L) and 
global pain assessment (worst pain in the 
last 24 hours) 
 
Response related endpoints per BICR 
 
Cohort 9:  
Objective(s) 
Endpoint(s) 
Primary 
 
To determine the antitumor activity of 
enfortumab vedotin in combination with 
pembrolizumab 
 
Confirmed ORR (CR + PR) per RECIST 
Version 1.1 as determined by investigator 
Secondary 
 
To assess other measures of antitumor 
activity of enfortumab vedotin in 
combination with pembrolizumab per 
investigator assessment 
 
 
 
 
To assess the OS of enfortumab vedotin in 
combination with pembrolizumab  
 
 
To assess the safety and tolerability of 
enfortumab vedotin in combination with 
pembrolizumab  
 
DOR per RECIST Version 1.1 by 
investigator assessment 
 
DCR (CR + PR + SD) per RECIST Version 
1.1 by investigator assessment 
 
PFS per RECIST Version 1.1 by investigator 
assessment 
 
 
OS 
 
 
 
Safety variables  
o AEs 
o Laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiogram 
o ECOG performance status 
Exploratory 
 
To evaluate potential genomic and/or other 
biomarkers that may correlate with 
treatment outcome, including Nectin-4 
expression 
 
 
To assess the pharmacokinetics of 
enfortumab vedotin and MMAE 
 
 
 
Exploratory genomic and/or other 
biomarkers that may correlate with treatment 
outcome, including Nectin-4 expression 
 
 
 
Selected pharmacokinetic parameters of 
enfortumab vedotin and MMAE 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 17 of 160 
Amendment 6 
 
To assess the immunogenicity of 
enfortumab vedotin 
 
 
To evaluate the treatment effect of 
enfortumab vedotin in combination with 
pembrolizumab on QOL 
 
 
To assess measures of antitumor activity 
of enfortumab vedotin in combination with 
pembrolizumab per BICR 
 
 
To assess measures of antitumor activity 
of enfortumab vedotin in combination with 
pembrolizumab per modified RECIST 
v1.1 for immune-based therapeutics 
(iRECIST) 
 
Incidence of ATA to enfortumab vedotin  
 
 
PRO per EORTC QLQ H&N43, global pain 
assessment (worst pain in the last 24 hours), 
FACT-G question G05 and 
symptom-specific questions from PRO-
CTCAE 
 
 
ORR, DOR, DCR and PFS per RECIST 
Version 1.1 by BICR 
 
 
ORR, DOR, DCR and PFS per iRECIST by 
investigator assessment 
 
 
Planned Total Number of Study Sites and Location(s): 
Approximately 50 study sites globally 
Study Population: 
Subjects with locally advanced or metastatic malignant solid tumors, including: 
 
Hormone receptor positive/ human epidermal growth factor receptor 2-negative (HR+/HER2-) 
breast cancer 
 
Triple negative breast cancer (TNBC) 
 
Squamous non-small cell lung cancer (Squamous NSCLC) 
 
Non-squamous non-small cell lung cancer (Non-squamous NSCLC) 
 
Head and neck cancer 
 
Gastric cancer and esophageal adenocarcinoma (EAC) including gastroesophageal junction 
(GEJ) adenocarcinoma  
 
Esophageal squamous cell carcinoma (ESCC) 
 
Head and neck squamous cell carcinoma (HNSCC) 
Number of Subjects to be Enrolled/Randomized:   
Approximately 320 subjects with malignant solid tumors in 8 cohorts; approximately 40 subjects in 
each cohort 
Study Design Overview: 
This is an open-label, multicenter, multicohort, phase 2 study designed to assess the antitumor 
activity and safety of enfortumab vedotin as a single agent (cohorts 1 to 8) and in combination with 
pembrolizumab (cohort 9) in adult subjects who have locally advanced or metastatic malignant 
solid tumors.  Approximately 40 subjects will be enrolled into each of the following cohorts. 
 
Cohort 1: HR+/HER2- breast cancer; or 
 
Cohort 2: TNBC; or 
 
Cohort 3: Squamous NSCLC; or 
 
Cohort 4: Non-squamous NSCLC; or 
 
Cohort 5: Head and neck cancer; or 
 
Cohort 6: Gastric or GEJ or esophageal cancer (reallocated to cohorts 7 or 8) 
 
Cohort 7: Gastric and EAC including GEJ adenocarcinoma 
 
Cohort 8: ESCC 
 
Cohort 9: First-line HNSCC 
For each cohort, one interim analysis is planned to assess the antitumor activity for that cohort.  
The interim analysis will be performed for a given cohort at the time when 20 subjects are 
evaluable for tumor response per investigator assessment following study treatment.  A Bayesian 
optimal design for phase 2 (BOP2) [Zhou et al, 2017] is used to guide interim decision rule.  For 
each cohort, based on the 2-stage BOP2 design, when the number of subjects with confirmed 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 18 of 160 
Amendment 6 
response (CR and PR) is less than the prespecified minimum number of responders at stage 1, the 
enrollment of the cohort may stop; otherwise, the enrollment will continue into Stage 2 until the 
planned size of the cohort is reached. 
In cohorts 1 to 8, subjects will receive enfortumab vedotin at a dose of 1.25 mg/kg as an 
intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. 
In cohort 9, subjects will receive enfortumab vedotin 1.25 mg/kg on days 1 and 8 and 
pembrolizumab 200 mg on day 1 of each 21-day cycle. 
For each subject, the study will consist of 3 periods: screening/baseline, treatment and follow-up. 
The screening/baseline period will take place up to 28 days prior to the first dose of study 
treatment.  For cohort 9, a local programmed death-ligand 1 (PD-L1) test result may be used for 
eligibility.  A PD-L1 combined positive score (CPS) 
 is required for enrollment.  An archival 
tumor sample will be submitted from each subject for central PD-L1 and other biomarker testing.  
If archival tumor tissue for central PD-L1 testing is insufficient or not available, a biopsy will be 
performed to obtain a tumor sample for central testing.  
In the treatment period, starting at cycle 1, subjects in cohorts 1 to 8 will receive enfortumab 
vedotin on days 1, 8, and 15 every 28-day cycle until one of the treatment discontinuation criteria 
are met. Subjects in cohort 9 will receive enfortumab vedotin on days 1 and 8 and pembrolizumab 
on day 1 of each 21-day cycle until a discontinuation criteria is met.  
For cohorts 1 to 8, imaging scan and disease assessment will be performed at screening/baseline 
and repeated every 8 weeks (56 days ± 7 days) from the first dose of study treatment throughout the 
study until the subject has radiologically-confirmed disease progression, initiates a new subsequent 
anticancer therapy, dies, withdraws consent, is lost to follow-up or the study closes, whichever 
occurs first. After 1 year on study treatment, the frequency of disease assessment will be reduced to 
every 12 weeks (84 days ± 7 days). Subjects in cohorts 1 to 8 who discontinue study treatment for 
reasons other than radiologically-confirmed disease progression by RECIST Version 1.1 will enter 
into a post treatment follow-up period and continue to receive imaging scans every 8 weeks 
(56 days ± 7 days) until the subject has radiologically-confirmed disease progression, initiates a 
new anticancer therapy, dies, withdraws consent, is lost to follow-up or the study closes, whichever 
occurs first. 
In cohort 9, the first on-study imaging will be performed 9 weeks (± 7 days) from the first dose of 
study treatment and then every 6 weeks (± 7 days) throughout the study until the subject has 
radiologically-confirmed disease progression (confirmed progressive disease [iCPD] per modified 
RECIST v1.1 for immune-based therapeutics [iRECIST]), initiates a new subsequent anticancer 
therapy, dies, withdraws consent, is lost to follow-up or the study closes, whichever occurs first. 
After 18 months on study treatment, the frequency of disease assessment will be reduced to every 
9 weeks (± 7 days). Subjects in cohort 9 with unconfirmed progressive disease per iRECIST 
guidelines [Seymour et al, 2017] who are clinically stable may continue on study treatment until 
progression is confirmed by the investigator (iCPD) at the next imaging assessment 6 weeks (± 7 
days) after iUPD. Treatment with pembrolizumab will be discontinued once the subject has 
received a maximum of 35 administrations of pembrolizumab (approximately 2 years). 
Subjects in cohort 9 who discontinue study treatment (both enfortumab vedotin and 
pembrolizumab) for reasons other than radiologically confirmed disease progression per iRECIST 
will enter into a post treatment follow-up period and have physical exams, ECOG and disease 
assessments every 6 weeks (± 7 days) up to 18 months after first dose, then every 9 weeks 
(± 7 days) until the subject has radiologically confirmed disease progression per iRECIST as 
determined by the investigator, initiates a subsequent anticancer therapy, dies, withdraws consent, 
or the study closes. During study treatment, palliative radiotherapy on a nontarget lesion that is not 
progressing will not be considered a subsequent anticancer therapy; however, radiotherapy on any 
target lesion will be a subsequent anticancer therapy. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 19 of 160 
Amendment 6 
Copies of all imaging scans will also be sent to the independent review facility in a timely manner. 
Images at the independent review facility will be stored.  Imaging scans for a cohort may be read at 
the independent review facility when the minimum number of responders per investigator 
assessment (subjects with confirmed CR and PR) to claim promising antitumor activity at stage 1 
are met based on the 2-stage BOP2 design.  Central images may also be read in certain 
circumstances as determined by the sponsor. 
After radiologically-confirmed disease progression or initiation of subsequent anticancer therapy, 
whichever occurs first, subjects will be contacted every 12 weeks in the long-term follow-up period 
for survival status until death, withdrawal of consent, lost to follow-up or study closure, whichever 
occurs first. 
Confirmed ORR per investigator assessment is the primary endpoint.  Confirmed ORR is defined 
as the proportion of subjects whose objective response is confirmed CR or PR according to 
RECIST Version 1.1.  Response (CR or PR) must be confirmed with a repeat imaging scan 
4 weeks (28 days + 7-day window) after first response.  
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 
enfortumab vedotin and MMAE in serum or plasma and to assess ATA.  Samples for exploratory 
biomarkers will be collected at protocol-specified time points.  Enfortumab vedotin biomarker 
assessments will not be used for subject selection. 
The following are discontinuation criteria from study treatment for individual subjects: 
 
Subject develops documented radiological disease progression (iCPD per iRECIST in cohort 9) 
 
Subject starts on a new anticancer therapy 
 
Subject develops unacceptable toxicity 
 
Female subject becomes pregnant 
 
Investigator decides it is in the subject’s best interest to discontinue 
 
Subject requests to stop treatment 
 
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment 
 
Subject has continuous dose interruption > 6 months 
 
Study is terminated by sponsor 
All subjects who discontinue study treatment will remain in the study and must continue to be 
followed for protocol-specific follow-up procedures.  Subjects may be discontinued from the study 
for any of the following reasons: 
 
Lost to follow-up 
 
Death 
 
Subject withdrawal of consent 
 
Study termination by sponsor 
On a periodic basis, a Safety Monitoring Committee (SMC) will review the safety data of the 
study.  The SMC may recommend whether the study should be terminated, modified or continue 
unchanged based on ongoing reviews of study safety data. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 20 of 160 
Amendment 6 
Investigational Product(s): 
Name:  
Enfortumab vedotin 
Dose, Mode of Administration and Dose Modification:   
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an IV infusion on days 1, 8 
and 15 of every 28-day cycle for cohorts 1 to 8 and on days 1 and 8 of every 21-day cycle for 
cohort 9.  Enfortumab vedotin will be administered based on the subject’s actual body weight on 
day 1 of each cycle except for subjects weighing greater than 100 kg; in such cases, the dose will 
be calculated based on a maximum weight of 100 kg.  Enfortumab vedotin will be administered 
intravenously over an approximately 30-minute period. 
Dose reduction to 1, 0.75 or 0.5 mg/kg will be allowed depending on the type and severity of 
toxicity.  Subjects requiring a dose reduction may be re-escalated by 1 dose level (i.e., subjects 
reduced to 0.75 mg/kg may only be re-escalated to 1 mg/kg) provided the toxicity does not require 
 grade 1.  If the toxicity recurs, 
re-
 grade 2 corneal AEs will not be permitted to 
dose re-escalate.   
Dose interruptions for any enfortumab vedotin associated toxicities are permitted at the discretion 
of the investigator.  Dose interruptions may last up to 8 weeks (2 cycles) for subjects in 
cohorts 1 to 8 and up to 6 weeks (2 cycles) for subjects in cohort 9.  Dose interruptions for subjects 
who are deriving clinical benefit from treatment may be extended beyond 8 weeks (cohorts 1 to 8) 
or 6 weeks (cohort 9) after consultation with the medical monitor on a monthly basis, if the 
subject’s toxicity does not otherwise require permanent discontinuation.  During dose interruptions, 
disease assessments must continue to be performed at the protocol-specified frequency and disease 
status must remain at least SD per RECIST v1.1. If dose interruption is continuous > 6 months, the 
subject’s study treatment will be permanently discontinued. 
Refer to Section 6.6.1 [Table 7] and [Table 8] for dose modification recommendations for 
enfortumab vedotin.  
Name:  
Pembrolizumab (cohort 9 only) 
Dose, Mode of Administration and Dose Modification:   
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for IV infusion.  Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution.  Each 1 mL of solution contains 25 mg of pembrolizumab and 
is formulated in L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for 
Injection, United States Pharmacopeia (USP).  Pembrolizumab will be administered as a dose of 
200 mg using a 30-minute intravenous infusion on day 1 of each 3-week cycle, approximately 
30 minutes after completion of the enfortumab vedotin administration.  Sites should make every 
effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window between -5 minutes and + 10 minutes is 
permitted (i.e., infusion time is 30 minutes (-5 min/+10 min). 
The pharmacy manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution.  
Refer to Section 6.6.2 [Table 9] and [Table 10] for dose modification recommendations for 
pembrolizumab. 
If the medical monitor and site investigator determine that a dose interruption for pembrolizumab is 
needed, an interruption of all day 1 dose of enfortumab vedotin must also occur and may last for up 
to 3 weeks (1 cycle). For subjects deriving benefit, interruption of pembrolizumab for longer than 
3 weeks should be discussed with the medical monitor. For delays longer than 12 weeks, the 
medical monitor should be consulted before resuming study therapy. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 21 of 160 
Amendment 6 
Concomitant Treatment (Medication and Nonmedication Therapy) Restrictions or 
Requirements: 
If the investigator determines that any of the following medications are necessary to provide 
adequate medical support to the subject, the subject must be withdrawn from further administration 
of the study treatment: 
 
Other investigational drugs 
 
Chemotherapy or other medications intended for antitumor activity.  This does not apply to 
subjects on endocrine therapy, or to subjects on agents intended for the treatment of bone 
metastasis where subjects should be on a stable dose of bone targeting agents for at least 
2 weeks prior to study entry (e.g., bisphosphonates, or receptor activator of nuclear factor 
kappa-
 
 
Radiation therapy except palliative radiation for nontarget lesions 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.  The radiated lesion must be a nontarget lesion per RECIST Version 1.1 and the 
subject must have clear measurable disease outside the radiated field.  Enfortumab vedotin 
may not be given concurrently with radiation therapy. 
 
Subjects who are receiving strong cytochrome P450 (CYP)3A4 inhibitors concomitantly 
with enfortumab vedotin should be closely monitored for adverse reactions. 
 
For cohort 9:  Live or attenuated vaccines within 30 days prior to the first dose of study 
treatment and while participating in the study. 
 
For cohort 9:  Systemic glucocorticoids except when used for the following purposes: 
o To modulate symptoms of an AE that is suspected to have an immunologic etiology 
o For the prevention of emesis 
o To premedicate for IV contrast allergies 
o To treat COPD exacerbations (only short-term oral or IV use in doses > 10 mg/day 
prednisone equivalent) 
o For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
o For topical use or ocular use 
o Intraarticular joint use 
o For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.  
 
Duration of Treatment:   
Subjects will be allowed to receive enfortumab vedotin (and pembrolizumab for cohort 9) until 
treatment discontinuation criteria are met. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 22 of 160 
Amendment 6 
Statistical Methods: 
Sample Size Justification:  
The planned sample size for cohorts 1 to 8 is 40 subjects in each cohort.  Assuming the ORR of 
current standard of care (reference ORR for the 7 tumor types chosen for the study) ranges from 
10% to 20%, and at least a 10% absolute increase in ORR is considered clinical meaningful 
improvement, the sample size of 40 subjects allows to have 80% confidence interval of ORR for 
the study drug to exclude the reference ORR. 
The planned sample size for cohort 9 is 40 subjects.  Assuming the reference ORR for cohort 9 is 
20%, and at least a 25% absolute increase in ORR is considered clinical meaningful improvement 
for combination therapy, the sample size of 40 subjects allows a 92% power to detect a statistically 
significant difference at type 1 error rate of 1-sided 0.025. 
Efficacy:   
Confirmed ORR (CR+PR) and DCR (CR+PR+SD) as per RECIST Version 1.1 will be calculated 
and the corresponding 95% confidence intervals will be constructed based on Clopper-Pearson 
method for each tumor type.  For cohort 9, analyses will also be calculated based on iRECIST.  
Other efficacy endpoints, including DOR, PFS and OS will be summarized using Kaplan-Meier 
method.  Efficacy analysis will include all subjects who were treated and with evaluable tumor 
response data upon analysis cutoff date.  
Safety: 
The Safety Analysis Set (SAF) will be used for the safety analysis.  All subjects who are enrolled 
and received study drug will be included in the SAF.  The frequency of AEs and the serious AEs 
will be summarized by MedDRA system organ class (SOC) and preferred term.  In addition, 
summary statistics will be provided for the following safety parameters: 
 
Laboratory values 
 
Vital sign measurements 
 
ECOG performance status 
Pharmacokinetics: 
Descriptive statistics (e.g., number, mean, standard deviation, minimum, median, maximum, 
coefficient of variation and geometric mean) will be provided for serum or plasma concentrations 
of enfortumab vedotin and MMAE.  Additional model-based analyses and exposure response may 
be performed and reported separately. 
Pharmacodynamics | Immunogenicity: 
The ATA to enfortumab vedotin will be summarized by cycle and overall, and possible relationship 
to pharmacokinetics will be explored. 
Exploratory Biomarkers: 
Descriptive statistics will be provided for exploratory biomarker parameters whenever applicable.  
Analysis of the relationship between exploratory biomarker measurements and pharmacokinetics, 
efficacy, safety profile in subjects may be performed. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
 
05 Feb 2024 
Astellas 
Page 23 of 160 
Amendment 6 
Interim Analyses:  
For each cohort, one planned interim analysis will be performed to evaluate confirmed ORR at the 
time when 20 subjects had evaluable tumor response data per investigator assessment following 
study treatment.  The 2-stage BOP2 design is used to guide the interim decision rule.  A cohort will 
proceed to stage 2 when the minimum number of responders (see table below) from stage 1 has 
been observed; otherwise the cohort may be closed for further enrollment.  The sponsor will make 
the final decision on stopping cohort enrollment based on the overall evaluation of antitumor 
activity and safety data including subject’s Nectin-4 expression data. 
Decision Rules Based on Objective Response Rate 
 
 
Cohort 
Cancer Type 
Number of 
Evaluable 
Subjects 
Planned at 
Interim 
Analysis 
(Stage 1) 
Minimum 
Number of 
Responders 
to Proceed 
to Stage 2 
Number of 
Evaluable 
Subjects at 
Final 
Analysis 
(Stage 2) 
Minimum 
number of 
Responders 
to Claim 
Promising 
Antitumor 
Activity 
Cohort 1 
HR+/HER2- breast cancer 
20 
4 
40 
12 
Cohort 2 
Triple negative breast cancer 
20 
3 
40 
10 
Cohort 3 
Squamous non-small cell 
lung cancer 
20 
2 
40 
7 
Cohort 4 
Non-squamous non-small cell 
lung cancer 
20 
3 
40 
10 
Cohort 5 
Head and neck cancer 
20 
2 
40 
7 
Cohort 6* 
Gastric or GEJ or esophageal 
cancer 
20 
2 
40 
7 
Cohort 7 
Gastric, EAC and GEJ 
adenocarcinoma 
20 
2 
40 
7 
Cohort 8 
ESCC 
20 
2 
40 
7 
Cohort 9 
HNSCC 
20 
5 
40 
14 
EAC: esophageal adenocarcinoma; ESCC: esophageal squamous cell carcinoma; GEJ: gastroesophageal 
junction; HR+: hormone receptor positive; HER2-: human epidermal growth factor receptor 2-negative; 
HNSCC: head & neck squamous cell carcinoma 
 
*All subjects initially enrolled in Cohort 6 under protocol version 1.0 and 2.0 will be reallocated to Cohort 7 or 
8 based on tumor type/histology and Cohort 6 closed to further enrollment.  

Pharmacokinetics 
ATA 
Biomarkers
Soluble Circulating 
Factors 
cf DNA 
Immuno-phenotyping

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 35 of 160 
Amendment 6 
2 
INTRODUCTION 
Cancer is the leading cause of death in the US for people 35 to 65 years of age and it is the 
second leading cause of death worldwide.  It was estimated in 2021 that there would be 
approximately 1.9 million new cancer cases and approximately 608000 deaths from cancer in 
the US [National Cancer Institute, 2021a].  Cancer accounted for nearly 10 million deaths 
worldwide in 2020 [World Health Organization, 2021a].  Most deaths now occur in patients 
with metastatic cancers.  In fact, in the last 20 years, advances in treatment, including 
surgery, radiotherapy and adjuvant chemotherapy cured most patients with localized cancer.  
Patients whose cancer presented or recurred as metastatic disease obtained only modest 
benefit from conventional therapies in terms of overall survival (OS) and were rarely cured. 
New therapeutic strategies for metastatic cancers include targeting molecular pathways 
important for cancer cell survival and novel cytotoxic compounds.  The benefit of these novel 
drugs is reflected in prolonged survival; however, the outcome for most patients with distant 
metastases is still poor and novel therapies are needed.   
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 et al, 2018a; Takano et al, 2009; Fabre-Lafay et al, 2007].  In several cancers, 
including breast cancer, lung cancer, gastric cancer and esophageal cancer, Nectin-4 
expression is associated with cancer progression and poor prognosis.  Although the exact role 
of Nectin-4 expression in cancer is not yet known, the high expression in certain cancers also 
creates an ideal treatment target for these malignancies.  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 et al, 2018a].  They are 
representative of tumors with moderate to high Nectin-4 expression, and for which there is 
preclinical or clinical evidence of sensitivity to enfortumab vedotin, or supportive evidence 
based on published literature, in addition to known sensitivity to microtubule-disrupting 
agents [Challita-Eid et al, 2016; Deng et al, 2019; Zhang et al, 2018b]. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 36 of 160 
Amendment 6 
2.1 
Background 
2.1.1 
Breast Cancer 
Globally, there were approximately 2.3 million newly diagnosed female breast cancer cases 
in 2020, accounting for almost 1 in 4 cancer cases among women [World Health 
Organization, 2021b].  The disease is the most frequently diagnosed cancer in the vast 
majority of countries and is also the leading cause of cancer-related death in women.  
Following metastatic diagnosis, prognosis is poor with a with a 5-year survival rate of 
approximately 28%. 
The selection of appropriate therapy for metastatic breast cancer is complex because of the 
many treatment options and biologic heterogeneity of the disease.  The potential treatment 
options are influenced by estrogen and progesterone receptors and by human epidermal 
growth factor receptor 2 (HER2) status of the tumor.  Treatment options for subjects 
presenting with metastatic breast cancer may also be influenced by what adjuvant therapy 
was used, how soon after adjuvant therapy the subject relapses, and by sites of metastasis. 
2.1.1.1 Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 
Negative Breast Cancer  
Hormone receptor positive (HR+)/HER2-negative breast cancer is the most common breast 
cancer subtype (> 70%), occurring predominantly in postmenopausal women.  The initial 
treatment for women with metastatic disease consists primarily of endocrine therapy.  This is 
usually administered alone, in combination with a cyclin-dependent kinase (CDK) 4/6 
inhibitor, or as dual endocrine blockade.  For women who are endocrine refractory or women 
who have symptomatic visceral disease, systemic chemotherapy is recommended.   
Several cytotoxic chemotherapy agents have shown activity in metastatic breast cancer, 
including anthracyclines, taxanes, gemcitabine, capecitabine, vinorelbine, eribulin and 
ixabepilone.  The response rates with these agents vary depending on the type of prior 
therapy, as well as the breast cancer subtype.  In general, anthracycline-based combination 
therapy and taxanes such as paclitaxel and docetaxel are thought to be the most active 
[Piccart, 2008].  Given the wide use of anthracyclines in the adjuvant setting and the 
increased risk of cardiotoxicity, the use of anthracyclines in the metastatic setting is limited.  
Taxanes are the most commonly used agent for patients with locally advanced or metastatic 
disease, particularly in the front-line setting [Greene & Hennessy, 2015].  About 70% of 
Stage II–III patients receive neoadjuvant anthracycline, cyclophosphamide with a taxane, 
which limits use of these agents in the metastatic setting [Kantar, 2019].  Sequential single 
agent therapies are recommended over combinations due to lower toxicities and limited 
survival benefit.  Responses to commonly used single agent chemotherapy patients with 
HR+/HER2-negative breast cancer are primarily limited to subgroup analysis, these have 
ranged between 11% to 36% [Robson et al, 2017; Kaufman et al, 2015; Cortes et al, 2011].  
In general, responses tended to be lower in pretreated patients with reported ranges between 
10% to 13% [Perez et al, 2007; Jones et al, 1995]. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 37 of 160 
Amendment 6 
2.1.1.2 Triple Negative Breast Cancer 
Triple negative breast cancer (TNBC) is defined by the absence of immunostaining for 
estrogen receptor (ER), progesterone receptor (PR) and HER2.  Overall, approximately 15% 
to 20% of breast cancers are classified as TNBC.  TNBC is associated with aggressive tumor 
biology, visceral metastasis, and a poor prognosis [Plasilova et al, 2016]. 
Taxane-based regimens are considered a standard of care in first-line therapy for patients 
with metastatic breast cancer, including TNBC.  More recently the FDA granted accelerated 
approval for atezolizumab in combination with nab-paclitaxel for the treatment of patients 
with unresectable locally advanced or metastatic TNBC whose tumors express programmed 
death-ligand 1 (PD-L1).  The approval was based on a median progression-free survival 
(PFS) of 7.5 months for atezolizumab plus nab-paclitaxel versus 5.0 months in the placebo 
plus nab-paclitaxel arm; objective response rate (ORR) of 56% versus 46%) 
[Schmid et al, 2019].  The FDA also granted accelerated approval to pembrolizumab in 
combination with chemotherapy for the treatment of patients with locally recurrent 
unresectable or metastatic TNBC whose tumors express PD-L1 (combined positive score 
[CPS]  10).  In patients with CPS > 10, the addition of pembrolizumab to chemotherapy 
improved median PFS by approximately 2 months (9.7 versus 5.6 months; HR 0.65, 95% CI 
0.49-0.86) [Cortes et al, 2020]. 
Options are limited for second- or further-line treatment, and options for chemotherapy are 
the same as those for other subtypes.  In 2021, the FDA granted approval to sacituzumab 
govitecan for patients with unresectable locally advanced or metastatic TNBC who have 
received 2 or more prior systemic therapies, at least one of them for metastatic disease.  
Single agent pembrolizumab is also approved by the FDA for patients with unresectable or 
metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid 
tumors, or TMB-H tumors that have progressed following prior treatment and who have no 
satisfactory alternative treatment options.  However, pembrolizumab is only an option for 
patients who have previously not been treated with a PD-1/ PD-L1 inhibitor 
[Keytruda prescribing information, 2021].  Single agent cytotoxic chemotherapeutic agents 
are generally preferred over combination chemotherapy due to the lack of survival benefit 
and increased toxicity except in the setting of aggressive disease and visceral involvement 
[Cardoso et al, 2017; National Comprehensive Cancer Network, 2019].  Standard 
chemotherapy among pretreated patients is associated with low response rates (10% to 15%) 
and short progression-free survival (2 to 3 months) [Hurvitz & Mead, 2016].   
2.1.2 
Non-small Cell Lung Cancer 
Lung cancer (both small cell and non-small cell) is the leading cause of cancer deaths in the 
US [American Cancer Society, 2021a].  Most patients diagnosed with lung cancer are 
65 years of age or older and, the average age at the time of diagnosis is approximately 
70 years of age. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 38 of 160 
Amendment 6 
Non-small cell lung cancer accounts for approximately 84% of all lung cancers and can be 
subclassified as squamous (approximately 30% of NSCLC cases) and non-squamous 
(approximately 70% of NSCLC cases) histological types [American Cancer Society, 2021a].   
2.1.2.1 Squamous Non-small Cell Lung Cancer 
Squamous NSCLC is a distinct histological subtype of NSCLC that is challenging to treat as 
a result of specific patient and disease characteristics, which include older age, advanced 
disease at diagnosis, comorbid disease, and the central location of tumors 
[Socinski et al, 2018].  These characteristics have a bearing on treatment outcomes in 
advanced squamous NSCLC, resulting in a median survival rate of approximately 30% 
shorter than for patients with other NSCLC subtypes.   
Once immunotherapy has been utilized, there are limited treatment options, especially for 
later line treatment of advanced squamous NSCLC, with a resultant impact on survival 
outcomes [National Comprehensive Cancer Network, 2021b; Novello et al, 2016; 
Masters et al, 2015].  Given the recent approvals of targeted therapies and immunotherapies 
for advanced NSCLC and continuation towards personalization of lung cancer treatment, 
there is also a need to evaluate the effectiveness of these new treatments for advanced 
squamous NSCLC.  In addition, as targeted and immunotherapies shift earlier in the 
treatment paradigm, there will be limited options for later line treatment. 
2.1.2.2 Non-squamous Non-small Cell Lung Cancer 
Non-squamous NSCLC is a heterogenous disease with multiple treatment options dependent 
upon staging, presence of metastasis, and patient factors, including presence of comorbidities 
among other considerations.  As such, current treatment options include surgical resection, 
chemotherapy, radiation, immunotherapy, and targeted therapy.  Currently, the first-line 
therapy for patients with advanced or metastatic non-squamous NSCLC without targetable 
genetic aberrations is platinum-doublet chemotherapy plus pembrolizumab followed by 
maintenance therapy with at least one of the agents used in first line, either as continuation 
maintenance or as switch maintenance.  Nivolumab with ipilimumab can also be used with 
platinum doublet chemotherapy.  For patients with contraindications to PD-1/ PD-L1 
inhibitors, bevacizumab is often used as an alternative regimen.  Second line therapy for 
patients who have received immunotherapy in first line consists of docetaxel with or without 
ramucirumab, or single agent pemetrexed or gemcitabine [National Comprehensive Cancer 
Network, 2019].  With the exception of bevacizumab, and despite extensive study of multiple 
targeted and cytotoxic agents, the addition of a third agent to platinum-doublet chemotherapy 
has not been shown to improve progression-free or OS over platinum-doublet chemotherapy 
alone in randomized studies [Reck et al, 2010; Sandler et al, 2006]. 
2.1.3 
Head and Neck Cancer 
Head and neck cancer is a group of cancers that starts in the mouth, nose, throat, pharynx, 
larynx, sinuses, or salivary glands [National Cancer Institute, 2017].  Squamous cell 
carcinoma is the most frequent histological subtype of head and neck cancers, beside other 
rare histological types.  Squamous cell carcinoma arises from the mucosal epithelium in the 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 39 of 160 
Amendment 6 
oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell 
carcinoma (HNSCC). 
Worldwide, HNSCC is the 7th most common cancer (excluding nonmelanoma skin cancer), 
and accounts for approximately 900 000 new cases and over 400 000 deaths annually.  The 
incidence of HNSCC continues to rise and is anticipated to increase by 30% (that is, 
1.08 million new cases annually) by 2030 [Global Cancer Observatory, 2021].  South Asia 
has the highest head and neck cancer incidence rate, followed by Europe, North America, and 
Australasia [Aupérin, 2020].  In the United States, head and neck cancer accounts for 3% of 
malignancies, with approximately 66 000 patients developing head and neck cancer annually 
and 14 600 dying from the disease [Siegel, 2021].  Men are at higher risk of developing 
HNSCC with a ratio of male to female ranging from 2:1 to 4:1 [Johnson et al, 2020].  The 
median age of diagnosis for non-HPV (human papilloma virus) HNSCC is 66 years, whereas 
the median age of diagnosis for HPV-associated oropharyngeal cancer is 55 years 
[Windon et al, 2018]. 
The most common and consistent risk factors for HNSCC is tobacco and alcohol, which have 
multiplicative (synergistic) effect increasing the risk of developing HNSCC by 35-fold in 
heavy users of both substances [Blot, 1988].  A more recently identified risk factor for 
HNSCC is exposure to high-risk types of HPV, with an increasing incidence in 
HPV-associated oropharyngeal cancer (OPC). 
The survival for HNSCC has only modestly improved over the past three decades, because 
patients often develop locoregional recurrences, distant metastases and second primary 
tumors.  About 50% of patients with locally advanced HNSCC at diagnosis, develop 
recurrent and/or metastatic HNSCC, despite advances in multimodality therapy (combination 
of surgery, radiation therapy, chemotherapy, and targeted therapy [Leeman et al, 2017].  
Patients with recurrent and/or metastatic HNSCC have a very poor prognosis with a median 
overall survival (OS) of less than one year [Argiris et al, 2017]. 
Immunotherapy with immune check point inhibitors, has recently made a breakthrough in 
medical oncology in many different tumor types, including recurrent/metastatic HNSCC. 
Nivolumab and Pembrolizumab were the two PD-1 monoclonal antibody inhibitors approved 
in 2016 by the FDA in the second-line setting in recurrent/metastatic HNSCC who had 
progression of disease on platinum, and thus established a new standard of care (SOC) in the 
second line setting.  They were later approved in Europe for the same indication and 
Nivolumab was approved in Japan [Ferris et al, 2019].  At the present time, no 
recommendations exist based on clinical trial data on how to treat recurrent/metastatic 
HNSCC patients after exposure to first-
 
There has also been a recent paradigm change (2019 in US, Europe, Japan) in first line 
therapy of recurrent/metastatic HNSCC with Pembrolizumab +/- chemotherapy (platinum 
plus 5FU) based on the results of KEYNOTE-048 trial, which is the first trial since the 
publication of the EXTREME study (2008) to show OS improvement in the first line setting 
[Vermorken et al, 2008; Burtness et al, 2019].  In the second interim analysis of the 
KEYNOTE-048 study, in the PD-L1 CPS > 1 population, the median overall survival was 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 40 of 160 
Amendment 6 
12.3 months (95% CI 10.8, 14.9) for the pembrolizumab monotherapy group versus 
10.3 months (95% CI 9.0, 11.5) in the cetuximab plus chemotherapy group; HR was 0.78 
(95% CI 0.64, 0.96, p = 0.0086).  The benefit of pembrolizumab monotherapy compared with 
cetuximab plus chemotherapy in the CPS > 1 population was maintained at the final analysis 
(median OS 13.6 months for pembrolizumab monotherapy vs. 10.4 months for cetuximab 
plus chemotherapy; HR 0.65 (95% CI 0.53, 0.80) 
In the NCCN, ESMO and ESMO Pan-Asian guidelines, single agent pembrolizumab is 
considered a preferred regimen for patients with first line unresectable recurrent/metastatic 
HNSCC with CPS > 1 (NCCN Category 1, ESMO MCBS 4).  Pembrolizumab plus 
chemotherapy is also a NCCN Category 1, ESMO MCBS 4 recommendation for first line 
unresectable recurrent/metastatic HNSCC patients regardless of PD-L1 status [National 
Comprehensive Cancer Network, 2023; Keam, 2021; Machiels, 2020].  The choice of 
pembrolizumab monotherapy or chemotherapy plus pembrolizumab is based on CPS, tumor 
burden and symptoms [Keam, 2021].  Despite these recent advancements in the treatment of 
recurrent/metastatic HNSCC in the first and second-line setting, there is still an unmet 
medical need for new therapies both in first line patients and following progression of disease 
on platinum and PD-1 inhibitors. 
2.1.4 
Gastric, Gastroesophageal Junction and Esophageal Cancer 
Gastroesophageal cancers which include esophageal squamous cell carcinoma (ESCC), 
esophageal adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma and gastric 
adenocarcinoma accounted for > 1.6 million new cases and more than 1 million deaths 
worldwide in 2020 [Global Cancer Observatory, 2021].  Gastroesophageal adenocarcinoma 
(GEAC) and squamous cell carcinoma have distinct epidemiological, genetic and molecular 
characteristics [Siewert, 2007].  The majority of gastric and GEJ cancers are 
adenocarcinomas, whereas the majority of esophageal cancers are of squamous histology 
[National Comprehensive Cancer Network, 2021d].  Gastroesophageal adenocarcinomas are 
generally more prevalent in North America and Western Europe, while ESCC is the most 
common histology in Eastern Europe and Asia.  At present, gastroesophageal 
adenocarcinomas including adenocarcinomas of the GEJ and proximal stomach are 
increasing in incidence in Western countries, whereas the incidence of adenocarcinomas of 
the distal stomach are decreasing [National Comprehensive Cancer Network, 2021c].  The 
incidence of ESCC, which is often associated with alcohol and/or tobacco use, is declining in 
the West due to reduced alcohol and tobacco use, and currently accounts for < 30% of all 
esophageal cancers in the US and Western Europe. 
In first line, the systemic therapy regimens used to treat advanced gastric, GEJ, and 
esophageal cancers are very similar.  The preferred chemotherapeutic backbone regimen 
includes a fluoropyrimidine combined with a platinum-based agent [National Comprehensive 
Cancer Network, 2021c,d].  Biomarker assessment has become critically important for 
selection of 1L systemic therapy and it is recommended that patients should have their 
tumors assayed for HER2, PD-L1, mismatch repair deficiency, and microsatellite instability.  
For patients who have tumors that overexpress HER2, trastuzumab should be added 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 41 of 160 
Amendment 6 
[Yoon, 2021a] to first line cytotoxic agents.  First-line therapy with an immune checkpoint 
inhibitor in combination with cytotoxic chemotherapy has been shown to improve outcomes 
over cytotoxic chemotherapy alone for both gastroesophageal adenocarcinoma and squamous 
cell carcinomas.  In adenocarcinomas, immune checkpoint inhibitors have shown benefit 
when added to cytotoxic chemotherapy in patients with tumoral overexpression of PD-L1 and 
a CPS of 5 or more, as well as in patients with tumors deficient in mismatch repair (dMMR).  
Recent evidence suggests that PD-L1 overexpression may be a predictor of efficacy in 
squamous cell carcinoma as well.  
Following failure of the first-line regimen, the currently available standard of care differs for 
GEAC (which has a variety of recommended 2L+ options) versus squamous cell carcinoma 
(where available treatment options are more limited).  Second-line therapy is guided on case-
by-case factors including performance status, comorbidity, patient preference, symptom 
burden and quality of life.  The tumor histologic type, molecular analysis and the nature of 
the first-line regimen are also key considerations for subsequent treatment.  For patients with 
GEAC, several options may be utilized after first-line progression.  For HER2-positive 
GEAC, potential benefit has been shown for the antibody-drug conjugate fam-trastuzumab 
deruxtecan after progression on first-line trastuzumab.  Patients with GEAC who have PD-L1 
overexpression, dMMR/MSI-H or high TMB may benefit from treatment with 
pembrolizumab, if an immune checkpoint inhibitor was not administered for first-line 
therapy.  Patients with HER2-negative adenocarcinoma who have disease progression on or 
after prior treatment with fluroropyrimidine- or platinum-containing chemotherapy, and who 
are not eligible for or had disease progression with PD-1 targeted immunotherapy, may be 
treated with ramucirumab monotherapy or with a taxane.  Trifluridine/tipiracil is a common 
third-line option for patients with adenocarcinoma that is PD-L1 negative and has proficient 
mismatch repair, and is utilized as a fourth-line option for patients with 
PD-L1-positive/dMMR adenocarcinoma [Yoon, 2021b].  
Patients with ESCC have more limited options after failure of the first-line regimen. Patients 
eligible for immunotherapy, regardless of PD-L1 or MMR or TMB status, may be treated 
with nivolumab monotherapy (or camrelizumab where available) if PD-1 targeted 
immunotherapy was not utilized in the first line.  Rechallenge with immunotherapy is 
generally not pursued, unless in the context of a clinical trial or if the immunotherapy was 
discontinued due to a specific toxicity that has since resolved [Yoon, 2021b].  For patients 
who are not eligible for immunotherapy, a combination cytotoxic chemotherapy regimen not 
used in the first line is the recommended standard of care for patients who maintain an 
excellent performance status, favorable comorbidity and who are amenable to intensive 
treatment.  
The differences in the pathophysiology and treatment algorithms between GEAC and ESCC 
support the rationale for their separation into distinct cohorts in EV-202.  
2.2 
Enfortumab Vedotin 
ADCs, which consist of novel, highly active cytotoxics linked to monoclonal antibodies 
(mAbs) against cancer-specific targets, are potentially safer and more effective than 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 42 of 160 
Amendment 6 
conventional chemotherapy.  The rationale underlying therapy with ADCs is to target drug 
delivery.  The antibody treatment typically targets molecules expressed or prevalent on the 
surface of cancer cells; therefore, delivering maximum anticancer effects with minimal 
toxicity. 
Enfortumab vedotin is an ADC comprised of a fully human immunoglobulin G1 kappa 
(IgG1 ) antibody conjugated to the microtubule-disrupting agent (MMAE) via a 
protease-cleavable linker [Challita-Eid et al, 2016].  Enfortumab vedotin is thought to induce 
antitumor activity by binding to Nectin-4 protein on the cell surface leading to internalization 
of the ADC-Nectin-4 complex, which then traffics to the lysosomal compartment where 
MMAE is released via proteolytic cleavage of the linker.  Intracellular release of MMAE 
subsequently disrupts tubulin polymerization resulting in G2/M phase cell cycle arrest and 
apoptotic cell death [Francisco et al, 2003]. 
Nectin-4 is a 66 kDa type I transmembrane protein that belongs to the Nectin family of 
adhesion molecules.  It is composed of an extracellular domain (ECD) containing 3 Ig-like 
subdomains, a transmembrane helix, and an intracellular region [Takai et al, 2008].  Nectins 
are thought to mediate Ca2+-independent cell-cell adhesion via both homophilic and 
heterophilic trans interactions at adherens junctions where they can recruit cadherins and 
modulate cytoskeletal rearrangements [Rikitake & Takai, 2008].  Sequence identity of 
Nectin-4 to other Nectin family members is low and ranges between 25% to 30% in the ECD 
[Reymond et al, 2001]. 
2.2.1 
Nonclinical and Clinical Data 
2.2.1.1 Pharmacology 
Immunohistochemical studies demonstrated expression of Nectin-4 and Nectin-4 mRNA on a 
variety of tumor types including, but not limited to, bladder, breast, pancreatic and lung.  In 
vitro pharmacology studies demonstrated specific, high affinity binding of AGS-22M6E and 
AGS-22M6 (unconjugated antibody) to Nectin-4 expressed on human cancer cells 
[Challita-Eid et al, 2016]. 
AGS-22M6E bound human Nectin-4 antigen with high affinity and cross-reacted with similar 
affinity to cynomolgus monkey, rat and, with lower affinity, mouse orthologs of Nectin-4.  In 
addition, enfortumab vedotin bound human Nectin-4 with comparable affinity to AGS 
22M6E.  AGS-22M6E did not cross-react with other Nectin family members, such as 
Nectin-1, -2 or -3. 
In vitro, AGS-22M6E was internalized by cells that endogenously express Nectin-4, as well 
as by cell lines engineered to express Nectin-4 on the cell surface.  Internalization reached 
maximum levels by 4 hours and decreased thereafter.  The released payload, MMAE, was 
shown to be specifically delivered following Nectin-4 antigen engagement.  MMAE was 
delivered to the intracellular compartment of Nectin-4-transfected cells by enfortumab 
vedotin, while the parent cell line that did not express Nectin-4 had undetectable levels of 
MMAE, indicating that enfortumab vedotin delivery is Nectin-4 dependent. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 43 of 160 
Amendment 6 
Nectin-1 has been shown to bind to Nectin-4; however, Nectin-1 inhibition of enfortumab 
vedotin induced cytotoxicity could not be demonstrated. Enfortumab vedotin produced direct 
cell killing of Nectin-4-positive tumor cells and indirect bystander effect killing of 
surrounding Nectin-4-negative tumor cells in a concentration-dependent manner. 
Pharmacodynamic bridging studies of AGS-22M6E and enfortumab vedotin confirmed 
comparable binding affinity, cytotoxicity and in vivo efficacy between the 2 ADCs. 
In vivo and in vitro safety pharmacology parameters showed no effects in the CNS, 
respiratory and cardiovascular systems indicating an acceptable safety profile for these organ 
systems [Investigator Brochure]. 
Refer to the current Investigator’s Brochure for detailed nonclinical pharmacology data.  
2.2.1.2 Toxicology 
The toxicities observed following intravenous administration of enfortumab vedotin in 
animals were consistent with target-mediated uptake of enfortumab vedotin as well as some 
target-independent effects of MMAE. Target-mediated skin toxicity correlated with Nectin-4 
expression.  Bone marrow hypocellularity was the primary target-independent toxicity 
observed, and was observed with both the ADC and MMAE.  The toxicological target organs 
of skin, bone marrow, eye (corneal epithelium) and intestine correlated with clinically 
observed toxicities and were reversible following cessation of treatment.  No toxicities were 
observed with the unconjugated antibody, suggesting no impact from antigen binding alone.  
There were no indications of altered glucose homeostasis in the nonclinical toxicology 
program.  
Intravesical administration of enfortumab vedotin was well tolerated with minimal systemic 
drug exposure and no local or systemic toxicities observed.   
Embryo-fetal toxicity was observed in pregnant rats intravenously administered enfortumab 
vedotin or MMAE at clinically relevant systemic exposures.  These toxicities are likely 
related to MMAE and not an effect of the anti-Nectin-4 antibody.  Testicular toxicity was 
observed only in rats and was shown to be partially reversible by the end of a 24-week 
recovery period.  
MMAE is genotoxic (aneugenic) by its intended pharmacological activity. 
Refer to the current Investigator’s Brochure for detailed nonclinical toxicology data. 
2.2.1.3 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.   
Safety data have been integrated from subjects who received single-agent enfortumab vedotin 
in the phase 3 study (EV-301), phase 2 study (EV-201) and 3 phase 1 studies 
(AGS-22M6E-11-1, EV-101, and EV-102).  As of the dates of last evaluation for the 
completed studies (AGS-22M6E-11-1 [27 Apr 2015] and EV-102 [25 Feb 2019]) and the ISS 
data cutoff dates for ongoing studies EV-101 (17 Feb 2020), EV-201 (08 Sep 2020) and 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 44 of 160 
Amendment 6 
EV-301 [15 Jul 2020], a total of 749 subjects had received at least 1 dose of enfortumab 
vedotin ranging from 0.5 to 1.25 mg/kg across the 5 studies.  Of these, 680 subjects overall 
received enfortumab vedotin at the 1.25 mg/kg dose level.  In this integrated safety 
population, 740 of 749 (98.8%) subjects experienced at least 1 TEAE and 701 (93.6%) 
subjects experienced a TEAE considered possibly or probably related to study drug by the 
 3 TEAEs were experienced by 507 of 749 (67.7%) subjects overall.  
 3 TEAEs considered possibly or probably related to study drug were observed in 
354 of 749 (47.3%) subjects overall.  Serious TEAEs were experienced by 336 of 
749 (44.9%) subjects and 142 of 749 (19.0%) subjects experienced serious TEAEs 
considered possibly or probably related to study drug.  TEAEs leading to study drug 
discontinuation (permanent withdrawal of study drug) were reported in 145 of 749 (19.4%) 
subjects and in 93 of these subjects (12.4% of subjects overall) the TEAE was considered as 
at least possibly related to study drug.  Fifty (6.7%) subjects died due to a TEAE; in 
14 (1.9%) of these subjects, TEAEs leading to death were assessed by the investigator as at 
least possibly related to study drug. 
In the 1.25 mg/kg safety population, 673 of 680 (99.0%) subjects experienced at least 
1 TEAE and 639 (94.0%) subjects experienced a TEAE considered possibly or probably 
 3 TEAEs were experienced by 
468 (68.8%) subjects overall.  
 3 TEAEs considered possibly or probably related to 
study drug were observed in 332 (48.8%) subjects overall.  Serious TEAEs were experienced 
by 306 of 680 (45.0%) subjects and 132 (19.4%) subjects experienced serious TEAEs 
considered possibly or probably related to study drug.  TEAEs leading to study drug 
discontinuation (permanent withdrawal of study drug) were reported in 126 (18.5%) subjects 
and, in 84 of these subjects (12.4% of subjects overall) the TEAE was considered at least 
possibly related to study drug.  Forty-seven (6.9%) subjects died due to a TEAE; in 
14 (2.1%) of these subjects, TEAEs leading to death were assessed by the investigator as at 
least possibly related to study drug. 
In Study EV-301, a total of 608 subjects were randomized 1:1 to either enfortumab vedotin or 
chemotherapy treatment and 587 were dosed as of the 17 Dec 2020 data cutoff (296 subjects 
in the enfortumab vedotin arm and 291 subjects in the chemotherapy arm).  In the enfortumab 
vedotin arm, 290 (98.0%) subjects have experienced at least 1 TEAE and 141 (47.6%) 
subjects have experienced at least 1 serious TEAE.  In the chemotherapy arm, 288 (99.0%) 
subjects have experienced at least 1 TEAE and 131 (45.0%) subjects have experienced at 
least 1 serious TEAE. 
In Study EV-901, a total of 26 subjects have received at least 1 infusion of enfortumab 
vedotin.  All 26 (100%) subjects have experienced at least 1 TEAE and 11 (42.3%) subjects 
have experienced at least 1 serious TEAE. 
Safety data observed to date in the current study EV-202 aligns with the known safety profile 
in the metastatic urothelial cancer (mUC) population and no new safety issues have been 
identified.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 45 of 160 
Amendment 6 
Population pharmacokinetic modeling demonstrated that dose adjustment is not warranted in 
subjects with mild, moderate or severe renal impairment nor subjects with mild hepatic 
impairment (the effect of moderate or severe hepatic dysfunction on the pharmacokinetics of 
enfortumab vedotin has not been assessed).  The effect of end-stage renal disease, with or 
without dialysis, on the pharmacokinetics of ADC or unconjugated MMAE is unknown. 
Based on the safety data from clinical studies, the identified risks for enfortumab vedotin 
monotherapy are skin reactions (severe cutaneous adverse reactions [SCAR] and rash), 
hyperglycemia and pneumonitis/interstitial lung disease (ILD) (important identified risks); 
peripheral neuropathy, diarrhea/nausea/vomiting, extravasation events, dry eye (ocular 
disorders), neutropenia and anemia (identified risks); corneal disorders and blurred vision, 
IRRs other than extravasation events, ATAs, embryo-fetal toxicity and testicular toxicity 
(potential risks). 
Efficacy analyses have shown that enfortumab vedotin demonstrates antitumor activity.  In 
Study EV-101 (efficacy data cutoff: 25 Oct 2018), the confirmed ORR (complete response 
[CR] + partial response [PR]) in the metastatic UC 1.25 mg/kg dose group, was 42.9% 
(48 out of 112 subjects), including 5 subjects (4.5%) with CR and 43 subjects (38.4%) with 
PR.  In Study EV-102 (date of last evaluation: 25 Feb 2019), the confirmed ORR was 35.3% 
(6/17 subjects).  The majority of subjects had tumor shrinkage.  In Study AGS-22M6E-11-1, 
(date of last evaluation: 27 Apr 2015), 9 subjects with various solid tumors were treated with 
enfortumab vedotin; 5 (55.6%) subjects achieved stable disease and 4 (44.4%) subjects had 
progressive disease.  In Study EV-201 (data cutoff: 01 Mar 2019 for Cohort 1 and 
08 Sep 2020 for Cohort 2), the confirmed ORR per blinded independent central review 
(BICR) assessment was 44% (55 of 125 subjects) in Cohort 1 (previously treated with a 
platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor) and 52% (46 out of 
89 subjects) in Cohort 2 (previously treated with a PD-1/PD-L1 inhibitor, platinum naïve and 
cisplatin ineligible).  Per an FDA request, a later data cutoff date of 04 Dec 2020 was also 
used to provide an update to the DOR for Cohort 2 after all responders had been followed for 
at least 6 months from the onset of response.  The updated confirmed ORR per BICR 
assessment was 51% (45 of 89 subjects); there was a loss of 1 responder when an equivocal 
new lesion identified at week 8 became unequivocal at a later time point.  In Study EV-301 
(data cutoff: 15 Jul 2020), the OS of subjects with locally advanced or metastatic UC treated 
with enfortumab vedotin was significantly prolonged on the enfortumab vedotin arm 
compared with the chemotherapy arm, with a 30% reduction in the risk of death (HR = 0.702, 
95% CI: 0.556, 0.886; P = 0.00142, with a predetermined 1-sided significance level of 
0.00679 based on the number of observed deaths).  The median OS was 12.88 months for the 
enfortumab vedotin arm and 8.97 months for the chemotherapy arm. 
In Study EV-103, Cohort K evaluated enfortumab vedotin and pembrolizumab combination 
treatment as first line therapy for cisplatin-ineligible subjects with locally advanced or 
metastatic urothelial cancer (data cutoff: 10 Jun 2022).  In Cohort K, the confirmed ORR per 
BICR for subjects receiving enfortumab vedotin and pembrolizumab combination therapy 
was 64.5% (49 of 76 subjects), including 8 subjects (10.5%) with CR and 41 subjects 
(53.9%) with PR.  Activity was seen regardless of PD-L1 expression level, and the 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 46 of 160 
Amendment 6 
combination treatment was tolerable with a manageable safety profile 
[Rosenberg et al, 2022]. 
A summary of the clinical and nonclinical safety data and efficacy data relevant to the 
enfortumab vedotin and its study in human subjects are provided in the Investigator’s 
Brochure.  Based upon the totality of the safety data available, the observed safety profile 
supports further clinical development of enfortumab vedotin in the tumors selected for this 
study. 
2.2.2 
Summary of Key Safety Information for Enfortumab Vedotin 
As of the data cutoff for Enfortumab vedotin IB Edition 12 (17 Dec 2022), 1220 subjects had 
been treated with EV in studies AGS-2M6E-11-1, EV-101, EV-102, EV-103, EV-201, 
EV-202, EV-203 and EV-301.  AEs of interest for EV are based on current safety data from 
clinical studies and known risks with similar ADCs.  The important identified risks for EV 
are skin reactions (severe cutaneous adverse reactions and rash), hyperglycemia and 
pneumonitis/ILD.  Other identified risks are extravasation events, peripheral neuropathy, 
diarrhea/nausea/vomiting, dry eye (ocular disorders), neutropenia and anemia. The potential 
risks are corneal disorders and blurred vision (ocular disorders), IRRs (other than 
extravasation events), ATAs, embryo-fetal toxicity and testicular and ovarian toxicity.  
Please refer to the current Investigator’s Brochure for further details.   
2.3 
Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
pembrolizumab Investigator’s Brochure. 
Refer to the pembrolizumab Investigator’s Brochure (IB)/approved labeling for detailed 
background information on MK-3475. 
2.3.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis 
in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T cells/FoxP3+ regulatory T cells (T-regs) correlates with improved prognosis and 
long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 47 of 160 
Amendment 6 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [Hunder et al, 2008; Dudley et al, 2005]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD-L2) 
[Greenwald et al, 2005; Okazaki et al, 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al, 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
kinase C-
-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Riley, 2009; Chemnitz et al, 2004; 
Sheppard et al, 2004; and Okazaki et al., 2001]. The mechanism by which PD-1 
down-modulates T cell responses is similar to, but distinct from, that of CTLA-4, because 
both molecules regulate an overlapping set of signaling proteins [Francisco et al, 2010; 
Parry et al, 2005].  
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities [Spranger et al, 2014; Curran et al, 2010; Pilon-Thomas et al, 2010; Weber, 2010; 
Hirano et al, 2005; Blank et al, 2004; Strome et al, 2003;].  Anti-mouse PD-1 or anti-mouse 
PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal 
carcinoma [Curran et al, 2010; Pilon-Thomas et al, 2010; Nomi et al, 2007; 
Zhang et al, 2004; Strome, 2003].  In such studies, tumor infiltration by CD8+ T cells and 
increased IFN-
mechanism underlying the antitumor activity of PD-1 checkpoint inhibition involved local 
infiltration and activation of effector T cell function in vivo [Curran et al, 2010].  
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a 
monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor 
models (see the pembrolizumab IB). 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 48 of 160 
Amendment 6 
2.4 
Study Rationale 
In cohorts 1 to 8, enfortumab vedotin will be administered at a dose of 1.25 mg/kg as an 
intravenous 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 subjects with urothelial cancer.  The tumors selected for this study were based on 
Nectin-4 expression, nonclinical data, sensitivity to microtubule inhibition, incidence rate and 
potential unmet clinical need.   
A phase 1 dose escalation and expansion study (EV-101) with enfortumab vedotin 
monotherapy in subjects with metastatic urothelial cancer and other malignant solid tumors 
demonstrated encouraging antitumor activity.  Enfortumab vedotin provided durable 
responses and meaningful survival results in subjects after anti-PD-(L)-1 therapy in a 
population with a high unmet medical need.  The confirmed ORR by central review was 45% 
in subjects with urothelial cancer [Rosenberg et al, 2019].  The median OS of 12.3 months is 
 
Study EV-102 is an open-label, randomized, dose escalation study assessing safety, 
tolerability and pharmacokinetics of enfortumab vedotin in Japanese subjects with locally 
advanced or metastatic urothelial cancer.  Enfortumab vedotin at a dose of 1.25 mg/kg was 
safe and generally well tolerated in Japanese subjects with locally advanced or metastatic 
urothelial cancer.  Pharmacokinetic profiles and clinical responses (ORR 35%; disease 
control rate [DCR] 77%) of enfortumab vedotin were encouraging and consistent with reports 
in a North American population. 
In a pivotal phase 2 study (EV-201) [Petrylak et al, 2019], urothelial cancer subjects must 
have had prior treatment with platinum-containing chemotherapy or be platinum-naïve and 
ineligible for cisplatin treatment.  The results for this study demonstrated that enfortumab 
vedotin was the first novel therapeutic to demonstrate substantial clinical activity in subjects 
who progressed after platinum chemotherapy and a PD-1/L1 inhibitor.  The confirmed ORR 
was 44% in subjects treated with enfortumab vedotin 1.25 mg/kg.  The median OS was 
11.7 months and the median DOR was 7.6 months.  These results are highly consistent with 
the phase 1 EV-101 trial in the same subject population.  
Phase 3 study EV-301 enrolled 608 subjects with locally advanced or metastatic urothelial 
cancer who received prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.  The 
primary efficacy endpoint of overall survival was 12.9 months in the EV arm versus 
9 months for those receiving chemotherapy.  Median PFS was 5.6 months compared with 
3.7 months, respectively.  The ORR was 40.6% versus 17.9%, respectively.  
Immunohistochemical studies have demonstrated expression of Nectin-4 and Nectin-4 
mRNA on a variety of tumor types including, but not limited to, bladder, breast, pancreatic 
and lung.  In vitro pharmacology studies have demonstrated specific high affinity binding of 
AGS-22M6E and AGS-22M6 (unconjugated antibody) to Nectin-4 expressed on human 
cancer cells [Challita-Eid et al, 2016]. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 49 of 160 
Amendment 6 
Given the broad expression of Nectin-4 across a variety of tumors and the activity seen to 
date in urothelial cancer, the sponsor has identified additional tumors to evaluate enfortumab 
vedotin including breast, lung, head and neck, gastric, GEJ, and esophageal cancers.  
Nectin-4 expression is not an inclusion requirement in this study because it is typically 
prevalent in these tumor types.  However, Nectin-4 expression will be assessed 
retrospectively.  
This study is designed to assess the safety and antitumor activity of enfortumab vedotin 
monotherapy in these selected tumors.  In addition, the study will identify the efficacy signal 
with enfortumab vedotin in well-defined patient populations. 
The tumors selected for the current study (breast, lung, head and neck, gastric, GEJ, and 
esophageal cancer) are representative of tumors with moderate to high Nectin-4 expression, 
and for which there is a need to improve outcomes in the advanced and treatment refractory 
setting.  Furthermore, the supportive preclinical sensitivity to enfortumab vedotin, along with 
the clinical data, and evidence based on published literature provide support for the current 
study.  Cohort 6 was designed as a mixed population of subjects with gastric, GEJ, and 
esophageal cancers.  Consistent with current clinical practice guidelines regarding standard of 
care treatment for different histologies of gastroesophgeal cancers, in Amendment 2, all 
subjects enrolled into Cohort 6 under protocol versions 1 and 2 are reallocated to 2 cohorts 
based on tumor histology:  Cohort 7, which will comprise subjects with gastric cancer, 
esophageal adenocarcinoma and GEJ adenocarcinoma and Cohort 8, which will comprise 
subjects with esophageal squamous cell carcinoma (ESCC).  Each cohort will continue to 
enroll and be assessed according to the guidance provided in [Section 4 Study Design].   
2.4.1 
Rationale for Cohort 9 – Enfortumab Vedotin and Pembrolizumab in 
Combination  
Pembrolizumab demonstrated effective antitumor activity as a single agent in 
KEYNOTE-048 in subjects with metastatic or unresectable, recurrent HNSCC whose tumors 
express PD-
 1), and it is approved for use as monotherapy in both first-line and 
second-line HNSCC [Burtness et al, 2019].  Although the approval of pembrolizumab in this 
patient population represents a significant advancement in the treatment of HNSCC, patients 
with recurrent/metastatic HSNCC continue to have poor prognosis and limited durability of 
response with the currently available standard of care [Burtness et al, 2019].  
The primary analysis of EV-202 cohort 5 was completed on 27 Jul 2022, and the number of 
subjects with confirmed responses exceeded the protocol pre-specified minimum number of 
responders to claim promising antitumor activity. Cohort 5 enrolled 46 subjects 
(30 North American, 16 Japanese; 40 were male) who had each received prior treatment with 
platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor.  The cORR (per Investigator 
assessment) for the cohort was 23.9%, including 1 subject with a CR and 10 subjects with 
PR, with a median duration of response of 9.4 months (median DOR was reached 
approximately 3 months after primary analysis). DCR (per Investigator assessment) was 
56.5%.  The safety data observed in cohort 5 were consistent with the known safety profile of 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 50 of 160 
Amendment 6 
enfortumab vedotin, and no new safety signals were identified.  These data suggest that 
enfortumab vedotin has promising antitumor activity in recurrent/metastatic HNSCC. 
Preclinical studies of vedotin ADCs, including enfortumab vedotin, show that these ADCs 
induce hallmarks of immunogenic cell death, including the release of damage-associated 
molecular patterns which ultimately may lead to engulfment of tumor cells by 
antigen-presenting cells and subsequent cross-presentation of tumor antigens to cytotoxic 
T cells.  These T cells mount antigen-specific responses that are further augmented by 
PD1/PD-L1 inhibitors, such as pembrolizumab [Hoimes, 2023]. Thus, combining enfortumab 
vedotin with pembrolizumab may enhance antitumor activity versus either agent alone on the 
basis of their distinct and complementary engagement of the immune system. 
In the EV-103 study, combination therapy of enfortumab vedotin and pembrolizumab 
demonstrated compelling efficacy in first line cisplatin-ineligible subjects with locally 
advanced/mUC, resulting in rapid and durable responses, with a manageable safety profile.  
These data suggest that the combination of enfortumab vedotin and pembrolizumab may have 
the potential to improve patient outcomes better as compared to the use of either agent alone.  
As discussed above, clinical trials in HNSCC such as KEYNOTE-040 and KEYNOTE-048 
have demonstrated that the PD 1/PD-L1 pathway is an effective target for therapeutic 
intervention in HNSCC [Burtness et al, 2019]. 
Based on the demonstrated efficacy of pembrolizumab in R/M HNSCC and the observed 
antitumor activity of enfortumab vedotin in HSNCC in the current study, and the favorable 
benefit/risk profile of the combination of enfortumab vedotin and pembrolizumab in the 
EV103 study, it is hypothesized that combination therapy with enfortumab vedotin and 
pembrolizumab may have potential as a first-line treatment in PD-L1 positive patients with 
R/M HNSCC.  
2.5 
Risk/Benefit Assessment 
Subjects with locally advanced or metastatic cancer selected for this study have cancer that 
recurred or progressed following standard of care therapy and have limited treatment options.  
Nonclinical and clinical data to date support a favorable benefit/risk ratio for enfortumab 
vedotin in subjects with urothelial cancer and supports further exploration of the use of 
enfortumab vedotin in other locally advanced or metastatic cancers including breast, lung, 
head and neck, gastric, GEJ, and esophageal cancer. 
The identified and potential risks associated with enfortumab vedotin are outlined in the 
[Sections 2.2.1.2, 2.2.1.3 and 2.2.2], and the enfortumab vedotin Investigator’s Brochure.  
Evidence of clinical activity in locally advanced or metastatic urothelial carcinoma has been 
observed in other single-arm studies of enfortumab vedotin (described in [Section 2.2.1.3 
Clinical Data]) and this may translate into an improvement in outcome for the tumors 
selected for this trial.  However, there may still be no direct benefit to subjects participating 
in the current clinical study. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 51 of 160 
Amendment 6 
For each cohort, one interim analysis is planned to assess the antitumor activity for that 
cohort and a decision rule will be in place in order to not expose subjects to an ineffective 
treatment.  A Bayesian optimal design for Phase 2 [Zhou et al, 2017] will be used to guide 
the interim decision rule [Section 9.11 Interim Analysis]. 
To assure an ongoing favorable benefit/risk assessment for subjects enrolled into the study, a 
Safety Monitoring Committee (SMC) will be utilized to monitor safety data as described in 
[Section 10.4.1 Safety Monitoring Committee]. 
2.5.1 
Risk/Benefit Assessment for Combination of Enfortumab Vedotin and 
Pembrolizumab 
Pembrolizumab has a positive benefit/risk profile and is well tolerated in the approved 
indications.  Publications of a significantly positive benefit/risk ratio have been reported for 
melanoma in a single arm study encompassing nearly 1000 subjects (KEYNOTE -001), 
which led to US FDA approval in September 2014.  Pembrolizumab has subsequently 
received approval for the treatment of patients with NSCLC and for the treatment of patients 
with R/M HNSCC.  In 2019, pembrolizumab received FDA approval for the first-line 
treatment of patients with metastatic or unresectable recurrent HNSCC.  Pembrolizumab was 
approved for use in combination with platinum and fluorouracil (FU) for all patients and as a 
single agent for patients whose tumors express PD-
.  The approval was based on 
the results of the KEYNOTE-048 trial in which subjects were randomized (1:1:1) to receive 
one of the following treatments: pembrolizumab as a single agent; pembrolizumab, 
carboplatin or cisplatin, and FU; or cetuximab, carboplatin or cisplatin, and FU.  
The KEYNOTE-048 trial demonstrated a statistically significant improvement in OS in the 
overall population for subjects randomized to pembrolizumab plus chemotherapy compared 
with cetuximab plus chemotherapy at a pre-specified interim analysis.  The median OS for 
 1 subgroup was 13.6 months for the pembrolizumab plus chemotherapy arm and 
10.4 months for the cetuximab plus chemotherapy arm (HR 0.65; 95% CI: 0.53, 0.80; 
p = 
 20 subgroup with median OS 14.7 vs 
11.0 months (HR 0.60; 95% CI: 0.45, 0.82). 
The trial also demonstrated statistically significant improvements in OS for the subgroups of 
subjects with PD-L1 CPS 
-
 20 HNSCC randomized to 
pembrolizumab as a single agent compared with cetuximab plus chemotherapy.  In the CPS 
 1 subgroup, the median OS was 12.3 months for the pembrolizumab arm and 10.3 months 
for the cetuximab plus chemotherapy arm (HR 0.78; 95% CI: 0.64, 0.96; p = 0.0171).  For 
10.7 months for the cetuximab plus chemotherapy arm (HR 0.61; 95% CI: 0.45, 0.83; 
p = 0.0015). At the time of the interim analysis, there was no significant difference in OS 
between the pembrolizumab as a single agent arm and the cetuximab plus chemotherapy arm 
for the overall population. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 52 of 160 
Amendment 6 
There were no significant differences in progression-free survival for either 
pembrolizumab-containing arm compared to the cetuximab plus chemotherapy arm in any 
population. 
While evidence of activity in this indication have been observed in the current study, there 
may still be no direct benefit to subjects participating in this cohort.  Additional details 
regarding specific benefits and risks for subjects participating in this clinical trial may be 
found in the accompanying iBs and Informed Consent documents. 
 20% of subjects who received 
pembrolizumab as a single agent in KEYNOTE-048 were fatigue, constipation, and rash. In 
KEYNOTE-048, pembrolizumab was discontinued for adverse reactions in 12% of subjects 
in the pembrolizumab single agent arm. The most common adverse events resulting in 
permanent discontinuation of pembrolizumab were sepsis (1.7%) and pneumonia (1.3%).  
Adverse events leading to the interruption of pembrolizumab occurred in 31% of subjects; the 
m
 2%) were 
pneumonia (2.3%), pneumonitis (2.3%) and hyponatremia (2%) [KEYTRUDA Prescribing 
Information, Merck Sharp & Dohme LLC, 2021].  
 20% of subjects who received 
pembrolizumab in combination with chemotherapy in KEYNOTE-048 were nausea, fatigue, 
constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and 
cough. 
The recommended pembrolizumab dose for HNSCC is 200 mg administered as an 
intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable 
toxicity, or up to 24 months in subjects without disease progression. 
The combination of enfortumab vedotin and pembrolizumab has demonstrated efficacy in 
previously untreated cisplatin ineligible subjects with locally advanced or metastatic 
urothelial cancer in Cohort K of study EV-103.  In this study, a total of 149 subjects were 
treated (76 subjects were treated with the combination and 76 subjects received enfortumab 
vedotin monotherapy).  The confirmed ORR for the combination of enfortumab vedotin plus 
pembrolizumab was 64.5% (95% CI 52.7, 75.1).  The median DOR was not reached 
[Rosenberg et al, 2022].   
TEAEs of special interest included skin reactions (EV+P, n = 51 [67.1%]; EV, n = 33 
[45.2%]), peripheral neuropathy (EV+P, n = 46 [60.5%]; EV, n = 40 [54.8%]), ocular 
disorders (e.g., dry eye and blurred vision; EV+P, n = 20 [26.3%]; EV, n = 21 [28.8%]) and 
hyperglycemia (EV+P, n = 11 [14.5%]; EV, n = 8 [11.0%]).  The majority of treatment 
related AESIs were g
 2. [Rosenberg et al, 2022].  The safety profile was generally 
consistent with the known profile for EV+P.  EV monotherapy was consistent with prior 
experience. 
The potential for overlapping toxicities in the combination of enfortumab vedotin and 
pembrolizumab is recognized by the sponsors and carefully monitored. In many cases it is not 
possible to attribute causality clearly to one agent or the other.  The sponsors’ approach has 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 53 of 160 
Amendment 6 
been to compare the emerging combination safety data to the known safety profile of each 
agent, also taking into consideration what is known about the mechanism of toxicity.  
Subjects receiving the combination of enfortumab vedotin and pembrolizumab have 
experienced identified risks observed with monotherapy enfortumab vedotin which include: 
pneumonitis, skin reactions (SCAR and rash), hyperglycemia, peripheral neuropathy, 
neutropenia, anemia, gastrointestinal symptoms (nausea, vomiting and diarrhea), and 
extravasation site reactions.  Subjects with mUC receiving the combination of enfortumab 
vedotin and pembrolizumab have also experienced potential risks observed with enfortumab 
vedotin monotherapy which include: ocular toxicity (blurred vision and corneal disorders).  
These risks should be managed according to the guidance described in the protocol. 
Immune-mediated adverse events (imAEs) known to occur with PD-1/PD-L1 inhibitors were 
observed.  The protocol-defined adverse event of interest category of imAEs was specific to 
the EV-103 study for treatment with enfortumab vedotin in combination with the PD-1 
inhibitor pembrolizumab and was aligned with the pembrolizumab search strategy.  
imAEs associated with pembrolizumab exposure may occur shortly after the first dose or 
several months after the last dose of pembrolizumab treatment and may affect more than one 
body system simultaneously.  Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on existing clinical study data regarding imAEs 
associated with pembrolizumab, most were reversible and could be managed with an 
interruption of pembrolizumab, administration of corticosteroids and/or other supportive care.  
For suspected imAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes.  Additional procedures or tests such as bronchoscopy, endoscopy, and/or skin biopsy 
may be included as part of the evaluation.  Based on the severity of imAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids.  Dose delay and 
toxicity management guidelines for imAEs associated with pembrolizumab are provided in 
the pembrolizumab package insert and IB. 
Reported events in EV-103 appear consistent with immune events reported with checkpoint 
inhibitors and no new safety signals have been observed.  To assure a favorable risk-benefit 
balance for subjects enrolled in cohort 9, careful monitoring by the safety monitoring 
committee will continue. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 54 of 160 
Amendment 6 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
The primary, secondary and exploratory objectives and endpoints for this study are listed in 
[Table 5] and [Table 6]. 
Table 5 
Cohorts 1 to 8 Objective(s) and Endpoint(s) 
Objective(s) 
Endpoint(s) 
Primary 
 
To determine the antitumor activity of 
enfortumab vedotin as measured by confirmed 
ORR per investigator assessment 
 
Confirmed ORR (complete response [CR] + 
PR) per Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 as determined 
by investigator 
Secondary 
 
To assess other measures of antitumor activity 
of enfortumab vedotin per investigator 
assessment 
 
 
 
 
 
 
To assess the OS 
 
 
To assess the safety and tolerability of 
enfortumab vedotin 
 
DOR per RECIST Version 1.1 per investigator 
assessment 
 
DCR (CR + PR + stable disease [SD]) per 
RECIST Version 1.1 per investigator 
assessment 
 
PFS per RECIST Version 1.1 by investigator 
assessment 
 
 
OS 
 
 
Safety variables  
o Adverse events (AEs) 
o Laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiogram 
o Eastern Cooperative Oncology Group 
(ECOG) performance status 
Exploratory 
 
To evaluate potential genomic and/or other 
biomarkers that may correlate with treatment 
outcome, including Nectin-4 expression 
 
 
To assess the pharmacokinetics of enfortumab 
vedotin and MMAE 
 
 
To assess the immunogenicity of enfortumab 
vedotin 
 
 
To evaluate the treatment effect of enfortumab 
vedotin on quality of life (QOL) 
 
 
To assess measures of antitumor activity of 
enfortumab vedotin per blinded independent 
central review (BICR) 
 
Exploratory genomic and/or other biomarkers 
that may correlate with treatment outcome, 
including Nectin-4 expression 
 
 
Selected pharmacokinetic parameters of 
enfortumab vedotin and MMAE 
 
 
Incidence of antitherapeutic antibodies (ATA) 
to enfortumab vedotin 
 
PRO per EuroQOL 5-dimensions (EQ-5D-5L) 
and global pain assessment (worst pain in the 
last 24 hours) 
 
 
Response related endpoints per BICR 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 55 of 160 
Amendment 6 
Table 6 
Cohort 9 Objective(s) and Endpoint(s) 
Objective(s) 
Endpoint(s) 
Primary 
 
To determine the antitumor activity of 
enfortumab vedotin in combination with 
pembrolizumab  
 
Confirmed ORR (CR + PR) per RECIST 
Version 1.1 as determined by investigator 
Secondary 
 
To assess other measures of antitumor activity 
of enfortumab vedotin in combination with 
pembrolizumab per investigator assessment 
 
 
 
 
 
To assess the OS of enfortumab vedotin in 
combination with pembrolizumab  
 
 
To assess the safety and tolerability of 
enfortumab vedotin in combination with 
pembrolizumab  
 
DOR per RECIST Version 1.1 by investigator 
assessment 
 
DCR (CR + PR + SD) per RECIST Version 1.1 
by investigator assessment 
 
PFS per RECIST Version 1.1 by investigator 
assessment 
 
 
OS 
 
 
Safety variables  
o AEs 
o Laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiogram 
o ECOG performance status 
Exploratory 
 
To evaluate potential genomic and/or other 
biomarkers that may correlate with treatment 
outcome, including Nectin-4 expression 
 
 
To assess the pharmacokinetics of enfortumab 
vedotin and MMAE  
 
 
 
To assess the immunogenicity of enfortumab 
vedotin 
 
 
To evaluate the treatment effect of enfortumab 
vedotin in combination with pembrolizumab on 
QOL 
 
 
 
To assess measures of antitumor activity of 
enfortumab vedotin in combination with 
pembrolizumab per BICR 
 
 
To assess measures of antitumor activity of 
enfortumab vedotin in combination with 
pembrolizumab per modified RECIST v1.1 for 
immune-based therapeutics (iRECIST) 
 
Exploratory genomic and/or other biomarkers 
that may correlate with treatment outcome, 
including Nectin-4 expression 
 
 
Selected pharmacokinetic parameters of 
enfortumab vedotin and MMAE 
 
 
 
Incidence of ATA to enfortumab vedotin  
 
 
 
PRO per EORTC QLQ H&N43, global pain 
assessment (worst pain in the last 24 hours), 
FACT-G question G05 and symptom-specific 
questions from PRO-CTCAE 
 
 
ORR, DOR, DCR and PFS per RECIST 
Version 1.1 by BICR 
 
 
 
ORR, DOR, DCR and PFS per iRECIST by 
investigator assessment 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 56 of 160 
Amendment 6 
4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Study Design 
This is an open-label, multicenter, multicohort, phase 2 study designed to assess the 
antitumor activity and safety of enfortumab vedotin as a single agent (cohorts 1 to 8) and in 
combination with pembrolizumab (cohort 9) in adult subjects with locally advanced or 
metastatic malignant solid tumors.  Approximately 40 subjects will be enrolled into each of 
the following cohorts in a 2 stage design.  
 Cohort 1: HR+/HER2- breast cancer; or 
 Cohort 2: TNBC; or 
 Cohort 3: Squamous NSCLC; or 
 Cohort 4: Non-squamous NSCLC; or 
 Cohort 5: Head and neck cancer; or 
 Cohort 6: Gastric or GEJ or esophageal cancer (reallocated to Cohorts 7 or 8) 
 Cohort 7: Gastric and EAC including GEJ adenocarcinoma 
 Cohort 8: ESCC 
 Cohort 9: First-line HNSCC 
Subjects enrolled into Cohort 6 will be reallocated based on disease type and histology into 
Cohorts 7 or 8.  
For each cohort, one interim analysis is planned to assess the antitumor activity for that 
cohort.  The interim analysis will be performed for a given cohort at the time when 
20 subjects are evaluable for tumor response per investigator assessment following study 
treatment.  A Bayesian optimal design for phase 2 (BOP2) [Zhou et al, 2017] is used to guide 
interim decision rule.  For each cohort, based on the 2-stage BOP2 design, when the number 
of subjects with confirmed response (CR and PR) is less than the prespecified minimum 
number of responders at stage 1, the enrollment of the cohort may stop; otherwise, the 
enrollment will continue into Stage 2 until the planned size of the cohort is reached.  
In cohorts 1 to 8, subjects will receive enfortumab vedotin at a dose of 1.25 mg/kg as an 
intravenous infusion on days 1, 8 and 15 of each 28-day cycle. 
In cohort 9, subjects will receive enfortumab vedotin 1.25 mg/kg on days 1 and 8 and 
pembrolizumab 200 mg on day 1 of each 21-day cycle. 
For each subject, the study will consist of 3 periods: screening/baseline, treatment and 
follow-up.  The screening/baseline period will take place up to 28 days prior to the first dose 
of study treatment.  For cohort 9, a local PD-L1 test result may be used for eligibility. A 
PD-
 is required for enrollment.  An archival tumor sample will be submitted from 
each subject for central PD-L1 and other biomarker testing.  If archival tumor tissue for 
central PD-L1 testing is insufficient or not available, a biopsy will be performed to obtain a 
tumor sample for central testing. 
In the treatment period, starting at cycle 1, subjects in cohorts 1 to 8 will receive enfortumab 
vedotin on days 1, 8, and 15 every 28-day cycle until one of the treatment discontinuation 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 57 of 160 
Amendment 6 
criteria are met.  Subjects in cohort 9 will receive enfortumab vedotin on days 1 and 8 and 
pembrolizumab on day 1 of each 21-day cycle until a discontinuation criteria is met.  
For cohorts 1 to 8, imaging scan and disease assessment will be performed at 
screening/baseline and repeated every 8 weeks (56 days ± 7 days) from the first dose of study 
treatment throughout the study until the subject has radiologically-confirmed disease 
progression, initiates a new subsequent anticancer therapy, dies, withdraws consent, is lost to 
follow-up or the study closes, whichever occurs first.  After 1 year on study treatment, the 
frequency of disease assessment will be reduced to every 12 weeks (84 days ± 7 days).  
Subjects in cohorts 1 to 8 who discontinue study treatment for reasons other than 
radiologically-confirmed disease progression by RECIST Version 1.1 will enter into a post 
treatment follow-up period and continue to receive imaging scans every 8 weeks (56 days 
± 7 days) until the subject has radiologically-confirmed disease progression, initiates a new 
anticancer therapy, dies, withdraws consent, is lost to follow-up or the study closes, 
whichever occurs first. 
In cohort 9, the first on-study imaging and disease assessment will be performed 9 weeks 
(63 days ± 7 days) from the first dose of study treatment and then every 6 weeks (42 days 
± 7 days) throughout the study until the subject has radiologically-confirmed disease 
progression (iCPD per iRECIST), initiates a new subsequent anticancer therapy, dies, 
withdraws consent, is lost to follow-up or the study closes, whichever occurs first.  Subjects 
in cohort 9 with unconfirmed progressive disease per iRECIST guidelines 
[Seymour et al, 2017] who are clinically stable may continue on study treatment until 
progression is confirmed by the investigator (iCPD) at the next imaging assessment 6 weeks 
(± 7 days) after iUPD.  Treatment with pembrolizumab will be discontinued once the subject 
has received a maximum of 35 administrations of pembrolizumab (approximately 2 years). 
Subjects in cohort 9 who discontinue study treatment (both enfortumab vedotin and 
pembrolizumab) for reasons other than radiologically confirmed disease progression per 
iRECIST will enter into a post treatment follow-up period and have physical exams, ECOG 
and disease assessments every 6 weeks (± 7 days) up to 18 months after first dose, then every 
9 weeks (± 7 days) until the subject has radiologically confirmed disease progression per 
iRECIST as determined by the investigator, initiates a subsequent anticancer therapy, dies, 
withdraws consent, or the study closes.  During study treatment, palliative radiotherapy on a 
nontarget lesion that is not progressing will not be considered a subsequent anticancer 
therapy; however, radiotherapy on any target lesion will be a subsequent anticancer therapy. 
Copies of all imaging scans will also be sent to the independent review facility in a timely 
manner.  Images at the independent review facility will be stored.  Imaging scans for a cohort 
may be read at the independent review facility when the minimum number of responders per 
investigator assessment (subjects with confirmed CR and PR) to claim promising antitumor 
activity at stage 1 are met based on the 2-stage BOP2 design.  Central images may also be 
read in certain circumstances as determined by the sponsor.  
An end of treatment (EOT) visit will be performed within 7 days after the last dose of 
enfortumab vedotin or the decision to discontinue treatment, or prior to initiation of another 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 58 of 160 
Amendment 6 
anticancer therapy, whichever occurs earlier. This will be followed by a 30-day safety 
follow-up to be completed 30 days (+ 7-day window) from the last dose of enfortumab 
vedotin.  The 30-day follow-up assessments should be completed prior to the initiation of 
another anticancer therapy. 
After radiologically-confirmed disease progression or initiation of subsequent anticancer 
therapy, whichever occurs first, subjects will be contacted every 12 weeks in the long-term 
follow-up period for survival status until death, withdrawal of consent, lost to follow-up or 
study closure, whichever occurs first.  Telephone contact with the subject is sufficient in the 
long-term follow-up period unless any assessment must be repeated to confirm resolution of 
drug-related AEs. 
Confirmed ORR per investigator assessment is the primary endpoint.  Confirmed ORR is 
defined as the proportion of subjects whose objective response is confirmed CR or PR 
according to RECIST Version 1.1.  Response (CR or PR) must be confirmed with a repeat 
imaging scan 4 weeks (28 days + 7-day window) after first response.   
Blood samples for pharmacokinetics and ATA will be collected at protocol-specified time 
points.  Validated assays will be used to measure the concentrations of enfortumab vedotin 
and MMAE in serum or plasma and to assess ATA.  Samples for exploratory biomarkers will 
be collected at protocol-specified time points.  Enfortumab vedotin biomarker assessments 
will not be used for subject selection. 
4.2 
Dose Rationale 
4.2.1 
 Enfortumab Vedotin 
In cohorts 1 to 8, subjects will receive enfortumab vedotin at a dose of 1.25 mg/kg as an 
intravenous infusion on days 1, 8 and 15 of each 28-day cycle.  This dose and regimen has 
demonstrated an acceptable safety profile and encouraging clinical activity in the phase 1 
study (EV-101 [ASG-22CE-13-2]), the phase 2 study (EV-201) and the phase 3 study 
(EV-301).  
The phase 1 study (EV-101) evaluated escalating dose levels of 0.5, 0.75, 1 and 1.25 mg/kg, 
with expansion cohorts at the 0.75, 1, and 1.25 mg/kg dose levels.  A maximum tolerated 
dose (MTD) was not reached in this study.  At the 1 mg/kg dose level, 2 dose-limiting 
toxicities (DLTs) were observed: grade 3 proctalgia (later changed to grade 2 by the 
investigator) thought related to radiation recall and grade 4 hyperuricemia without clinical 
sequelae.  No DLT was observed at 1.25 mg/kg and doses above 1.25 mg/kg were not tested. 
EV-201 is a single-arm study of enfortumab vedotin (1.25 mg/kg intravenously on days 1, 8, 
and 15 of every 28-day cycle) in subjects with urothelial carcinoma from the US and Japan.  
Results from this study were consistent with the EV-101 study.  AEs in cohort 1 (n = 125) 
were consistent with those previously reported in enfortumab vedotin clinical development 
program. 
EV-301 (7465-CL-0301) is a phase 3 study evaluating the safety and efficacy of enfortumab 
vedotin given as monotherapy on days 1, 8 and 15 of each 28-day cycle versus chemotherapy 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 59 of 160 
Amendment 6 
in subjects with locally advanced or metastatic UC who were previously treated with 
chemotherapy and PD-1/PD-L1 inhibitors. The observed safety and efficacy results of 
EV-301 further support the 1.25 mg/kg dose regimen.   
Incidence of some of the most frequent drug-related AEs, such as diarrhea and rash, although 
primarily grades 1 to 2 and clinically manageable, increased with increasing dose levels.  
Moreover, dose reductions due to AEs were more frequent for the 1.25 mg/kg vs lower dose 
levels.  Safety assessments of both metastatic urothelial cancer subjects and nonmetastatic 
urothelial cancer subjects showed that frequency of all TEAEs, AEs leading to withdrawal, 
and grade 3 to 4 TEAEs were comparable across all dose levels. 
While all doses of enfortumab vedotin demonstrated activity, the 1.25 mg/kg dose was 
associated with the highest activity and had an acceptable safety profile. 
Enfortumab vedotin exposure response analyses of best overall response (BOR), PFS and OS 
outcomes suggested an apparent efficacy plateau at higher systemic exposure levels for 
subjects in exposure quartiles Q2 to Q4, therefore, further increases in enfortumab vedotin 
exposures at doses greater than 1.25 mg/kg may not provide additional benefit.  Although 
logistic regression analyses revealed relationships between enfortumab vedotin exposure and 
some reported safety outcomes, treatment with 1.25 mg/kg enfortumab vedotin was 
associated with a manageable safety profile across the entire range of concentrations in 
subjects who had received a platinum containing chemotherapy in the locally advanced or 
metastatic setting [7465-PK-0004]. 
In summary, the dose regimen of 1.25 mg/kg on days 1, 8 and 15 of each 28-day cycle 
proposed for cohorts 1 to 8 of this study has demonstrated an acceptable safety profile and 
encouraging clinical activity that was higher than at lower dose levels. 
In cohort 9, subjects will receive enfortumab vedotin at the 1.25 mg/kg dose on days 1 and 8 
of each 21-day cycle. Justification for this dose includes the following: 
 PK analysis from the EV-103 study indicates when comparing the same dose level the 
average weekly total exposure of enfortumab vedotin following administration on 
days 1 and 8 of a 21-day cycle is similar to that observed for dosing on days 1, 8 and 15 
of a 28-day cycle.   
 Clinical data from EV-103 cohorts A and K indicated efficacy in the mUC population 
with this dosing schedule  
 Safety data from EV-103 shows this combination dosing schedule to be tolerable and 
consistent with the AE profiles for each individual agent.  
4.2.2 
Pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is an 
appropriate dose of pembrolizumab for adults across all indications. As outlined below, this 
dose is justified by: 
 Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 60 of 160 
Amendment 6 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold exposure 
range (refer to the pembrolizumab IB)  
 Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 
 Clinical data showing meaningful improvement in benefit/risk including overall 
survival at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied.  Subsequently, flat dose-exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as 
the appropriate dose independent of the tumor type.  These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and not 
via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W.  Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression.  This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other subject covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 61 of 160 
Amendment 6 
4.3 
End of Study Definition 
The study start is defined as the date the first subject signs informed consent.  End of the 
study is defined as the last visit or scheduled procedure shown in schedules of assessments 
for the last subject in the study.  The study will be closed 5 years after enrollment of the last 
subject, or when no subjects remain in long-term follow-up, whichever occurs first.  
Additionally, the sponsor may terminate the study at any time. 
5 
STUDY POPULATION 
The study population will consist of subjects with locally advanced or metastatic malignant 
solid tumors, including: 
 HR+/HER2- breast cancer; or 
 TNBC; or 
 Squamous NSCLC; or 
 Non-squamous NSCLC; or 
 Head and neck cancer/HNSCC; or 
 Gastric or GEJ or esophageal cancer 
All screening assessments must be completed and reviewed by the investigator to confirm the 
potential subject meets all eligibility criteria.  Prospective approval of protocol deviations to 
eligibility criteria (also known as protocol waivers or exemptions) will not be granted. 
5.1 
Inclusion Criteria 
Subject 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 (e.g., Health 
Insurance Portability and Accountability Act Authorization for US study sites) must be 
obtained from the subject prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable). 
2. Subject is considered an adult according to local regulation at the time of signing the 
informed consent form (ICF).  
3. Subject has measurable disease by RECIST Version 1.1. 
4. Subject has accessible archival tumor tissue from either the primary tumor or a 
metastatic site, for which source and availability have been confirmed prior to study 
treatment.  If no archival tumor tissue is available, the subject will have a biopsy to 
obtain tumor tissue prior to study treatment.  If the subject is unable to undergo a biopsy 
due to safety concerns, enrollment into the study must be discussed with the medical 
monitor. 
a. For cohort 9 only: Subject should submit archival or fresh tumor tissue sample for 
PD-L1 central testing during screening if no local PD-L1 test result is available. 
Central test result for PD-L1 will be required prior to subject enrollment. For 
cohort 9 subjects with local PD-

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 62 of 160 
Amendment 6 
fresh tissue sample for exploratory analysis should be submitted within 5 days of 
enrollment.  
5. Subject has ECOG performance status of 0 or 1. 
6. Subject has the following baseline laboratory data. If a subject has received a recent 
transfusion. 
 
9/L 
 
 
9/L 
 
 9 g/dL 
 
ULN for subjects 
with Gilbert’s disease 
 
 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). 
 Cohorts 1-8: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
 3  ULN 
 Cohort 9: 
 2.5  ULN 
 
 ULN for subjects with liver metastases) 
7. Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply:  
a. Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3 
Contraception Requirements]) 
b. WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3 
Contraception Requirements]) from the time of informed consent through at 
least 6 months after the last dose of study treatment administration 
8. Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 6 months after the last dose of study treatment administration. 
9. Female subject 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. 
10. Male subject with female partner(s) of childbearing potential (including breastfeeding 
partner) must agree to use contraception (see [Appendix 12.3 Contraception 
Requirements]) throughout the treatment period and for 6 months after the last dose of 
study treatment administration. 
11. Male subject must not donate sperm during the treatment period and for 6 months after 
the last dose of study treatment administration. 
12. Male subject 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. 
13. Subject agrees not to participate in another interventional study while receiving study 
treatment in the present study. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 63 of 160 
Amendment 6 
Disease Specific Inclusion Criteria: 
A line of therapy is defined as a course of treatment at the end of which there was 
disease progression, toxicity, or in the investigator’s opinion, maximum benefit has been 
achieved. If the subject discontinued therapy due to any other reason but progressed 
without receiving other treatment, this would be considered a line of therapy. 
Cohort 1: HR+/HER2- breast cancer 
14. Subject has evidence of radiographic progression on or after the last regimen received. 
15. Subject has histologically or cytologically-confirmed HR+/HER2- (estrogen receptor 
[ER] positive and/or progesterone receptor [PR] positive, and HER2 negative) breast 
cancers and are not considered a candidate for further hormonal therapy. Subject will be 
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 
guidelines.  
16. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
17. Subject must have received a taxane or anthracycline in the neoadjuvant, adjuvant or 
incurable, locally advanced or metastatic setting. 
 
Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count as 
a prior cytotoxic regimen if disease recurrence occurred during or within 6 months 
of completing the regimen. 
18. Subject has progressed, relapsed, or discontinued for toxicity during or after at least 
1 prior standard of care cytotoxic regimen in the incurable, unresectable locally advanced 
or metastatic setting, and has not received > 2 prior lines of cytotoxic therapy in the 
locally advanced or metastatic setting.  No limit applies to endocrine therapies. 
Poly(ADP-ribose) polymerases (PARP) inhibitors do not count as a line of cytotoxic 
therapy. 
19. Subject has progressed, relapsed, or discontinued for toxicity during or after receiving 
endocrine therapy or with hormonally-directed therapy with cyclin-dependent kinase 
(CDK) inhibitors. Prior therapy with CDK inhibitors is not required. 
Cohort 2: triple negative breast cancer 
20. Subject has evidence of radiographic progression on or after the last regimen received. 
21. Subject has histologically or cytologically-confirmed TNBC; defined as unequivocal 
TNBC histology (ER-negative/PR-negative/HER2-negative).  This is defined by < 1% 
expression of ER and PR by immunohistochemistry (IHC), and that are, for HER2, either 
0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not 
amplified) as per current ASCO/CAP guidelines. 
22. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
23. Subject must have received a taxane or anthracycline in the neoadjuvant, adjuvant or 
incurable, locally advanced or metastatic setting. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 64 of 160 
Amendment 6 
a. Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count 
as a prior cytotoxic regimen if disease recurrence occurred during or within 
6 months of completing the regimen. 
24. Subject has progressed, relapsed, or discontinued for toxicity during or after at least 1 
prior standard of care cytotoxic regimen in the incurable, unresectable locally advanced 
or metastatic setting, and has not received > 2 prior lines of cytotoxic therapy in the 
locally advanced or metastatic setting. Poly(ADP-ribose) polymerases (PARP) inhibitors 
do not count as a line of cytotoxic therapy. 
25. Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1) 
or an anti-programmed cell death-ligand 1 (PD-L1) based on subject’s tumor PD-1 or 
PD-L1 expression and local treatment guidelines and has progressed or discontinued 
treatment due to toxicity, or therapy is contraindicated for subject. 
Cohort 3: squamous non-small cell lung cancer 
26. Subject has evidence of radiographic progression on or after the last regimen received. 
27. Subject has histologically- or cytologically-confirmed squamous NSCLC. 
a. Subjects with mixed histology NSCLC are eligible provided there is not any 
component of neuroendocrine histology. 
b. Subjects with known epidermal growth factor receptor (EGFR), anaplastic 
lymphoma kinase (ALK), reactive oxygen species (ROS), BRAF, or other 
actionable mutations are eligible if treated with mutation targeted therapy and 
have progressed, relapsed, or discontinued treatment due to toxicity. 
28. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
29. Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1 
platinum-based standard of care regimen for locally advanced or metastatic disease, and 
has not received > 2 prior lines of cytotoxic anticancer therapy in the locally advanced or 
metastatic setting. 
a. Subjects with locally advanced disease who previously received curative intent 
treatment with platinum-based standard of care regimen in the adjuvant or 
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible 
if they have progressed or relapsed within 6 months of completion.   
b. Maintenance therapy does not constitute a new chemotherapy regimen provided 
there was no progression after the initial platinum-based regimen. 
c. Changing chemotherapy agents during platinum-based treatment for the 
management of toxicities does not constitute a new chemotherapy regimen 
provided no progression had occurred while on the initial therapy. 
30. Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1) 
or anti-programmed cell death-ligand 1 (PD-L1) based on subject’s tumor PD-1 or 
PD-L1 expression and local treatment guidelines and has progressed, relapsed, or 
discontinued treatment due to toxicity, or therapy is contraindicated for subject. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 65 of 160 
Amendment 6 
Cohort 4: non-squamous non-small cell lung cancer 
31. Subject has evidence of radiographic progression on or after the last regimen received. 
32. Subject has histologically or cytologically-confirmed non-squamous NSCLC. 
a. Subjects with mixed histology NSCLC are eligible provided there is not any 
component of neuroendocrine histology. 
b. Subjects with known EGFR, ALK, ROS, BRAF, or other actionable mutations 
are eligible if treated with mutation targeted therapy and have progressed, 
relapsed, or discontinued treatment due to toxicity. 
33. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
34. Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1 
platinum-based standard of care regimen for locally advanced or metastatic disease, and 
has not received > 2 prior lines of cytotoxic anticancer therapy in the locally advanced or 
metastatic setting. 
a. Subjects with locally advanced disease who previously received curative intent 
treatment with platinum-based standard of care regimen in the adjuvant or 
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible 
if they have progressed or relapsed within 6 months of completion. 
b. Maintenance therapy does not constitute a new chemotherapy regimen provided 
there was no progression after the initial platinum-based regimen. 
c. Changing chemotherapy agents during platinum-based treatment for the 
management of toxicities does not constitute a new chemotherapy regimen 
provided no progression has occurred while on the initial therapy. 
35. Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject’s 
tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, 
relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for 
subject. 
Cohort 5: second-line or later head and neck cancer 
36. Subject has evidence of radiographic progression on or after the last regimen received. 
37. Subject has histologically- or cytologically-confirmed head and neck cancer. 
a. Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, 
and larynx; tumors arising from the nasopharynx are excluded. Salivary gland 
tumors and/or parotid gland tumors are not eligible for Cohort 5. 
38. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
39. Subject has progressed, relapsed, or discontinued treatment due to toxicity after 
1 platinum-based standard of care regimen for locally advanced or metastatic disease, 
and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally 
advanced or metastatic setting. 
a. Subjects with locally advanced disease who previously received curative intent 
treatment with platinum-based standard of care regimen in the adjuvant or 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 66 of 160 
Amendment 6 
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible 
if they have progressed or relapsed within 6 months of completion. 
40. Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject’s 
tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, 
relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for 
subject. 
Cohorts 6, 7 and 8: gastric or gastroesophageal junction or esophageal adenocarcinoma 
41. Subject has evidence of radiographic progression on or after the last regimen received. 
42. Subject has histologically- or cytologically-confirmed gastric, GEJ, or esophageal 
cancer. 
43. Subject has locally advanced or metastatic disease that is not amenable to curative intent 
treatment. 
44. Subject has progressed, relapsed, or discontinued due to toxicity after 1 platinum-based 
standard of care regimen for locally advanced or metastatic disease, and has not received 
> 2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic 
setting. 
a. Neoadjuvant or adjuvant cytotoxic regimens will count as a prior regimen if 
 
45. Subject must have received a HER2 directed therapy if known to have HER2 positive 
cancer. 
46. Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject’s 
tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, 
relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for 
subject.  
Cohort 9: 1L HNSCC 
47. Subject has histologically- or cytologically-confirmed head and neck squamous cell 
carcinoma. 
b. Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, 
and larynx; tumors arising from the nasopharynx are excluded. Salivary gland 
tumors and/or parotid gland tumors are not eligible for Cohort 9. 
48. Subject has recurrent or metastatic disease that is incurable by local therapies.  
49. Subject’s tumor sample has PD-L1 CPS of 
 as determined by local or central IHC 
testing. 
50. Subject has had no prior systemic therapy administered with the exception of systemic 
therapy completed > 6 months prior if given as part of multimodal treatment for locally 
advanced disease. Subjects who have received a PD-1 or PD-L1 inhibitor in the curative 
setting are eligible if it has been at least 12 months since last dose of the anti PD-L1 
agent.  
51. Subject has a
5 
9/L 
52. International normalized ratio (INR) OR prothrombin time (PT) and activated partial 
receiving anticoagulant 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 67 of 160 
Amendment 6 
therapy as long as PT or aPTT is within the therapeutic range of intended use of 
anticoagulants. PTT may be used if local lab is unable to perform aPTT.  
53. For subjects with oropharynx tumors, subject has results from testing of HPV status by 
p16 testing.  
5.2 
Exclusion Criteria 
Subject will be excluded from participation in the study if any of the following apply: 
For all subjects: 
1. Subject has preexisting sensory or motor neuropathy g
 2. 
2. Subject has active central nervous system (CNS) metastases.  Subjects with treated CNS 
metastases are permitted on study if all the following are true: 
 
 
 If requiring steroid treatment for CNS metastases, the subject is on a stable dose 
 20 
 2 weeks 
 Baseline imaging scans show no evidence of new or enlarged brain metastasis 
 Subject does not have leptomeningeal disease 
3. Subject has ongoing clinically significant toxicity (grade 2 or higher with the exception of 
alopecia) associated with prior treatment (including systemic therapy, radiotherapy or 
surgery). 
4. 
grade 3 immunotherapy-related hypothyroidism or 
panhypopituitarism are excluded.  Subjects with ongoing immunotherapy-related colitis, 
uveitis, myocarditis or pneumonitis, or subjects with other immunotherapy-related AEs 
requiring high doses of steroids (> 20 mg/day of prednisone or equivalent), are excluded.  
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. Subject has a history of uncontrolled diabetes mellitus within 3 months before the first 
dose of study treatment.  Uncontrolled diabetes (within 3 months before first dose) is 
 8% or HbA1c between 7 and < 8% with 
associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 
The lowest HbA1c during the screening period will be used to determine eligibility.  
6. Subject has prior treatment with enfortumab vedotin or other monomethyl auristatin E 
(MMAE) based antibody-drug conjugates (ADCs). 
7. Subject 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.  Subjects 
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) 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 68 of 160 
Amendment 6 
localized prostate cancer under active surveillance/watchful waiting without intent to 
treat, or carcinoma in situ of any type (if complete resection was performed) are allowed. 
8. Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or 
fungal infection at the time of first dose of study treatment. Routine antimicrobial 
prophylaxis is permitted. 
9. Subject has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) 
or active hepatitis C (e.g., hepatitis C virus [HCV] RNA [qualitative] is detected).  
10. Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 
2). 
11. Subject has documented history of a cerebral vascular event (stroke or transient ischemic 
attack), unstable angina, myocardial infarction or cardiac symptoms (including congestive 
heart failure) consistent with New York Heart Association Class III-IV within 6 months 
prior to the first dose of study drug.  
12. Subject has major surgery within 4 weeks prior to first dose of study drug.  
13. Subject had radiotherapy, chemotherapy, biologics, investigational agents, and/or 
antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose 
of study drug.  
14. Subject has known hypersensitivity to enfortumab vedotin or to any excipient contained 
in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate 
and polysorbate 20) OR subject has known hypersensitivity to biopharmaceuticals 
produced in Chinese hamster ovary cells. 
15. Subject has known active keratitis or corneal ulcerations.  Subject with superficial 
punctate keratitis is allowed if the disorder is being adequately treated in the opinion of 
the investigator. 
16. Subject has any condition, which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
Cohort 9: 1L HNSCC 
17. Had PD within 6 months of completion of curatively intended systemic treatment for 
locoregionally advanced HNSCC. 
18. Has had an allogeneic tissue/solid organ transplant. 
19. 
 grade 3) to pembrolizumab and/or any of its excipients. 
20. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease. 
21. Has a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 69 of 160 
Amendment 6 
22. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g., 
tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator. 
23. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
a. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a 
form of systemic treatment and is allowed.  
b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered 
standard of care.  
c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or 
resolved childhood asthma/atopy will not be excluded.  
d. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections will not be excluded.  
e. Subjects with hypothyroidism that is stable with hormone replacement or 
Sjögren's syndrome will not be excluded.  
24. Has an active infection requiring systemic therapy. 
25. Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent in the 
recurrent/metastatic setting. If anti-PD-1 or anti-PD-L1 agent was given as part of 
curative intent therapy, it must be at least 1 year since last dose.  
26. Has received a live vaccine within 30 days of planned start of study therapy. Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette Guérin, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed.  
27. Subject has active tuberculosis 
5.3 
Restrictions During the Study 
Not applicable. 
5.4 
Screen Failures 
A screen failure is defined as a subject 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, ECG, etc.) may be 
repeated within the 28-day screening period without the need to register the subject as a 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 70 of 160 
Amendment 6 
screen failure.  If more than 28 days elapses from the date of signing the ICF, the subject 
must be documented as a screen failure.  In order to re-screen, a new ICF must be signed and 
the subject entered into screening with a new subject identification number.  Rescreening is 
only allowed once for an individual subject. 
6 
INVESTIGATIONAL PRODUCT(S) 
6.1 
Investigational Product(s) Administered 
6.1.1 
Enfortumab Vedotin 
The investigational product, enfortumab vedotin (ASG-22CE), is a sterile, preservative-free, 
white to off-white lyophilized powder to be reconstituted for intravenous administration.  The 
investigational product is supplied by Astellas in single-use glass vials containing 30 mg 
and/or 20 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. 
6.1.1.1 Dosing and Administration of Enfortumab Vedotin 
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an intravenous infusion 
over approximately 30 minutes on days 1, 8, and 15 of every 28-day cycle (days 1 and 8 of 
every 21-day cycle for cohort 9).  In the absence of IRRs, the infusion rate for all subjects 
should be calculated in order to achieve an approximate 30-minute infusion period.  
Enfortumab vedotin must not be administered as an intravenous push or bolus.  Enfortumab 
vedotin should not be mixed with other medications.  At least 7 days must elapse between 
doses of enfortumab vedotin. 
Subject weight must be measured during all relevant assessment time points as described in 
the Schedules of Assessments [Table 1] and [Table 2].  Weight-based dosing is calculated 
using the subject’s actual body weight on day 1 of each cycle.  An exception to weight-
based dosing is made for subjects weighing greater than 100 kg; doses will be based on 
100 kg for these individuals.  The maximum dose permitted on this study is 125 mg. 
Subjects 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 subject care should be given throughout the study according to institutional 
standards. 
The injection site should be monitored closely for redness, swelling, pain, and infection 
during and at any time after administration.  Subjects should be advised to report redness or 
discomfort promptly at the time of administration or after infusion. Events of extravasation 
should be managed per institutional guidelines and precautions should be taken to prevent 
extravasation per institutional standards.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 71 of 160 
Amendment 6 
6.1.2 
Pembrolizumab (Cohort 9 Only) 
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for IV infusion.  Each vial contains 100 mg 
of pembrolizumab in 4 mL of solution.  Each 1 mL of solution contains 25 mg of 
pembrolizumab and is formulated in L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose 
(70 mg), and Water for Injection, United States Pharmacopeia (USP).  Pembrolizumab will 
be administered as a dose of 200 mg using a 30-minute intravenous infusion on day 1 of each 
3-week cycle, approximately 30 minutes after completion of the enfortumab vedotin 
administration.  Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes 
(-5 min/+ 10 min). 
Pembrolizumab may be administered for a maximum of 35 cycles. 
The pharmacy manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution.  
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
Investigational products (enfortumab vedotin [ASG-22CE] and pembrolizumab) used in this 
study will be prepared, packaged and labeled under the responsibility of qualified personnel 
at APGD-Astellas US Technologies (AUST) or sponsor’s designee in accordance with 
APGD-AUST or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable local laws/regulations. 
Each carton and vial will bear a label conforming to regulatory guidelines, GMP and local 
laws and regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual for detailed information regarding packaging and labeling of 
the investigational products. 
6.2.2 
Handling, Storage and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all investigational products received and any discrepancies 
are reported and resolved before use of investigational products. 
2. Only subjects enrolled in the study may receive investigational products and only 
authorized study site personnel may supply or administer investigational products.  Only 
investigational products with appropriate expiry/retest dating may be dispensed. 
3. All investigational products 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. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 72 of 160 
Amendment 6 
4. 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). 
5. Further guidance and instruction on final disposition of used and unused investigational 
product is provided in the pharmacy manual. 
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the investigational products. 
6.3 
Randomization and Blinding 
This is an open-label study.  Subject enrollment and dispensation of investigational product 
will be performed via the interactive response technology (IRT) system.  Prior to initiation of 
study treatment, study site personnel will obtain the subject number and medication 
assignment from the 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 and pembrolizumab administered to each 
subject will be recorded on the eCRF for each dose.  Reasons for dose delay, reduction or 
omission will be documented.  Dosing noncompliance for enfortumab vedotin of less than or 
greater than 10% from each intended dose will be considered a major protocol deviation. 
Dosing noncompliance for pembrolizumab of 1000 mg or greater will be considered a major 
protocol deviation. 
6.5 
Previous and Concomitant Treatment (Medication and 
Nonmedication Therapy) 
If the investigator determines that any of the following medications are necessary to provide 
adequate medical support to the subject, the subject must be withdrawn from further 
administration of the study treatment: 
 Other investigational drugs 
 Chemotherapy or other medications intended for antitumor activity.  This does not apply 
to subjects on endocrine therapy, or to subjects on agents intended for the treatment of 
bone metastasis where subjects should be on a stable dose of bone targeting agents for at 
least 2 weeks prior to study entry (e.g., bisphosphonates, or receptor activator of nuclear 
factor kappa-
 
 Radiation therapy except palliative radiation for nontarget lesions 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.  The radiated lesion must be a nontarget lesion per RECIST Version 1.1 and the 
subject must have clear measurable disease outside the radiated field.  Enfortumab 
vedotin may not be given concurrently with radiation therapy. 
 Subjects who are receiving strong cytochrome P450 (CYP)3A4 inhibitors concomitantly 
with enfortumab vedotin should be closely monitored for adverse reactions.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 73 of 160 
Amendment 6 
 For cohort 9:  Live or attenuated vaccines within 30 days prior to the first dose of study 
treatment and while participating in the study. 
 For cohort 9:  Systemic glucocorticoids except when used for the following purposes: 
o To modulate symptoms of an AE that is suspected to have an immunologic 
etiology 
o For the prevention of emesis 
o To premedicate for IV contrast allergies 
o To treat COPD exacerbations (only short-term oral or IV use in doses 
> 10 mg/day prednisone equivalent) 
o For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
o For topical use or ocular use 
o Intraarticular joint use 
o For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.  
 
6.6 
Dose Modification 
6.6.1 
Enfortumab Vedotin 
For all cohorts, dose reduction to 1, 0.75 or 0.5 mg/kg will be allowed depending on the type 
and severity of toxicity.  Subjects requiring a dose reduction may be re-escalated by 1 dose 
level (i.e., subjects reduced to 0.75 mg/kg may only be re-escalated to 1 mg/kg) provided the 
 grade 1.  
If the toxicity recurs, re-
grade 2 corneal 
AEs will not be permitted to dose re-escalate. 
Dose modification recommendations for enfortumab vedotin associated toxicity are presented 
in [Table 7] and [Table 8].   
Dose interruptions for any enfortumab vedotin associated toxicities are permitted at the 
discretion of the investigator.  Dose interruptions may last up to 8 weeks (2 cycles) for 
subjects in cohorts 1 to 8 and up to 6 weeks (2 cycles) for subjects in cohort 9.  Dose 
interruptions for subjects who are deriving clinical benefit from treatment may be extended 
beyond 8 weeks (cohorts 1 to 8) or 6 weeks (cohort 9) after consultation with the medical 
monitor on a monthly basis, if the subject’s toxicity does not otherwise require permanent 
discontinuation.  During dose interruptions, disease assessments must continue to be 
performed at the protocol-specified frequency and disease status must remain at least SD per 
RECIST v1.1.  If dose interruption is continuous > 6 months, the subject’s study treatment 
will be permanently discontinued. 
For all cohorts, if toxicities are present on day 1 of any cycle and enfortumab vedotin cannot 
be administered, then the start of the cycle may be delayed.   
For cohorts 1 to 8, if toxicities are present on days 8 or 15 of any cycle and require the dose 
to be held > 3 days, then the dose(s) must be eliminated (skipped), rather than delayed.  If a 
subject only receives the day 1 dose and days 8 and 15 doses need to be eliminated (skipped), 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 74 of 160 
Amendment 6 
then the subject could resume the next cycle as early as day 22 (new day 1), if the toxicity has 
resolved by that time. 
For cohort 9, if the medical monitor and site investigator determine that a dose interruption 
for enfortumab vedotin is needed, an interruption of all day 1 dose of pembrolizumab must 
also occur and may last for up to 3 weeks (1 cycle).  Dose interruptions for subjects without 
prior dose reductions and who are responding to treatment may be dose interrupted beyond 
3 weeks with approval of the medical monitor, if the subject’s toxicity does not otherwise 
require permanent discontinuation. 
If toxicities warranting a dose delay occur after day 1 dosing and are not resolved prior to 
day 8 dosing (up to day 10), day 8 enfortumab vedotin administration must be skipped rather 
than delayed.  If a subject is dose-reduced due to toxicity that subsequently resolves, the 
subject may resume treatment at the original dose at the discretion of the medical monitor and 
site investigator.  The day 8 dose of enfortumab vedotin must be given within 4 days of the 
planned dose (day 8 + 4 days).  If the day 8 dose cannot be administered within this 
timeframe, the dose should be held until day 1 of the next treatment cycle.  
Enfortumab vedotin treatment may be interrupted/delayed for other situations such as 
medical/surgical events or logistical reasons not related to study therapy.  If such situations 
occur, the same dose interruption/delay instructions above will apply.  If there is a dose 
interruption, the schedule for response assessments will not be adjusted and should still be 
calculated from cycle 1 day 1.  The reason for interruption should be documented in the 
subject’s study record.  Participants who experience an unacceptable AE that is clearly 
attributable only to pembrolizumab may continue on enfortumab vedotin monotherapy until a 
discontinuation criterion is met. 
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 
 grade 1 or 
has returned to 
baseline, then resume 
treatment at the same 
dose level. 
Withhold dose until 
 grade 1 or 
has returned to baseline, 
then resume treatment at 
the same dose level or 
consider dose reduction 
by 1 dose level. 
Transfusions or growth 
factors may be used as 
indicated per institutional 
guidelines. 
Withhold dose until toxicity is 
 grade 1 or has returned to 
baseline, then reduce dose by 
1 dose level and resume treatment 
or discontinue at the discretion of 
the investigator. 
Transfusions or growth factors 
may be used as indicated per 
institutional guidelines. 
For anemia, treatment 
discontinuation should be strongly 
considered. 
*Hematologic toxicity refers to anemia, thrombocytopenia, neutropenia and febrile neutropenia. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 75 of 160 
Amendment 6 
Table 8 
Recommended Dose Modifications for Enfortumab Vedotin Associated  
Non-hematologic Toxicity 
Toxicity 
Grade 
Skin reactions 
Any grade 
For suspected SJS, suspected TEN or bullous lesions, immediately withhold EV 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 6.6.1.1] 
for recommended 
management of 
rash. 
Continue at same 
dose level. 
 
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 consider 
dose reduction by 
1 level. Consider 
referral of the 
subject to a 
dermatologist/ 
specialist for 
diagnosis and 
specialized care. 
Withhold 
enfortumab 
vedotin until 
toxicity is 
 grade 1 or has 
returned to 
baseline, and then 
resume treatment 
at the same 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 4 AEs, 
discontinue 
treatment.2 
 
For confirmed SJS 
or TEN, or grade 
4 rash or skin 
reactions, 
permanently 
discontinue 
treatment. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 76 of 160 
Amendment 6 
Toxicity 
Grade 
Ocular 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
If ocular symptoms 
and/or changes in 
vision are 
identified, the 
subject should be 
evaluated with an 
ophthalmologic 
exam.1 
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 corneal 
AEs withhold dose 
until toxicity is 
 grade 1, and then 
reduce the dose by 
1 dose level and 
resume treatment.  
 
If ocular 
symptoms and/or 
changes in vision 
are identified, the 
subject should be 
evaluated with an 
ophthalmologic 
exam.1 
Discontinue 
treatment at the 
discretion of the 
investigator. 
 
If ocular 
symptoms and/or 
changes in vision 
are identified, the 
subject should be 
evaluated with an 
ophthalmologic 
exam.1 
For grade 4 AEs, 
discontinue 
treatment.  
Neuropathy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
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  
withhold dose until 
toxicity is 
 grade 1, and then 
reduce the dose by 
1 dose level and 
resume treatment.  
Discontinue 
treatment at the 
discretion of the 
investigator. 
For grade 4 AEs, 
discontinue 
treatment.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 77 of 160 
Amendment 6 
Toxicity 
Grade 
Gastrointestinal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level.  
Continue at same 
dose level.  
Withhold dose 
until toxicity is 
 grade 1 or has 
returned to 
baseline, then 
resume treatment 
at the same dose 
level or consider 
dose reduction by 
1 dose level.2  
For grade 4 AEs, 
discontinue 
treatment.  
grade 4 vomiting 
and/or diarrhea 
that improves to 
 grade 2 within 
72 hours with 
supportive 
management does 
not require 
discontinuation. 
Hyperglycemia 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
Continue at same 
dose level. 
Withhold study 
treatment.  
Resume treatment 
once 
hyperglycemia/ele
vated blood 
glucose has 
improved to 
 grade 2 and 
subject is 
clinically and 
metabolically 
stable. 
Withhold 
enfortumab 
vedotin treatment 
and undertake a 
full evaluation of 
the hyperglycemia 
to determine the 
underlying 
diagnosis. Once 
blood glucose 
returns to 
 grade 2, drug 
dosing may 
resume with close 
monitoring after 
consultation with 
the medical 
monitor. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 78 of 160 
Amendment 6 
Toxicity 
Grade 
Pneumonitis/ILD 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level.  
Withhold dose 
grade 1, 
then resume at the 
same dose level or 
consider dose 
reduction by 
1 dose level. 
Permanently 
discontinue 
treatment. 
Permanently 
discontinue 
treatment. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
All Other  
(not previously 
mentioned) 
Continue at same 
dose level. 
Continue at same 
dose level. 
Withhold dose 
until toxicity is 
 grade 1 or has 
returned to 
baseline, then 
resume treatment 
at the same dose 
level or consider 
dose reduction by 
1 dose level.3 
For grade 4 AEs, 
discontinue 
treatment.3 
AEs: adverse events; SJS: Stevens-Johnson Syndrome; TEN: toxic epidermal necrolysis 
1.  Ophthalmologic exam should be performed by an ophthalmologist.  In countries where optometrists can 
perform exams and prescribe medications, an optometrist may be used instead. 
2.  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). 
3.  Grade 3 or 4 elevations of amylase or lipase, if asymptomatic do not require treatment delay. 
 
6.6.1.1 Enfortumab Vedotin-Related Skin Reactions (Rash and SCAR) 
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 17 Dec 2022 identified reports of adverse reactions. 
In enfortumab vedotin monotherapy studies of urothelial carcinoma, 52.3% participants 
experienced at least 1 TEAE of rash and 3.8% experienced serious rash events. SAEs of rash 
included rash maculo-papular (1.1%), rash (0.6%), dermatitis bullous (0.5%), drug eruption 
(0.4%), rash vesicular (0.3%), Stevens-Johnson syndrome (SJS) (0.2%), toxic skin eruption 
(0.2%), and blister, eczema, erythema, erythema multiforme, rash pruritic, and symmetrical 
drug-related intertriginous and flexural exanthema (SDRIFE) (0.1% each). 
SCAR events accounted for 22.3% of TEAEs; 1.8% of participants experienced serious 
SCAR, while the majority had grade 1 or 2 as the worst grade. The SAEs of SCAR included 
dermatitis bullous (0.5%), drug eruption (0.4%), SJS (0.2%), toxic skin eruption (0.2%), and 
blister, conjunctivitis, dermatitis exfoliative, erythema multiforme, stomatitis, and SDRIFE 
(0.1% each). 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 79 of 160 
Amendment 6 
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]. 
6.6.1.2 Management of Pneumonitis/Interstitial Lung Disease related to Enfortumab 
Vedotin 
Severe, life-threatening or fatal pneumonitis/ILD have occurred in subjects receiving 
enfortumab vedotin. Monitor subjects for signs and symptoms indicative of pneumonitis/ILD 
such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams.  For all 
subjects, including subjects with asymptomatic/grade 1 pneumonitis/ILD, clinical monitoring 
and supportive measures consistent with local medical guidelines should be followed as 
appropriate throughout the study.  Medical intervention per standard of care should be 
considered for gra
e of 1-2 mg/kg/day prednisone 
or equivalent followed by a taper).  For recommendations regarding dose modifications for 
pneumonitis/ILD due to enfortumab vedotin, refer to [Table 8].  
6.6.1.3 Management of Hyperglycemia 
Investigators should monitor blood glucose levels and are advised to perform additional 
assessments if any symptoms of hyperglycemia are observed, including a thorough 
evaluation for infection.  In addition, if steroids are used to treat any other condition, blood 
glucose levels may require additional monitoring.  If elevated blood glucose levels are 
observed, subjects should be treated according to local standard of care and referral to 
endocrinology may be considered. 
Subjects, especially those with a history of or ongoing diabetes mellitus or hyperglycemia, 
should be advised to immediately notify their physician if their glucose level becomes 
difficult to control or if they experience symptoms suggestive of hyperglycemia such as 
frequent urination, increased thirst, blurred vision, fatigue, and headache. 
 6.5%) at baseline should be referred 
to an appropriate provider during cycle 1 for glucose management.  Blood glucose should be 
checked prior to each dosing and dose should be withheld for blood glucose > 250 mg/dL 
(13.9 mmol/L) (grade 3 or higher).  Dosing may continue once the subject’s blood glucose 
 grade 2 and subject 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 subject experiences new onset diabetes mellitus, evaluate 
subjects with a metabolic panel, urine ketones, HbA1c, and C-peptide to assess for new onset 
diabetes. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 80 of 160 
Amendment 6 
6.6.1.4 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 subject care should be given throughout the 
study according to institutional standards.  Supportive measures may include administering 
medications for IRRs. 
Subjects 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 subject 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. 
6.6.2 
Pembrolizumab 
6.6.2.1 Dose Modification and Toxicity Management for Immune-mediated AEs 
Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  
These imAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  
The dose of pembrolizumab should not be reduced.  Based on existing clinical study data, 
most imAEs were reversible and could be managed with a delay of pembrolizumab, 
administration of corticosteroids and/or other supportive care.  For suspected imAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes.  Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation.  Based on the severity of imAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids.  Dose delay and toxicity management 
guidelines for imAEs associated with pembrolizumab are provided in [Table 9]. Participants 
who experience unacceptable toxicity that is clearly attributable only to enfortumab vedotin 
may continue on pembrolizumab monotherapy up to a maximum of 35 cycles. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 84 of 160 
Amendment 6 
6.6.2.2 Dose modification and toxicity management of infusion reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reactions are provided in [Table 10]. 
Table 10 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI-CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
 
 
Stop Infusion. 
 
Additional appropriate medical therapy may 
include but is not limited to: 
o 
IV fluids 
o 
antihistamines 
o 
NSAIDs 
o 
acetaminophen 
o 
narcotics 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr). Otherwise, dosing 
will be held until symptoms resolve, and the 
subject should be premedicated for the next 
scheduled dose. 
Subjects who develop grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug 
treatment. 
Subject may be 
premedicated 1.5 hrs 
(± 30 minutes) prior to 
infusion of study 
intervention with: 
diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine), 
acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 85 of 160 
Amendment 6 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; 
pressor or ventilator 
support indicated 
 
Stop Infusion. 
 
Additional appropriate medical therapy may 
include but is not limited to: 
o 
Epinephrine** 
o 
IV fluids 
o 
antihistamines 
o 
NSAIDs 
o 
acetaminophen 
o 
narcotics 
o 
oxygen 
o 
pressors 
o 
corticosteroids 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from further 
study drug treatment. 
No subsequent dosing 
IV: intravenous; NSAID: nonsteroidal anti-inflammatory drug; po: by mouth 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. For further information, please refer to the National Cancer Institute 
Common Terminology Criteria for Adverse Events v5.0 (NCI-CTCAE) at http://ctep.cancer.gov/. 
 
6.6.2.3 Other allowed dose interruption for pembrolizumab 
If the medical monitor and site investigator determine that a dose interruption for 
pembrolizumab is needed, an interruption of all day 1 dose of enfortumab vedotin must also 
occur and may last for up to 3 weeks (1 cycle).  Pembrolizumab may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study therapy.  However, pembrolizumab is to be 
restarted within 3 weeks of the originally scheduled dose and within 42 days of the 
previously administered dose, unless otherwise discussed with the sponsor. The reason for 
interruption is to be documented in the subject’s eCRF. 
6.7 
Overlapping Adverse Reactions 
Some AEs, including rash or skin reactions, may represent overlapping toxicities for 
enfortumab vedotin and pembrolizumab, and attribution of skin reactions to an individual 
study treatment may be difficult.  The management actions (i.e., to withhold or discontinue 
study treatment) for skin reactions should apply to both enfortumab vedotin and 
pembrolizumab, and the investigator should follow the most conservative dose modification 
guidelines as described in [Section 6.6].  However, for grade 2 skin reactions that are stable 
(not worsening and in the absence of fever) with supportive measures and not limiting the 
subject’s activities of daily living, continued dosing of enfortumab vedotin may be 
considered following consultation with the sponsor. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 86 of 160 
Amendment 6 
6.8 
Criteria for Continuation of Treatment  
Options to provide enfortumab vedotin and/or pembrolizumab to subjects who are continuing 
to receive treatment and are benefiting will be determined at the time of cohort closure or 
study closure. The continued access to pembrolizumab will end when a criterion for 
discontinuation is met or 35 doses of pembrolizumab have been administered. 
6.9 
Treatment of Overdose 
In the event of an overdose of > 10% of enfortumab vedotin, the site should notify the 
sponsor as soon as they are aware of the overdose.  The subject should be closely monitored 
for adverse reactions. Supportive care per institutional standards should be administered.  
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.  No specific information is available on the treatment of overdose of pembrolizumab. 
In the event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.  
7 
STUDY PROCEDURES AND ASSESSMENTS 
7.1 
Efficacy Assessments 
Radiographic and response assessments will be performed according to the Schedules of 
Assessments [Table 1] and [Table 2]. For all cohorts, disease response and progression will 
be evaluated using RECIST Version 1.1 (see [Appendix 12.9, RECIST Version 1.1]).  In 
addition, for cohort 9, disease assessments will also be evaluated using iRECIST (see 
Section 7.1.3).   
7.1.1 
Imaging for Disease Assessment (Computed Tomography/Magnetic Resonance 
Imaging) 
For cohorts 1 to 8, imaging/disease assessment will be performed at screening/baseline and 
every 8 weeks (56 days ± 7 days) from the first dose of study treatment throughout the study 
until the subject has radiologically-confirmed disease progression, initiates a new subsequent 
anticancer therapy, dies, withdraws consent, is lost to follow-up or the study closes, 
whichever occurs first.  Baseline imaging performed prior to informed consent as standard of 
care may be used as long as it is performed within 28 days prior to the first dose of study 
treatment.  
Disease response and progression will be assessed by the investigator. If disease response is 
assessed as CR or PR by investigator, a confirmatory imaging scan is required 4 weeks 
(28 days + 7 days) after the first response.  After 1 year on study treatment, the frequency of 
disease response assessments will be reduced to every 12 weeks (84 days ± 7 days).  
In cohort 9, the first on-study imaging/disease assessment will be performed 9 weeks 
(63 days ±7 days) from the first dose of study treatment and then every 6 weeks (42 days 
± 7 days) throughout the study.  After 18 months on study treatment, the frequency of disease 
response assessments will be reduced to every 9 weeks (± 7 days).  Baseline imaging 
performed prior to informed consent as part of standard of care may be used as long as it is 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 87 of 160 
Amendment 6 
performed within 28 days prior to the first dose of study treatment.  Tumor imaging should 
also be performed whenever disease progression is suspected.  Objective responses will be 
confirmed per RECIST Version 1.1 with repeat scans at least 4 weeks (+7 days) after first 
documentation of response.  
Imaging for cohort 9 should include the head, neck, chest and abdomen at the specified 
timepoints.  A CT from the vertex of the head to the thoracic inlet or a brain CT is strongly 
preferred. Imaging of the pelvis is optional. 
Treatment beyond disease progression per RECIST Version 1.1 may be considered for 
subjects in cohort 9 who are deriving clinical benefit.  Subjects with unconfirmed progressive 
disease (iUPD) who are clinically stable may continue on study treatment until iCPD per 
iRECIST guidelines [Seymour et al, 2017] as assessed by the investigator.  Confirmatory 
scans should be performed at the next scheduled disease assessment (6 weeks ± 1 week). 
Subjects in cohorts 1 to 8 who discontinue study treatment for reasons other than 
radiologically-confirmed disease progression by RECIST Version 1.1 will continue to receive 
imaging scans every 8 weeks (56 days ± 7 days) until subject has radiologically-confirmed 
disease progression, initiates a new anticancer therapy, dies, withdraws consent, lost to 
follow-up, or the study closes, whichever occurs first.  Tumor imaging should also be 
performed whenever disease progression is suspected.   
Subjects in cohort 9 who discontinue study treatment for reasons other than radiographically 
confirmed disease progression will continue to receive response assessments, including CT 
scans with contrast, every 6 weeks (±7 days) according to the original schedule calculated 
from cycle 1 day 1 up to 18 months after first dose, then every 9 weeks (±7 days).  Scans are 
to be done until the subject has radiologically confirmed disease progression per iRECIST 
guidelines as determined by the investigator, initiates a subsequent anticancer therapy, dies, 
the study closes, or the subject withdraws consent, whichever occurs first.  The investigator 
will make treatment decisions based on site assessments of scans by iRECIST guidelines.  
Clinical response will be determined at each assessment per RECIST Version 1.1 or per 
iRECIST guidelines when applicable.  Clinical response of CR, PR, SD, or PD will be 
determined at each assessment. 
Brain scan and bone imaging will be performed according to the Schedules of Assessments 
for Cohorts 1-8 in [Table 1] and brain scan according for Cohort 9 [Table 2]  will be repeated 
at response assessment time points if metastases were identified at screening/baseline, or if 
metastasis is known or suspected, or as clinically indicated throughout the study. 
A CT scan with contrast is the preferred modality for tumor assessment.  Magnetic resonance 
imaging is acceptable if local standard practice or if CT scans are contraindicated in a subject 
(e.g., subject is allergic to contrast media).  All other RECIST-approved scanning methods 
such as x-ray are optional.  The same imaging modality should be used throughout the study.  
Additional instructions for imaging assessments can be found in the study procedures 
manual.   

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 88 of 160 
Amendment 6 
The assessment will include tumor measurements for target lesions, nontarget lesions and any 
new lesions.  A response assessment will be characterized for a given time point evaluation.  
At the end of study for each subject, the best overall response (BOR) to the study regimen 
will be derived.  To ensure comparability, the screening and subsequent assessment of 
response should be performed using identical techniques.  The same individual should assess 
images for any 1 subject for the duration of the study if possible.   
The site of disease progression including target, nontarget and/or new lesions should be 
documented in the eCRF.  Additional imaging may be performed at any time to confirm 
suspected progression of disease. 
This study will be analyzed based on the results of local (investigator) radiological 
assessments.  Copies of all imaging scans will also be sent to the independent review facility 
in a timely manner.  Images at the independent review facility will be stored.  Imaging scans 
for a cohort may be read at the independent review facility when the minimum number of 
responders per investigator assessment (subjects with confirmed CR and PR) to claim 
promising antitumor activity at stage 1 are met based on the 2-stage BOP2 design.  Central 
images may also be read in certain circumstances as determined by the sponsor. 
7.1.2 
RECIST Version 1.1 Assessment 
7.1.2.1 Evaluation of Target Lesions  
7.1.2.1.1 
Complete Response 
CR is defined as disappearance of all target and nontarget lesions.  Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from 
baseline measurement. 
7.1.2.1.2 
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 
diameters. 
7.1.2.1.3 
Stable Disease 
SD is defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify 
for progressive disease taking as reference the smallest sum of diameters while on study drug. 
7.1.2.1.4 
Progressive Disease 
PD is defined as at least a 20% increase in the sum of diameters (longest for nonnodal 
lesions; short axis for nodal lesions) of the target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  The appearance of 1 or more new lesions is also considered progression.   

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 89 of 160 
Amendment 6 
7.1.2.2 Evaluation of Nontarget Lesions 
To achieve unequivocal progression on the basis of nontarget lesions, there must be an 
overall level of substantial worsening in nontarget disease such that, even in presence of SD 
or PR of target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of 1 or more nontarget lesions is 
usually not sufficient to qualify for unequivocal progression.   
7.1.2.2.1 
Non-complete Response/Non-progressive disease 
NonCR/NonPD of nontarget lesions is defined as persistence of 1 or more nontarget lesions. 
7.1.2.2.2 
Progressive Disease 
PD of nontarget lesions is defined as unequivocal progression of existing nontarget lesions or 
the appearance of 1 or more new lesions. 
7.1.3 
iRECIST Assessment 
Response will also be assessed using iRECIST guidelines [Seymour et al, 2017] for Cohort 9.  
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in 
the size in malignant lesions, or undetectable lesions becoming detectable.  The criteria are 
identical to those of RECIST Version 1.1 in many respects but have been adapted to account 
for instances where an increase in tumor burden, or the appearance of new lesions, does not 
reflect true tumor progression. 
Key differences are described below.  All responses defined using iRECIST guidelines are 
designated with a prefix. iRECIST time point and best responses will be recorded separately. 
Confirming Disease Progression 
Unlike RECIST Version 1.1, the iRECIST guidelines require the confirmation of progression 
and uses the terms iUPD (unconfirmed immune progressive disease) and iCPD (confirmed 
immune progressive disease).  Confirmatory scans should be performed at the next scheduled 
disease assessment (6 weeks ± 1 week).  iCPD is confirmed if further increase in tumor 
burden, compared to the last assessment, is seen as evidenced by 1 or more of the following: 
 Continued increase in tumor burden (from iUPD) where RECIST Version 1.1 definitions 
of progression had been met (from nadir) in target, nontarget disease or new lesions 
 Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
 Continued unequivocal progression in nontarget disease with an increase in tumor burden 
 Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions 
 RECIST Version 1.1 criteria are met in lesions types (target and/or nontarget and/or new 
lesions) where progression was not previously identified, including the appearance of 
additional new lesions 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 90 of 160 
Amendment 6 
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD [immune stable disease], 
iPR [immune partial response] or iCR [immune complete response] if those criteria are met 
compared to baseline).  Please refer to the iRECIST guidelines [Seymour et al, 2017] for 
more details. 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST Version 1.1 
criteria (maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis or 15 mm 
in short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New 
Lesion-Non-Target (NLNT) to allow clear differentiation from baseline target and nontarget 
lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  
However, the measurements of target lesions should NOT be included in the sum of measures 
of original target lesions identified at baseline.  Rather, these measurements will be collected 
separately in the case report form. 
7.1.4 
Evaluation of Time Point Response 
The response status at each time point for all subjects will be reported. 
7.1.5 
Survival Status 
After radiologically-confirmed disease progression or initiation of subsequent anticancer 
therapy, whichever occurs first, subjects will be contacted every 12 weeks in the long-term 
follow-up period for survival status until death, withdrawal of consent, lost to follow-up, or 
study closure, whichever occurs first.  Sponsor may choose to discontinue the collection of 
survival status for any cohort. 
7.2 
Safety Assessments 
7.2.1 
Adverse Events 
See [Section 7.3, Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling. 
7.2.2 
Laboratory Assessments 
See [Appendix 12.7 Laboratory Assessments] for the list of clinical laboratory tests 
(including hematology, biochemistry, HbA1c and lipid panel) to be performed and refer to 
Schedules of Assessments [Table 1] and [Table 2] for timing and frequency.  Laboratory tests 
will be sent to the local laboratory for analysis.  Redacted copies of laboratory reports for all 
local laboratory testing will be submitted electronically by the site to a central vendor for data 
entry processing.  Clinical laboratory tests will be performed locally prior to dosing. Tests 
will be obtained as indicated in the Schedules of Assessments [Table 1] and [Table 2].  If 
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 and on cycle 1 day 8 are to 
be performed after the subject has been fasting in order to ensure accurate interpretation of 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 91 of 160 
Amendment 6 
lab test values such as glucose values.  Subject will be provided with 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 
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 obtained at screening/baseline only. 
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, 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 EOT and follow-up visits.  After EOT, a monthly (±7 days) pregnancy 
test will be maintained until 6 months after the last dose of study treatment. 
The investigator or subinvestigator must review the laboratory report and document this 
review.  Clinical significance of out-of-range laboratory findings is to be determined and 
documented by the investigator or subinvestigator who is a qualified physician. 
7.2.3 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats/minute) 
and temperature will be obtained as indicated in the Schedules of Assessments [Table 1] and 
[Table 2].  All vital sign measures will be taken prior to dosing with the subject 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.  The investigator will continue to monitor the subject 
until the parameter returns to g
investigator determines that follow-up is no longer medically necessary. 
7.2.4 
Physical Examination 
Standard, full physical examinations will be obtained as indicated in the Schedules of 
Assessments [Table 1] and [Table 2] to assess general appearance, skin, eyes, ears, nose, 
throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, neurologic status, 
mental status and lymphatic systems.  Height measurement is only required at 
screening/baseline.  Weight measurement will also be performed as indicated in the 
Schedules of Assessments [Table 1] and [Table 2].  If physical examination 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 that has medical relevance that could result in an alteration in 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 92 of 160 
Amendment 6 
medical care.  The investigator will continue to monitor the subject until the parameter 
returns to grade  1, or to the baseline condition, or until the investigator determines that 
follow-up is no longer medically necessary. 
7.2.5 
Electrocardiogram 
Routine 12-lead ECGs will be performed and assessed using local standard procedures as 
indicated in the Schedules of Assessments [Table 1] and [Table 2].  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, subjects should rest in supine position (or 
semi-recumbent, if supine is not tolerated) for 10 minutes. ECGs will be read and assessed 
locally. 
7.2.6 
Complete Eye Examination 
Subjects will have a complete eye examination at screening performed by a qualified 
ophthalmologist or optometrist who can perform exams and prescribe medications in the 
country.  The complete eye examination includes but not limited to: visual acuity, slit lamp, 
tonometry examination, and dilated fundus examination.  Subsequent eye examinations are to 
be conducted as clinically indicated. EOT slit lamp examinations are required for subjects 
who experience ocular AEs during the study.  EOT slit lamp examinations (only required for 
subjects who experience ocular AEs during the study) must be performed at least 4 weeks 
from last dose.  
7.2.7 
Cohort 9 Follow-Up Assessments 
Subjects who discontinue study treatment will receive physical exams, ECOG assessment, 
and response assessments every 6 weeks (±1 week) after EOT up to 18 months after first 
dose, then every 9 weeks (±1 week).  Scans are to be done until radiologically confirmed 
disease progression on or following study treatment per iRECIST guidelines as determined 
by the investigator; initiation of a subsequent anticancer therapy, subject death, study closure, 
or withdrawal of consent, whichever occurs first.  During study treatment, palliative 
radiotherapy on a nontarget bone lesion that is not progressing (as long as a target lesion is 
not within the field of radiation) will not be considered a subsequent anticancer therapy; 
however, radiotherapy on any target lesion will be a subsequent anticancer therapy. 
7.2.8 
Order of Assessments  
The following order should be followed when more than 1 assessment is required at a time 
point with blood sampling for pharmacokinetics/biomarker profiling being collected nearest 
to the scheduled time point: 
 ECG and/or vital signs 
 Blood collection 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 93 of 160 
Amendment 6 
7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in [Appendix 12.4 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up or Reporting].   
The investigator and medically qualified designee(s) are responsible for detecting, 
documenting and recording events that met the definition of an AE or SAE.   
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received investigational product.  AE and ECI collection begins after the signing of the ICF 
and will be collected until 30 days after the last dose of investigational product administration 
or when the subject is determined to be a screen failure. SAEs related to pembrolizumab will 
be collected until 90 days after following cessation of study treatment, or 30 days following 
cessation of study treatment if the subject initiates new anticancer therapy, whichever is 
earlier. 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The methods of recording, evaluating and assessing seriousness, causality and severity of 
AEs and SAEs are described in [Appendix 12.4 Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up or Reporting].  Care will be taken not to introduce bias 
when detecting AEs and/or SAEs.  Open-ended and nonleading verbal questioning of the 
subject is the preferred method to inquire about AE occurrences. 
An AE with a change in severity is recorded as a new AE. 
7.3.3 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.   
If after the protocol-defined AE collection period (see [Section 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 
investigational product or study participation, the investigator must promptly notify the 
sponsor. 
7.3.4 
Reporting of Serious Adverse Events 
Prompt notification by the investigator to the sponsor of an SAE is essential, so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 94 of 160 
Amendment 6 
In the case of an SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness). 
Procedures for reporting SAEs to the sponsor are described in [Section 12.4.5 Reporting 
Procedures for Serious Adverse Events]. 
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 including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs.  These data will be captured as efficacy assessment data as outlined in 
[Section 7.1 Efficacy Assessments].  If there is any uncertainty as to whether an event is 
due to anticipated disease progression and/or if there is evidence suggesting a causal 
relationship between the investigational product and the event, it should be reported as an 
(S)AE.  All deaths up to 30 days after the final administration of investigational product 
must be reported as an SAE, even if attributed to disease progression. For subjects in 
Cohort 9 receiving pembrolizumab, all deaths up to 90 days after the final administration 
of pembrolizumab must be reported as an SAE, even if attributed to disease progression. 
 Pre-planned and elective hospital/clinical procedures/interventions or procedures for 
diagnostic, therapeutic, or surgical procedures for a preexisting condition that did not 
worsen during the course of the study.  These procedures are collected per the eCRF’s 
completion guidelines. 
7.3.6 
Events of Clinical Interest Requiring Immediate Reporting (Cohort 9 only) 
For cohort 9, selected non-serious and SAEs are also known as Events of Clinical Interest 
(ECI) and must be collected via the SAE worksheet or an applicable form (Unique to Japan) 
and reported to the sponsor within 24 hours of awareness as described in [Section 12.4.5 
Reporting Procedures for Serious Adverse Events].  
ECIs for this study include:  
1. An overdose of sponsor's product, as defined in [Section 6.9 Treatment of Overdose], 
that is not associated with clinical symptoms or abnormal laboratory results. 
2. 
 as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing. 
Note:  These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria are to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The study site guidance for 
assessment and follow up of these criteria can be made available.  It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin and alkaline 
phosphatase that do not meet the criteria noted above.  In these cases, the decision to 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 95 of 160 
Amendment 6 
proceed with additional evaluation will be made through consultation between the study 
investigators and the sponsor Medical Expert.  However, abnormalities of liver blood 
tests that do not meet the criteria noted above are not ECIs for this study. 
7.3.7 
Special Situations  
Certain special situations observed in association with the investigational product, such as 
incorrect administration (e.g., wrong dose of investigational product or background therapy) 
are collected in the eCRF, as protocol deviation per [Section 10.3 Major Protocol Deviations] 
or may require special reporting, as described below.  These special situations are not 
considered AEs but do require to be communicated to Astellas as per the timelines defined 
below. 
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 12.4.5 Reporting 
Procedures for Serious Adverse Events] and the details of the associated special situation are 
to be included in the clinical description on the SAE worksheet. 
The special situations are: 
 Pregnancy  
 Lack of efficacy 
 Medication error, overdose and use outside protocol 
 Misuse/abuse 
 Occupational exposure 
 Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in [Appendix 12.4.6 
Reporting Procedures for Special Situations].   
7.3.8 
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 subjects, who will be required to sign an updated ICF in 
order to continue in the study. 
For investigational sites located in Japan: 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, in compliance with Article 80-2 
Paragraph 6 of the Pharmaceutical Affairs Law, the sponsor should inform all 
investigators involved in the study, head of the study site and appropriate regulatory 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 96 of 160 
Amendment 6 
authorities of such information.  The head of the study site who receives such 
information will decide whether the study should be continued after hearing the opinions 
of the IRB.  The investigator will supply the new information to the subjects, in 
compliance with [Appendix 12.1.4.2 Supply of New and Important Information 
Influencing the Subject’s Consent and Revision of the Written Information]. 
2. In addition, when the head of the study site receives the revisions of the investigator’s 
brochure, protocol, written information, information on the matters covering the quality 
of the test product, efficacy and safety, information necessary for conducting the study 
properly or documents to be examined by the IRB, these documents should be sent to the 
IRB. 
7.3.9 
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 
subjects 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.   
7.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the medical monitor/medical 
expert and/or Astellas study team member (within 24 hours of awareness).  Full details of the 
potential USM are to be recorded in the subject’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 subjects.  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. 
7.4 
Pharmacokinetics 
Blood samples (7 mL/sample) for the analysis of ADC and MMAE will be collected as 
indicated in the Schedules of Assessments [Table 1] and [Table 2] for the evaluation of 
pharmacokinetics. 
Blood samples should be collected via a peripherally placed intravenous cannula or by direct 
venipuncture, which should always be performed on the opposite arm of the study drug 
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 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 97 of 160 
Amendment 6 
blood is collected from central line, use the lumen that was not used to administer the study 
drug.   
Bioanalysis of ADC 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. 
When deemed appropriate, plasma samples remaining after the pharmacokinetic analysis may 
be used for exploratory metabolic profiling or exploratory biomarker analysis after the study.  
These tests will be described in a separate report and will not be incorporated in the 
integrated clinical study report (CSR). 
7.5 
Pharmacodynamics | Immunogenicity 
Blood samples will be collected during the study treatment period, at EOT and safety follow-
up visits for determination of ATA concentrations.  Blood samples (4 mL/sample) will be 
collected at the time points indicated in the Schedules of Assessments ([Table 1] for 
cohorts 1 to 8 and [Table 2] for cohort 9).   
Blood samples should be collected via a peripherally placed intravenous cannula or by direct 
venipuncture, which should always be performed on the opposite arm of the study drug 
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 
Other Assessments 
7.6.1 
Banked Pharmacogenomic Sample (Optional) 
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety.  A 4 to 6 mL sample of whole blood 
for possible banked PGx analysis will be collected as indicated in the Schedules of 
Assessments [Table 1] and [Table 2].  Samples will be shipped to a sponsor-designated 
banking contract research organization (CRO). 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 98 of 160 
Amendment 6 
See [Appendix 12.8 Pharmacogenomic Analysis with Banked Sample] for further details on 
the banking procedures. 
7.6.2 
Exploratory Biomarker(s)  
The procedures for the collection, handling and shipping of laboratory samples submitted to 
the central laboratory will be specified in a laboratory manual. 
The samples described in [Section 7.6.2.1 Blood Sample for Biomarker Analysis,  
Section 7.6.2.2 Tumor Tissue Samples for Biomarker Analysis, and Section 7.5 
Pharmacodynamics/Immunogenicity] may be analyzed for other biomarkers including DNA, 
RNA and protein, to investigate possible associations with mechanisms of resistance or 
sensitivity to study treatment, dynamic changes associated with study treatment (in terms of 
dose, safety, tolerability and efficacy, etc.) and method development or validation of 
diagnostic assays related to enfortumab vedotin.   
The samples will be stored at the study sponsor’s facility or a contract laboratory facility for 
up to 15 years after study database hard-lock, at which time the samples will be destroyed. 
7.6.2.1 Blood Sample for Biomarker Analysis 
Blood samples for biomarker analysis will be collected from all subjects at the time points 
indicated in the Sample Collection Schedule [Table 3 and Table 4] for the isolation of 
plasma, serum, and peripheral blood mononuclear cells (PBMCs).  A subset of the plasma 
samples may be used for the next-generation sequencing (NGS) analysis of circulating free 
DNA (cfDNA).  A subset of the serum samples may be used to characterize soluble Nectin-4 
levels.  The plasma, serum, and PBMC samples may undergo cytokine or immune-
phenotyping analysis to identify markers of immune function and immune cell subsets.  The 
blood samples may be used for additional exploratory analyses as described in [Section 7.6.2 
Exploratory Biomarker(s)]. 
7.6.2.2 Tumor Tissue Samples for Biomarker Analysis  
For all cohorts, pretreatment tumor tissue sample (from primary or metastatic site) in the 
form of a formalin-fixed, paraffin-embedded tumor tissue block or unstained charged slides 
as indicated in the Schedules of Assessments [Table 1] and [Table 2] is required for 
submission to the sponsor (unless prior approval is obtained from the sponsor).  Either 
archival or pretreatment fresh tumor tissue is acceptable.  If an archival tumor tissue sample 
is not available, the subject will have a biopsy to obtain tumor tissue prior to study treatment.  
If freshly sectioned, unstained charged slides are submitted, a minimum of 10 and up to 
20 slides are needed from each subject for the planned biomarker studies.  If at least 10 slides 
cannot be sectioned from available block, site will be required to provide as many as possible 
and discuss with the sponsor.  If multiple blocks will be used to produce slides, site should 
contact the sponsor before cutting the blocks.  See the laboratory manual for details, 
including FFPE stability requirements. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 99 of 160 
Amendment 6 
For cohort 9, the pretreatment tumor tissue will be sent for central testing using the Agilent 
PD-L1 IHC 22C3 pharmDx assay to evaluate PD-L1 status. A PD-
enrollment in cohort 9. A local test result may be used for eligibility.  
If biopsy is performed as standard of care while on study treatment or during follow-up 
period, subject’s tumor tissue samples are requested to be submitted to sponsor, if available. 
The tumor tissue samples may be analyzed for Nectin-4 and PD-L1 expression, markers of 
disease subtype and markers related to the tumor immune microenvironment.  The tumor 
tissue sample may be used for additional exploratory analyses as described in [Section 7.6.2 
Exploratory Biomarker(s)]. 
For biopsies, the investigator, in consultation with other specialists, as needed (e.g., radiology 
staff) will assess the risk associated with obtaining a tumor tissue sample and determine if the 
subject is an appropriate candidate for the procedure.  Biopsies should be obtained in 
accordance with institutional policies/guidelines to minimize risk.  Procedures requiring 
general anesthesia should not be performed to obtain a tumor tissue sample; however, if a 
surgical procedure under general anesthesia is performed for a clinical indication, excess 
tumor tissue may be used for research purposes with the consent of the subject. 
7.6.3 
Quality of Life and Patient Reported Outcome Assessment 
Quality of life (QOL) questionnaires will be assessed using EQ-5D-5L and pain assessment 
rating scale at the time point as indicated in the Schedules of Assessments [Table 1] and 
[Table 2].  The PRO data will be completed on paper forms by the subject and should always 
be completed first at every schedule clinic visit prior to dosing and any other study 
assessments, especially discussion of disease status.  Subjects who do not speak a language 
for which translated QOL questionnaires are available or who is illiterate and therefore will 
not be able to complete the QOL questionnaires may be enrolled into the study and exempted 
from completing QOL questionnaires after consultation with the sponsor. 
7.6.3.1 Cohorts 1 to 8: 
7.6.3.1.1 
Global Pain Assessment 
The subject will rate his/her pain on a 0 to 10 scale that best describes the pain at its worst in 
the last 24 hours.  See [Appendix 12.11 Pain Assessment]. 
7.6.3.1.2 
Euro Quality of Life-5 Dimensions 
The EQ-5D-5L is a standardized instrument developed by the EuroQOL Group for use as a 
generic, preference-based measure of health outcomes.  It is applicable to a wide range of 
health conditions and treatments and provides a simple descriptive profile and a single index 
value for health status.  The EQ-5D-5L is a 5-item self-reported measure of functioning and 
well-being, which assesses 5 dimensions of health, including mobility, selfcare, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension comprises 5 levels (no 
problems, slight problems, moderate problems, severe problems, extreme problems).  A 
unique EQ-5D-5L health state is defined by combining 1 level from each of the 
5 dimensions.  This questionnaire also records the respondent’s self-rated health status on a 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 100 of 160 
Amendment 6 
vertical graduated (0 to 100) visual analogue scale [Herdman et al, 2011].  See 
[Appendix 12.12 EQ-5D-5L]. 
7.6.3.2 Cohort 9 
7.6.3.2.1 
EORTC QLQ H&N43 
The EORTC H&N43 contains 43 items of 6 multi-item and 13 single-item symptom 
subscales namely pain, swallowing, senses problems, speech problems, trouble with social 
eating, less sexuality, teeth, dry mouth/sticky saliva, body image, shoulder pain, skin 
problems, anxiety, trouble with social contact, opening mouth, coughing, lymphedema, 
problems wound healing, weight loss, neurological problems. 
7.6.3.2.2 
Global Pain Assessment 
The subject will rate his/her pain on a 0 to 10 scale that best describes the pain at its worst in 
the last 24 hours.  See [Appendix 12.11 Pain Assessment]. 
7.6.3.2.3 
PRO-CTCAE 
Three questions will be utilized from the PRO-CTCAE to obtain subject assessment of 
fatigue and diarrhea symptoms.  
7.6.3.3 FACT-G 
Functional Assessment of Cancer Therapy – General (FACT-G) Version 4 is a 27-item 
questionnaire designed to measure four domains of HRQOL in cancer patients: Physical, 
social, emotional, and functional well-being.  Original development and validation involved 
854 patients with cancer and 15 oncology specialists.  Subjects with cancer aged 18 years and 
older are asked to recall the past 7 days and complete the questionnaire.  EV-202 cohort 9 
will include a single question from the “Physical Well-Being” domain, GP5 “I am bothered 
by side effects of treatment” which is self-scored from “0 to 4” (0 - not at all; 1 - A little bit; 
2 - Somewhat; 3 - Quite a bit; 4 - very much). 
7.7 
Total Amount of Blood 
The total amount of blood for each subject 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 subject, additional blood may be drawn for safety 
monitoring. 
For cohorts 1 to 8, the maximum amount of blood collected is approximately 52 mL on 
cycle 1 day 1, 41 mL on cycle 1 day 8, and 48 mL on cycle 1 day 15. The maximum amount 
of blood collected for subjects that participate from cycle 2 up to cycle 6 and completes the 
EOT visit is approximately 185 mL. 
For cohort 9, the maximum amount of blood collected is approximately 52 mL on cycle 1 
day 1, 41 mL on cycle 1 day 8, and 8 mL on cycle 1 day 15. The maximum amount of blood 
collected for subjects that participate from cycle 2 up to cycle 6 and completes the EOT visit 
is approximately 233 mL. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 101 of 160 
Amendment 6 
8 
DISCONTINUATION 
8.1 
Discontinuation of Individual Subject(s) From Study Treatment  
A discontinuation from treatment is defined as a subject who enrolled in the study and for 
whom study treatment is permanently discontinued for any reason.   
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice.  The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject’s involvement in the study at any time if the subject’s clinical condition warrants it. 
The reason for discontinuation from study treatment must be documented in the subject’s 
medical records. 
A subject must discontinue study treatment for any of the following reasons: 
 Subject develops documented radiological disease progression (iCPD per iRECIST) in 
cohort 9). 
 Subject starts a new anticancer therapy. 
 Subject develops unacceptable toxicity. 
 Female subject becomes pregnant. 
 Investigator decides it is in the subject’s best interest to discontinue. 
 Subject requests to stop treatment. 
 Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment. 
 Subject has continuous dose interruption > 6 months. 
 Study is terminated by sponsor. 
For subjects in cohort 9, Pembrolizumab may be administered for up to a total of 35 cycles 
(approximately 2 years).  Subjects who experience an unacceptable AE that is clearly 
attributable only to pembrolizumab may continue on enfortumab vedotin monotherapy until a 
discontinuation criterion is met.  Subjects who experience unacceptable toxicity that is clearly 
attributable only to enfortumab vedotin may continue on pembrolizumab monotherapy up to 
a maximum of 35 cycles.  
8.2 
Discontinuation of Individual Subject(s) From Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in the Schedules of 
Assessments [Table 1] and [Table 2].  The only exception to this is when the subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the subject to provide this information.  A subject may be discontinued from 
the study for any of the following reasons: 
 Lost to follow-up 
 Death 
 Subject withdrawal of consent 
 Study termination by sponsor 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 102 of 160 
Amendment 6 
8.2.1 
Lost to Follow-up 
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments and record outstanding data.   
8.3 
Discontinuation of the Study Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor and, if applicable, the head of the study site. 
8.4 
Discontinuation of the Study 
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns.  If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.   
9 
STATISTICAL METHODOLOGY 
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced.  The SAP will be finalized 
before the database hard-lock at the latest.  Changes from the planned analyses in the final 
SAP that impact the statistical analyses will be justified in the clinical study report (CSR). 
In general, data will be summarized by cohort and overall with descriptive statistics for 
continuous endpoints, and frequency and percentage for categorical endpoints.  Kaplan-Meier 
estimates will be provided for time-to-event endpoints. 
9.1 
Sample Size 
The planned sample size for cohorts 1 to 8 is 40 subjects in each cohort.  Assuming the 
reference ORR for the 7 tumor types chosen for the study, ranges from 10% to 20%, and at 
least a 10% absolute increase in ORR is considered clinical meaningful improvement, the 
sample size of 40 subjects allows an 80% confidence interval of enfortumab vedotin ORR to 
exclude the reference ORR.  The actual sample size for each cohort may be less than the 
planned sample size depending on the ORR analysis result at the planned interim analysis.  
Per Bayesian optimal design for phase 2 (BOP2), the enrollment of a cohort maybe stopped 
after interim analysis.  
The planned sample size for cohort 9 is 40 subjects. Assuming the reference ORR for cohort 
9 is 20%, and at least a 25% absolute increase in ORR is considered clinical meaningful 
improvement for combination therapy, the sample size of 40 subjects allows a 92% power to 
detect a statistically significant difference at type 1 error rate of 1-sided 0.025.  The actual 
sample size for cohort 9 may be less than the planned sample size depending on the ORR 
analysis result at the planned interim analysis.  Per Bayesian optimal design for phase 2 
(BOP2), the enrollment of a cohort maybe stopped after interim analysis.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 103 of 160 
Amendment 6 
9.2 
Analysis Sets 
The allocation of subjects to analysis sets will be determined prior to database hard-lock. 
9.2.1 
Full Analysis Set 
The full analysis set (FAS) consists of all enrolled subjects who receive any amount of study 
drug.  The FAS is used for primary analysis on OS and PFS. 
9.2.2 
Response Evaluable Set 
The response evaluable set (RES) is a subset of the FAS.  It consists of the FAS subjects who 
have measurable disease at baseline per investigator assessment and have at least 
2 postbaseline scans or no longer in the follow-up of response at the time of analysis.  The 
RES is the primary analysis set for the response related efficacy analysis. 
9.2.3 
Safety Analysis Set 
The safety analysis set (SAF) consists of all subjects who receive at least 1 dose of study 
drug.  The SAF will be used for all summaries of the safety data. 
9.2.4 
Pharmacokinetic Analysis Set 
The pharmacokinetics analysis set (PKAS) consists of subjects who receive at least 1 dose of 
study drug and for whom at least 1 blood sample is collected and assayed for measurement of 
enfortumab vedotin and MMAE serum/plasma concentrations and for whom the time of 
sampling and the time of dosing on the day of sampling is known. 
9.3 
Demographics and Baseline Characteristics  
9.3.1 
Demographics 
Demographics and baseline characteristics will be summarized by cohort and overall for all 
treated subjects.  Descriptive statistics will include number of subjects, mean, standard 
deviation, minimum, median and maximum for continuous endpoints, and frequency and 
percentage for categorical endpoints. 
9.3.2 
Subject Disposition  
The number and percentage of subjects who discontinued treatment and reasons for treatment 
discontinuation will be presented for subjects in the SAF by cohort and overall.  Similar 
tables for screening disposition and follow-up disposition will also be presented. 
9.3.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy)  
All previous and concomitant treatment will be listed.  The frequency of concomitant 
treatment will be summarized by cohort and overall. 
9.3.4 
Medical History  
Medical history for each subject will be listed. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 104 of 160 
Amendment 6 
9.3.5 
Investigational Product Exposure 
The number and percentage of subjects exposed to study drug will be summarized by cohort. 
All study drug exposure data will be listed. 
9.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the RES and FAS as specified in [Section 9.2 
Analysis Sets].  For cohorts 1 to 8, tumor related analyses will be summarized based on 
RECIST Version 1.1.  For cohort 9, tumor related analyses will be summarized based on 
RECIST Version 1.1 and iRECIST. 
9.4.1 
Analysis of Primary Endpoint  
9.4.1.1 Primary Analysis 
The primary efficacy endpoint is the confirmed ORR per investigator assessment.  Confirmed 
ORR is defined as the proportion of subjects whose BOR is a confirmed CR or PR according 
to RECIST Version 1.1.  The confirmed ORR for each cohort will be calculated and its 95% 
confidence interval will be constructed by the Clopper-Pearson method.  The primary 
analysis set for confirmed ORR is RES.  Additionally, confirmed ORR by Nectin-4 
expression analysis may be conducted. 
9.4.2 
Analysis of Secondary Endpoints  
9.4.2.1 Duration of Response 
DOR is defined as the time from the date of first documented response (CR or PR that is 
subsequently confirmed) to the date of first documented PD per RECIST Version 1.1 or death 
due to any cause, whichever occurs first.  DOR will only be calculated for subjects achieving 
a confirmed CR or PR.  DOR will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided.  The median DOR and its 2-sided 95% CI will be 
calculated. 
9.4.2.2 Disease Control Rate 
DCR is defined as the proportion of subjects whose BOR is confirmed CR or PR or SD per 
RECIST Version 1.1.  DCR for each cohort will be calculated and its 95% confidence 
interval will be constructed by Clopper-Pearson method. 
9.4.2.3 Progression-free Survival 
PFS is defined as the time from start of study treatment to first documentation of PD per 
RECIST Version 1.1 or death due to any cause, whichever comes first.  PFS will be analyzed 
using Kaplan-Meier methodology and Kaplan-Meier plots will be provided.  The median PFS 
and its 2-sided 95% CI will be calculated. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 105 of 160 
Amendment 6 
9.4.2.4 Overall Survival 
OS is defined as the time from start of study treatment to date of death due to any cause.  OS 
will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be provided.  
The median OS and its 2-sided 95% CI will be calculated.  
9.4.3 
Analysis of Other Efficacy Endpoints  
9.4.3.1 Best Overall Response 
BOR will be determined based on all available tumor time point response data for the subject.  
Responses recorded after new anticancer therapy or progressive disease (PD), will be 
excluded from BOR derivation.  A frequency table of BOR will be presented for each cohort 
and overall.  
The BOR will be derived according to below criteria per RECIST Version 1.1: 
 If a subject has at least 2 CR and the first and the last CR dates are more than 28 days 
apart, then the BOR is defined as confirmed CR. 
 If a subject has PR and another CR/PR more than 28 days apart, then the BOR for this 
subject is confirmed PR. 
 For those subjects who do not have confirmed CR or PR, if the subject has at least 
1 tumor assessment record of CR/PR/SD which is at least 49 days after the date of the 
first dose, then BOR is defined as SD. 
 For subjects who do not have confirmed CR, confirmed PR or SD defined as above, but 
they have the last tumor assessment as PD, their BOR is PD. 
 Otherwise, BOR is defined as Not Evaluable (NE) or No Data (ND) for the subjects 
without any post-baseline tumor assessment data. 
9.4.3.2 Sum of Diameters 
Per RECIST Version 1.1, tumor burden is measured by the sum of diameters (SOD) of all 
target lesions at each tumor assessment.  The maximum percent reduction from baseline in 
SOD will be calculated for each subject and presented graphically with a waterfall plot. 
9.4.3.3 Time to Response 
Time to response (TTR) will be calculated as the time from the first dose of study drug to the 
first documentation of objective response (CR or PR that is subsequently confirmed) per 
RECIST Version 1.1.  TTR will only be calculated for subjects achieving a confirmed CR or 
PR.  TTR will be summarized by descriptive statistics. 
9.4.3.4 iRECIST Efficacy Endpoints 
For Cohort 9, separate endpoints of iORR, iDCR, iDOR, and iPFS will be analyzed based on 
iRECIST guidelines.  
Confirmed iORR is defined as the proportion of subjects whose BOR is a confirmed iCR or 
iPR according to iRECIST as assessed by investigator.  The confirmed iORR for cohort 9 
will be calculated and its 95% confidence interval will be constructed by the Clopper-Pearson 
method.  The analysis set for confirmed iORR is RES.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 106 of 160 
Amendment 6 
iDCR with confirmed response is defined as the proportion of subjects whose BOR is 
confirmed iCR or confirmed iPR or iSD per iRECIST as assessed by investigator.  iDCR for 
cohort 9 will be calculated and its 95% confidence interval will be constructed by 
Clopper-Pearson method. 
iDOR is defined as the time from the date of first documented response (iCR or iPR 
whichever is first recorded) to the date of first documented radiological disease progression 
per iRECIST as assessed by investigator or death due to any cause, whichever occurs first.  
iDOR will only be calculated for subjects achieving a confirmed iCR or iPR.  iDOR will be 
analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be provided.  The 
median iDOR and its 2-sided 95% CI will be calculated. 
iPFS is defined as the time from start of study treatment to first documentation of 
radiological disease progression per iRECIST as assessed by investigator or death due to any 
cause, whichever comes first.  iPFS will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided.  The median iPFS and its 2-sided 95% CI will be 
calculated. 
9.4.4 
Analysis of the Central Imaging Data 
Imaging scans for a cohort may be read at the independent review facility when the minimum 
number of responders per investigator assessment (subjects with confirmed CR and PR) to 
claim promising antitumor activity at stage 1 are met based on the 2-stage BOP2 design.  
Central images may also be read in certain circumstances as determined by the sponsor. 
Confirmed ORR, DOR, DCR, and PFS will be analyzed for the cohort with response 
assessment evaluated by BICR.  These endpoints will be analyzed similarly as the 
corresponding endpoint per investigator assessment except that subjects are required to have 
measurable disease at baseline per BICR. 
9.5 
Analysis of Safety 
9.5.1 
Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).   
A TEAE is defined as an AE observed after starting administration of study drug and within 
30 days after the final administration of study drug.  A drug-related TEAE is defined as any 
TEAE with a causal relationship assessed as “yes” by the investigator. 
The number and percentage of subjects with TEAEs, drug-related TEAEs, serious TEAEs, 
drug-related serious TEASs, TEAEs leading to withdrawal of treatment and drug-related 
TEAEs leading to withdrawal of treatment will be summarized by system organ class (SOC), 
preferred term, cohort, and overall.  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 subject.   
AE data will be listed. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 107 of 160 
Amendment 6 
9.5.2 
Laboratory Assessments  
For quantitative clinical laboratory measurements, observed value and changes from baseline 
will be summarized with descriptive statistics at each visit.  
Shift from baseline to worst post-baseline National Cancer Institute-Common Terminology 
Criteria for Adverse Event (NCI-CTCAE) grade will be summarized for each the selected lab 
parameters. 
Laboratory data will be listed. 
9.5.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by cohort and overall at each visit. 
Vital signs data will be listed. 
9.5.4 
Physical Examination  
Physical examinations will be listed.  
9.5.5 
Electrocardiogram 
9.5.5.1 Routine 12-lead Electrocardiogram 
The routine 12-lead ECG results will be summarized by cohort and overall at each visit.  
9.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores 
Number and percent of subjects for each category of the ECOG performance status at each 
assessment time will be provided.  Grades range from 0 (fully active) to 5 (dead).  Negative 
change in scores indicates an improvement and positive change in scores indicates a decline 
in performance.  ECOG will also be summarized using shift table from baseline to maximum 
post-baseline. 
9.6 
Analysis of Pharmacokinetics 
Concentrations of enfortumab vedotin and MMAE will be summarized using descriptive 
statistics (n, mean, SD, coefficient of variation [CV], geometric mean, geometric CV, 
median, minimum and maximum) at each pharmacokinetic sampling time point for the 
PKAS.  Additional model-based analyses and exposure response may be performed and 
reported separately. 
9.7 
Analysis of Pharmacodynamics | Immunogenicity 
The number and percentage of subjects with positive ATA for enfortumab vedotin will be 
presented.  In addition, for subjects with positive antibodies, individual subject titer levels 
will be displayed at each visit in a listing. 
9.8 
Analyses of Exploratory Biomarker(s) 
Associations between potential genomic and/or other biomarkers (including Nectin-4 
expression), and clinical results (efficacy, safety or pharmacodynamics) may be performed on 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 108 of 160 
Amendment 6 
subjects who have the necessary baseline and on study measurements to provide interpretable 
results for specific parameters of interest.  Biomarkers may be summarized graphically or 
descriptively as they relate to clinical measures, as applicable.  Summary statistics may be 
tabulated.  Additional post-hoc analyses, such as alternative modeling approaches, may be 
conducted.  All analyses described in this section are based on availability of the data. 
9.9 
Analysis of Quality of Life and Patient Reported Outcome 
Parameters 
Descriptive QOL and PRO analyses will be performed.  Completion rate for each 
questionnaire will be summarized.  Additional analyses will be discussed in detail in the 
SAP. 
9.10 
Major Protocol Deviations  
Major protocol deviations as defined in [Section 10.3 Major Protocol Deviations] will be 
summarized for all enrolled subjects by cohort and overall, as well as by study site. 
Major protocol deviation data will be listed by study site and subject. 
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. 
9.11 
Interim Analysis (and Early Discontinuation of the Study) 
For each cohort, one planned interim analysis will be performed to evaluate confirmed ORR 
at the time when 20 subjects had evaluable tumor response data per investigator assessment 
following study treatment.  The interim analysis decision rule is based on Bayesian optimal 
phase 2 (BOP2) design [Zhou et al, 2017].  
Specifically, let n denote the interim sample size and N denote the maximum sample size.  
For cohort , let 
 denote the reference ORR, 
 denote the target ORR and  
,  denote 
the treatment ORR of cohort , and define the null hypothesis 
:
,
, representing 
that the treatment is inefficacious.  At the time of the interim analysis for each cohort, the 
sponsor will stop enrolling subjects and claim that the treatment is not promising if 
(
, >
|
) <
( ) , 
where  and  are design parameters optimized to minimize the chance of incorrectly 
claiming that an efficacious treatment is not promising (i.e., type II error) under the 
alternative hypothesis 
:
, =
, while controlling the type I error rate at 0.1 (i.e., the 
chance of incorrectly claiming that an inefficacious treatment is promising is no more than 
10%) for cohorts 1 to 8 and 0.025 for cohort 9.  For this study, 
= 1 is selected for all 
9 cohorts to have reasonable probability of early stopping, grid search was performed to 
identify an optimal  for each cohort depending on their corresponding reference ORR 
(i.e., 
 ) and target ORR (i.e. 
 ).  Optimal  for each cohort are included in [Table 11].  
Assuming a Beta(
, 1
) prior distribution for 
, , the above decision rules are 
corresponding to the following stopping boundaries: 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 109 of 160 
Amendment 6 
Table 11 
or Each Cohort 
Cohort (Reference ORR  vs. 
Target ORR) 
,
   
Interim Analysis (Stage 1) 
Final Analysis (Stage 2) 
Number of 
Evaluable 
Subjects 
Minimum number 
of Responders to 
Proceed to Stage 2 
Number of 
Evaluable 
Subjects 
Minimum 
number of 
Responders to 
Claim 
Promising 
Antitumor 
Activity 
Cohort 1 (
= 0.2 vs. 
= 0.3) 
= 0.91,
= 1   
20 
4 
40 
12 
Cohort 2/4 (
= 0.15 vs. 
=
0.25) 
= 0.885,
= 1   
20 
3 
40 
10 
Cohort 3/5/6†/7/8 (
= 0.1 vs. 
= 0.2) 
= 0.84,
= 1   
20 
2 
40 
7 
Cohort 9 (
= 0.2 vs. 
= 0.45) 
= 0.98,
= 1   
20 
5 
40 
14 
†Interim analysis for Cohort 6 will be conducted when applicable under protocol versions 1.0 and 2.0 based on 
enrollment status. Subjects initially enrolled in Cohort 6 will be reallocated to Cohort 7 or 8 based on tumor 
type/histology.  
Based on the above table, using cohort 1 as an example, the sponsor will perform the interim 
analysis when the number of evaluable subjects with HR+/HER2- breast cancer reaches 20.  
If the total number of responders among the 20 evaluable subjects is less than 4, the 
enrollment of cohort 1 may stop; otherwise the enrollment will continue until the total 
number of evaluable subjects reaches the maximum sample size of 40.  The sponsor will 
make the final decision on stopping cohort enrollment based on the overall evaluation of 
antitumor activity and safety data including subject’s Nectin-4 expression data.  At the final 
analysis, taking into account overall antitumor activity (including central imaging data) and 
safety data, the sponsor will conclude that the treatment is promising if the number of 
responders among 40 are greater or equal to 12; otherwise the sponsor will conclude that the 
treatment is not promising.  
9.12 
Additional Conventions 
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses will be outlined in the SAP. 
10 
OPERATIONAL CONSIDERATIONS 
10.1 
Data Collection 
The investigator or site designee will enter data collected using an electronic data capture 
system.  In the interest of collecting data in the most efficient manner, the investigator or 
designee should record data (including clinical laboratory values, subject questionnaire data, 
if applicable) in the eCRF within 5 days after the subject’s visit. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 110 of 160 
Amendment 6 
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with the source.  These 
documents should be appropriately maintained by the study site. 
The monitor should perform source data review on all critical data and processes. 
Clinical laboratory tests and ECG will be performed at a local laboratory.  Redacted copies of 
all clinical laboratory reports will be submitted to a central vendor for data entry processing. 
The central data entry vendor will transfer data to the sponsor at predefined intervals during 
the study and provide the sponsor or designee with a complete and clean copy of the data.   
Subject quality of life questionnaires and PRO data as described in [Section 6.6.1.4 
Management of Enfortumab Vedotin Infusion Related Reactions] will be completed on paper 
forms by the subject and entered into the eCRF by the site study personnel.  The investigator 
or designee will review the questionnaire data throughout the study to ensure completion and 
protocol compliance. 
10.2 
Demographics and Baseline Characteristics 
10.2.1 Demographics 
Demographic information will be collected for all subjects as allowed per local regulation 
and will include date of birth, sex, race, ethnicity and tobacco use history (pack years). 
10.2.2 Medical History 
Medical history will include all significant medical conditions other than the target disease 
have resolved prior to informed consent or are ongoing at the time of consent.  Details that 
will be collected include the onset date and recovery date and Common Terminology Criteria 
for Adverse Events (CTCAE) grade, if applicable for ongoing conditions. 
10.2.3 Diagnosis of the Target Disease, Severity and Duration of Disease  
For the target disease (HR+/HER2-, TNBC, Squamous NSCLC, Non-squamous NSCLC, 
head and neck cancer, gastric, GEJ, or esophageal cancer), the following information 
including but not limited to will be collected during the screening period, and be entered in 
the eCRF:  
 
Date of initial diagnosis of the primary cancer, histological type, date of histopathological 
or cytopathological diagnosis  
 
Date of diagnosis for the locally advanced or metastatic or recurrent disease  
 
Disease stage at screening  
 
Sampling method and the biopsy site of the tumor tissues (primary vs. metastatic) for 
Nectin-4 expression analysis 
Previous treatment (including medication, radiotherapy and surgery) for underlying disease. 
10.2.4 Performance Status 
The ECOG Scale [Oken, 1982] will be used to assess performance status.  Refer to 
[Appendix 12.10 Eastern Cooperative Oncology Group Performance Status]. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 111 of 160 
Amendment 6 
10.3 
Major Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  All deviations from the protocol are to be 
recorded.  A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol.  Protocol waivers are strictly prohibited. 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety and 
well-being of subjects.  The investigator should not implement any deviation from, or 
changes of, the protocol, unless it is necessary to eliminate an immediate hazard to subjects.   
A major protocol deviation is one that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or 
well-being of a subject.  Major protocol deviations will have additional reporting 
requirements. 
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified.  The sponsor will follow-up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy of the subject to determine subject continuation in the study.   
The major protocol deviation criteria that will be summarized at the end of the study are as 
follows: 
PD1 - Entered into the study even though the subject did not satisfy entry criteria  
PD2 - Developed withdrawal criteria during the study and was not withdrawn 
PD3 - Received wrong treatment or incorrect dose. For enfortumab vedotin, incorrect dose 
will be defined as less than or greater than 10% from the intended dose. For pembrolizumab, 
any dose of 1000 mg or greater will be considered incorrect dose.  
PD4 - Received excluded concomitant treatment 
The investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File.   
10.4 
STUDY ORGANIZATION 
10.4.1 Safety Monitoring Committee 
A Safety Monitoring Committee (SMC), which consists of the sponsor and investigators, will 
be responsible for the review of study safety data for all cohorts on a periodic basis.  The 
SMC may recommend whether the study should be terminated, modified or continue 
unchanged based on ongoing reviews of study safety data.  Further details regarding 
responsibilities and membership requirements will be outlined in the SMC charter.   

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 112 of 160 
Amendment 6 
11 
REFERENCES 
American Cancer Society. Key Statistics for Lung Cancer. 2021a. 
https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.  Accessed 09 Aug 2021. 
American Cancer Society. Key Statistics for Esophageal Cancer. 2021b.   
https://www.cancer.org/cancer/esophagus-cancer/about/key-statistics.html. Accessed 09 Aug 
2021. 
Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Castro AF et al. Evidence-based 
treatment options in recurrent and/or metastatic squamous cell carcinoma of the head and neck. 
Front. Oncol. 2017;7:72 
Aupérin A. Epidemiology of head and neck cancers: an update. Current Opinion in Oncology. 
2020;32(3):178-186. 
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line 
therapy for advanced urothelial carcinoma. N Eng J Med. 2017;376(11):1015–26. 
Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al., PD-L1/B7H-1 inhibits the 
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
Blot WJ, Mclaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston S, et al. Smoking and 
drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48:3282–7. 
Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, et al. Pembrolizumab alone 
or with chemotherapy versus cetuximab with chemotherapy for recurrent or meta-static 
squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, 
phase 3 study. Lancet 2019;394:1915–28. 
Cardoso F, Harbeck N, Barrios CH, Bergh J, Cortes J, El Saghir N, et al. Research needs in breast 
cancer.  Ann Oncol. 2017;28(2):208-17. 
Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, et al. Enfortumab vedotin 
antibody-drug conjugate targeting Nectin-4 is a highly potent therapeutic agent in multiple 
preclinical cancer models. Cancer Res. 2016;76(10):3003-13. 
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. The Journal of 
Immunology. 2004;173:945–54. 
Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al; KEYNOTE-355 Investigators. 
Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated 
locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a 
randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 
2020;396(10265):1817-28. 
Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy 
versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a 
phase 3 open-label randomized study. Lancet.  2011;377:914-23.   

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 113 of 160 
Amendment 6 
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
Deng H, Shi H, Chen L, Zhou Y, Jiang J. Over-expression of Nectin-4 promotes progression of 
esophageal cancer and correlates with poor prognosis of the patients. Cancer Cell Int 
2019;19:106. 
Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531-8.  
Dudley ME, Wunderlich JE, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive Cell 
Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the 
Treatment of Patients With Refractory Metastatic Melanoma. Journal of Clinical Oncology. 
2005;0732-183. 
Fabre-Lafay S, Monville F, Garrido-Urbani S, Berruyer-Pouyet C, Ginestier C, Reymond N, et al. 
Nectin-4 is a new histological and serological tumor associated marker for breast cancer. BMC 
Cancer 2007;7:73. 
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for 
recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 2016;375:1856–67. 
Francisco, LM, Sage, PT, Sharpe, AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunological Reviews. 2010;0105-2896. 
Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, 
an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. 
Blood. 2003;102(4):1458-65. 
Global Cancer Observatory. International Agency for Research on Cancer. World Health 
Organization. https://gco.iarc.fr/ Accessed 18 Aug 2021. 
Greene J, Hennessy B. The role of anthracyclines in the treatment of early breast cancer. J Oncol 
Pharm Pract 2015;201-12. 
Greenwald, RJ, Freeman, GJ, Sharpe, AH. The B7 Family Revisited. Annual Reviews. 
2005;23:515-48. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-36. 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and PD-1 
by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65(3):1089-96. 
Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, et al. Enfortumab Vedotin 
Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 
2023;41(1):22-31. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 114 of 160 
Amendment 6 
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic 
melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703. 
Hurvitz S, Mead M. Triple-negative breast cancer: advancements in characterization and treatment 
approach. Curr Opin Obstet Gynecol. 2016;28(1):59-69. 
Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus 
chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, 
and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. 
Lancet. 2021;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5. 
PMID: 34102137. 
Johnson DE, Burtness B, Leemans, CR, Lui VWY, Bauman JE, Grandis JR. Head and neck 
squamous cell carcinoma. Nat Rev Dis Primers. 2020; 6(92). 
Jones S, Winer E, Vogel C, Laufman L, hutchins L, O’Rourke M, et al. Randomized comparison of 
vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol.  
1995;13(10):2567-74. 
Kantar Group. CancerMPact® Treatment Architecture, Breast Cancer, US. Dec 2019 (proprietary 
report) 
Kaufman PA, Awada A, Twelves C, Yelle L, Perex EA, Velikova G, et al. Phase III open-label 
randomized study of eribulin mesylate versus capecidabine in patients with locally advanced or 
metastatic breast cancer previously treated with an anthracycline and taxane. J Clin Onco. 
2015;33(6):594-601. 
Keam B, Machiels JP, Kim HR, Licitra L, Golusinski W, Gregoire V, et al. Pan-Asian adaptation of 
the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-
up of patients with squamous cell carcinoma of the head and neck. ESMO Open. 2021 
Dec;6(6):100309. 
Keytruda (prescribing information). Merck Sharp & Dohme LLC. Rahway, NJ, USA. July 2021. 
Leeman JE, Li JG, Pei X, Venigalla P, Zumsteg ZS, Katsoulakis E, et al. Patterns of treatment failure 
and postrecurrence outcomes among patients with locally advanced head and neck squamous 
cell carcinoma after chemoradiotherapy using modern radiation techniques. JAMA Oncol. 
2017;3:1487–94 
Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V; EHNS Executive 
Board. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: 
EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2020 Nov;31(11):1462-1475. doi: 10.1016/j.annonc.2020.07.011. Epub 2020 Oct 
23. PMID: 33239190. 
Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S, Brahmer JR, et al. Systemic therapy for 
stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice 
guideline update. J Clin Oncol 2015;33(30):3488-3515. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 115 of 160 
Amendment 6 
National Cancer Institute. 2021a. Cancer Stat Facts: Common Cancer Sites. 
https://seer.cancer.gov/statfacts/html/common.html. Accessed 16 Aug 2021. 
National Cancer Institute.  Head and Neck Cancers. 29 Mar 2017. 
https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet. Accessed 05 Jun 2019. 
National Comprehensive Cancer Network. Principles Of Systemic Therapy for Non-nasopharyngeal 
Cancers (Version 1.2023) https://www.nccn.org/professionals/physician_gls/pdf/head-and-
neck.pdf. Accessed 10 Jan 2023. 
National Comprehensive Cancer Network. 2021b. Non-small cell lung cancer (Version 5, 15 June 
2021). http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 30 Aug 2021. 
National Comprehensive Cancer Network. Gastric Cancer (Version 4, 03 Aug 2021c). 
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed 05 Oct 2021. 
National Comprehensive Cancer Network. Esophageal and Esophagogastric Junction Cancers 
(Version 4, 03 Aug 2021d). 
https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed 05 Oct 2021. 
National Comprehensive Cancer Network. Bladder Cancer (Version 3, 2019). 
https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed 01 Jul 2019. 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7. 
Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, et al. Metastatic non-small-cell lung 
cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 
2016;27 (Supple 5):v1-v27. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response 
criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol. 1982;5:649-55. 
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 
and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms. Mol Cell Biol. 
2005;9543-53. 
Pembrolizumab (Keytruda®) Investigator's Brochure, Ed. 22.  Merck Sharp & Dohme, Rahway, NJ, 
US. May 2022. 
Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of 
ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant 
to anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407-14. 
Petrylak D, Balar AV, O’Donnell PH, McGregor BA, Heath EI, Yu EY, et al. EV-201: Results of 
enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 116 of 160 
Amendment 6 
previously treated with platinum and immune checkpoint inhibitors (NCT03219333). 2019 
ASCO Annual Meeting.  
Piccart, M.  Circumventing de novo and acquired resistance to trastuzumab: new hope for the care of 
ErbB2-positive breast cancer. Clin Breast Cancer 2008;100-13. 
Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 enhances the 
therapeutic efficacy of combination immunotherapy against melanoma. J Immunol, 2010. 
184(7):3442-9. 
Plasilova ML, Hayse B, Killelea BK, Horowitz NR, Chagpar AB, Lannin DR. Features of triple-
negative breast cancer: Analysis of 38,813 cases from the national cancer database. Medicine 
(Baltimore). 2016;95(35):e4614. 
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Overall survival with 
cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-
small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 
2010;1804-09. 
Reymond N, Fabre S, Lecocq E, Adelaide J, Dubreuil P, and Lopez M. Nectin4/PRR4, a new afadin-
associated member of the nectin family that trans-interacts with nectin1/PRR1 through V 
domian interaction. J Biol Chem 2001;43205-15. 
Rikitake Y, Takai Y. Interactions of the cell adhesion molecule Nectin with transmembrane and 
peripheral membrane proteins for pleiotropic functions. Cell Mol Life Sci. 2008;65(2):253-63. 
Riley, JL. PD-1 signaling in primary T cells. Immunological Reviews. 2009; 0105-2896 
Robson M, Goessl C, Domchek S. Olaparib for Metastatic Germline BRCA-Mutated Breast Cancer. 
N Engl J Med. 2017;377(18):1792-3. 
Rosenberg JE, Milowsky M, Ramamurthy C, Mar N, McKay RR, Friedlander T, et al.  ESMO 12 Sep 
2022: Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or 
in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients 
(pts) with locally advanced or metastatic urothelial cancer (la/mUC). ESMO 12 Sep 2022. 
Annals of Oncology.2022;33(suppl_7):S808-S869. 
Rosenberg J, Sridhar SS, Zhang J, Smith D, Ruether D, Flaig TW, et al. Mature results from EV-101: 
a phase 1 study of enfortumab vedotin in patients with metastatic urothelial cancer. 
genitourinary cancers symposium of the American Society of Clinical Oncology. February 14-
16, 2019. San Francisco, CA.  
Sakisaka T, Ikeda W, Ogita H, Fujita N, Takai Y. The roles of nectins in cell adhesions: cooperation 
with other cell adhesion molecules and growth factor receptors. Current Opinion in Cell 
Biology 2007;19:593-602. 
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone 
or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542–50. 
Schmid P, Chui SY, Emens LA. Atezolisumab and nab-paclitaxel in advanced triple-negative breast 
Cancer. N Engl J Med. 2019;380(10):987-988. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 117 of 160 
Amendment 6 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines 
for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
2017;18(3):e143-52. 
Sheppard, K, Fitz, LJ, Lee, JM, Benander, C, George, JA, Wooter, J, et al. PD-1 inhibits T-cell 
receptor  induced  phosphorylation of the ZAP70/CD3 signalosome  and downstream signaling 
to PKC. FEBS Letters. 2004;0014-5793 
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021; 71:7. 
Siewert J, Ott K. Are Squamous and Adenocarcinomas of the Esophagus the Same Disease? Seminars 
in Radiation Oncology. 2007;17(1):38-44 
Socinski M, Obasaju C, Gandara D, Hirsch FR, Bonomi P, Bunn PA, et al. Current and emergent 
therapy options for advance squamous. Cell Lung Cancer 2018;165-183. 
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor 
rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 
production and proliferation of CD8(+) T cells directly within the tumor microenvironment. 
J Immunother Cancer. 2014;2:3. 
Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade augments 
adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-5. 
Takai Y, Ikeda W, Ogita H, and Rikitake Y. The immunoglobulin-like cell adhesion molecule nectin 
and its associated protein afadin. Annu Rev Cell Dev Biol. 2008;24:309-42. 
Takano A, Ishikawa N, Nishino R, Masuda K, Yasui W, Inai K, et al. Identification of nectin-4 
oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Res. 
2009;69(16):6694-6703. 
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based 
chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27. 
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37(5):430-9. 
Windon MJ, D’Souza G, Rettig EM, Westra WH, van Zante A, Wang SJ, et al. Increasing prevalence 
of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 
2018;124:2993–9. 
World Health Organization. Cancer Fact Sheet. 03 Mar 2021a.  https://www.who.int/news-room/fact-
sheets/detail/cancer. Accessed 16 Aug 2021. 
World Health Organzation. Breast Cancer Fact Sheet. 26 Mar 2021b.  https://www.who.int/news-
room/fact-sheets/detail/breast-cancer. Accessed 16 Aug 2021.Wu AW, Ji JF. Adenocarcinoma 
of esophagogastric junction requires a clearer definition. Transl Gastrointest Cancer 2013;2:5-9. 
Yoon H. Initial systemic therapy for locally advanced unresectable and metastatic esophageal and 
gastric cancer. 30 Jun 2021(a).  https://www.uptodate.com/contents/initial-systemic-therapy-

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 118 of 160 
Amendment 6 
for-locally-advanced-unresectable-and-metastatic-esophageal-and-gastric-cancer. Accessed 18 
Aug 2021.  
Yoon H. Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: 
Approach to later lines of systemic therapy. 09 Jul 2021(b).  
https://www.uptodate.com/contents/progressive-locally-advanced-unresectable-and-metastatic-
esophageal-and-gastric-cancer-approach-to-later-lines-of-systemic-therapy/print. Accessed 18 
Aug 2021.  
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Bhatia S, Cao E,et al. Structural and Functional Analysis 
of the Costimulatory Receptor Programmed Death-1. Immunity.2004;20(3):337-47 
Zhang Y, Chen P, Yin W, Ji Y, Shen Q, Ni Q et al. Nectin-4 promotes gastric cancer progression via 
the PI3K/AKT signaling pathway. Human Pathology 2018a;72:107-116. 
Zhang Y, Zhang J, Shen Q, Yin W, Huang H, Liu Y et al. High expression of Nectin-4 is associated 
with unfavorable prognosis in gastric cancer. Oncology Letters 2018b;15:8789-8795. 
Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and 
complex endpoints. Stat Med. 2017;36(21):3302-3314. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 119 of 160 
Amendment 6 
12 
APPENDICES 
12.1 
Ethical, Regulatory and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing study conduct and the ethical principles that have their 
origin in the Declaration of Helsinki.   
12.1.2 Institutional Review Board/Independent Ethics Committee/Competent 
Authorities 
GCP requires that the protocol, any protocol amendments, investigator’s brochure, ICF and 
all other forms of subject information related to the study (e.g., advertisements used to recruit 
subjects) and any other necessary documents be reviewed by an IRB/IEC.  The IRB/IEC will 
review the ethical, scientific and medical appropriateness of the study before it is conducted.  
IRB/IEC approval of the protocol, ICF and subject information and/or advertising, as 
relevant, will be obtained prior to initiation of any study-specific procedures. 
Any substantial amendments to the protocol will require competent authority and IRB/IEC 
approval before implementation, except for changes necessary to eliminate an immediate 
hazard to subjects. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC. 
 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 
Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation No. 536/2014 for 
studies (if applicable), and all other applicable local regulations. 
12.1.3 Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or nonsubstantial amendments.  
Depending on the nature of the amendment, either IRB/IEC or competent authority approval 
or notification may be required.  The changes will become effective only after the approval of 
the sponsor, investigator, IRB/IEC and appropriate regulatory authorities. 
Amendments to this protocol must be signed by the sponsor and investigator.  Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented.  
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 120 of 160 
Amendment 6 
If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor.  An approved copy of the new ICF must also be forwarded to the sponsor. 
12.1.4 Informed Consent of Subjects 
12.1.4.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject  
and answer all questions regarding this study.  Prior to any study-related screening 
procedures being performed on the subject, the ICF will be reviewed, signed  and dated by 
the subject or his/her guardian or legal representative, the person who administered the ICF 
and any other signatories according to local requirements.  A copy of the signed ICF will be 
given to the subject and the original will be placed in the subject’s medical record.  An entry 
must also be made in the subject’s dated source documents to confirm that the ICF was 
signed prior to any study-related procedures and that the subject received a signed copy of the 
ICF. 
The signed ICFs will be retained by the investigator and made available (for review only) to 
the study monitor, auditor and appropriate regulatory authorities and other applicable 
individuals upon request. 
12.1.4.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction).  The communication must be documented 
in the subject’s medical records and whether the subject is willing to remain in the study 
or not must be confirmed and documented.   
2. The investigator must update the subject’s ICF and submit it for approval to the 
IRB/IEC.  The investigator or his/her representative must obtain written informed 
consent from the subject on all updated ICFs throughout their participation in the study.  
The investigator or his/her designee must reconsent subjects with the updated ICF even if 
relevant information was provided verbally.  The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the ICF 
(place a personal seal, if applicable).  A copy of the signed or sealed ICF will be given to 
the subject and the original will be placed in the subject’s medical record.  An entry must 
be made in the subject’s records documenting the reconsent process. 
12.1.5 Source Documents 
Source data must be available at the study site to document the existence of the subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.   

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 121 of 160 
Amendment 6 
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, and/or drug accountability.   
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 audit trail information, if applicable).  All 
printed records must be kept in the subject file and be available for archiving.   
12.1.6 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data 
CRFs and investigator's file) and relevant correspondence.  These documents are to be kept 
on file for the appropriate term determined by local regulation (for US study sites, 2 years 
after approval of the NDA or discontinuation of the IND).  The sponsor will notify the study 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/investigational 
medicinal product dossier/CHIKEN TODOKE is discontinued.  The investigator agrees to 
obtain the sponsor’s agreement prior to disposal, moving or transferring of any study-related 
records.  The sponsor will archive and retain all documents pertaining to the study according 
to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subject’s 
medical records and/or study progress notes. 
For investigational sites located in Japan, the following are the major documents to be 
retained at the study site. 
1. Source documents (clinical data, documents and records for preparing the eCRF, hospital 
records, medical records, test records, memoranda, or checklists for evaluation, 
administration records, data recorded by automatic measuring instruments, reproductions 
or transcripts verified as precise copies, microfiche, negative films, microfilms/magnetic 
media, X-ray films, subject files and study-related records kept at either a pharmacy, a 
laboratory, or medical technical office, as well as subject registration forms, laboratory test 
slips, worksheets specified by the sponsor, records of clinical coordinators, and records 
related to the study selected from those verified in other departments or hospitals).   
2. Study contracts, written ICFs, written information and other documents or their copies 
prepared by the study personnel.  A letter of request for study (including a request for 
continuation/amendment), letter of request for review, notice of study contract, study 
contract, notification of discontinuation or completion of clinical study, written 
information for informed consent (including revisions), signed and dated written informed 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 122 of 160 
Amendment 6 
consent (including revisions), curriculum vitae of investigators, list of subinvestigators, list 
of signatures and print of seals (copy) and eCRF (copy), etc.   
3. The protocol, documents obtained from the IRB related to the adequacy of conducting the 
study by the head of the study sites (Article 32-1, MHW Ordinance No. 28), documents 
obtained from the IRB related to the adequacy of conducting a study whose period exceeds 
1 year or the adequacy of continuously conducting the study from which information on 
adverse drug reactions is obtained, and other documents obtained.  A finalized protocol 
(including revisions), finalized investigator’s brochure (including revisions), operational 
procedures for the investigator, materials and information supplied by the sponsor (e.g., 
AE report), matters reported by the investigator (revisions of the protocol, AE reports, 
etc.), operational procedures for the IRB, the list of names of the IRB members, materials 
for IRB review (including continuous deliberation), IRB review records (including 
continuous deliberation) and the review result report of the IRB (including continuous 
deliberation), etc.   
4. Records of control for investigational product and other duties related to the study.  
Procedure for controlling the investigational product, drug inventory and accountability 
record, vouchers for the receipt and return of the investigational product, and the 
prescriptions for concomitant medications 
12.1.7 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent or approval.  Additional medical information may be given only after approval of the 
subject to the investigator or to other appropriate medical personnel responsible for the 
subject’s well-being. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the 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 subject’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 subject’s right to protection against invasion of privacy.  Only a 
subject identification number will identify subject data retrieved by the sponsor.  However, 
the sponsor requires the investigator to permit the sponsor, sponsor’s representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US.  If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then 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 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 123 of 160 
Amendment 6 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the DPD. 
12.1.8 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 drug and 
therefore may disclose it as required to other clinical investigators or to regulatory agencies.  
In order to allow for the use of the information derived from this 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. 
12.1.9 Insurance of Subjects and Others  
If a subject suffers any study-related injury, the sponsor will compensate the subject 
appropriately according to the severity and duration of the damage.  However, if the injury 
was caused intentionally or was due to gross negligence by the study site, the sponsor will 
consult with the study site about handling the injury, based on the agreed study contract.  
Compensation for the study-related injury is provided by the following procedures: 
1. If a subject incurs an injury as a result of participation in the study, the study site should 
provide medical treatment and other necessary measures.  The sponsor should be notified 
of the injury.   
2. When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the sponsor.  Both parties should work together towards a 
compensation settlement. 
3. The sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the study contract. 
4. The sponsor shall make an arrangement for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
12.1.10 Signatory Investigator for Clinical Study Report 
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 hard-lock. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 124 of 160 
Amendment 6 
12.2 
Procedure for Study Quality Control 
12.2.1 Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP and the study data reported by the 
investigator/subinvestigator are accurate, complete and verifiable with the source.  The 
sponsor is responsible for assigning the study monitor(s) to this study for proper monitoring.  
They will monitor the study in accordance with planned monitoring procedures.   
12.2.2 Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO, as well as inspections from the IRB/IEC and appropriate regulatory 
authorities.  In these instances, they must provide all study-related records including source 
documents when they are requested by the sponsor monitors and auditors, the CRO, the 
IRB/IEC or appropriate regulatory authorities.  The confidentiality of the subject’s identity 
shall be well protected consistent with local and national regulations when the source 
documents are subject to direct access. 
12.2.3 Data Management 
Data management will be coordinated by the Data Science department of the sponsor in 
accordance with the SOPs for data management.  All study-specific processes and definitions 
will be documented by data management.  eCRF completion will be described in the eCRF 
instructions.  Coding of medical terms and medications will be performed using MedDRA 
and the World Health Organization (WHO) Drug Dictionary, respectively. 
12.2.4 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. 
Quality tolerance limits (QTLs) will be predefined in the applicable plan(s) to identify 
systematic issues that can impact subject safety and/or reliability of study results. These 
predefined parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 125 of 160 
Amendment 6 
12.3 
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 schedules of assessments.  
Pregnancy test results must confirm that the subject 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 1 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 1 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 1 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 subject’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use a condom plus 1 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 investigational product administration. a 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 126 of 160 
Amendment 6 
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 
 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. 
 Male is sterile due to a bilateral orchiectomy or radical cystoprostatectomy/removal of 
seminal vesicles 
 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 subject.  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 
subjects participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL. 
Male subjects 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 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 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 127 of 160 
Amendment 6 
 Female partners of male subjects who have not undergone a vasectomy with the absence 
of sperm confirmed or a bilateral orchiectomy require use one form of highly effective 
methods of contraception 
a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 128 of 160 
Amendment 6 
12.4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
12.4.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject administered an investigational 
product (IP), and which does not necessarily have to have a causal relationship with this 
treatment.  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 IP whether or not considered related to the IP. 
12.4.1.1 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 subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE. 
12.4.1.2 Potential Cases of Drug-induced Liver Injury 
Refer to [Appendix 12.5 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 [Appendix 12.5 Liver Safety 
Monitoring and Assessment], in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and are always to be 
considered important medical events and reported per [Section 12.4.5 Reporting Procedures 
for Serious Adverse Events]. 
12.4.2 Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or sponsor, the event:  
 Results in death 
 Is life-threatening (An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death; it 
does not include an AE that, had it occurred in a more severe form, might have caused 
death). 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
 Results in congenital anomaly, or birth defect 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 129 of 160 
Amendment 6 
 Requires inpatient hospitalization (except for planned procedures as allowed per study) or 
leads to prolongation of hospitalization (except if prolongation of planned hospitalization 
is not caused by an AE)  
 Other medically important events (defined in paragraph below) 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These events, including those that may result in disability/incapacity, 
usually are considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.   
12.4.3 Criteria for Causal Relationship to Investigational Product 
A medically qualified investigator is obligated to assess the relationship between IP and each 
occurrence of each (S)AE.  This investigator will use medical judgment as well as the 
reference safety information to determine the relationship.  The causality assessment is one of 
the criteria used when determining regulatory reporting requirements. 
The investigator is requested to provide an explanation for the causality assessment for each 
(S)AE and must document in the medical notes that he/she has reviewed the (S)AE and has 
provided an assessment of causality. 
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 subject been administered IP?  
 Plausibility (i.e., could the event have been caused by the suspect drug? 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?  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 130 of 160 
Amendment 6 
 
Laboratory or other test results: a specific laboratory investigation supports the 
assessment of the relationship between the (S)AE and the IP (e.g., based on values 
pretreatment, during and posttreatment) 
 
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  
 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
temporal relationship between exposure to the IP and (S)AE onset and/or resolution will 
be provided.  Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the IP? 
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 assesses causality for every event before the initial transmission of the 
SAE data to the sponsor.  With limited or insufficient information about the event to make an 
informed 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.  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.   
12.4.4 Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the NCI-CTCAE 
guidelines Version 4.03.  The items that are not stipulated in the NCI-CTCAE Version 4.03 
will be assessed according to the criteria below and entered into the eCRF: 
Table 12 
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 selfcare 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. 
‡Selfcare ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications and 
not bedridden. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 131 of 160 
Amendment 6 
12.4.5 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 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 worksheet to: 
Astellas Pharma Global Development Inc. 
Pharmacovigilance  
North America fax number: [+1-888-396-3750] 
North America alternate fax number: [+1-847-317-1241] 
International fax number: +44-800-417-5263 
Email: safety-us@astellas.com 
For investigational sites located in Japan: 
In the case of a SAE, the investigator or subinvestigator must report to the head of the study 
site and must contact the sponsor by fax or email immediately (within 24 hours of 
awareness).   
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the appropriate regulatory 
authorities to the sponsor (by fax or email immediately [within 24 hours of awareness]) and 
to the head of the hospital.   
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE/special situations worksheet to: 
Astellas Pharma Inc.  – Japan 
Pharmacovigilance 
Fax number: +81-(0)3-3243-5747 
Email: rk-safety-jp@jp.astellas.com 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or 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 situations 
worksheet and on the eCRF. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 132 of 160 
Amendment 6 
The following minimum information is required: 
 International study number/study number  
 Subject 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., suspected unexpected serious adverse reaction [SUSAR] 
reporting) according to current local/regional 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 (e.g., EMA, FDA) where required.  
Documentation of the submission to and receipt by the IRB/ IEC of expedited safety reports 
should be retained by the study site.  In the US, FDA expedited IND reporting guidelines will 
be followed. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements IRB/IEC. 
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 subject. 
12.4.6 Reporting Procedures for Special Situations 
12.4.6.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 6 months from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 12.4.5 Reporting Procedures for Serious Adverse 
Events] using the pregnancy reporting form as a special situation and in the eCRF.   
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 6 months from 
the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 12.4.5 Reporting Procedures for Serious Adverse Events] using the 
pregnancy reporting form as a special situation.   
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. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 133 of 160 
Amendment 6 
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 
subject as an AE in the eCRF or SAE per [Section 12.4.5 Reporting Procedures for Serious 
Adverse Events].  For (S)AEs experienced by a female partner of a male subject, (S)AEs are 
to be reported via the SAE worksheet.   
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
 “Spontaneous abortion” includes miscarriage, abortion and missed abortion. 
 Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the 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). 
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. 
12.4.6.2 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 subject), overdose or “off-label use” (i.e., use 
outside of what is stated in the protocol) is suspected, refer to [Section 10.3 Major Protocol 
Deviations].  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 12.4.5 Reporting 
Procedures for Serious Adverse Events] together with the details of the medication error, 
overdose and/or “off-label use.” 
In the event of suspected IP overdose, the subject should receive supportive care and 
monitoring.  The medical monitor/expert should be contacted as applicable. 
12.4.6.3 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 situations 
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 12.4.5 Reporting Procedures for 
Serious Adverse Events] together with details of the misuse or abuse of the IP. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 134 of 160 
Amendment 6 
12.4.6.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situations 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. 
12.4.6.5 (Suspicion of) Transmission of Infectious Agent  
If transmission of an infectious agent associated with the IP is suspected, the investigator 
must forward the special situations 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 12.4.5 Reporting Procedures for Serious Adverse Events] together with the details of 
the suspected transmission of infectious agent.   
12.4.6.6 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situations 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 12.4.5 Reporting 
Procedures for Serious Adverse Events] together with details of the suspected drug-drug 
interaction. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 135 of 160 
Amendment 6 
12.5 
Liver Safety Monitoring and Assessment  
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury 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 subject enrolled in a study with active drug therapy and who reveals 
an increase of serum aminotransferases (AT) to > 3 
ULN (to > 5 
ULN in subjects with liver 
metastases) or total bilirubin > 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 
notification of the test results.  For studies for which a central laboratory is used, alerts will be 
generated by the central laboratory regarding moderate and severe liver abnormality to inform 
the investigator and study team.  Subjects should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below. 
Table 13 
Moderate and Severe Liver Abnormalities 
 
ALT or AST 
 
TBL 
Moderate 
> 3  ULN (in subjects without liver metastases), > 5  ULN (in 
subjects 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 subject should be considered to have severe hepatic abnormalities for any of 
the following: 
 ALT or AST > 8  ULN 
 ALT or AST > 5  ULN for more than 2 weeks (in the absence of liver metastases) 
 ALT or AST > 3  
> 1.5 (If INR testing is applicable/evaluated) 
 ALT or AST > 3 
ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)  
† 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 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 136 of 160 
Amendment 6 
abnormality case report form (LA-CRF).  Subjects 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 
then weekly or less if abnormalities stabilize or the investigational product has been 
discontinued and the subject 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 subjects for whom severe hepatic liver function 
abnormalities possibly attributable to investigational product are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
 Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset diseases 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 subjects 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 subject’s history, other testing may be appropriate including:  
o Acute viral hepatitis (A, B, C, D, E or other infectious agents)  
o Ultrasound or other imaging to assess biliary tract disease 
o Other 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 subject may be discontinued from study treatment.  The 
investigator may determine that it is not in the subject’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 subjects without liver metastases) 
 ALT or AST > 3 
ULN and† TBL > 2 
ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 137 of 160 
Amendment 6 
 ALT or AST > 5 
ULN and† (TBL > 2  ULN in subjects 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 subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
Hy’s Law Definition:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by a higher 
 
common in treated and untreated subjects to be discriminating). 
2. 
-
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: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug 
or placebo.   
2. Among subjects showing such AT elevations, often with AT levels much greater than 
3  
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
References 
Temple R.  Hy’s Law: Predicting Serious Hepatotoxicity.  Pharmacoepidemiol Drug Saf.  
2006;15(4):241-3. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 138 of 160 
Amendment 6 
12.6 
List of Cautionary Concomitant Medications 
The following list describes medications and foods that are common strong inhibitors of 
CYP3A4 that should be 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. 
Strong CYP3A4 Inhibitors 
boceprevir 
cobicistat 
conivaptan 
danoprevir/ ritonavir 
elvitegravir/ ritonavir  
grapefruit juice 
indinavir/ ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
paritaprevir/ ritonavir/ (ombitasvir and/or dasabuvir)  
posaconazole 
ritonavir 
saquinavir/ ritonavir 
telaprevir 
tipranavir/ritonavir 
troleandomycin 
voriconazole 
CYP: cytochrome 
Note: Any additional strong inhibitors of CYP3A4 that are identified or become commercially available while 
the clinical study in ongoing are also applicable.   
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 139 of 160 
Amendment 6 
12.7 
Laboratory Assessments  
Laboratory tests will be performed according to the schedules of assessments and sent to the 
local laboratory for analysis. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 140 of 160 
Amendment 6 
Table 14 
Clinical Laboratory Tests 
Panel/Assessments 
Parameters to be Analyzed 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Platelets 
Red blood cell count (RBC) 
White blood cell count (WBC) 
White blood cell count differential 
(Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes) 
Absolute neutrophil count (ANC) 
Biochemistry 
Albumin (Alb) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bicarbonate (HCO3) 
Bilirubin (total and direct) 
Blood urea nitrogen (BUN) 
Calcium Corrected (CCa) 
Chloride (Cl) 
Creatinine 
Glucose 
Hemoglobin A1c (HbA1c, screening and EOT only) 
Lactate dehydrogenase (LDH) 
Magnesium (Mg) 
Phosphate (P) 
Potassium (K) 
Sodium (Na) 
Total protein (TP) 
Uric Acid 
Lipid panel (screening only), including: 
Total cholesterol (T chol)  
High-density lipoprotein cholesterol (HDL-C) 
Low-density lipoprotein cholesterol (LDL-C)  
Triglycerides (Trig) 
Thyroid Function Tests 
Triiodothyronine (T3) or Free Triiodothyronine (FT3) 
Free thyroxine (FT4) 
Thyroid stimulating hormone (TSH) 
Coagulation (Cohort 9 only) 
INR 
PT 
PTT 
Pregnancy Test 
-human Chorionic Gonadotropin (hCG). See Schedules 
of Assessments for women of childbearing potential. 
Note: Fasting blood samples are required at screening and on cycle 1 day 8 only.  

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 141 of 160 
Amendment 6 
12.8 
Pharmacogenomic Analysis with Banked Sample (Optional)  
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring differences in a 
subject’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the subject.  Through investigation of PGx by 
technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood.  As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory.  The objective of this research will be to analyze or determine genes of 
relevance to clinical response, pharmacokinetics and/or toxicity/safety. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in the PGx substudy.  
Subjects must provide written consent prior to providing any blood samples that may be used 
at a later time for PGx analysis. 
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this substudy will provide 4 to 6 mL of whole blood 
sample per Astellas’ instructions.  Each sample will be identified by the unique subject 
number.  Samples will be shipped to a design banking CRO as directed by Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet.  Astellas may initiate the 
PGx analysis if evidence suggests that genetic variants may be influencing the drug’s 
pharmacokinetics, efficacy and/or safety.   
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard-lock.  If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period.  The subject has the right to withdraw consent at 
any time.  When a subject’s withdraw notification is received, the PGx sample will be 
destroyed.  The results of any PGx analysis conducted on a sample prior to its withdrawal 
will be retained at Astellas indefinitely unless otherwise specified by local regulation. 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 142 of 160 
Amendment 6 
INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the study, if 
applicable.  The results of the PGx analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date.  Any information that is obtained 
from the PGx analysis will be the property of Astellas.   
 

Sponsor: APGD
ISN/Protocol 7465-CL-202
- CONFIDENTIAL -
05 Feb 2024
Astellas
Page 143 of 160
Amendment 6
12.9
RECIST Version 1.1

Sponsor: APGD
ISN/Protocol 7465-CL-202
- CONFIDENTIAL -
05 Feb 2024
Astellas
Page 144 of 160
Amendment 6
Reproduced from:  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumors: revised RECIST guideline (Version 1.1).  Eur J Cancer.  
2009;45:228-47.

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 146 of 160 
Amendment 6 
12.11 Global Pain Assessment 
 
 
 
 
 
 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 147 of 160 
Amendment 6 
12.12 EQ-5D-5L 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 148 of 160 
Amendment 6 
 
 

Sponsor: APGD
ISN/Protocol 7465-CL-202
- CONFIDENTIAL -
05 Feb 2024
Astellas
Page 149 of 160
Amendment 6
12.13 EORTC QLQ H&N43

Sponsor: APGD
ISN/Protocol 7465-CL-202
- CONFIDENTIAL -
05 Feb 2024
Astellas
Page 150 of 160
Amendment 6

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 151 of 160 
Amendment 6 
12.14 PRO-CTCAE Questions 
NCI-PRO-CTCAE® CUSTOM SURVEY  
Item subset derived from PRO-CTCAE® Item Library Version 1.0  
English  
Form Created on 10-January-2023  
https://healthcaredelivery.cancer.gov/pro-ctcae/builder.html  
  
As individuals go through treatment for their cancer they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days…  
  
1a.  In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA/DIARRHOEA)?  
 
 
 
 
constantly  
  
2a.  In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at 
its WORST?  
 
 
 
 
 
2b.  In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with 
your usual or daily activities?  
 
 
 
 
 
  
OTHER SYMPTOMS 
Do you have any other symptoms that you wish to report? 
 
 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
 
 
O Severe 
O Very Severe
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
 
 
O Severe 
O Very Severe
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
 
 
O Severe 
O Very Severe

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 152 of 160 
Amendment 6 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
 
 
O Severe 
O Very Severe
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
 
 
O Severe 
O Very Severe
 
 

Sponsor: APGD
ISN/Protocol 7465-CL-202
- CONFIDENTIAL -
05 Feb 2024
Astellas
Page 153 of 160
Amendment 6
12.15
FACT-G

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 154 of 160 
Amendment 6 
12.16 List of Abbreviations and Definition of Key Study Terms 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADC 
antibody-drug conjugate 
ADL 
activities of daily living 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count  
APGD 
Astellas Pharma Global Development Inc. 
aPTT 
activated partial thromboplastin 
ASCO/CAP 
American Society of Clinical Oncology/College of American Pathologists 
AST 
aspartate aminotransferase 
AT 
aminotransferase  
ATA 
antitherapeutic antibodies 
AUST 
Astellas US Technologies 
BICR 
blinded independent central review 
BOP2 
Bayesian optimal design for phase 2 
BOR 
best overall response 
CA 
competent authorities 
CD28 
cluster of differentiation 28 
CDK 
cyclin-dependent kinase  
cfDNA 
circulating free deoxyribonucleic acid 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CPS 
combined positive score 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CYP 
cytochrome 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 155 of 160 
Amendment 6 
Abbreviations 
Description of abbreviations 
dMMR 
mismatch repair deficient 
DOR 
duration of response 
DPD 
data protection directive 
EAC 
esophageal adenocarcinoma 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EEA 
European economic area 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
end of treatment 
EQ-5D-5L 
EuroQOL 5-dimensions 
ER 
estrogen receptor 
ESCC 
esophageal squamous cell carcinoma 
ESMO 
European Society for Medical Oncology  
FACT-G 
Functional Assessment of Cancer Therapy – General  
FAS 
full analysis set 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
FU 
fluorouracil 
GCP 
Good Clinical Practice 
GEAC 
gastroesophageal adenocarcinoma 
GEJ 
gastroesophageal junction 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HDL-C 
high-density lipoprotein cholesterol 
HER2 
human epidermal growth factor receptor 2 
HER2- 
human epidermal growth factor receptor 2-negative  
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma  
HPV 
human papillomavirus 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 156 of 160 
Amendment 6 
Abbreviations 
Description of abbreviations 
HR 
hazard ratio 
HR+ 
Hormone receptor positive  
HRQOL 
health-related quality of life 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCPD 
confirmed progressive disease (based on iRECIST guidelines) 
IEC 
Independent Ethics Committee 
IFN-  
interferon gamma 
Ig 
immunoglobulin 
IgG4 
immunoglobulin G4 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
imAE 
immune-mediated adverse event 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
iRECIST 
modified RECIST v1.1 for immune-based therapeutics 
IRR 
infusion-related reactions 
IRT 
Interactive response technology 
ISS 
integrated summary of safety 
iUPD 
unconfirmed progressive disease (based on iRECIST guidelines) 
LA-CRF 
liver abnormality case report form 
LDL-C 
low-density lipoprotein cholesterol 
mAbs 
monoclonal antibodies 
MCBS 
Magnitude of Clinical Benefit Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MMR 
mismatch repair 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
mUC 
metastatic urothelial cancer  
NCCN 
National Comprehensive Cancer Network  
NCI 
National Cancer Institute- 
ND 
no data 
NDA 
new drug application 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 157 of 160 
Amendment 6 
Abbreviations 
Description of abbreviations 
NE 
not evaluable 
NGS 
next-generation sequencing 
NLNT 
New Lesion-Non-Target 
NLT 
New Lesion-Target 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
OPC 
oropharngeal cancer 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PBMC 
peripheral blood mononuclear cells 
PBPK 
physiologically-based pharmacokinetics 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PGx 
pharmacogenomic 
PK 
pharmacokinetics 
PKAS 
pharmacokinetics analysis set 
PR 
partial response 
PRO 
patient reported outcome 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QA 
quality assurance 
QC 
quality control 
QOL 
quality of life 
QTL 
quality tolerance limits 
R/M 
recurrent/metastatic 
RANK 
receptor activator of nuclear factor kappa-  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES 
response evaluable set 
ROS 
reactive oxygen species 
(S)AE 
serious adverse event or adverse event 
SAE 
serious adverse event 
SAF 
safety analysis set 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 158 of 160 
Amendment 6 
Abbreviations 
Description of abbreviations 
SAP 
statistical analysis plan 
SCAR 
severe cutaneous adverse reactions 
SD 
stable disease 
SDRIFE 
symmetrical drug-related intertriginous and flexural exanthema 
SJS 
Stevens-Johnson Syndrome 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SOD 
sum of diameters 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
T1DM 
type 1 diabetes mellitus  
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
tmax 
time of maximum concentration  
TMDD 
target-mediated drug disposition 
TNBC 
triple negative breast cancer 
TTR 
time to response 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USM 
urgent safety measure 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 159 of 160 
Amendment 6 
Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline  
Assessments of subjects 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 subject into a study after screening. 
Intervention 
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 QOL, efficacy, safety and pharmacoeconomics).   
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test product or comparative drug (sometimes without 
randomization) is given to a subject and continues until the last assessment 
after completing administration of the test product or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained AEs and/or survival are done in this period. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
study. 
Screen failure 
Potential subject who signed the ICF but did not meet 1 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 subject signs the consent form until just before the test product 
or comparative drug (sometimes without randomization) is given to a 
subject.   
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. 
 

Sponsor: APGD 
ISN/Protocol 7465-CL-202 
- CONFIDENTIAL - 
05 Feb 2024 
Astellas 
Page 160 of 160 
Amendment 6 
13 
SPONSOR SIGNATURE