Conditions: Carcinoma, Transitional Cell Urinary Bladder Neoplasms Urologic Neoplasms Renal Pelvis Neoplasms Urothelial Cancer Ureteral Neoplasms Urethral Neoplasms
Keywords: Enfortumab vedotin Metastatic Urothelial Cancer ASG-22CE Locally Advanced Urothelial Cancer Antibody-Drug Conjugate Nectin-4 Platinum-naïve Cisplatin-ineligible Antineoplastic Agents Drug Therapy ASG-22ME
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 219
Healthy volunteers: no

Brief summary:
This is a study that will test how an experimental drug (enfortumab vedotin) affects patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra that has spread to nearby tissues or to other areas of the body.

This clinical trial will enroll patients who were previously treated with a kind of anticancer drug called an immune checkpoint inhibitor (CPI). Some CPIs have been approved for the treatment of urothelial cancer.

This study will test if the cancer shrinks with treatment. This study will also look at the side effects of the drug. A side effect is a response to a drug that is not part of the treatment effect.

Patients who sign up for this trial must also fall into one of these categories:

* Patients have already received treatment with platinum-containing chemotherapy
* Patients have never received platinum-containing treatment and are not eligible for treatment with cisplatin.

Detailed description:
Japan Pharmaceuticals and Medical Devices Agency (PMDA) has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan.

This study will examine the safety and anticancer activity of enfortumab vedotin given intravenously to patients with locally advanced or metastatic urothelial cancer who previously received a CPI and either previously received platinum-containing chemotherapy (Cohort 1) or are platinum-naïve and cisplatin-ineligible (Cohort 2). Patients who received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-naïve. Approximately 100 patients are expected to be enrolled in each cohort. The primary goal of the study is to determine the confirmed ORR of enfortumab vedotin.

Arms:
arm 1: Enfortumab vedotin on days 1, 8 and 15 every 28 days

Interventions: intervention 1: Enfortumab vedotin
Intervention descriptions: intervention 1: Intravenous (IV) infusion on days 1, 8 and 15 every 28 days

Protocol document:
Prot_002.pdf: 
 
 
 
This document contains information proprietary to Seagen Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Seagen Inc. You may disclose the contents of this document to study 
personnel under your supervision and to your Institutional Review Board (IRB) or Ethics Committee (EC) for 
the same purpose. You may not disclose the contents of this document to any other party, unless government 
regulations or laws require such disclosure, without prior written permission from Seagen Inc. Any 
supplemental information that may be added to this document is proprietary to Seagen Inc. and should be 
handled using the disclosure procedure described above. 
 
Protocol Number: 
SGN22E-001 
Version: 
Amendment 9; 15-Feb-2023 
Protocol Title: 
A single-arm, open-label, multicenter study of enfortumab 
vedotin (ASG-22CE) for treatment of patients with locally 
advanced or metastatic urothelial cancer who previously 
received immune checkpoint inhibitor (CPI) therapy. 
Study Name 
EV-201 
Investigational Drug: 
Enfortumab vedotin (ASG-22CE) 
Phase: 
2 
IND Number: 
116360  
EudraCT Number 
2017-003479-78 
Study Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
IND Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062, USA 
Medical Monitor: 
 MD, PhD 
Seagen Inc. 
Tel:
E-mail:
SAE Email or Fax: 
See email or fax number(s) specified on the SAE report form. 
 
PPD
PPD
PPD


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PROTOCOL SYNOPSIS  
Protocol Number  
SGN22E-001 
Version  
Amendment 9; 15-Feb-2023 
Phase  
2 
Product Name  
Enfortumab vedotin (ASG-22CE) 
Study Sponsor  
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
IND Sponsor 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062, USA 
 
Protocol Title  
A single-arm, open-label, multicenter study of enfortumab vedotin (ASG-22CE) for treatment of patients with 
locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) 
therapy. 
Study Objectives  
Primary: 
● To determine the antitumor activity of single-agent enfortumab vedotin as measured by confirmed 
objective response rate (ORR) in patients with locally advanced or metastatic urothelial cancer who have 
previously received systemic therapy with a CPI and either previously received platinum-containing 
chemotherapy or are platinum-naïve and cisplatin-ineligible 
Secondary: 
● To assess duration of response (DOR) 
● To assess disease control rate (DCR) 
● To assess progression-free survival (PFS) 
● To assess overall survival (OS) 
● To assess the safety and tolerability of enfortumab vedotin  
● To assess the pharmacokinetics (PK) of enfortumab vedotin 
● To assess the incidence of antitherapeutic antibodies (ATA) 
Additional:  
● To explore potential correlations between biomarkers and clinical outcomes 
● To evaluate the treatment effect of enfortumab vedotin on quality of life (QoL) 
Study Population  
The population to be studied includes patients with locally advanced or metastatic urothelial cancer who 
previously received therapy with CPI, with measurable disease according to Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1. Patients who received CPI therapy in the neoadjuvant/adjuvant setting 
and had recurrent or progressive disease (PD) either during therapy or within 3 months of therapy completion 
are eligible. Patients must also be either:  
1) Platinum-treated (Cohort 1): Patients who received prior treatment with platinum-containing chemotherapy 
defined as those who received platinum in the adjuvant/neoadjuvant setting and had recurrent or 
progressive disease within 12 months of completion OR received treatment with platinum in the locally 
advanced (defined as unresectable with curative intent) or metastatic setting; 


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OR 
2) Platinum-naïve and cisplatin ineligible (Cohort 2): Patients who have not received prior platinum-
containing or other chemotherapy in the locally advanced or metastatic setting and are ineligible for 
treatment with cisplatin at time of enrollment. Patients who received platinum in the 
adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered 
platinum-naïve.  
Patients must have PD during or following their most recent therapy. Eligible patients must be ≥18 years of age, 
and legally an adult according to local regulation. Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status score of ≤1 for Cohort 1, or ECOG ≤2 for Cohort 2. Patients must have an 
anticipated life expectancy of ≥3 months as assessed by the investigator. Patients must have adequate baseline 
hematologic, hepatic, and renal function.  
Patients must not have ongoing sensory or motor neuropathy (Grade 2 or higher), or active central nervous 
system metastases. Patients must not have been previously enrolled in an enfortumab vedotin study or 
previously treated with other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs). There 
are no limits for prior lines of therapy, including taxanes. Patients must not have a history of another 
malignancy within 3 years, or any evidence of residual disease from a previously diagnosed malignancy. 
Patients are also excluded if they are currently receiving systemic antimicrobial treatment for active infection or 
high dose steroids. Patients with uncontrolled diabetes are excluded. Uncontrolled diabetes is defined as 
hemoglobin A1C (HbA1c) ≥8% or HbA1c 7–<8% with associated diabetes symptoms (polyuria or polydipsia) 
that are not otherwise explained. Patients must not have uncontrolled tumor-related bone pain or impending 
spinal cord compression. Patients requiring pain medication must be on a stable regimen at the time of 
enrollment (a minimum of 2 weeks). 
Number of Planned Patients  
Approximately 200 patients will be enrolled in this study, including approximately 100 or more platinum-
treated patients (Cohort 1), and up to approximately 100 platinum-naïve and cisplatin-ineligible patients 
(Cohort 2).  
Study Design  
This is a single-arm, open-label, multicenter trial designed to assess the efficacy and safety of enfortumab 
vedotin as a single agent in locally advanced or metastatic urothelial cancer patients who have previously 
received systemic therapy with a CPI. For the purpose of this study a CPI is defined as a programmed cell death 
protein 1 (PD-1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor (including, but not limited to: 
atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab).  Patients must either have received prior 
treatment with platinum-containing chemotherapy (Cohort 1) or received no prior treatment with platinum-
containing or other chemotherapy and are ineligible for treatment with cisplatin at time of enrollment 
(Cohort 2). 
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an intravenous (IV) infusion over 
approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients will continue to receive study 
treatment until disease progression, unacceptable toxicity, investigator decision, consent withdrawal, start of a 
subsequent anticancer therapy, pregnancy, or study termination by the sponsor. After discontinuation of study 
treatment, patients will be followed every 8 weeks (±1 week) for response assessments, ECOG performance 
status, and physical exams. After 1 year of on study, the frequency of follow-up exams including response 
assessments will be reduced to every 12 weeks (±1 week). Patients that have progressed or begun subsequent 
anticancer therapy will be contacted every 8 weeks (±1 week) up to 1 year on study, and every 12 weeks 
(±1 week) thereafter to obtain information on subsequent anticancer therapy, and survival status until death, 
study closure, or withdrawal of consent, whichever occurs first. The study will be closed 5 years after 
enrollment of the last patient, or when no patients remain in long-term follow-up, whichever occurs first. 
Additionally, the sponsor may terminate the study at any time. 


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On a periodic basis, an independent data monitoring committee (IDMC) will monitor the safety of patients 
participating in this trial. The IDMC will be responsible for evaluating the results of safety analyses and will 
make recommendations to the sponsor. 
An ongoing real-time review of patient safety and serious adverse events (SAEs) will also be conducted by the 
sponsor’s Drug Safety Department.  
Test Product, Dose, and Mode of Administration  
Enfortumab vedotin 1.25 mg/kg will be administered as an IV infusion over approximately 30 minutes on 
Day 1, 8, and 15 of each 28-day cycle.  
Duration of Treatment  
Patients may continue on study treatment until disease progression, unacceptable toxicity, investigator decision, 
consent withdrawal, start of a subsequent anticancer therapy, pregnancy, or study termination by the sponsor. 
Efficacy Assessments  
Measures of anticancer activity will be assessed by computed tomography (CT) scans with contrast 
approximately every 8 weeks (±1 week). After 1 year on study, response assessments will be reduced to every 
12 weeks (±1 week). The schedule of response assessments should not be adjusted for dose delays/interruptions 
or other reasons for changes in the timing of a patient’s study activities; timepoints for response assessments 
should be calculated from Cycle 1 Day 1 during treatment. For patients who cannot receive CT scans with 
contrast, other protocol-specified imaging methods may be used. Patients must be evaluated using the same 
imaging method throughout the study for efficacy assessments. CT scans with contrast at the minimum will 
include the chest, abdomen, and pelvis. Other regions should be scanned if the patient has known or suspected 
disease in that region. Responses (complete response [CR] or partial response [PR]) will be confirmed with 
repeat scans 4 weeks (+1 week window) after first documentation of response. The determination of antitumor 
activity will be based on confirmed objective response assessments as defined by RECIST Version 1.1. 
Response and progression will be assessed by an independent review facility (IRF). The investigator will make 
treatment decisions based on site assessments of scans by RECIST. 
Patients who discontinue study treatment for reasons other than objective disease progression by RECIST will 
continue to receive scans 8 weeks (±1 week) after the previous response assessment scan and every 8 weeks 
(±1 week) following the previous scan thereafter. After 1 year on study the frequency of response assessments 
will be reduced to every 12 weeks (±1 week). The tumor assessments will continue until the patient has 
radiologically-confirmed progression per the investigator, initiates a new anticancer therapy, dies, withdraws 
consent, or the study closes, whichever comes first.  
Pharmacokinetic and ATA Assessments  
Blood samples for PK and ATA will be collected throughout the study. Qualified or validated assays will be 
used to measure the concentrations of enfortumab vedotin ADC, total antibody (TAb), and MMAE in serum or 
plasma and assess ATA. 
Biomarker Assessments  
Samples for exploratory biomarkers will be collected at protocol-specified timepoints. Biomarker assessments 
will not be used for patient selection. Biomarker assessments in tumor tissue may include, but will not be 
limited to, tumor expression of Nectin-4 protein, messenger ribonucleic acid (mRNA) expression, markers of 
disease subtype, and markers of the immune microenvironment in tumor. Assessments in blood samples may 
include, but will not be limited to, markers of immune function, including abundance and phenotype of immune 
cell subsets, circulating tumor DNA (ctDNA), and abundance of cytokines. Methods of analysis may include 
immunohistochemistry (IHC), next generation sequencing, polymerase chain reaction (PCR), mutation and gene 
expression profiling, T-cell receptor beta chain sequencing, flow cytometry, and immunoassays. 


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Safety Assessments  
Safety assessments will be based on the information collected through the safety surveillance process and will 
include the data from recorded adverse events (AEs) including SAEs, recording of concomitant medication, 
physical examination findings, cardiac monitoring, and laboratory tests. 
Quality of Life Assessments  
Patient reported outcomes (PRO) assessments will be used to obtain QoL information at protocol-specified 
timepoints. The following validated tools will be used: European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and EuroQol 5-dimensions (EQ-5D). 
Statistical Methods  
Analysis for primary endpoint: 
The primary endpoint of this study is the confirmed ORR per IRF. The ORR is defined as the proportion of 
patients with confirmed CR or PR according to RECIST Version 1.1. The ORR per IRF and its exact 2-sided 
95% confidence interval (CI) using the Clopper-Pearson method (Clopper 1934) will be calculated. 
There are 2 cohorts of CPI-treated patients in the study: Cohort 1) platinum-treated patients as defined in the 
study population above, and Cohort 2) platinum-naïve and cisplatin-ineligible patients also defined in the study 
population above. The primary endpoint will be analyzed separately for each cohort and may be analyzed for all 
patients, combining both Cohorts 1 and 2. 
The primary analysis on Cohort 1 (platinum-treated patients) will be conducted when enrollment is completed 
in Cohort 1, and all patients in the cohort have been followed for at least 6 months, or have discontinued from 
study, or had 30 days safety follow-up after PD, whichever comes first. Analysis for Cohort 2 will occur at 
4 timepoints: 1) at the time of analysis of Cohort 1, 2) when approximately 50 patients in Cohort 2 have had the 
opportunity to be followed for approximately 8 months from the first dose of enfortumab vedotin, 3) when 
approximately 70 patients in Cohort 2 have had the opportunity to be followed for approximately 8 months 
from the first dose of enfortumab vedotin, and 4) when all patients in Cohort 2 have had the opportunity to be 
followed for approximately 8 months from the first dose of enfortumab vedotin. All patients may also be 
analyzed at the time of analysis of Cohort 1 and/or Cohort 2. 
The primary analysis of efficacy endpoints will be based on the full analysis set, including all patients who 
enrolled and received any amount of enfortumab vedotin. At the time of the interim analyses for Cohort 2, 
additional analyses of efficacy endpoints will be performed based on the efficacy evaluable set, including all 
patients in the full analysis set who started treatment with enfortumab vedotin at least 8 months before the 
analysis data cutoff. 
Sample size: 
The study is designed to estimate the confirmed ORR in patients receiving enfortumab vedotin and to detect an 
improvement in the ORR compared with a historical response rate of 10%. Approximately 200 patients will be 
enrolled in this study to ensure collection of sufficient efficacy and safety data, including approximately 100 or 
more platinum-treated patients (Cohort 1), and up to approximately 100 platinum-naïve and cisplatin-ineligible 
patients (Cohort 2). Using the estimate of approximately 100 patients Cohort 1, the study will have 98% power 
to detect a 15% increase in ORR from 10% to 25% and 81% power to detect a 10% increase in ORR from 10% 
to 20%, at one-sided significant level of 0.025, based on exact methods using EAST®, Version 6.0, by 
Cytel Inc.  
The confirmed ORR and 95% exact CI in Cohort 2 will be summarized at 4 timepoints: 1) at the time of 
analysis of Cohort 1, 2) when approximately 50 patients in Cohort 2 have had the opportunity to be followed for 
approximately 8 months from the first dose of enfortumab vedotin, 3) when approximately 70 patients in 
Cohort 2 have had the opportunity to be followed for approximately 8 months from the first dose of enfortumab 
vedotin, and 4) when all patients treated in Cohort 2 have had the opportunity to be followed for approximately 
8 months from the first dose of enfortumab vedotin. 


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For illustration purposes, below is the summary of expected 95% CIs for Cohort 2 at various analysis 
timepoints, assuming a 30% observed ORR: 
Number of Patients 
Expected 95% Confidence Interval 
N=20 
12%–54% 
N=50 
18%–45% 
N=70 
20%–42% 
N=100 
21%–40% 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................................... 10 
1 
INTRODUCTION ......................................................................................................................................... 12 
1.1 
Urothelial Cancer ................................................................................................................................ 12 
1.2 
Second-Line Therapy Options for Metastatic Urothelial Cancer ........................................................ 13 
1.3 
Nectin-4 ............................................................................................................................................... 14 
1.4 
Nectin-4 as a Target in Metastatic Urothelial Cancer ......................................................................... 14 
1.5 
Enfortumab Vedotin ............................................................................................................................ 15 
1.6 
Rationale for Enfortumab Vedotin in Metastatic Urothelial Cancer, Clinical Safety and Efficacy .... 15 
2 
OBJECTIVES ............................................................................................................................................... 17 
2.1 
Primary Objective ............................................................................................................................... 17 
2.2 
Secondary Objectives .......................................................................................................................... 17 
2.3 
Additional Objectives .......................................................................................................................... 17 
2.4 
Endpoints ............................................................................................................................................. 18 
2.4.1 
Primary Endpoint ................................................................................................................... 18 
2.4.2 
Secondary Endpoints .............................................................................................................. 18 
2.4.3 
Additional Endpoints .............................................................................................................. 18 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 18 
3.1 
Summary of Study Design .................................................................................................................. 18 
3.2 
Discussion and Rationale for Study Design ........................................................................................ 20 
3.2.1 
Method of Assigning Patients to Treatment Groups .............................................................. 21 
3.2.2 
Rationale for Selection of Doses ............................................................................................ 21 
3.2.3 
Blinding .................................................................................................................................. 22 
4 
STUDY POPULATION................................................................................................................................ 22 
4.1 
Inclusion Criteria ................................................................................................................................. 22 
4.2 
Exclusion Criteria ................................................................................................................................ 25 
4.3 
Removal of Patients From Therapy or Assessment ............................................................................. 26 
4.3.1 
Discontinuation of Study Treatment ....................................................................................... 26 
4.3.2 
Patient Withdrawal From Study ............................................................................................. 27 
5 
TREATMENTS ............................................................................................................................................ 27 
5.1 
Treatments Administered .................................................................................................................... 27 
5.2 
Investigational Study Drug .................................................................................................................. 27 
5.2.1 
Description ............................................................................................................................. 27 
5.2.2 
Dose and Administration ........................................................................................................ 27 
5.2.3 
Dose Modifications ................................................................................................................ 28 
5.2.4 
Storage and Handling ............................................................................................................. 31 
5.2.5 
Packaging and Labeling ......................................................................................................... 31 
5.2.6 
Preparation.............................................................................................................................. 31 
5.3 
Concomitant Therapy .......................................................................................................................... 31 
5.3.1 
Required Concomitant Therapy.............................................................................................. 31 
5.3.2 
Allowed Concomitant Therapy .............................................................................................. 31 
5.3.3 
Prohibited Concomitant Therapy ............................................................................................ 32 
5.4 
Management of Adverse Reactions ..................................................................................................... 32 
5.4.1 
Management of Infusion Reactions ........................................................................................ 32 
5.4.2 
Management of Hyperglycemia ............................................................................................. 33 
5.4.3 
Management of Rash Related to Enfortumab Vedotin ........................................................... 33 
5.4.4 
Management of Pneumonitis/ILD Related to Enfortumab Vedotin ....................................... 34 
5.5 
Treatment Compliance ........................................................................................................................ 34 
6 
STUDY ACTIVITIES ................................................................................................................................... 34 
6.1 
Schedule of Events .............................................................................................................................. 34 
6.2 
Screening Visit (Days –28 to Day 1) ................................................................................................... 34 


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6.2.1 
Baseline Visit (Days –7 to Day 1) .......................................................................................... 35 
6.3 
Treatment Period (Day 1 to Day 22) ................................................................................................... 35 
6.3.1 
Day 1 (±2 days) ...................................................................................................................... 35 
6.3.2 
Day 3 ...................................................................................................................................... 36 
6.3.3 
Day 8 (+2 days) ...................................................................................................................... 36 
6.3.4 
Day 15 (+2 days) .................................................................................................................... 36 
6.3.5 
Day 17 .................................................................................................................................... 37 
6.3.6 
Day 22 .................................................................................................................................... 37 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study drug) .................................................. 37 
6.5 
Every Month for 6 Months After End of Treatment Visit (±1 week) .................................................. 38 
6.6 
Follow-up (Every 8 Weeks [±1 week]) ............................................................................................... 38 
6.7 
Long-term Follow-up (Every 8 Weeks [±1 week]) ............................................................................. 38 
6.8 
End of Study/End of Follow-up .......................................................................................................... 39 
7 
STUDY ASSESSMENTS ............................................................................................................................. 39 
7.1 
Screening/Baseline Assessments ......................................................................................................... 39 
7.2 
Response/Efficacy Assessments .......................................................................................................... 39 
7.3 
Pharmacokinetic and ATA Assessments ............................................................................................. 40 
7.4 
Biomarker Studies ............................................................................................................................... 40 
7.4.1 
Biomarkers in Blood............................................................................................................... 40 
7.4.2 
Biomarkers in Pre-Treatment Tumor Tissue .......................................................................... 43 
7.5 
Biospecimen Repository...................................................................................................................... 43 
7.6 
Quality of Life ..................................................................................................................................... 43 
7.6.1 
EORTC Core Quality of Life Questionnaire, QLQ-C30 ........................................................ 43 
7.6.2 
EuroQol-5 Dimensions ........................................................................................................... 44 
7.7 
Safety Assessments ............................................................................................................................. 44 
7.7.1 
Adverse Events ....................................................................................................................... 44 
7.7.2 
Clinical Laboratory Tests ....................................................................................................... 49 
7.7.3 
Physical Examination Including Weight ................................................................................ 50 
7.7.4 
Vital Signs .............................................................................................................................. 50 
7.7.5 
ECOG Performance Status ..................................................................................................... 50 
7.7.6 
Cardiac Monitoring ................................................................................................................ 50 
7.7.7 
Eye Examination .................................................................................................................... 51 
7.8 
Post-treatment Assessments ................................................................................................................ 51 
7.8.1 
Follow-up Assessments .......................................................................................................... 51 
7.8.2 
Long-term follow-up Assessments ......................................................................................... 51 
7.9 
Appropriateness of Measurements ...................................................................................................... 51 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 52 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 52 
8.2 
Data Management Procedures ............................................................................................................. 53 
8.3 
Access to Source Data ......................................................................................................................... 53 
8.4 
Accuracy and Reliability of Data ........................................................................................................ 53 
8.5 
Quality Assurance Procedures ............................................................................................................. 54 
8.6 
Data Handling and Record Keeping .................................................................................................... 54 
8.6.1 
Data Handling ......................................................................................................................... 54 
8.6.2 
Investigator Record Retention ................................................................................................ 54 
9 
DATA ANALYSIS METHODS ................................................................................................................... 54 
9.1 
Determination of Sample Size ............................................................................................................. 54 
9.2 
Study Endpoint Definitions ................................................................................................................. 55 
9.2.1 
Objective Response Rate ........................................................................................................ 55 
9.2.2 
Duration of Response ............................................................................................................. 56 
9.2.3 
Disease Control Rate at Week 16 ........................................................................................... 56 
9.2.4 
Progression-free Survival ....................................................................................................... 56 
9.2.5 
Overall Survival ..................................................................................................................... 56 
9.3 
Statistical and Analytical Plans ........................................................................................................... 56 


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9.3.1 
General Considerations .......................................................................................................... 57 
9.3.2 
Patient Disposition ................................................................................................................. 59 
9.3.3 
Patient Characteristics ............................................................................................................ 59 
9.3.4 
Treatment Administration ...................................................................................................... 59 
9.3.5 
Efficacy Analyses ................................................................................................................... 59 
9.3.6 
Pharmacokinetic and ATA Analyses ...................................................................................... 60 
9.3.7 
Quality of Life Analyses ........................................................................................................ 60 
9.3.8 
Biomarker Analyses ............................................................................................................... 60 
9.3.9 
Safety Analyses ...................................................................................................................... 60 
9.3.10 Interim Analyses ..................................................................................................................... 61 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 62 
10.1 Informed Consent ................................................................................................................................ 62 
10.2 Ethical Review .................................................................................................................................... 62 
10.3 Regulatory Considerations .................................................................................................................. 63 
10.3.1 Investigator Information ......................................................................................................... 63 
10.3.2 Protocol Amendments and Study Termination ....................................................................... 63 
10.4 Study Documentation, Privacy and Records Retention ....................................................................... 63 
10.5 Clinical Trial Agreement ..................................................................................................................... 63 
11 REFERENCES .............................................................................................................................................. 64 
APPENDIX A: SCHEDULE OF EVENTS ......................................................................................................... 67 
APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION ............................................................. 69 
APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION .................................................... 70 
APPENDIX D: RECIST CRITERIA SUMMARY (VERSION 1.1) ................................................................... 71 
APPENDIX E: LIVER SAFETY MONITORING AND ASSESSMENT .......................................................... 72 
APPENDIX F: SCANNING AND CONTRAST GUIDELINES ........................................................................ 74 
APPENDIX G: INVESTIGATOR SIGNATURE PAGE .................................................................................... 75 
APPENDIX H: DOCUMENT HISTORY ............................................................................................................ 76 
 
LIST OF IN-TEXT TABLES  
Table 1: Recommended dose modifications for enfortumab vedotin-associated hematologic toxicity ............. 29 
Table 2: Recommended dose modifications for enfortumab vedotin-associated nonhematologic toxicity ....... 29 
Table 3: Pharmacokinetic, ATA, and biomarker blood sample collection timepoints ...................................... 42 
 
LIST OF IN-TEXT FIGURES  
Figure 1: Study schema....................................................................................................................................... 20 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
BSC 
best supportive care 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CPI 
checkpoint inhibitor 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography 
ctDNA 
Circulating tumor DNA 
DCR 
disease control rate 
DCR16 
disease control rate at 16 weeks 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organization for the Research and Treatment of Cancer 
EOT 
end of treatment 
EQ-5D 
EuroQol 5-dimensions 
FDA 
Food and Drug Administration 
HbA1c 
hemoglobin A1c 
ICH 
International Council for Harmonisation  
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
IV 
intravenous 
LFT 
liver function test 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCI CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 


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PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PP 
per-protocol 
PR 
partial response 
PRO 
patient reported outcomes 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QLQ-C30 
EORTC Quality of Life Questionnaire 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SJS 
Stevens-Johnson Syndrome 
TAb 
total antibody 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
ULN 
upper limit of normal 
US 
United States 
vc 
valine-citrulline 
 


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1 
INTRODUCTION  
1.1 Urothelial Cancer  
According to the International Agency for Research on Cancer urothelial cancer kills more 
than 165,000 patients annually and is the ninth most common cancer overall worldwide. 
Approximately 151,000 new cases of urothelial cancer are diagnosed annually in Europe, 
with 52,000 deaths per year. Over 22,000 new cases are diagnosed annually in Japan, with 
7,600 deaths per year (Cancer Today, http://gco.iarc.fr/today/. Accessed Jan 31, 2017). 
According to National Cancer Institute estimates, approximately 77,000 new cases of 
urothelial cancer were diagnosed in 2016, and more than 16,000 people died from the disease 
in the United States (US) alone (National Cancer Institute 2016). Metastatic urothelial cancer 
has a 5-year mortality rate exceeding 85%. 
First-line therapy for metastatic urothelial cancer in patients with sufficient renal function 
consists of cisplatin-based combinations, like methotrexate, vinblastine, doxorubicin, and 
cisplatin (MVAC) and gemcitabine with cisplatin, which demonstrate an overall response 
rate up to 50%, including approximately 10%–15% complete responses (CRs) (Bellmunt 
2011). Despite initial chemosensitivity, patients are not cured and the outcome of metastatic 
urothelial cancer after these regimens is poor: median time to progression is only 7 months 
and median overall survival (OS) is 14 months. Approximately 15% of patients experience 
5-year survival and the prognosis is particularly poor among patients with visceral metastases 
for whom the 5-year OS rate is 7% (von der Maase 2005). 
Almost half of urothelial cancer patients are unfit for cisplatin-containing chemotherapy due 
to impaired renal function, poor performance status or comorbidity (Dash 2006). In this 
setting, long term survival is even lower (De Santis 2009). In April 2017, the Food and Drug 
Administration (FDA) approved the anti-programmed death-ligand 1 (PD-L1) immune 
checkpoint inhibitor (CPI) atezolizumab (TECENTRIQ®) as first line treatment for patients 
ineligible for cisplatin. The accelerated approval was based on an open-label single arm study 
that showed long durations of response, indicating activity in this difficult-to-treat 
population, with an objective response rate (ORR) of 23% that was similar across varying 
levels of target expression. The median OS for these patients was 15.9 months, although this 
is a single arm study and any OS benefit will need to be confirmed in a randomized 
experience (Balar 2017). 
Pembrolizumab (Keytruda®) received accelerated approval from the FDA in May 2017 as 
first line treatment for patients ineligible for cisplatin. The approval was based on an open 
label single arm study in 370 patients showing an ORR of 29% (Keytruda Prescribing 
Information, Merck, May 2017). 
Other options for first line cisplatin-ineligible patients typically include carboplatin-based 
regimens or single-agent taxane or gemcitabine (Cathomas 2015). 


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1.2 Second-Line Therapy Options for Metastatic Urothelial Cancer  
Few options are available for second-line treatment of metastatic disease. In the European 
Union, the small-molecule tubulin inhibitor vinflunine (Javlor®) was authorized in 2009 
based on modest activity (overall response rate 9%), moderate survival benefit of 2 months 
(6.9 months for vinflunine + best supportive care [BSC] vs 4.6 months for BSC alone, hazard 
ratio 0.88), and a favorable safety profile (Bellmunt 2009). In May 2016, the FDA provided 
accelerated approval of atezolizumab as the first salvage therapy following platinum agents 
for locally advanced or metastatic urothelial carcinoma in the US, followed by EU approval 
in September 2017. In February 2017, nivolumab (Opdivo®) became the second 
immunotherapy granted accelerated approval by the FDA, which was followed by EU 
approval in June 2017. In March and May 2017, the FDA granted accelerated approval for 
avelumab (Bavencio®) and durvalumab (ImfinziTM), respectively, both PD-L1 blocking 
antibodies indicated for the treatment of patients with locally advanced or metastatic 
urothelial carcinoma who have disease progression during or following platinum-containing 
chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum-containing chemotherapy. Pembrolizumab received regular approval 
from the FDA in May 2017 as second-line treatment (Keytruda Prescribing Information, 
Merck, May 2017). The approval was based on the first randomized experience reported for a 
CPI in the locally advanced or metastatic post-platinum urothelial cancer setting, a phase 3 
study in 542 patients showing an OS of 10.3 months as compared to 7.4 months with taxane 
chemotherapy or vinflunine. Additionally, ORR was 21% for pembrolizumab and 11% for 
chemotherapy. No statistically significant difference in progression-free survival (PFS) 
between the two arms was observed (Bellmunt 2017). EU approval for the same indication 
was granted in September 2017 and Japanese approval in January 2018. Other programmed 
cell death protein 1 (PD-1) and PD-L1 inhibitors are currently being evaluated in clinical 
trials for urothelial cancer, as first and second-line therapy (Mullane 2016). 
While CPIs offer a new approach to treatment of metastatic urothelial cancer, tumor 
responses have occurred in a minority of patients and the improvement in long-term survival 
is only a few months. For example, in May 2017, Roche announced that a confirmatory 
phase 3 trial of second-line atezolizumab had failed to meet its primary endpoint of OS 
(Roche, press release “Roche provides update on phase III study of Tecentriq [atezolizumab] 
in people with previously treated advanced bladder cancer,” 10-May-2017). Most patients 
with locally advanced or metastatic urothelial cancer do not respond to CPIs and many who 
do respond ultimately develop disease progression (Rosenberg 2016). Novel treatments are 
still needed, particularly for patients who have not responded to CPIs or who have progressed 
following CPI therapy. 
Currently, no therapies are approved for patients previously treated with a CPI. Although 
taxanes are not approved in this setting, they are a common choice for third line treatment 
(and were a standard second-line treatment before atezolizumab was approved). Taxanes 
have response rates of approximately 10% as second-line therapy, with progression-free 
survival (PFS) and OS of only 3.3 months and 7.4 months, respectively (Bellmunt 2017). No 


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data are currently available regarding the clinical activity of taxanes in the third line setting 
after CPI therapy. 
The lack of approved therapies for patients with metastatic urothelial cancer after treatment 
with a CPI and the limited activity observed with second-line chemotherapy adequately 
demonstrate that this population has significant unmet medical need. This patient population 
appears appropriate for this phase 2 study. 
1.3 Nectin-4  
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 
immunoglobulin (Ig)-like subdomains, a transmembrane helix, and an intracellular region 
(Takai 2008a). 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 2008). Sequence identity of 
Nectin-4 to other Nectin family members is low and ranges between 25%–30% in the ECD 
(Reymond 2001). 
The 3 Ig-like subdomains in the ECD of Nectin-4 are designated V, C1 and C2. The C1 
domain is responsible for cis-interaction (homodimerization), while V domains of most 
Nectin molecules contribute to trans-interaction and cell-cell adhesion (Mandai 2015; Takai 
2008b). 
Nectin-4 was originally identified by bioinformatics and cloned from human trachea 
(Reymond 2001). Nectin-4 was identified as markedly upregulated in urothelial cancer using 
suppression subtractive hybridization on a pool of urothelial cancer specimens. 
Characterization of expression in multiple tumor specimens, both at the ribonucleic acid 
(RNA) level and by immunohistochemistry (IHC), also demonstrated high levels of Nectin-4 
in breast, pancreatic, lung, and other cancers (Challita-Eid 2016). 
1.4 Nectin-4 as a Target in Metastatic Urothelial Cancer  
Nectin-4 has been found to be expressed in multiple cancers, particularly urothelial, breast, 
lung, pancreatic, and ovarian cancers. Higher levels of expression are associated with disease 
progression and/or poor prognosis (Fabre-Lafay 2007). 
Although no longer required for metastatic urothelial cancer patients prior to enrollment, in 
an ongoing phase 1 study of enfortumab vedotin in multiple cancer types including 
metastatic urothelial cancer (Study ASG-22CE-13-2), patients were initially prescreened for 
Nectin-4 expression. Nectin-4 expression is still assessed in archival tissue, though metastatic 
urothelial cancer patients may enroll regardless of Nectin-4 expression. An H-score, derived 
from the intensity of staining with anti-Nectin-4 antibody and the percentage of cells 
expressing Nectin-4 in the tumor tissue, was determined for each screened patient. H-score 
values range between 0 (no expression) and 300 (maximal expression). 


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Of 186 patients with metastatic urothelial cancer whose tumor tissue was screened using a 
central Clinical Laboratory Improvement Amendments laboratory-validated test, more than 
97% had detectable Nectin-4 expression. Ninety-three percent of these patients met the initial 
criterion for enrollment in the phase 1 study (H-score ≥150). The median H-score was 280. 
Based upon the prevalence of high Nectin-4 expression in this population of metastatic 
urothelial cancer patients, this phase 2 study does not include an eligibility requirement for a 
minimum level of Nectin-4 expression. However, Nectin-4 expression will be assessed with 
tumor tissue collected at screening. 
1.5 Enfortumab Vedotin  
Enfortumab vedotin is a Nectin-4 targeted monoclonal antibody (AGS-22C3) covalently 
linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). Enfortumab 
vedotin consists of three functional subunits: 
● 
A fully human IgG1Κ antibody (AGS-22C3)  
● 
The microtubule-disrupting agent MMAE 
● 
A protease-cleavable maleimidocaproyl-valine-citrulline (vc) linker that covalently 
attaches MMAE to AGS-22C3 
Enfortumab vedotin binds the V domain of Nectin-4 (Challita-Eid 2016). In the presumed 
mechanism of action, the drug binds Nectin-4 protein on the cell surface and is internalized, 
causing proteolytic cleavage of the vc linker and intracellular release of MMAE. Free 
MMAE subsequently disrupts tubulin polymerization and leads to mitotic arrest. 
1.6 Rationale for Enfortumab Vedotin in Metastatic Urothelial Cancer, Clinical 
Safety and Efficacy  
A phase 1 dose escalation and expansion study with enfortumab vedotin monotherapy in 
patients with metastatic urothelial cancer and other malignant solid tumors is ongoing 
(Study ASG-22CE-13-2). In this study, patients received doses of enfortumab vedotin 
ranging from 0.5 to 1.25 mg/kg on Days 1, 8, and 15 of each 28-day cycle. 
As of the data cut-off date of 02 October 2017, 140 metastatic urothelial cancer patients had 
been enrolled in the phase 1 study. Interim data suggest that enfortumab vedotin is generally 
well tolerated at doses up to 1.25 mg/kg, and induces multiple objective responses in this 
patient population. 
Among metastatic urothelial cancer patients, 137 (98%) experienced a treatment-emergent 
adverse event (TEAE), and 122 (87%) of these patients’ TEAEs were deemed possibly or 
probably related to study drug by the investigator. The most common TEAEs among 
metastatic urothelial cancer patients were fatigue (49%), nausea (45%), decreased appetite 
(39%), alopecia (37%), diarrhea (36%), dysgeusia (31%), pruritus (29%), anemia (26%), 
abdominal pain (24%), constipation (24%), vomiting (24%), and weight decreased (20%). 


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Drug doses were reduced in 18 out of 140 metastatic urothelial cancer patients (13%) due to 
adverse events (AEs), including 16 out of 97 patients (17%) in the 1.25 mg/kg dose group. 
Drug was withdrawn in 26 out of 140 (19%) metastatic urothelial cancer patients due to AEs, 
including 13 out of 97 (13%) from the 1.25 mg/kg dose group. Across all dose levels, drug 
was withdrawn from 12 out of 140 (9%) metastatic urothelial cancer patients due to AEs 
deemed possibly or probably related to enfortumab vedotin. In the 1.25 mg/kg dose group, 
drug was withdrawn from 6 out of 97 (6%) metastatic urothelial cancer patients due to AEs 
deemed as possibly or probably related to enfortumab vedotin. TEAEs leading to study drug 
discontinuation among urothelial cancer patients included peripheral neuropathy, urosepsis, 
increased aspartate aminotransferase (AST), acute kidney injury, and increased blood 
creatinine in 2 patients each. 
Fifty-five metastatic urothelial cancer patients (39%) experienced at least one treatment 
emergent serious adverse event (SAE). Sixteen patients (11%) had SAEs that were deemed 
by the investigator to be possibly or probably related to treatment. At the 1.25 mg/kg dose 
level, 31 out of 97 patients (32%) had at least one treatment emergent SAE. Nine patients 
(9%) had SAEs that were deemed by the investigator to be possibly or probably related to 
treatment. As of the 02 October 2017 data cut-off date, there were 6 fatal TEAEs in the 
metastatic urothelial cancer patients during this study, and 2 were deemed to be drug-related. 
As of the 02 October 2017 data cut-off date, 1 of the related fatal events in Study 
ASG-22CE-13-2 was reported in conjunction with serious hyperglycemia. Following the data 
cut-off date, 2 additional treatment-related fatal events associated with serious hyperglycemia 
were reported in October 2017. All active enfortumab vedotin study protocols were 
immediately amended to address this new safety information (See Appendix H 
Amendment 1). No additional treatment-related fatal events have been reported as of 
15 March 2018. 
A summary of the clinical and nonclinical safety data relevant to the investigational product 
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 metastatic urothelial cancer patients. 
Enfortumab vedotin shows encouraging antitumor activity in patients with metastatic 
urothelial cancer with either post-baseline imaging or who had discontinued treatment before 
imaging. As of the data cut-off date of 02 October 2017, there were 5 CRs and 50 partial 
responses (PRs) (ORR=45%, 55 of 121 patients) across dose levels. The ORR at 1.25 mg/kg 
(the dose level for the present study) was 54% (42 out of 78 patients). Disease control 
(CR + PR + stable disease [SD]) was reached in 69% of metastatic urothelial cancer patients 
(84 of 121 patients), including 71% in the 1.25 mg/kg dose group (55 of 78 patients). 
Enfortumab vedotin also shows promising antitumor activity in metastatic urothelial cancer 
patients previously treated with CPIs who had either post-baseline imaging or had 
discontinued treatment before imaging. Across dose levels, the ORR was 50% (35 out of 
70 patients), and at 1.25 mg/kg the ORR was 53% (29 out of 55 patients). Disease control 


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was reached in 73% (51 of 70 patients), including 75% (41 of 55 patients) of the 1.25 mg/kg 
dose group. 
Confirmed ORR was 27% across all dose levels (33 of 121 patients) and 32% at 1.25 mg/kg 
(25 of 78 patients). In patients previously treated with a CPI, the confirmed ORR was 31% 
(17 out of 55 patients) at 1.25 mg/kg. 
This phase 2 study is designed to further investigate the encouraging clinical safety and 
efficacy data observed in the ongoing phase 1 trial of enfortumab vedotin in metastatic 
urothelial cancer patients, including patients previously treated with CPIs. 
Clinical data to date support a favorable benefit-risk ratio for enfortumab vedotin in patients 
with locally advanced or metastatic urothelial carcinoma who previously received CPI 
therapy. To assure an ongoing favorable benefit-risk assessment for subjects enrolled into the 
study, an Independent Data Monitoring Committee (IDMC) will be utilized to monitor safety 
data and may request interim efficacy data, if needed. 
2 
OBJECTIVES  
2.1 Primary Objective  
● 
To determine the antitumor activity of single-agent enfortumab vedotin as measured 
by confirmed ORR in patients with locally advanced or metastatic urothelial cancer 
who have previously received systemic therapy with a CPI and either previously 
received platinum-containing chemotherapy or are platinum-naïve and cisplatin-
ineligible 
2.2 Secondary Objectives  
● 
To assess DOR 
● 
To assess disease control rate (DCR) 
● 
To assess PFS 
● 
To assess OS 
● 
To assess the safety and tolerability of enfortumab vedotin  
● 
To assess the pharmacokinetics (PK) of enfortumab vedotin 
● 
To assess the incidence of antitherapeutic antibodies (ATA) 
2.3 Additional Objectives  
● 
To explore potential correlations between biomarkers and clinical outcomes  
● 
To evaluate the treatment effect of enfortumab vedotin on quality of life (QoL) 


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2.4 Endpoints  
2.4.1 Primary Endpoint  
● 
The primary efficacy endpoint of this study is ORR (confirmed CR or PR per 
Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) as determined 
by an independent review facility (IRF) 
2.4.2 Secondary Endpoints  
● 
DOR (confirmed CR or PR) per IRF 
● 
DCR16 (disease control rate [CR, PR or SD] at 16 weeks) per IRF 
● 
PFS per IRF 
● 
ORR per investigator assessment 
● 
DOR per investigator assessment 
● 
DCR16 per investigator assessment 
● 
PFS per investigator assessment 
● 
OS 
● 
Type, incidence, severity, seriousness, and relatedness of AEs 
● 
Laboratory abnormalities  
● 
Selected plasma or serum PK parameters of enfortumab vedotin, MMAE, and total 
antibody (TAb) 
● 
Incidence of ATA to enfortumab vedotin 
2.4.3 Additional Endpoints  
● 
Biomarkers of biological and clinical activity, including Nectin-4 expression 
● 
Patient reported outcomes (PRO) per the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) 
● 
PRO per EuroQol 5-dimensions (EQ-5D), including health utility values, and visual 
analog scale 
3 
INVESTIGATIONAL PLAN  
3.1 Summary of Study Design  
This is a single-arm, open-label, multicenter trial designed to assess the efficacy and safety of 
enfortumab vedotin as a single agent in locally advanced or metastatic urothelial cancer 
patients who have previously received systemic therapy with a CPI. Patients must also either 
have received prior treatment with platinum-containing chemotherapy (Cohort 1) or received 


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no prior platinum-containing or other chemotherapy and are ineligible for treatment with 
cisplatin at time of enrollment. (Cohort 2). Patients must have progressive disease (PD) 
during or following their most recent therapy. There are no limits for prior lines of therapy, 
including taxanes. 
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an intravenous (IV) 
infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Measures 
of anticancer activity will be assessed by computed tomography (CT scans with contrast, 
unless contraindicated) every 8 weeks (±1 week) timed from Cycle 1 Day 1 during treatment. 
After 1 year on study the frequency of response assessments will be reduced to every 
12 weeks (±1 week). Patients will continue to receive study treatment until disease 
progression, unacceptable toxicity, investigator decision, consent withdrawal, start of 
subsequent anticancer therapy, pregnancy, or study termination by the sponsor. After 
discontinuation of study treatment, patients will be followed every 8 weeks (±1 week) for 
response assessments, Eastern Cooperative Oncology Group (ECOG) performance status, 
and physical exams. After 1 year on study the frequency of follow up visits including 
response assessments will be reduced to every 12 weeks (±1 week). Patients that have 
radiologically-confirmed disease progression (per RECIST 1.1 as determined by the 
investigator) or have begun subsequent anticancer therapy will be contacted every 8 weeks 
(±1 week) up to 1 year on study, and every 12 weeks (±1 week) thereafter to obtain 
information on subsequent anticancer therapy, and survival status until death, study closure, 
withdrawal of consent, or patient is lost to follow-up, whichever occurs first (see Figure 1). 
The study will be closed 5 years after enrollment of the last patient, or when no patients 
remain in long-term follow-up, whichever occurs first. Additionally, the sponsor may 
terminate the study at any time. 
On a periodic basis, an IDMC will monitor the safety of patients participating in this trial. 
The IDMC will be responsible for evaluating the results of safety analyses and will make 
recommendations to the sponsor. The IDMC may also request efficacy data, if needed, to 
evaluate risk/benefit before making recommendations. The IDMC will make 
recommendations to either continue the study unchanged, to modify the study, or to 
discontinue the study. If corneal AEs are observed in <15% of the first 60 enrolled patients 
(from Cohorts 1 and/or 2) and if the events are generally low grade or asymptomatic, the 
IDMC may make a recommendation to cease Cycle 2 Day 22 and/or Cycle 6 Day 22 slit 
lamp exams for the remaining patients if warranted based on review of the cumulative ocular 
safety data. The IDMC will communicate the recommendations to the sponsor. The final 
decision to act on the IDMC recommendations will be made by the sponsor. The IDMC 
recommended to cease Cycle 2 Day 22 and Cycle 6 Day 22 slit lamp exams in Jul 2018 and 
Aug 2019, respectively. 
An ongoing real-time review of patient safety and SAEs will also be conducted by the 
sponsor’s Drug Safety Department. 


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Figure 1: 
Study schema  
 
3.2 Discussion and Rationale for Study Design  
This study will enroll patients who have previously received CPI therapy. Based on prior 
treatment patterns, taxanes or vinflunine are anticipated to be the next line of therapy to 
address post-CPI relapsed disease, but response rates are expected to be only 9%–13% 
(Bellmunt 2017; Bellmunt 2009; Choueiri 2012; McCaffrey 1997). Data presented from a 
recent study of patients treated with docetaxel after platinum and CPI therapy showed a 
10.5% ORR (n=2/19) (Drakaki 2018). Recently, 10% has been used as the historical response 
rate expected for both platinum pre-treated second-line and cisplatin ineligible first-line 
patients (Balar 2017; Rosenberg 2016). Given that patients enrolled in the current study have 
a poor prognosis and represent an area of unmet medical need, the lower bound of the exact 
95% confidence interval (CI) for ORR that excludes a historical response rate of 10% is 
considered to be a meaningful improvement over currently available therapies with the 
proposed enrollment of approximately 100 patients. 
The primary endpoint of this study, confirmed ORR, is a direct measure of antitumor activity 
and is an acceptable surrogate endpoint (FDA Guidance for Industry “Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics”). To further assess the 
significance of ORR in this study, the durability of response will be evaluated as a secondary 
endpoint. Furthermore, standardized RECIST (Version 1.1, see Appendix D) criteria 
(Eisenhauer 2009) will be employed by investigators and the IRF to evaluate responses. 
Responses will be confirmed per IRF with repeat scans 4 weeks (+1 week) after initial 
documentation of response. 
ORR may be evaluated in a single-arm study when it is defined as the sum of PR plus CR 
(FDA Guidance for Industry “Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics”). Moreover, to ensure consistent unbiased application of the RECIST criteria in 
this open-label study, all imaging assessments performed to confirm disease status at study 
Pre-study
End of Treatment
Follow-up
Response 
assessments every 
8 weeksb (±1 week)
30-37 days 
post last 
dose of 
study 
treatment
Until progression or 
subsequent anticancer 
therapy
Each 28-day cycle
enfortumab vedotin 
1.25 mg/kg IV on Day 1, 8, 15 
Response assessments every 
8 weeksb (±1 week), with 
confirmatory repeat scans 4 
weeks (+1 week) after first 
documentation of response
Screening
Enrollmenta
Until patient 
death, study 
closure, 
withdrawal of 
consent, or 
patient is lost 
to follow-up
Long-term 
Follow-up
Survival and 
subsequent 
anticancer 
therapies
a There are 2 cohorts of CPI-treated patients in the study: Cohort 1) platinum-treated patients, and Cohort 2) platinum-
naïve/cisplatin-ineligible patients.
b After 1 year on study, the frequency of response assessments will be reduced to every 12 weeks (±1 week). 


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entry and to assess responses during the study will be submitted to an independent third-party 
imaging core laboratory. 
3.2.1 Method of Assigning Patients to Treatment Groups  
This is a single-arm study in which all patients will receive 1.25 mg/kg enfortumab vedotin 
administered as an IV infusion over approximately 30 minutes on Day 1, 8, and 15 of each 
28-day treatment cycle. 
3.2.2 Rationale for Selection of Doses  
Enfortumab vedotin will be administered at a dose of 1.25 mg/kg as an IV infusion over 
approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle. This dose and regimen 
has demonstrated an acceptable safety profile and encouraging antitumor activity in the phase 
1 study (Study ASG-22CE-13-2). 
In the phase 1 study, enfortumab vedotin was administered on Days 1, 8, and 15 of every 
28-day treatment cycle. The study tested 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 was not reached in this study. 
As of the 02 October 2017 data cut-off date, at the 1 mg/kg dose level, increased alanine 
aminotransferase levels was the only dose-limiting toxicity observed (1 out of 14). No DLT 
was observed at 1.25 mg/kg and doses above 1.25 mg/kg were not tested. Incidence of some 
of the most frequent drug-related AEs, such as decreased appetite, alopecia, diarrhea and 
rash, although primarily Grades 1–2 and clinically manageable, increased with increasing 
dose levels among patients with urothelial cancer. The most common study drug-related AE, 
fatigue, occurred in 21%, 33%, and 43% of urothelial cancer patients in the 0.75, 1, and 
1.25 mg/kg dose groups, respectively. Similarly, study-drug related nausea, alopecia, 
decreased appetite, and diarrhea were all more common in the 1.25 mg/kg dose group than 
the 0.75 mg/kg dose group. Moreover, dose reductions due to AEs were more frequent for 
the 1.25 mg/kg vs lower dose levels. Safety assessments of metastatic urothelial cancer 
patients (N=140) showed that frequency of all TEAEs were comparable across all dose 
levels. AEs leading to withdrawal and Grade 3–4 TEAEs were less frequent in the 
1.25 mg/kg dose level than at lower 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. The confirmed ORR 
in patients with metastatic urothelial cancer treated at the 1.25 mg/kg dose was 32% (25 out 
of 78 patients) versus 19% (8 out of 43) for patients treated with doses less than 1.25 mg/kg. 
Based on PK data from the phase 1 study (Study ASG-22CE-13-2), the half-life of 
enfortumab vedotin is ~1–2 days. No notable (<30%) intra-cycle accumulation of 
antibody-drug conjugate (ADC) was observed with the current dosing regimen (on Days 1, 8, 
and 15 of every 28-day cycle) at any dose level. Minimal (<50%) intra-cycle accumulation of 
MMAE was observed. It is anticipated that the dosing schedule in the study will maintain 


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ADC exposures over each 28-day cycle, contributing to a favorable balance of activity and 
safety, as observed in the phase 1 trial (Study ASG-22CE-13-2). 
In summary, the dose regimen of 1.25 mg/kg on Days 1, 8, and 15 of each 28-day cycle 
proposed for the phase 2 study has demonstrated an acceptable safety profile and 
encouraging clinical activity that was higher than at lower dose levels. 
3.2.3 Blinding  
This is an open-label, single-arm study. 
4 
STUDY POPULATION  
All relevant medical and non-medical conditions should be taken into consideration when 
deciding whether this protocol is suitable for a particular patient. Patients must meet all of the 
enrollment criteria to be eligible for this study. Eligibility criteria may not be waived by the 
investigator and are subject to review in the event of a good clinical practice audit and/or 
health regulatory authority inspection. 
4.1 Inclusion Criteria  
1. Patients must have histologically documented urothelial (previously known as 
transitional cell) carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). 
Patients with squamous differentiation or mixed cell types are eligible. Patients with 
resectable locally advanced disease are ineligible. 
2. Patient must have received prior treatment with a CPI in the locally advanced or 
metastatic urothelial cancer setting. Patients who received CPI therapy in the 
neoadjuvant/adjuvant setting and had recurrent or progressive disease either during 
therapy or within 3 months of therapy completion are eligible. A CPI is defined as a PD-1 
inhibitor or PD-L1 inhibitor (including, but not limited to: atezolizumab, pembrolizumab, 
durvalumab, avelumab, and nivolumab). 
3. Patients must be one of the following: 
a. Platinum-treated (Cohort 1): Patients who received prior treatment with platinum-
containing chemotherapy defined as those who received platinum in the 
adjuvant/neoadjuvant setting and had recurrent or progressive disease within 
12 months of completion OR received treatment with platinum in the locally 
advanced (defined as unresectable with curative intent) or metastatic setting; 
 
OR 
 
b. Platinum-naïve and cisplatin ineligible (Cohort 2): Patients who have not received 
prior treatment with platinum-containing or other chemotherapy in the locally 
advanced or metastatic setting and are ineligible for treatment with cisplatin at time of 
enrollment due to one of the following: ECOG performance status score of 2; 
impaired renal function (defined as creatinine clearance [CrCl] ≥30 and <60 mL/min), 


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or a ≥ Grade 2 hearing loss. Patients who received platinum in the 
adjuvant/neoadjuvant setting and did not progress within 12 months of completion 
will be considered platinum-naïve. 
4. Patients must have had progression or recurrence of urothelial cancer during or following 
receipt of most recent therapy. 
5. Tumor tissue samples must be available for submission to the sponsor prior to study 
treatment. 
6. Legally an adult according to local regulation at the time of signing informed consent, 
and minimum age of 18 years. 
7. Patients must have measurable disease according to RECIST (Version 1.1) (Eisenhauer 
2009). Lesions in a prior radiation field must have progressed subsequent to radiotherapy 
to be considered measurable. 
8. An ECOG performance status score of ≤1 for Cohort 1, or ≤2 for Cohort 2. 
9. The following baseline laboratory data, assessed locally (no transfusions are permitted 
within 2 weeks prior to screening): 
● 
absolute neutrophil count ≥1.0 × 109/L 
● 
platelet count ≥100 × 109/L 
● 
hemoglobin ≥9 g/dL 
● 
serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients with 
Gilbert’s disease 
● 
CrCl ≥30 mL/min as measured by 24-hour urine collection or estimated by the 
Cockcroft-Gault criteria  
● 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN 
10. Female patient must either: 
● 
Be of nonchildbearing potential: 
○ 
Postmenopausal* (defined as at least 1 year without any menses) prior to 
screening, or  
○ 
Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, bilateral tubal occlusion) 
*Those who are amenorrheic due to an alternative medical cause are not considered 
postmenopausal and must follow the criteria for childbearing potential patients 
 
● 
Or, if of childbearing potential,  
○ 
Agree not to try to become pregnant during the study and for at least 6 months 
after the final study drug administration, 


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○ 
And have a negative urine or serum pregnancy test within 7 days prior to Day 1 
(Females with false positive results and documented verification of negative 
pregnancy status are eligible for participation), 
○ 
And if heterosexually active, agree to abstinence (if in line with the usual 
preferred lifestyle of the patient) or consistently use a condom plus 1 form of 
highly effective birth control† per locally accepted standards starting at screening 
and throughout the study period and for at least 6 months after the final study 
drug administration 
11. Female patient must agree not to breastfeed or donate ova starting at screening and 
throughout the study period, and for at least 6 months after the final study drug 
administration. 
12. A sexually active male patient with female partner(s) who are of childbearing potential is 
eligible if: 
• Agree to abstinence (if in line with the usual preferred lifestyle of the patient) or to 
use a male condom starting at screening and continue throughout study treatment and 
for at least 6 months after the final study drug administration. If the male patient has 
not had a vasectomy or is not sterile as defined below their female partner(s) is 
utilizing 1 form of highly effective birth control† per locally accepted standards 
starting at screening and continuing throughout study treatment and for at least 
6 months after the male patient receives their final study drug administration. 
13. Male patient must not donate sperm starting at screening and throughout the study period, 
and for at least 6 months after the final study drug administration. 
14. Male patient with a pregnant or breastfeeding partner(s) must agree to abstinence or use a 
condom for the duration of the pregnancy or time their partner is breastfeeding 
throughout the study period and for at least 6 months after the final study drug 
administration. 
†Highly effective forms of birth control include: 
○ 
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation 
○ 
Established intrauterine device (IUD) or intrauterine hormone releasing system 
(IUS) 
○ 
Vasectomy (a vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used) 
○ 
Male is sterile due to a bilateral orchiectomy or radical 
cystoprostatectomy/removal of seminal vesicles 
15. The patient must provide written informed consent. 
16. Patients must have an anticipated life expectancy of ≥3 months as assessed by the 
investigator. 


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4.2 Exclusion Criteria  
1. Ongoing sensory or motor neuropathy Grade ≥2. 
2. Active central nervous system (CNS) metastases. Patients with treated CNS metastases 
are permitted on study if all the following are true: 
● 
CNS metastases have been clinically stable for at least 6 weeks prior to screening and 
baseline scans show no evidence of new or enlarged metastasis 
● 
If requiring steroid treatment for CNS metastases, the patient is on a stable dose 
≤20 mg/day of prednisone or equivalent for at least 2 weeks 
● 
Patient does not have leptomeningeal disease 
3. Ongoing clinically significant toxicity (Grade 2 or higher) associated with prior treatment 
(including systemic therapy, radiotherapy or surgery). Patients with ≤ Grade 2 
hypothyroidism or panhypopituitarism related to treatment with PD-1 and PD-L1 
inhibitors may be enrolled. Patients on hormone replacement therapy may be enrolled if 
on a stable dose. Patients with ≥ Grade 3 immunotherapy-related hypothyroidism or 
panhypopituitarism are excluded. Patients with immunotherapy related myocarditis, 
colitis, uveitis, or pneumonitis are excluded. Patients with other immunotherapy related 
adverse events requiring high doses of steroids (>20 mg/day of prednisone or equivalent) 
are excluded. 
4. Prior enrollment in an enfortumab vedotin study or prior treatment with other 
MMAE-based ADCs. 
5. History of another malignancy within 3 years before the first dose of study drug, or any 
evidence of residual disease from a previously diagnosed malignancy. Patients with 
nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no 
evidence of progression, low-risk or very low-risk (per standard guidelines) localized 
prostate cancer under active surveillance/watchful waiting without intent to treat, or 
carcinoma in situ of any type (if complete resection was performed) are allowed. 
6. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, 
or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial 
prophylaxis is permitted. 
7. Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody. 
Patients with a negative polymerase chain reaction (PCR) assay are permitted with 
appropriate antiviral prophylaxis. 
8. Active hepatitis C infection or known human immunodeficiency virus (HIV) infection. 
Patients who have been treated for hepatitis C infection are permitted if they have 
documented sustained virologic response of ≥12 weeks. 
9. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart 


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failure) consistent with New York Heart Association Class III-IV (see Appendix C) 
within 6 months prior to the first dose of enfortumab vedotin. 
10. Radiotherapy or major surgery within 2 weeks prior to first dose of study drug. 
11. Chemotherapy, biologics, investigational agents, and/or antitumor treatment with 
immunotherapy that is not completed 2 weeks prior to first dose of study drug. 
12. Known hypersensitivity to enfortumab vedotin or to any excipient contained in the drug 
formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and 
polysorbate 20). 
13. Patients with active keratitis or corneal ulcerations. Patients with superficial punctate 
keratitis are allowed if the disorder is being adequately treated in the opinion of the 
investigator. 
14. Other underlying medical condition that, in the opinion of the investigator, would impair 
the ability of the patient to receive or tolerate the planned treatment and follow-up. 
15. Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c 
(HbA1c) ≥8% or HbA1c 7–<8% with associated diabetes symptoms (polyuria or 
polydipsia) that are not otherwise explained. 
16. Uncontrolled tumor-related bone pain or impending spinal cord compression. Patients 
requiring pain medication must be on a stable regimen at the time of enrollment (a 
minimum of 2 weeks). 
4.3 Removal of Patients From Therapy or Assessment  
Seagen or their designee must be notified if a patient is withdrawn from study treatment or 
from the study. The reason(s) for withdrawal must be documented in the patient’s medical 
records and case report form (CRF). 
4.3.1 Discontinuation of Study Treatment  
A patient’s study treatment may be discontinued for any of the following reasons: 
● 
PD 
● 
AE 
● 
Investigator decision 
● 
Patient decision, non-AE 
● 
Study termination by sponsor 
● 
Other, non-AE 
● 
Pregnancy 
 
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 


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4.3.2 Patient Withdrawal From Study  
Any patient may be discontinued from the study for any of the following reasons: 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
5 
TREATMENTS  
5.1 Treatments Administered  
Patients in this study will receive enfortumab vedotin 1.25 mg/kg administered as an IV 
infusion over approximately 30 minutes on Days 1, 8, and 15 of every 28-day cycle. 
5.2 Investigational Study Drug  
Detailed information describing the preparation, administration, and storage of enfortumab 
vedotin is located in the Pharmacy Binder. 
5.2.1 Description  
Enfortumab vedotin is generated by conjugation of a chemical intermediate that contains 
both the MMAE and linker subunits, to cysteine residues of the antibody. The resulting ADC 
contains an average of 3.8 drug molecules per antibody. The enfortumab vedotin drug 
product is a sterile, preservative free, white to off-white lyophilized powder to be 
reconstituted for IV administration. Enfortumab vedotin is supplied in 30 mg single-dose 
vials. Please refer to the Pharmacy Binder for further information. 
5.2.2 Dose and Administration  
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an IV infusion over 
approximately 30 minutes on Days 1, 8, and 15 of every 28-day cycle. In the absence of 
infusion-related reactions (IRRs), the infusion rate for all patients should be calculated in 
order to achieve an approximate 30-minute infusion period. Enfortumab vedotin must not be 
administered as an IV push or bolus. Enfortumab vedotin should not be mixed with other 
medications. At least 1 week must elapse between doses of enfortumab vedotin. 
Weight-based dosing is calculated using the patient’s actual body weight. An exception to 
weight-based dosing is made for patients 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. 
Doses must be adjusted for patients who experience a ≥10% change in weight from baseline, 
or previous cycle. Patient weight must be measured during all relevant assessment windows 
as described in the schedule of events. Other dose adjustments for changes in body weight 
<10% are permitted per institutional standard. 


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The injection site should be monitored closely for redness, swelling, pain, and infection 
during and at any time after administration. Patients should be advised to report redness or 
discomfort promptly at the time of administration or after infusion. Institutional guidelines 
will be followed for the administration of chemotherapy agents and precautions taken to 
prevent extravasation per institutional standards and as described in “Chemotherapy and 
Biotherapy Guidelines and Recommendations for Practice” (Polovich 2014) and 
“Management of Chemotherapy Extravasation:  ESMO-EONS Clinical Practice Guidelines” 
(Perez Fidalgo 2012). 
The patient should be observed during administration of enfortumab vedotin and for at least 
60 minutes following the infusion during the first 3 cycles. All supportive measures 
consistent with optimal subject care should be given throughout the study according to 
institutional standards. 
5.2.3 Dose Modifications  
Intrapatient dose reduction to 1 mg/kg (dose level –1), and to 0.75 mg/kg (dose level –2) will 
be allowed depending on the type and severity of toxicity. Patients requiring a dose reduction 
may be re-escalated by 1 dose level (e.g., patients reduced to 0.75 mg/kg may only be 
re-escalated to 1 mg/kg) provided the toxicity does not require study drug discontinuation 
and has returned to baseline or ≤ Grade 1. If the toxicity recurs, re-escalation will not be 
permitted. Patients with ≥ Grade 2 corneal AEs will not be permitted to dose re-escalate. 
Enfortumab vedotin should not be administered to patients with known CrCl <30 mL/min. 
Dose modification recommendations for enfortumab vedotin-associated toxicity are 
presented in Table 1 and Table 2. 
If toxicities occur on Day 1 of any cycle and require the enfortumab vedotin dose to be held, 
then the start of the cycle may be delayed. If toxicities occur on Days 8 or 15 of any cycle 
and require the dose to be held >2 days, then the dose(s) must be eliminated, rather than 
delayed. If a patient only receives enfortumab vedotin on Day 1 and needs to skip Days 8 and 
15, the patient could resume the next cycle as early as Day 22 (new Day 1) if the toxicity has 
resolved by that time. 
Intrapatient dose reduction or delay for other enfortumab vedotin-associated toxicity is 
permitted at the discretion of the site investigator. Dose delays may last up to 8 weeks 
(2 cycles). Dose delays for patients who are responding to treatment may be extended beyond 
8 weeks, if the patient’s toxicity does not otherwise require permanent discontinuation. 
Patients may not receive other investigational drugs, radiotherapy (except palliative 
radiotherapy as described in Section 5.3.2), or systemic antineoplastic therapy during dose 
delays. If there is a dose delay, the schedule for response assessments will not be adjusted 
and will continue to be timed from Cycle 1 Day 1 during treatment. 


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Table 1: 
Recommended dose modifications for enfortumab vedotin-associated 
hematologic toxicity  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same dose level. 
Continue at same dose level. 
 
For Grade 2 
thrombocytopenia, withhold 
dose until toxicity is 
≤ Grade 1 or has returned to 
baseline, then resume 
treatment at the same dose 
level. 
Withhold dose until toxicity 
is ≤ Grade 1 or has returned 
to baseline, then resume 
treatment at the same dose 
level or consider dose 
reduction by 1 dose level. 
Transfusions or growth 
factors may be used as 
indicated per institutional 
guidelines.  
Withhold dose until toxicity 
is ≤ Grade 1 or has returned 
to baseline, then reduce dose 
by 1 dose level and resume 
treatment, or discontinue at 
the discretion of the 
investigator. Transfusions or 
growth factors may be used 
as indicated per institutional 
guidelines. 
For anemia, treatment 
discontinuation should be 
strongly considered. 
 
Table 2: 
Recommended dose modifications for enfortumab vedotin-associated 
nonhematologic toxicity  
Any Grade 
For suspected Stevens-Johnson syndrome (SJS), suspected toxic epidermal necrolysis (TEN), or bullous lesions, 
immediately withhold enfortumab vedotin and refer the subject to a dermatologist/specialist for diagnosis and 
specialized care. 
For confirmed SJS or TEN, permanently discontinue treatment. 
If SJS or TEN is ruled out, see recommendations provided below for skin reactions. 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same dose level. 
 
For Grade 1 rash or skin 
reactions, may continue at 
same dose level. See also 
Section 5.4.3 for 
recommended management 
of rash. 
 
If ocular symptoms and/or 
changes in vision are 
identified, the patient should 
be evaluated by a qualified 
optometrist or 
ophthalmologist. 
Continue at same dose level, 
except in the event of 
Grade 2 neuropathy,corneal 
AEs, or pneumonitis/ILD. 
 
For worsening rash or skin 
reactions or skin reactions 
with concominant fever, 
withhold enfortumab 
vedotin until toxicity is 
≤ Grade 1 or has returned to 
baseline, 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.  
 
For Grade 2 neuropathy or 
corneal AEs, withhold dose 
until toxicity is ≤ Grade 1 or 
has returned to baseline, 
then resume treatment at the 
same dose level. For the 
second occurrence of 
Grade 2 neuropathy or 
corneal AEs, withhold dose 
until toxicity is ≤ Grade 1, 
then reduce the dose by 1 
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.a 
 
For Grade 3 rash or skin 
reactions withhold 
enfortumab vedotin until 
toxicity is ≤ Grade 1 or has 
returned to baseline, 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 3 neuropathy or 
corneal AEs, discontinue 
treatment.  
 
For Grade 4 AEs, 
discontinue treatment.a 
 
For confirmed SJS or TEN, 
or Grade 4 rash, 
permanently discontinue 
treatment. 
 
Grade 4 vomiting and/or 
diarrhea that improves to 
≤ Grade 2 within 72 hours 
with supportive 
management does not 
require discontinuation. 
 
For Grade 4 
pneumonitis/ILD, 
permanently discontinue 
treatment. 


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dose level and resume 
treatment.  
 
If ocular symptoms and/or 
changes in vision are 
identified, the patient should 
be evaluated by a qualified 
optometrist or 
ophthalmologist. 
 
For Grade 2 
pneumonitis/ILD, withhold 
dose until ≤ Grade 1, then 
resume at the same dose 
level or consider dose 
reduction by 1 dose level. 
For Grade 3 
hyperglycemia/elevated 
blood glucose withhold 
enfortumab vedotin 
treatment. Resume treatment 
once 
hyperglycemia/elevated 
blood glucose has improved 
to ≤ Grade 2 and patient is 
clinically and metabolically 
stable. 
 
If ocular symptoms and/or 
changes in vision are 
identified, the patient should 
be evaluated by a qualified 
optometrist or 
ophthalmologist. 
 
For Grade 3 
pneumonitis/ILD, 
permanently discontinue 
treatment. 
a 
Grade 3/4 electrolyte imbalances/laboratory abnormalities, except hyperglycemia, that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours of their onset do not require 
discontinuation (e.g., Grade 4 hyponatremia). 
 
See Section 5.4.1 for recommended management of infusion reactions. See Section 5.4.2 for 
recommended management of hyperglycemia. See Section 5.4.3 for recommended 
management of rash. 
5.2.3.1 Treatment Discontinuation Recommendations Related to Liver Safety  
In the absence of an explanation for increased liver function tests (LFTs), such as viral 
hepatitis, preexisting or acute liver disease, or exposure to other agents associated with liver 
injury, the patient may be discontinued from the study treatment. The investigator may 
determine that it is not in the patient’s best interest to continue study treatment. 
Discontinuation of treatment should be considered if: 
● 
ALT or AST >8 × ULN 
● 
ALT or AST >5 × ULN for more than 2 weeks 
● 
ALT or AST >3 × ULN and total bilirubin >2 × ULN or international normalized 
ratio (INR) >1.5 (if INR testing is applicable/evaluated) 
● 
ALT or AST >3 × ULN with the appearance of symptoms suggestive of liver injury 
(e.g., right upper quadrant pain or tenderness) and/or eosinophilia (>5%) 
These treatment discontinuation recommendations are based on the FDA Guidance for 
Industry (Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009). The 
recommendations are a basic guide to the investigator based on accumulated clinical 
experience with drugs in development, and are not specific to clinical experience with 
enfortumab vedotin. 


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See Appendix E for recommended liver safety monitoring and assessment criteria in patients 
with Grade 2 or greater elevations in ALT, AST, or bilirubin. 
5.2.4 Storage and Handling  
Refrigeration should be set at 2–8°C for storage of vials and solutions containing enfortumab 
vedotin. The controlled location must be accessible only to the pharmacist, the investigator, 
or a duly designated person. Study drug must be reconstituted before administration. Please 
refer to the Pharmacy Binder for information regarding stability of reconstituted study drug. 
The effect of light on the study drug has not been assessed; therefore, it is recommended that 
vials of enfortumab vedotin lyophilized powder, reconstituted drug product and/or dosing 
solutions be protected from light until the time of use. 
Do not shake reconstituted vials of the study drug. 
Any partially used vials or prepared dosing solutions should be destroyed by the site 
according to institutional drug disposal procedures. Unused vials should be destroyed by the 
site or returned to the sponsor after authorization by the sponsor or designee. Drug 
accountability procedures are provided in the Pharmacy Binder. 
5.2.5 Packaging and Labeling  
Refer to the Pharmacy Binder for information regarding packaging and labeling. 
5.2.6 Preparation  
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves (double glove with nitrile gloves), and vertical laminar airflow safety 
cabinets. 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
5.3 Concomitant Therapy  
All concomitant medications and blood products will be recorded from Day 1 (predose) 
through the safety reporting period (30 days after the last study treatment). Any concomitant 
medication given for a study protocol-related adverse event should be recorded from the time 
of informed consent. 
5.3.1 Required Concomitant Therapy  
There are no required concomitant therapies. 
5.3.2 Allowed Concomitant Therapy  
Concomitant chronic prednisone (or equivalent) may be used at a dose of ≤20 mg/day. 
Higher doses of prednisone (or equivalent) are permitted for limited duration to treat acute 
conditions that arise during the study as medically indicated. The use of anti-emetics are 
permitted. Premedications for IRRs per Section 5.4.1 are permitted. 


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Therapy to manage enfortumab vedotin-associated toxicity as recommended in Section 5.2.3 
are permitted, including growth factors, and transfusions. 
Patients who are receiving strong CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors 
concomitantly with enfortumab vedotin should be closely monitored for adverse reactions. 
Routine prophylaxis with vaccines is permitted; it is recommended that vaccines used do not 
contain live micro-organisms. 
Palliative radiotherapy on a non-target bone lesion that is not progressing is allowed after 
3 cycles of treatment; must be administered after the initial response assessment and repeat 
scans described in Section 7.2. This will not be considered a subsequent anticancer therapy, 
but must not interfere with the assessment of tumor target lesions. Treatment with 
enfortumab vedotin should be interrupted during palliative radiotherapy. 
Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody and a 
negative PCR assay at baseline should receive appropriate antiviral prophylaxis or regular 
surveillance monitoring as per local or institutional guidelines. 
5.3.3 Prohibited Concomitant Therapy  
Patients may not receive other investigational drugs, radiotherapy (except palliative 
radiotherapy as described in Section 5.3.2), or systemic anti-neoplastic therapy during the 
treatment period. Patients who receive prohibited concomitant therapy must be discontinued 
from the study. 
5.4 Management of Adverse Reactions  
5.4.1 Management of Infusion 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 patient care should be given throughout the 
study according to institutional standards. Supportive measures may include administering 
medications for IRRs. 
Patients who have experienced an IRR may be premedicated for subsequent infusions. 
Premedication may include pain medication (e.g., acetaminophen or equivalent), an 
antihistamine (e.g., diphenhydramine hydrochloride), and a corticosteroid administered 
30–60 minutes prior to each infusion or according to institutional standards. Should a patient 
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. 


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5.4.2 Management of Hyperglycemia  
Investigators should monitor blood glucose levels and are advised to perform additional 
assessments if any symptoms of hyperglycemia are observed, including a thorough 
evaluation for infection. In addition, if steroids are used to treat any other condition, blood 
glucose levels may require additional monitoring. If elevated blood glucose levels are 
observed, patients should be treated according to local standard of care and referral to 
endocrinology may be considered. 
Patients, 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. 
Patients who enter the study with an elevated HbA1c (≥6.5%) at baseline should be referred 
to an appropriate provider during Cycle 1 for glucose management. Blood glucose should be 
checked prior to each dosing and dose should be withheld for blood glucose >250 mg/dL 
(Grade 3 or higher), regardless of relatedness to enfortumab vedotin. Dosing may continue 
once the patient’s blood glucose has improved to ≤250 mg/dL (≤ Grade 2) and the patient is 
clinically and metabolically stable. Patients with blood glucose >500 mg/dL (Grade 4) 
considered unrelated to enfortumab vedotin may continue dosing once the patient’s blood 
glucose has improved to ≤250 mg/dL (≤ Grade 2) and the patient is clinically and 
metabolically stable. Blood glucose >500 mg/dL (Grade 4) considered related to enfortumab 
vedotin requires treatment discontinuation. If a patient experiences new onset diabetes 
mellitus, evaluate patients with a metabolic panel, urine ketones, glycosylated hemoglobin, 
and C-peptide to assess for new onset type 1 diabetes in the setting of prior CPI. 
5.4.3 Management of Rash Related to Enfortumab Vedotin  
Enfortumab vedotin is a Nectin-4 directed antibody drug conjugate. Nectin-4 is a cell 
adhesion molecule that is highly expressed in urothelial carcinoma. Low to moderate levels 
of Nectin-4 are also expressed on normal tissues, including skin keratinocytes, sweat glands 
and hair follicles; thus, skin reactions are anticipated events. As such, skin reactions are 
adverse events of interest in all clinical studies with enfortumab vedotin. 
A cumulative review of post-marketing safety data from 18 Dec 2019 (the approval date of 
enfortumab vedotin in the US) through 22 Oct 2020 identified reports of severe cutaneous 
adverse reactions in 15 patients receiving enfortumab vedotin, some of whom had fatal 
outcomes. These reactions occurred predominantly during the first cycle of treatment. 
Adverse events reported in these cases included SJS (5 cases), blister (3 cases), dermatitis 
bullous (3 cases), symmetrical drug-related intertriginous and flexural exanthema (SDRIFE; 
2 cases), and 1 case each of dermatitis exfoliative, exfoliative rash, epidermal necrosis, 
oropharyngeal blistering, stomatitis, and TEN. 
In enfortumab vedotin monotherapy studies of urothelial carcinoma, serious adverse events 
of severe cutaneous adverse reactions were reported in 11 of 749 subjects (1.5%) and 


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included dermatitis bullous (0.4%), drug eruption (0.4%), blister (0.1%), conjunctivitis 
(0.1%), SJS (0.1%), stomatitis (0.1%), and toxic skin eruption (0.1%). 
Subjects should be informed that rash and severe skin reactions have occurred after 
administration of enfortumab vedotin and advised 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 
enfortumab vedotin, refer to Section 5.2.3. 
5.4.4 Management of Pneumonitis/ILD Related to Enfortumab Vedotin 
Severe, life-threatening or fatal pneumonitis/interstitial lung disease (ILD) have occurred in 
patients receiving enfortumab vedotin. Monitor patients for signs and symptoms indicative of 
pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic 
exams. For recommendations regarding dose modifications for pneumonitis/ILD due to 
enfortumab vedotin, refer to Section 5.2.3. 
5.5 Treatment Compliance  
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES  
6.1 Schedule of Events  
Adverse events and concomitant medications will be recorded from Day 1 (predose) through 
the safety reporting period (30 days after the last study treatment, see Section 7.7.1.3). Day 1 
is the first day of treatment with study drug in each cycle. Any study protocol-related AE 
(defined in Section 7.7.1.1) as well as any concomitant medications given for treatment of 
the adverse event, should be recorded from the time of informed consent. A schedule of 
events is provided in Appendix A. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. 
Local laboratory testing should be performed on all dosing days. All local laboratory results 
must be reviewed prior to study drug administration in order to determine whether to proceed 
with dosing or whether dose modification is required. 
6.2 Screening Visit (Days –28 to Day 1)  
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history (see Section 7.1) 
● 
Acquire and submit tumor specimen (see Section 7.4.2). Either archival tissue or 
pre-treatment fresh tumor tissue (obtained from a fresh biopsy) is acceptable. 


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● 
Complete eye examination (see Section 7.7.7) 
● 
Brain scan (magnetic resonance imaging [MRI] with gadolinium preferred; if 
contraindicated, see Appendix F) to determine eligibility with respect to CNS 
metastases) 
● 
Bone scan 
● 
CT scan with contrast (if contraindicated, see Appendix F), including chest, abdomen, 
and pelvis. Other regions should be scanned if the patient has known or suspected 
disease in that region.  
● 
INR/prothrombin time (PT) and partial thromboplastin time (PTT) 
● 
Serology for hepatitis B surface antigen and antihepatitis B core antibody 
● 
Serology for antihepatitis C antibody. If positive, follow up with PCR testing. 
● 
Urinalysis (with reflexive microscopy) 
● 
HbA1c. If HbA1c is elevated (≥6.5%), refer patient to appropriate provider during 
Cycle 1 for glucose management. 
6.2.1 Baseline Visit (Days –7 to Day 1)  
● 
Pregnancy test (either serum or urine) for females of childbearing potential (see 
Section 7.7.2) 
● 
Physical exam (including weight; see Section 7.7.3) 
● 
Collect height 
● 
Vital signs (see Section 7.7.4) 
● 
Complete blood count (CBC) with differential (see Section 7.7.2) 
● 
Serum chemistry panel (see Section 7.7.2) 
● 
CrCl (see Section 7.7.2) 
● 
ECOG performance status (see Section 7.7.5) 
● 
Electrocardiogram (ECG) (see Section 7.7.6) 
6.3 Treatment Period (Day 1 to Day 22)  
6.3.1 Day 1 (±2 days)  
● 
Predose (to occur on day of dosing unless noted below) 
○ 
QLQ-C30 (see Section 7.6.1) 
○ 
EQ-5D (see Section 7.6.2) 
○ 
Pregnancy test (either serum or urine) for females of childbearing potential  
○ 
Physical exam (including weight; may be conducted the day prior to dosing) 
○ 
Vital signs 
○ 
CBC with differential (may be collected the day prior to dosing) 
○ 
Serum chemistry panel (may be collected the day prior to dosing) 
○ 
ECOG performance status (may be conducted the day prior to dosing) 


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○ 
Blood samples for PK assessments (within 24 hours prior to dose; Cycles 1–4 and 
every even-numbered cycle thereafter; see Table 3) 
○ 
Blood samples for ATA assessments (within 24 hours prior to dose; Cycles 1–4 
and every even-numbered cycle thereafter; see Table 3) 
○ 
Blood samples for biomarker assessments (within 24 hours prior to dose; 
Cycles 1–4; see Table 3) 
● 
Enfortumab vedotin administration (see Section 5.2.2) 
● 
Postdose 
○ 
Blood samples for PK assessments (Cycles 1–2; see Table 3) 
 
If Baseline Visit activities occur within 1 day prior to Cycle 1, Day 1, the following 
assessments do not need to be repeated at the Cycle 1 Day 1 visit: physical exam (including 
weight), vital signs, ECOG performance status, serum chemistry panel, and CBC with 
differential. If the baseline pregnancy test occurs within 7 days prior to Cycle 1 Day 1, the 
pregnancy test does not need to be repeated at the Cycle 1 Day 1 visit. 
6.3.2 Day 3  
● 
Blood samples for PK assessments (±24 hours; Cycles 1 and 2) 
● 
Blood samples for biomarker assessments (±24 hours; Cycle 1) 
6.3.3 Day 8 (+2 days)  
● 
Predose (to occur on day of dosing unless noted below) 
○ 
Vital signs 
○ 
CBC with differential (may be collected the day prior to dosing) 
○ 
Serum chemistry panel (may be collected the day prior to dosing) 
○ 
Blood samples for PK assessments (within 24 hours prior to dose; Cycles 1 and 2) 
○ 
Blood samples for biomarker assessments (within 24 hours prior to dose; Cycle 1) 
● 
Enfortumab vedotin administration. At least 1 week must elapse between doses of 
enfortumab vedotin. 
● 
Postdose 
○ 
Blood samples for PK assessments (Cycles 1 and 2) 
6.3.4 Day 15 (+2 days)  
● 
Predose (to occur on day of dosing unless noted below) 
○ 
Vital signs 
○ 
CBC with differential (may be collected the day prior to dosing) 
○ 
Serum chemistry panel (may be collected the day prior to dosing) 
○ 
Blood samples for PK assessments (within 24 hours prior to dose; Cycles 1 and 2) 
○ 
Blood samples for biomarker assessments (within 24 hours prior to dose; Cycle 1) 


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● 
Enfortumab vedotin administration. At least 1 week must elapse between doses of 
enfortumab vedotin. 
● 
Postdose 
○ 
Blood samples for PK assessments (Cycles 1 and 2) 
6.3.5 Day 17  
● 
Blood samples for PK assessments (-24/+48 hours; Cycles 1 and 2) 
6.3.6 Day 22  
● 
Blood samples for PK assessments (Cycles 1 and 2 [±48 hours]) 
● 
CT scan with contrast (if contraindicated, see Appendix F) of the chest, abdomen, 
pelvis and any other region of known or suspected disease (every 8 weeks [±1 week] 
from Cycle 1 Day 1 during treatment, with repeat scans 4 weeks [+1 week] after first 
documentation of response). Brain and/or bone scans should also be repeated at this 
timepoint if metastases were identified at baseline, or if metastasis is suspected. After 
1 year on study the frequency of scans will be reduced to every 12 weeks (±1 week). 
Following confirmation scans, response assessments should continue with the 
previous scan schedule (i.e., the schedule should not be adjusted). If there is a dose 
delay due to toxicity, the schedule for response assessments will not be adjusted and 
will continue to be timed from Cycle 1 Day 1 during treatment. Tumor imaging 
should also be performed whenever disease progression is suspected. 
6.4 End of Treatment Visit (30 to 37 days after last dose of study drug)  
EOT visits should occur 30 to 37 days after the last dose of study drug unless delayed due to 
an AE. However, EOT evaluations must be performed before initiation of a new therapy for 
cancer, with the exception of the slit lamp examination. If EOT evaluations are completed 
before 30 days after the last study treatment, the patient will be contacted 30 to 37 days 
following the last treatment to assess for adverse events. 
● 
QLQ-C30 
● 
EQ-5D 
● 
Slit lamp examination (for patients who experience corneal adverse events during the 
study). Performed ≥4 weeks from last dose. 
● 
Pregnancy test (either serum or urine) for females of childbearing potential 
● 
Physical exam (including weight) 
● 
Vital signs 
● 
CBC with differential 
● 
Serum chemistry panel 
● 
ECOG performance status 
● 
ECG 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments 


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● 
CT scan with contrast (if contraindicated, see Appendix F) of the chest, abdomen, 
pelvis and any other region of known or suspected disease. Responses will be 
confirmed with repeat scans at 4 weeks after first documentation of response 
(+1 week). Following confirmation scans, response assessments should continue with 
the previous scan schedule (i.e., the schedule should not be adjusted and should all be 
timed every 8 weeks [±1 week] from Cycle 1 Day 1 during treatment). Tumor 
imaging should also be performed whenever disease progression is suspected. Bone 
and/or brain scans should also be repeated at this timepoint if metastases were 
identified at baseline, or if metastasis is suspected. Scans not required if previous scan 
conducted <4 weeks prior to EOT. 
6.5 Every Month for 6 Months After End of Treatment Visit (±1 week)  
● 
Pregnancy test (either serum or urine) for females of childbearing potential 
6.6 Follow-up (Every 8 Weeks [±1 week])  
Prior to initiation of subsequent anticancer therapy or radiologically-confirmed disease 
progression (per investigator according to RECIST), patients will have the assessments listed 
below done 8 weeks (±1 week) after the previous response assessment scan and every 
8 weeks (±1 week) following the previous visit thereafter until radiologically-confirmed 
disease progression (per investigator according to RECIST), initiation of a new anticancer 
therapy, patient death, study closure, or withdrawal of consent, whichever comes first. After 
1 year on study the frequency of visits including response assessments will be reduced to 
every 12 weeks (±1 week). 
● 
Physical exam 
● 
ECOG performance status 
● 
CT scan with contrast (if contraindicated, see Appendix F) of the chest, abdomen, 
pelvis and any other region of known or suspected disease (with repeat scans 4 weeks 
[+1 week] after first documentation of response). Brain and/or bone scans should also 
be repeated at this timepoint if metastases were identified at baseline, or if metastasis 
is suspected. Following confirmation scans, response assessments should continue 
with the previous scan schedule (i.e., the schedule should not be adjusted). Tumor 
imaging should also be performed whenever disease progression is suspected. 
6.7 Long-term Follow-up (Every 8 Weeks [±1 week])  
After initiation of subsequent anticancer therapy or radiologically-confirmed disease 
progression (per investigator according to RECIST), patients will be contacted every 8 weeks 
(±1 week) after EOT (or 8 weeks from previous protocol visit, whichever is later) for 
survival status and collection of subsequent anticancer therapy information until death, study 
closure, or withdrawal of consent, or patient is lost to follow-up, whichever occurs first. After 
1 year on study, the frequency of contacts will be reduced to every 12 weeks (±1 week). 


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6.8 End of Study/End of Follow-up  
The study will be closed 5 years after enrollment of the last patient, or when no patients 
remain in long-term follow-up, whichever occurs first. Additionally, the sponsor may 
terminate the study at any time. 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 
7 
STUDY ASSESSMENTS  
7.1 Screening/Baseline Assessments  
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. Enrollment status and date will be recorded in CRF. 
Patient medical history includes a thorough review of significant past medical history, 
current conditions, tobacco history, any treatment for prior malignancies and response to 
prior treatment, and any concomitant medications. 
A complete eye examination, brain scan, bone scan, CT scan with contrast for baseline 
response efficacy assessment, INR/PT/PTT, serology for hepatitis B and C, urinalysis with 
reflexive microscopic analysis, HbA1c, and pregnancy test (either urine or serum, for 
females of childbearing potential) are required for all patients at screening. 
7.2 Response/Efficacy Assessments  
Measures of anticancer activity will be assessed by CT scans with contrast approximately 
every 8 weeks (±1 week). After 1 year on study, response assessments will be reduced to 
every 12 weeks (±1 week). The schedule of response assessments should not be adjusted for 
dose delays/interruptions or other reasons for changes in the timing of a patient’s study 
activities; timepoints for response assessments should be calculated from Cycle 1 Day 1 
during treatment. For patients who cannot receive CT scans with contrast, other acceptable 
imaging methods are detailed in Appendix F (Scanning and Contrast Guidelines). For brain 
scans, MRI with gadolinium is the preferred method of assessment; however, other imaging 
methods are detailed in Appendix F if contrast is contraindicated. Patients must be evaluated 
using the same imaging method throughout the study for efficacy assessments. CT scans with 
contrast at the minimum will include the chest, abdomen, and pelvis. Other regions should be 
scanned if the patient has known or suspected disease in that region. Brain and/or bone scans 
should also be repeated at response assessment timepoints if bone metastases were identified 
at baseline, or if metastasis is known or suspected. Responses (CR or PR) will be confirmed 
with repeat scans 4 weeks (+1 week window) after first documentation of response. The 
schedule for response assessments should not be adjusted after the confirmatory scan 
(e.g., CR at Week 8, confirmatory scans at Week 12, next assessment due at Week 16). 
Tumor imaging should also be performed whenever disease progression is suspected. 
Patients who discontinue study treatment for reasons other than objective disease progression 
by RECIST Version 1.1 (see Appendix D) will continue to receive CT scans with contrast 


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8 weeks (±1 week) after the previous response assessment scan and every 8 weeks (±1 week) 
following the previous scan thereafter. After 1 year on study the frequency of response 
assessments will be reduced to every 12 weeks (±1 week). The tumor assessments will 
continue until the patient has radiologically-confirmed disease progression per RECIST as 
determined by the investigator, initiates a new anticancer therapy, dies or withdraws consent, 
or the study closes, whichever comes first. The determination of antitumor activity will be 
based on confirmed objective response assessments as defined by RECIST Version 1.1 (see 
Appendix D) (Eisenhauer 2009). Patients who do not have at least 2 (initial response and 
confirmation scan) post-baseline response assessments will be counted as non-responders. 
The investigator will make treatment decisions based on site assessments of scans by 
RECIST. Clinical response of CR, PR, SD, or PD will be determined at each assessment. 
Response and progression will also be assessed by an IRF.  
Survival status will be updated every 8 weeks (±1 week) after EOT (or 8 weeks from 
previous protocol visit, whichever is later) until death, study closure, or withdrawal of 
consent, whichever occurs first. After 1 year on study the frequency of survival status 
updates will be reduced to every 12 weeks (±1 week). 
Patients’ clinical data must be available for CRF source verification. Tumor images will be 
submitted to a central imaging lab. 
7.3 Pharmacokinetic and ATA Assessments  
Blood samples for PK and ATA will be collected throughout the study per the sample 
collection schedule provided in Table 3. Validated or qualified assays will be used to 
measure the concentrations of enfortumab vedotin ADC, TAb, and MMAE in serum or 
plasma. PK samples will be collected and archived for possible analysis of other enfortumab 
vedotin-related species, such as circulating metabolites of MMAE. A qualified assay will be 
used to determine the levels of ATA in serum. 
Refer to the Central Laboratory Manual for information on collection, processing, storage, 
and shipment of sample. 
7.4 Biomarker Studies  
Samples for exploratory biomarkers will be collected at protocol-specified timepoints (see 
Table 3 and Appendix A). Biomarker assessments will not be used for patient selection. 
Methods of analysis may include IHC, next generation sequencing, PCR, mutation and gene 
expression profiling; T-cell receptor beta chain sequencing, flow cytometry and 
immunoassays. 
7.4.1 Biomarkers in Blood  
The primary effects of enfortumab vedotin on urothelial carcinoma tumor cells may lead to 
changes in the activation state of local, tumor-associated and peripheral immune cells. 
Biomarker assessments in blood samples may include but may not be limited to: markers of 
immune function, including abundance and phenotype of immune cell subsets, circulating 


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tumor DNA (ctDNA), and abundance of cytokines. These may provide insight into 
treatment-related changes in activation state of peripheral immune system associated with 
enfortumab vedotin-induced tumor cell death. 


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Table 3: 
Pharmacokinetic, ATA, and biomarker blood sample collection timepoints  
 
Study 
Day 
Time 
Window 
Relative Time 
Blood 
PK 
ATA 
Biomarkers 
Plasma 
PBMC 
Cytokines 
Research 1 
Research 2 
Immuno-
phenotyping 
Research 
Cycles 1 and 2 
Day 1 
Pre-dose 
within 24 hr 
START of infusion 
X 
X 
X 
X 
X 
X 
X 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 3 
48 hr 
±24 hr 
END of Day 1 infusion 
X 
 
Xa 
 
Xa 
Xa 
Xa 
Day 8 
Pre-dose 
within 24 hr 
START of infusion 
X 
 
Xa 
Xa 
Xa 
Xa 
Xa 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 15 
Pre-dose 
within 24 hr 
START of infusion 
X 
 
Xa 
 
Xa 
Xa 
Xa 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 17 
48 hr 
–24 hr/+48 hr 
END of Day 15 infusion 
X 
 
 
 
 
 
 
Day 22 
168 hr 
±48 hr 
END of Day 15 infusion 
X 
 
 
 
 
 
 
Subsequent 
dosing cycles 
Day 1 
Pre-dose 
within 24 hr 
START of infusion 
Xb 
Xb 
Xc 
Xc 
Xc 
Xc 
Xc 
End of Treatment (within 30–37 days of last dose) 
X 
X 
X 
X 
X 
X 
X 
a 
Cycle 1 only 
b 
Cycles 3 and 4 and every even-numbered cycle thereafter 
c 
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7.4.2 Biomarkers in Pre-Treatment Tumor Tissue  
To better understand relationships between pre-treatment urothelial carcinoma biological 
characteristics, and patient outcome, submission of a tumor block or freshly sectioned, 
unstained charged slides (at least 10 slides are mandatory unless prior approval is obtained 
from the sponsor) of pretreatment tumor tissue are required. Either archival tissue or 
pre-treatment fresh tumor tissue (obtained from a fresh biopsy) is acceptable. See the 
Laboratory Manual for details. 
Biomarker assessments in tumor tissue may include, but not be limited to:  
● 
Tumor expression of Nectin-4 protein 
● 
Messenger ribonucleic acid (mRNA) expression  
● 
Markers of disease subtype (e.g., The Cancer Genome Atlas [TCGA] subtypes) 
● 
Tumor mutational burden 
● 
Markers of the tumor immune microenvironment 
7.5 Biospecimen Repository  
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by the sponsors and used for future research, including 
but not limited to the evaluation of targets for novel therapeutic agents, the biology of ADC 
sensitivity and resistance mechanisms, and the identification of biomarkers for ADCs. Blood 
and tissue samples donated for future research will be retained for a period of up to 25 years. 
If additional consent is not provided, any remaining biological samples will be destroyed 
following study completion and when the samples are no longer required to be maintained 
for potential regulatory submissions. 
7.6 Quality of Life  
Two validated tools will be used: the QLQ-C30, and the EQ-5D. 
If possible, PRO assessments should be completed before any other procedures at the study 
visits noted in the schedule of events (Appendix A). 
7.6.1 EORTC Core Quality of Life Questionnaire, QLQ-C30  
The QLQ-C30 was developed to measure aspects of QoL pertinent to patients with a broad 
range of cancers who are participating in clinical trials (Aaronson 1993; Sneeuw 1998). The 
current version of the core instrument (QLQ-C30, Version 3) is a 30-item questionnaire 
consisting of the following: 
● 
5 functional domains (physical, role, cognitive, emotional, social); 
● 
3 symptom scales (fatigue, pain, nausea & vomiting); 


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● 
Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease; and 
● 
2 global items (health, overall QoL). 
7.6.2 EuroQol-5 Dimensions  
The EQ-5D 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 is a 5-item self-reported measure of functioning and well-
being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension comprises 3 levels (no problems, 
some/moderate problems, extreme problems). A unique EQ-5D health state is defined by 
combining 1 level from each of the 5 dimensions. This questionnaire also records the 
respondent’s self-rated health status on a vertical graduated (0 to 100) visual analogue scale. 
Responses to the 5 items will also be converted to a weighted health state index (utility score) 
based on values derived from general population samples. The EQ-5D is recommended for 
use in cost-effectiveness analyses commonly employed in health technology assessments by 
the Washington Panel on Cost Effectiveness in Health and Medicine (Gold 1996). 
7.7 Safety Assessments  
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication, and measurements 
of protocol-specified physical examination findings, cardiac monitoring, and laboratory tests. 
Safety will be monitored over the course of the study by an IDMC as described in 
Section 9.3.10. 
7.7.1 Adverse Events  
7.7.1.1 Definitions  
Adverse Event  
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, 
Investigational New Drug (IND) Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product 
and which does not necessarily have a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF: 


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● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (pre-dose) through the end of the safety reporting period (see Section 7.7.1.3). 
Complications that occur in association with any procedure (e.g., biopsy) should be 
recorded as AEs whether or not the procedure was protocol mandated. 
● 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 
or results in study termination or interruption/discontinuation of study treatment. 
When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (e.g., record “anemia” 
rather than “low hemoglobin”). 
Serious Adverse Events  
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
 
Life threatening: 
The AEs placed the patient at immediate risk of death. This classification does not apply to 
an AE that hypothetically might cause death if it were more severe. 
 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or treatments planned before 
the signing of informed consent in the study or routine check-ups are not SAEs by this 
criterion. Admission to a palliative unit or hospice care facility is not considered to be a 
hospitalization. Pre-planned hospitalizations for therapeutic, diagnostic, or surgical 
procedures of the underlying cancer or study target disease that did not worsen during the 
clinical trial need not be captured as SAEs. 
 
Disabling/incapacitating: 
An AE that resulted in a persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 
 
Congenital anomaly or birth 
defect: 
An adverse outcome in a child or fetus of a patient exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the patient and 
might have required medical or surgical intervention to prevent one of the outcomes listed 
above or involves suspected transmission via a medicinal product of an infectious agent. 


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Adverse Event Severity  
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. These criteria are provided in the 
study manual. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above). 
Relationship of the Adverse Event to Study Treatment  
The relationship of each AE to enfortumab vedotin should be evaluated by the investigator 
using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such as: 
● A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture) 
 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established with the 
onset of the AE and administration of the study treatment, or a causal relationship is 
considered biologically implausible 
 
7.7.1.2 Procedures for Eliciting and Recording Adverse Events  
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events  
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events  
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 


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Diagnosis vs Signs or Symptoms  
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate adverse event. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug. For IRRs, record the NCI CTCAE term of ‘infusion related reaction’ with an 
overall level of severity (per NCI CTCAE). In addition, record each sign or symptom of the 
reaction as an individual AE. If multiple signs or symptoms occur with a given infusion-
related event, each sign or symptom should be recorded separately with its level of severity. 
Recording Serious Adverse Events  
For SAEs, record the event(s) on both the CRF and an SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer  
Do not report radiographic signs of disease progression (e.g., ‘tumor progression’ or 
‘metastases’) as an AE (this data is captured in the efficacy assessment). Report the 
symptoms and signs of disease progression (e.g., “fatigue”, “dyspnea”) as AEs; do not report 
disease progression as the AE term. 
For disease progression with a fatal outcome, report the immediate cause of death as the 
event term. If the immediate cause of death cannot be determined and it is thought by the 
investigator to be related to disease progression, report the AE using the term ‘disease 
progression’ with a fatal outcome. 
Pregnancy  
Notification to Drug Safety:  Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 6 months after the last dose of study drug(s) 
including any pregnancies that occur in the partner of a male study patient. Only report 
pregnancies that occur in a male patient’s partner if the estimated date of conception is after 
the male patient’s first study drug dose. Email or fax to the sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy. All pregnancies will be 


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monitored for the full duration; all perinatal and neonatal outcomes should be reported. 
Infants should be followed for a minimum of 8 weeks. 
Collection of data on the CRF:  All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and 
Pre-Existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.7.1.1) should be reported as SAEs. 
Corneal Adverse Events  
Corneal ulcer or keratitis AEs ≥ Grade 2 should be graded within their respective categories. 
Grade 1 corneal ulcer or keratitis AEs should be graded per “Eye disorders – Other, specify” 
criteria. Other corneal AEs should be recorded and graded per “Eye disorders – Other, 
specify” criteria. 
Adverse Events of Possible Hepatic Origin  
If an AE is accompanied by increases in LFT values (e.g, AST, ALT, bilirubin, etc.) or is 
suspected to be due to hepatic dysfunction, see Appendix E for detailed information on 
recommended monitoring and assessment of liver abnormalities. See Section 5.2.3.1 for 
treatment discontinuation recommendations related to hepatic safety. 
Patients with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored. 
7.7.1.3 Reporting Periods for Adverse Events and Serious Adverse Events  
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through 30 
days after the last study treatment. However, all study protocol-related AEs are to be 
recorded from the time of informed consent. All SAEs that occur after the safety reporting 
period and are considered study treatment-related in the opinion of the investigator should 
also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of clinical interest may be followed 
(including collection of relevant concomitant medications) until resolution, return to baseline, 
study closure, or the events become chronic to the extent that they are adequately 
characterized. 
7.7.1.4 Serious Adverse Events Require Immediate Reporting  
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 


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For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
Patient number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the study 
sponsor’s Drug Safety Department or designee within 24 hours (see email or fax number[s] 
specified on the SAE report form). 
Relevant follow-up information is to be submitted to the study sponsor as soon as it becomes 
available. 
7.7.1.5 Sponsor Safety Reporting to Regulatory Authorities  
Investigators are required to report all SAEs, including anticipated SAEs, to the study 
sponsor (see Section 7.7.1.4). 
The study sponsors will report all SAEs to regulatory authorities as applicable and as 
required per local regulatory reporting requirements. In the US, endpoints that assess disease-
related mortality or major morbidity, as well as other SAEs that are not study endpoints but 
are known consequences of the underlying disease or condition that are anticipated to occur 
in the study population, should not be reported to the FDA as individual IND safety reports 
per the final rule amending the IND safety reporting requirements under 21 CFR 312.32 and 
the FDA’s guidance Safety Assessment for IND Safety Reporting Guidance for Industry 
(draft guidance December 2015). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
progression of the underlying cancer. These anticipated SAEs will be reviewed periodically 
by an IDMC and Seagen Drug Safety Department. If upon review, an SAE is occurring at a 
higher rate than that which would be expected for the study population, then an IND safety 
report for the SAE will be submitted to the FDA. 
7.7.2 Clinical Laboratory Tests  
Samples will be drawn for central and local labs. 
Local laboratory testing will include institutional standard tests for study eligibility, 
evaluating safety, and making clinical decisions. Local laboratory testing should be 
performed on all dosing days. All local laboratory results must be reviewed prior to study 
drug administration in order to determine whether to proceed with dosing or whether dose 
modification is required. 
The following laboratory assessments will be performed by the central lab to evaluate safety 
at scheduled timepoints (see Appendix A) during the course of the study: 


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● 
The serum chemistry panel is to include the following tests: albumin, alkaline 
phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, creatinine, 
chloride, glucose, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, 
total bilirubin, amylase, lipase, and uric acid. 
● 
The CBC with differential is to include the following tests:  white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, hemoglobin, and hematocrit. 
The following laboratory assessment(s) will be performed by local laboratories at scheduled 
timepoints (see Appendix A) during the course of the study: 
● 
CrCl at baseline using the Cockcroft-Gault criteria or 24-hour urine collection 
● 
Standard urinalysis (with reflexive microscopy) 
● 
INR/PT/PTT 
● 
A serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test for 
females of childbearing potential 
● 
HbA1c  
● 
Serology for hepatitis B surface antigen and antihepatitis B core antibody 
● 
Serology for antihepatitis C antibody. If positive, follow up with PCR testing 
7.7.3 Physical Examination Including Weight  
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Height will be collected at 
the Baseline visit. Weight will be collected at specified timepoints (see Appendix A), but 
does not need to be collected at visits following EOT. 
7.7.4 Vital Signs  
Vital sign measurements will be performed to include heart rate (bpm), diastolic and systolic 
blood pressure (mmHg), and temperature. Vital sign values will be recorded, and any 
diagnosis associated with clinically significant abnormal vital signs will be recorded as an 
adverse event or pre-existing condition. 
7.7.5 ECOG Performance Status  
ECOG performance status (Appendix B) will be evaluated at protocol-specified timepoints. 
7.7.6 Cardiac Monitoring  
ECGs will be conducted at baseline and at the EOT visit. Additional ECGs should be 
conducted if clinically indicated. Routine 12-lead ECGs will be performed after the patient 
has been in a supine position for at least 5 minutes. The ECG assessments should be 
performed prior to obtaining the PK and biomarker samples if possible. 


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7.7.7 Eye Examination  
Patients will have a complete eye examination at baseline performed by a qualified 
ophthalmologist or optometrist, including but not limited to: uncorrected, corrected and best 
corrected visual acuity, slit lamp, tonometry examination, and dilated fundus examination. 
EOT slit lamp examinations are required for all patients who experience corneal adverse 
events during the study. EOT slit lamp examinations must be performed ≥4 weeks from last 
dose. Additional eye examinations are to be conducted as clinically indicated. 
7.8 Post-treatment Assessments  
7.8.1 Follow-up Assessments  
Patients who discontinue study treatment will continue to receive physical exams (no weight 
collection is required), ECOG assessment, and response assessments every 8 weeks 
(±1 week) after the previous response assessment scan and every 8 weeks (±1 week) 
following the previous visit thereafter until radiologically-confirmed disease progression (per 
RECIST as determined by the investigator), initiation of a new anticancer therapy, patient 
death, study closure, or withdrawal of consent, whichever comes first. After 1 year on study 
the frequency of follow-up visits will be reduced to every 12 weeks (±1 week). 
7.8.2 Long-term follow-up Assessments  
After radiologically-confirmed progression (per RECIST as determined by the investigator) 
or initiation of a new anticancer therapy, patients will be contacted every 8 weeks (±1 week) 
after EOT (or 8 weeks from previous protocol visit, whichever is later) to obtain information 
on subsequent anticancer therapy and survival status. Long-term follow-up will continue 
until patient death, study closure, withdrawal of consent, or patient is lost to follow-up, 
whichever occurs first. After 1 year on study the frequency of long-term follow-up visits will 
be reduced to every 12 weeks (±1 week). 
7.9 Appropriateness of Measurements  
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
The determination of antitumor activity will be based on confirmed objective response 
assessments as defined by RECIST Version 1.1 (see Appendix D) (Eisenhauer 2009) and 
treatment decisions by the Investigator will be based on these assessments. These criteria are 
considered standard in oncological practice for this type of neoplasm, and the intervals of 
evaluation in this protocol are appropriate for disease management. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to enfortumab vedotin.  
Pharmacokinetic assessments are also common in clinical studies to help characterize dose-
exposure-response relationships. 


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Exploratory biomarker measurements in peripheral blood samples enable correlation with PK 
assessments and are common in clinical studies. Assessments conducted on pretreatment 
tumor tissue are similarly common. Both peripheral blood and tumor biomarker samples will 
be assessed using commonly employed, standard tests. 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE  
8.1 Site Training and Monitoring Procedures  
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of patients at the site, Seagen or its designated clinical and 
medical personnel will review the following items with the investigator and clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, 
registration, and withdrawal processes 
● 
Current Investigator’s Brochure 
● 
Recording and reporting AEs and SAEs 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional review board/independent ethics committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good clinical practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing, and record 
keeping 
● 
Patient coding 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study supplies and record keeping, document retention, and administrative 
requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seagen representative, Astellas 
Pharma Global Development representative, or designated contract research organization will 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability. The CRFs will be reviewed for completeness, 


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adherence to the provided guidelines, and accuracy compared to the source documents. The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study patients, and must cooperate with the monitor to ensure that any problems 
noted in the course of the trial are resolved. The investigator must maintain a comprehensive 
and centralized filing system of all study-related documentation that is suitable for inspection 
by Seagen or its designated monitors or collaborators, and by quality assurance auditors, or 
representatives of regulatory authorities. 
8.2 Data Management Procedures  
Seagen will provide CRF Completion Guidelines for electronic CRF (eCRF) data entry. 
Study specific data management procedures will be maintained in the data management plan. 
Queries resulting from edit checks and/or data verification procedures will be posted 
electronically in the eCRF. 
8.3 Access to Source Data  
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect patient confidentiality are to be employed 
during monitoring. The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for 
review. This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct. Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected. All source data and study 
records must also be available for inspection by representatives of regulatory authorities and 
IRB/IEC. 
8.4 Accuracy and Reliability of Data  
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers. Any discrepancies will be resolved with 
the investigator or designees as appropriate. 


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8.5 Quality Assurance Procedures  
Research and Development Quality or its designee may conduct audits at the clinical site or 
other study-related facilities and organizations. Audit reports will be retained by Research 
and Development Quality of Seagen as part of the written record. 
8.6 Data Handling and Record Keeping  
8.6.1 Data Handling  
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
8.6.2 Investigator Record Retention  
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by Seagen, whichever is longer. The investigator must 
contact Seagen prior to destroying any records associated with the study. If the investigator 
withdraws from the study (due to relocation, retirement, etc.), the records shall be transferred 
to a mutually agreed upon designee, such as another investigator or IRB/IEC. Notice of such 
transfer will be provided in writing prior to the transfer to Seagen. 
9 
DATA ANALYSIS METHODS  
9.1 Determination of Sample Size  
The study is designed to estimate the confirmed ORR in patients receiving enfortumab 
vedotin and to detect an improvement in the ORR compared with a historical 10% response 
rate. The rationale for the historical response rate is provided in Section 3.2. 
Approximately 200 patients will be enrolled in this study to ensure collection of sufficient 
efficacy and safety data, including approximately 100 or more platinum-treated patients as 
defined in the eligibility criteria in Section 4.1 (Cohort 1), and up to approximately 
100 platinum-naïve and cisplatin-ineligible patients also defined in the eligibility criteria in 
Section 4.1 (Cohort 2). Using the estimate of approximately 100 patients in Cohort 1, the 
study will have 98% power to detect a 15% increase in ORR from 10% to 25% and 81% 
power to detect a 10% increase in ORR from 10% to 20%, at one-sided significance level of 
0.025, based on exact methods using EAST®, Version 6.0, by Cytel Inc. 
The confirmed ORR and 95% exact CI in Cohort 2 will be summarized at 4 timepoints: 1) at 
the time of analysis of Cohort 1, 2) when approximately 50 patients in Cohort 2 have had the 


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opportunity to be followed for approximately 8 months from the first dose of enfortumab 
vedotin, 3) when approximately 70 patients in Cohort 2 have had the opportunity to be 
followed for approximately 8 months from the first dose of enfortumab vedotin, and 4) when 
all patients in Cohort 2 have had the opportunity to be followed for approximately 8 months 
from the first dose of enfortumab vedotin. 
For illustration purposes, below is the summary of expected 95% CIs for Cohort 2 at various 
analysis timepoints, assuming a 30% observed ORR: 
Number of Patients 
Expected 95% Confidence Interval 
N=20 
12%–54% 
N=50 
18%–45% 
N=70 
20%–42% 
N=100 
21%–40% 
 
Slit lamp examinations will be conducted on at least the first 60 enrolled patients (from 
Cohorts 1 and/or 2) on Cycle 2 Day 22 (±1 week) and Cycle 6 Day 22 (±1 week). If corneal 
AEs are observed in <15% of the first 60 enrolled patients and if the events are generally low 
grade or asymptomatic, the IDMC may make a recommendation to cease Cycle 2 Day 22 
and/or Cycle 6 Day 22 slit lamp exams for the remaining patients if warranted based on 
review of the cumulative ocular safety data. Based on the results from the Phase 1 study 
(Study ASG-22CE-13-2), as of the data cut-off date of 14 November 2016, there were 
3 patients who reported experiencing corneal adverse events out of 33 patients on 1.25 kg/mg 
of enfortumab vedotin. Assuming an event rate of 9% (3/33), with a sample size of 60, the 
probability of observing >3 events (5%) is 80.0% and the probability of observing <9 events 
(15%) is 91.2%. If the event rate is higher, the probability of observing <9 events is 
decreased. For example, if the event rate is 20%, the probability of observing <9 events is 
decreased to 12.7%. Based on the analysis described above and the review of cumulative 
ocular safety data, the IDMC recommended that the Cycle 2 Day 22 and Cycle 6 Day 22 slit 
lamp exams be discontinued in Jul 2018 and Aug 2019, respectively. 
Sample size calculations were performed using EAST®, Version 6.0, by Cytel Inc. 
9.2 Study Endpoint Definitions  
9.2.1 Objective Response Rate  
The primary endpoint of this study is the confirmed ORR per IRF. The ORR is defined as the 
proportion of patients with confirmed CR or PR according to RECIST Version 1.1 (see 
Appendix D) (Eisenhauer 2009). Patients who do not have at least 2 (initial response and 
confirmation scan) post-baseline response assessments as described in Section 7.2 of the 
protocol will be counted as non-responders. 
In addition, ORR per investigator will be analyzed as a secondary endpoint. 


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9.2.2 Duration of Response  
The DOR is defined as the time from first documentation of objective response (CR or PR 
that is subsequently confirmed) to the first documentation of PD (per RECIST Version 1.1) 
or to death due to any cause, whichever comes first. 
DOR data will be censored as described below: 
● 
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the last disease assessment documenting absence of PD; 
● 
Patients who have started an antitumor treatment other than the study treatment (with 
the exception of palliative radiotherapy as described in Section 5.3.2) prior to 
documentation of PD will be censored at the date of the last disease assessment prior 
to start of new therapy; 
● 
Patients who are removed from the study prior to documentation of PD will be 
censored at the date of the last disease assessment documenting absence of PD. 
DOR will only be calculated for the patients achieving a confirmed CR or PR. 
9.2.3 Disease Control Rate at Week 16  
DCR16 per IRF is defined as the proportion of patients with CR, PR, or SD at Week 16 visit, 
based on IRF assessment. Responses do not need to be confirmed to be scored as responders 
for the purpose of determining DCR16. Patients whose disease response cannot be assessed as 
CR, PR, or SD at Week 16 or later will be scored as non-responders for calculating the DCR. 
An exception is patients who have a CR, PR, or SD subsequent to Week 16, but who miss 
Week 16; these patients will be counted as having disease control at Week 16. 
In addition, DCR16 per investigator will be also summarized. 
9.2.4 Progression-free Survival  
PFS is defined as the time from start of study treatment to first documentation of objective 
tumor progression (PD per RECIST Version 1.1), or to death due to any cause, whichever 
comes first. 
The same censoring rules outlined in Section 9.2.2 for DOR will be applied to PFS. Patients 
lacking an evaluation of tumor response after their first dose will have their event time 
censored at Day 1. 
9.2.5 Overall Survival  
OS is defined as the time from start of study treatment to date of death due to any cause. In 
the absence of death, OS will be censored at the last date the patient is known to be alive. 
9.3 Statistical and Analytical Plans  
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods 


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described in the protocol will require a protocol amendment only if it alters a principal 
feature of the protocol. The SAP will be finalized prior to database lock. Any changes to the 
methods described in the final SAP will be described and justified in the clinical study report. 
9.3.1 General Considerations  
In general, descriptive statistics will be presented that include the number of observations, 
mean, median, standard deviation, minimum and maximum for continuous variables, and the 
number and percentages (of non-missing) per category for categorical variables. 
Unless otherwise specified, CIs will be calculated at 2-sided 95% level. 
The 2-sided 95% exact CI using Clopper-Pearson method (Clopper 1934) will be calculated 
for the response rates where applicable (e.g., ORR). 
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
Unless otherwise specified, summaries and analyses will be provided by cohort 
(i.e., platinum-treated and platinum-naïve and cisplatin-ineligible). Summaries and analyses 
may also be provided overall. 
9.3.1.1 Randomization and Blinding  
This is a single-arm, open-label study. No randomization will be utilized. 
9.3.1.2 Adjustments for Covariates  
No adjustment for covariates is planned in the analyses. 
9.3.1.3 Handling of Dropouts and Missing Data  
With the exception of time-to-event endpoints, no imputation will be conducted for missing 
data unless otherwise specified. 
9.3.1.4 Multicenter Studies  
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
9.3.1.5 Multiple Comparisons and Multiplicity  
No multiple comparisons are planned and no alpha adjustment is needed because only one 
primary endpoint will be tested in this single arm study. 
9.3.1.6 Data Transformations and Derivations  
Time variables based on two dates, e.g., Start Date and End Date, will be calculated as (End 
Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis section. 
Unless otherwise specified, baseline values used in all analyses will be the most recent non-
missing measurement prior to the first dose of study drug. 


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9.3.1.7 Analysis Sets  
The full analysis set will include all patients who are enrolled and receive any amount of 
enfortumab vedotin in the study. A patient is considered enrolled if he/she has met all criteria 
for participation in the study and has Seagen approval as documented in the eCRF. The full 
analysis set will be used as the primary dataset for efficacy analysis. Patient demographics 
and baseline disease characteristics will be summarized based on the full analysis set. 
The safety analysis set will include all patients who receive any amount of enfortumab 
vedotin. The safety analysis set will be used for all safety analyses. 
The efficacy evaluable set will include all patients in the full analysis set who started 
treatment with enfortumab vedotin at least 8 months before the analysis data cutoff. The 
efficacy evaluable set will be used for the additional analyses of efficacy endpoints at the 
time of the interim analyses of Cohort 2 to allow adequate follow up for a stable estimate of 
ORR and DOR. 
The PK analysis set will include all patients who received enfortumab vedotin and from 
whom at least one blood sample was collected and assayed for enfortumab vedotin, MMAE, 
or TAb concentration. Corresponding records of the time of dosing and sample collection 
must also be available for all enfortumab vedotin, MMAE, and TAb concentration data. The 
PK analysis set will be used for PK analyses. 
Additional analysis sets of patients may be defined in the SAP. 
9.3.1.8 Examination of Subgroups  
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Subgroups may include but are not limited to the following: 
● 
Number of Bellmunt risk factors (ECOG performance status >0; hemoglobin level 
<10 g/dL; presence of liver metastases) (Bellmunt 2010) 
● 
Number of prior systemic therapies 
● 
Best response to prior CPI therapy 
● 
Liver metastasis at baseline 
9.3.1.9 Timing of Analyses  
The primary analysis on Cohort 1 (platinum-treated patients) will be conducted when 
enrollment is completed in Cohort 1, and all patients in the cohort have been followed for at 
least 6 months, or have discontinued from study, or had 30 days safety follow-up after PD, 
whichever comes first. Analysis for Cohort 2 will occur at 4 timepoints: 1) at the time of 
analysis of Cohort 1, 2) when approximately 50 patients in Cohort 2 have had the opportunity 
to be followed for approximately 8 months from the first dose of enfortumab vedotin, 3) 
when approximately 70 patients in Cohort 2 have had the opportunity to be followed for 
approximately 8 months from the first dose of enfortumab vedotin, and 4) when all patients 


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in Cohort 2 have had the opportunity to be followed for approximately 8 months from the 
first dose of enfortumab vedotin. All patients may also be analyzed at the time of analysis of 
Cohort 1 and/or Cohort 2. 
Additional cutoff dates may be defined and corresponding database locks may occur to allow 
for more precise estimates of time-to-event endpoints. 
9.3.2 Patient Disposition  
An accounting of study patients by disposition will be tabulated and the number of patients in 
each analysis set will be summarized. Patients who discontinue study treatment and patients 
who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal using the full analysis set. 
9.3.3 Patient Characteristics  
Demographics and other baseline characteristics will be summarized using the full analysis 
set. Details will be provided in the SAP. 
9.3.4 Treatment Administration  
Treatment administration will be summarized for safety analysis set. Summary statistics for 
duration of therapy (weeks) and the number of cycles per patient will be presented, as well as 
the number and percentage of patients who were treated at each cycle and completed each 
cycle. Details will be provided in the SAP. 
9.3.5 Efficacy Analyses   
The primary analysis of efficacy endpoints will be based on the full analysis set. At the time 
of the interim analysis for Cohort 2, the efficacy evaluable set will be used for the additional 
analyses of efficacy endpoints to allow adequate follow up for a stable estimate of ORR and 
DOR. 
9.3.5.1 Primary Efficacy Analyses  
The primary endpoint of this study is the confirmed ORR per IRF. The ORR is defined as the 
proportion of patients with confirmed CR or PR according to RECIST Version 1.1 (see 
Appendix D) (Eisenhauer 2009). Patients who do not have at least 2 (initial response and 
confirmation scan) post-baseline response assessments as described in Section 7.2 of the 
protocol will be counted as non-responders. 
The ORR per IRF and its exact 2-sided 95% CI using the Clopper-Pearson method (Clopper 
1934) will be calculated. 
There are 2 cohorts of CPI-treated patients in the study: Cohort 1) platinum-treated patients, 
and Cohort 2) platinum-naïve and cisplatin-ineligible patients. The primary endpoint will be 
analyzed separately for each cohort and may be analyzed for all patients, combining both 
Cohorts 1 and 2. 


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9.3.5.2 Secondary Efficacy Analyses  
The analyses on secondary endpoints, confirmed ORR per investigator, DCR16 per IRF, and 
DCR16 per investigator assessment will be summarized, and their exact 2-sided 95% CIs 
using the Clopper-Pearson method (Clopper 1934) will be calculated. 
Secondary endpoints, such as DOR per IRF, DOR per investigator, PFS per IRF, PFS per 
investigator, and OS, are time-to-event endpoints, and they will be analyzed using Kaplan-
Meier methodology and Kaplan-Meier plots will be provided. Details on the censoring 
algorithm will be provided in the SAP. 
9.3.6 Pharmacokinetic and ATA Analyses  
Plasma enfortumab vedotin ADC, TAb, and MMAE concentrations will be summarized with 
descriptive statistics at each PK sampling timepoint using the PK analysis set. These data 
may be combined with data from previous studies for population PK and 
PK/pharmacodynamics analyses. The relationship between enfortumab vedotin PK and 
pharmacodynamics endpoints, safety, or efficacy may be explored. 
The incidence of ATA will be summarized by visit and overall using the safety analysis set. 
9.3.7 Quality of Life Analyses  
The PRO based on EQ-5D, and QLQ-C30 will be summarized over time with descriptive 
statistics by visit, using the full analysis set. 
9.3.8 Biomarker Analyses  
Relationships of biomarker parameters (e.g., pre-treatment values, absolute and relative 
changes from pre-treatment) to efficacy, safety, and pharmacokinetic parameters will be 
explored. Relationships and associated data that are determined to be of interest will be 
summarized. Details of these analyses will be described separately. 
9.3.9 Safety Analyses  
The safety analysis set will be used to summarize all safety endpoints. 
9.3.9.1 Extent of Exposure  
Duration of treatment, number of cycles, total dose and dose intensity will be summarized. 
Dose modifications will also be summarized. Details will be provided in the SAP. 
9.3.9.2 Adverse Events  
An overview of AEs will provide a tabulation of the incidence of all AEs, treatment-
emergent AEs, treatment-related AEs, Grade 3 and higher AEs, SAEs, treatment-related 
SAEs, deaths, and AEs leading to study treatment discontinuation. Adverse events will be 
defined as treatment emergent if they are newly occurring or worsened following study 
treatment. 


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AEs will be classified by system organ class and preferred tem using the Medical Dictionary 
for Regulatory Activities (MedDRA) and graded using NCI CTCAE, Version 4.03. 
The incidence of AEs will be summarized by system organ class, preferred term, severity and 
relationship to study drug. In the event of multiple occurrences of the same AE in one 
patient, the AE will be counted once as the occurrence for the maximum grade. AEs leading 
to premature discontinuation of study drug will be summarized and listed in the same 
manner. 
All AEs will be listed. 
9.3.9.3 Deaths and Serious Adverse Events  
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. 
9.3.9.4 Clinical Laboratory Results  
Summary statistics for lab values and for change from baseline will be tabulated as 
appropriate by scheduled visit. Laboratory values will be listed with grade per NCI CTCAE 
v4.03 and flagged when values are outside the normal reference range. 
9.3.9.5 Other Safety Analyses  
ECOG Status  
ECOG status will be summarized for each visit. Shifts from baseline to the best and worst 
postbaseline score may be tabulated. 
ECG  
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
may be summarized for each scheduled and unscheduled ECG, and shifts from baseline may 
be tabulated. 
9.3.10 Interim Analyses  
An IDMC will periodically monitor the trial for safety. The IDMC will review expedited 
SAEs as they are received. Further details will be provided in the IDMC Charter. 
In addition, an ongoing real-time review of SAEs will be conducted by Seagen 
Pharmacovigilance. 
Additionally, available data for Cohort 2 will be summarized at the time of the primary 
analysis of Cohort 1 (e.g., the estimated ORR and its 2-sided 95% exact Clopper-Pearson 
CI), after approximately 50 patients in Cohort 2 have had the opportunity to be followed for 
approximately 8 months from the first dose of enfortumab vedotin, and after approximately 
70 patients in Cohort 2 have had the opportunity to be followed for approximately 8 months 
from the first dose of enfortumab vedotin. All patients may also be analyzed at the time of 
analysis of Cohort 1 and/or Cohort 2. 


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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS  
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 [R1]; FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1 Informed Consent  
The investigator is responsible for ensuring that the risks and benefits of study participation 
are presented to the patient in simple terms using the IRB/IEC approved informed consent 
document and for ensuring patients are re-consented when the informed consent document is 
updated during the study, if required. The investigator will ensure that written informed 
consent is obtained from each patient, or legally acceptable representative, if applicable to 
this study, by obtaining the signature and date on the informed consent document prior to the 
performance of protocol evaluations or procedures. 
If informed consent is obtained from a legally acceptable representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
patient. 
10.2 Ethical Review  
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 


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10.3 Regulatory Considerations  
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information  
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination  
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling patients who have met protocol eligibility criteria. Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention  
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study. If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing patient medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of patient identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 
10.5 Clinical Trial Agreement  
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 


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methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based 
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PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, 
Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, 
Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016). Atezolizumab in patients with 
locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-
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Takai Y, Ikeda W, Ogita H, Rikitake Y (2008a). The immunoglobulin-like cell adhesion molecule nectin and its 
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Takai Y, Miyoshi J, Ikeda W, Ogita H (2008b). Nectins and nectin-like molecules: roles in contact inhibition of 
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Temple R (2006). Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15(4): 241-3. 
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4602-8. 
 


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APPENDIX A: SCHEDULE OF EVENTS 
Screening/ 
Baseline 
Enrollment 
Every 28-day cycle 
EOT 
Follow-
up 
LTFU 
Day 
D –28 
to 1 
D –7 
to 1 
Within 7D 
of 1st dose 
D1 
D3A 
D8 
D15 
D17A 
D22 
Within 30–37d 
of last doseB 
Every 8 
weeks 
Every 8 
weeks 
Visit window 
±2d 
±24h 
+2d
+2d
–24h 
/+48h
±7 d 
±7 d 
Screening/baseline 
assessments  
Inclusion/exclusion, medical history 
X 
Submit confirmation of elligibility prior to treatment 
Informed consent 
X 
Acquire and submit tumor specimenC 
X 
Complete eye examinationD 
X 
Slit lamp eye examinationD 
XO 
Brain scan 
X 
XE 
XE 
XE 
Bone scan 
X 
XE 
XE 
XE 
INR/PT/PTT 
X 
Hepatitis B and C screening 
X 
Urinalysis with microscopic analysis 
X 
HbA1cN 
X 
Pregnancy test (females of childbearing 
potential)F 
X 
X 
X 
Safety assessments 
Physical exam (including weight)P 
X 
XG 
X 
XH 
Height 
X 
Vital signs 
X 
XG 
X 
X 
X 
CBC with differentialP 
X 
XG 
X 
X 
X 
Chemistry panelP 
X 
XG 
X 
X 
X 
CrCl 
X 
ECOG performance statusP 
X 
XG 
X 
XH 
ECG 
X 
X 
Concomitant medications 
Related to study procedures 
from time of informed consent 
Collect from Day 1 predose through 30 days post last study 
treatment 
Adverse event collection 
PRO/QoL 
QLQ-C30 and EQ-5D 
X 
X 
Treatment 
Study drug administrationI 
X 
X 
X 
PK/ATA/biomarker 
Blood sample collection 
See PK, ATA and Biomarker Table (Table 3) for sample collection details 
Response assessment 
CT scan with contrast of chest, abdomen, pelvis 
and any other region of known or suspected 
diseaseQ 
X 
XJ,K 
XJ,L 
XH,J 
Survival status 
XM 
Footnotes


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A 
Cycles 1 and 2. See PK, ATA and Biomarker Table (Table 3) for sample collection details. 
B 
EOT evaluations must be obtained before the initiation of subsequent anticancer therapy, with the exception of slit lamp examinations. If EOT evaluations are completed before 30 days following the 
last study treatment, conduct a phone screen 30–37 days following the patient’s last study treatment to ensure that no changes in AE profile have occurred. 
C 
Pretreatment tumor tissue (from primary or metastatic site) for biomarker studies must be available for submission to the sponsor prior to study treatment. A minimum of 10 freshly sectioned, unstained 
charged slides are required. Either archival tissue or pre-treatment fresh tumor tissue (obtained from a fresh biopsy) is acceptable. 
D 
Repeated as clinically indicated throughout the study. 
E 
Repeated at disease assessment timepoints if disease present at baseline, or as clinically indicated throughout the study. 
F 
Either serum or urine pregnancy test. Not required for Cycle 1 if baseline assessment performed within 7 days. Repeat every month (±1 week) for 6 months after EOT. 
G 
Not required for Cycle 1 if baseline assessments performed within 1 day. 
H 
Patients who discontinue study treatment for reasons other than objective disease progression by RECIST Version 1.1 will continue to have physical exams (no weight collection is required), ECOG, 
and response assessments 8 weeks (±1 week) after the previous response assessment scan and every 8 weeks (±1 week) following the previous visit thereafter. After 1 year on study the frequency of 
follow-up visits and response assessments will be reduced to every 12 weeks (±1 week). The tumor assessments will continue until the patient has radiologically-confirmed disease progression per 
RECIST as determined by the investigator, initiates a new anticancer therapy, patient death, study closure, or withdrawal of consent, whichever comes first. 
I 
At least 1 week must elapse between doses of enfortumab vedotin. 
J 
Responses will be confirmed with repeat scans at 4 weeks after first documentation of response (+1 week). Following confirmation scans, response assessments should continue with the previous scan 
schedule (i.e., the schedule should not be adjusted). Tumor imaging should also be performed whenever disease progression is suspected. 
K 
Response assessment will be performed every 8 weeks (±1 week). After 1 year on study, response assessments will be reduced to every 12 weeks (±1 week). The schedule of response assessments 
should not be adjusted for dose delays/interupptions or other reasons for changes in the timing of a patient’s study activities; timepoints for response assessments should be calculated from Cycle 1 
Day 1 during treatment. 
L 
Not required if conducted <4 weeks prior to EOT. 
M 
Contact patient for survival status and collection of subsequent anticancer treatment information every 8 weeks (±1 week) after EOT (or 8 weeks from previous protocol visit, whichever is later) until 
death, study closure, or withdrawal of consent, or patient is lost to follow-up, whichever occurs first. After 1 year on study the frequency of follow-up contacts will be reduced to every 12 weeks 
(±1 week).  
N 
If HbA1c is elevated (≥6.5%), refer patient to appropriate provider during Cycle 1 for glucose management. 
O 
EOT slit lamp examination required for all patients who experience corneal adverse events during the study and must be performed ≥4 weeks from last dose. 
P 
May be collected or conducted up to 1 day prior to dosing. Local laboratory results must be reviewed prior to study drug administration in order to determine whether to proceed with dosing or whether 
dose modification is required. 
Q 
If contrast is contraindicated, see Appendix F. 


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APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky 
Lansky 
ECOG 
Percent 
Description 
Percent 
Description 
Score 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
0 
Normal activity. Fully 
active, able to carry on all 
pre-disease performance 
without restriction. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
90 
Minor restrictions in 
physically strenuous 
activity. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more 
quickly. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to 
carry on normal activity or 
to do active work. 
70 
Both greater restriction 
of, and less time spent in, 
play activity. 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
2 
In bed <50% of the time. 
Ambulatory and capable of 
all self-care, but unable to 
carry out any work 
activities. Up and about 
more than 50% of waking 
hours. 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies 
around much of the day; 
no active play; able to 
participate in all quiet 
active play and activities. 
40 
Disabled, requires special 
care and assistance. 
40 
Mostly in bed, 
participates in quiet 
activities. 
3 
In bed >50% of the time. 
Capable of only limited self-
care, confined to bed or 
chair more than 50% of 
waking hours. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed, needs assistance 
even for quiet play. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
20 
Often sleeping, play 
entirely limited to very 
passive activities. 
4 
100% bedridden. 
Completely disabled. 
Cannot carry on any self-
care. Totally confined to bed 
or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play, does not get out 
of bed. 
0 
Dead. 
0 
Dead. 
5 
Dead. 


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APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION 
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Patients  
Class I: 
patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II: 
patients with slight, mild limitation of activity; they are comfortable with rest or 
with mild exertion. 
Class 
III: 
patients with marked limitation of activity; they are comfortable only at rest. 
Class 
IV: 
patients who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
On-line source:  
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp 


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


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APPENDIX E: LIVER SAFETY MONITORING AND ASSESSMENT  
The following recommendations are from the Food and Drug Administration (FDA) Guidance 
for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued July 
2009. 
Any patient with an increase of serum aminotransferases to >3 × upper limit of normal (ULN) or 
bilirubin >2 × ULN should undergo detailed testing for liver enzymes (including at least alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and 
total bilirubin [TBL]). To confirm the abnormality, testing should be repeated within 72 hours of 
notification of the test results. 
Definition of Liver Abnormalities  
Confirmed liver abnormalities will be characterized as Moderate and Severe: 
Moderate: 
●
ALT or AST >3 × ULN OR Total Bilirubin >2 × ULN
Severe: 
●
ALT or AST >3 × ULN AND Total Bilirubin >2 × ULN (*See Hy’s Law Definition)
●
ALT or AST >8 × ULN
●
ALT or AST >5 × ULN for more than 2 weeks
●
ALT or AST >3 × ULN and International Normalized Ratio (INR) >1.5 (if INR testing is
applicable/evaluated)
●
ALT or AST >3 × ULN with the appearance of symptoms suggestive of liver injury
(e.g., right upper quadrant pain or tenderness) and/or eosinophilia (>5%)
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a significant
obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality (or transplant). The
2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause hepatocellular-type injury, generally
shown by an increase in transaminase elevations higher 3 × ULN (“2 × ULN elevations are too common in
treated and untreated patients to be discriminating”). 2) Cases of increased bilirubin (at least 2 × ULN) with
concurrent transaminase elevations at least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin
obstruction (elevated ALP) or Gilbert’s syndrome (Temple 2006).
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 


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examination and laboratory tests. Patients with confirmed abnormal liver function testing should 
be followed as described below. 
Confirmed moderately abnormal liver function tests (LFTs) should be repeated 2 to 3 times 
weekly then weekly or less if abnormalities stabilize or the study drug has been discontinued and 
the patient 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 a SAE. The sponsor 
should be contacted and informed of all patients for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory finding, it is recommended that the investigator: 
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Illnesses
and conditions such as hypotensive events, and decompensated cardiac disease that may
lead to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is
seen in obese hyperlipoproteinemic and/or diabetic patients, and may be associated with
fluctuating aminotransferase levels.
●
Obtain a history of concomitant drug use (including nonprescription medication,
complementary and alternative medications), alcohol use, recreational drug use and
special diets
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the patient’s history, other testing may be appropriate including:
○
Acute viral hepatitis (A, B, C, D, E or other infectious agents),
○
Ultrasound or other imaging to assess biliary tract disease,
○
Other laboratory tests including INR, direct bilirubin.
●
Consider gastroenterology or hepatology consultations.
Conduct additional testing as determined by the investigator to further evaluate possible etiology. 
See Section 5.2.3.1 for treatment discontinuation recommendations related to hepatic safety. 


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


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APPENDIX G: INVESTIGATOR SIGNATURE PAGE 
Investigator Statement and Signature 
I have read the attached protocol entitled “A single-arm, open-label, multicenter study of 
enfortumab vedotin (ASG-22CE) for treatment of patients with locally advanced or metastatic 
urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy” 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed 
above in my role as principal investigator for the study. 
Investigator Signature 
Date 
Investigator Name, Printed 


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APPENDIX H: DOCUMENT HISTORY 
Version 
Date 
Original 
24-May-2017
Amendment 1 
14-Nov-2017
Amendment 2 
13-Feb-2018
Amendment 3 
13-Apr-2018
Amendment 4 
16-Apr-2018
Amendment 5 
14-Nov-2018
Amendment 6 
05-Dec-2019
Amendment 7 
10-Feb-2021
Amendment 8 
01-Apr-2022
Amendment 9 
15-Feb-2023


 
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Summary of Changes in Amendment 1  
 
Section(s) 
Change 
Rationale 
Title page 
Added study name, EudraCT Number, and updated study 
medical monitor 
Administrative changes 
Synopsis and 4.2 
Added exclusion criterion: 
 
15. Patients with uncontrolled diabetes. Uncontrolled 
diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or 
HbA1c 7–<8% with associated diabetes symptoms 
(polyuria or polydipsia) that are not otherwise explained. 
Adds an exclusion criterion for patients with uncontrolled 
diabetes 
5.2.2 
Revised text as follows: 
 
An exception to weight-based dosing is made for 
patients weighing greater than 120 100 kg; doses will 
be based on 120 100 kg for these individuals. The 
maximum dose permitted on this study is 150 125 mg. 
Revises cap on weight-based dosing from 120 kg to 100 kg 
 
5.2.3 
Added text as follows to Table 2, Grade 3 column: 
 
For Grade 3 hyperglycemia/elevated blood glucose 
withhold enfortumab vedotin treatment. Resume 
treatment once hyperglycemia/elevated blood glucose has 
improved to ≤ Grade 2 and patient is clinically and 
metabolically stable. 
 
Added text to refer to Management of Hyperglycemia 
section:  
 
See Section 5.4.2 for recommended management of 
hyperglycemia. 
Provides dose modification guidance for hyperglycemia.  
5.4.2 
Added Management of Hyperglycemia section as 
follows: 
 
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 
Adds new section on management of hyperglycemia 


 
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Section(s) 
Change 
Rationale 
may require additional monitoring. If elevated blood 
glucose levels are observed, patients should be treated 
according to local standard of care and referral to 
endocrinology may be considered. 
 
Patients, 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. 
 
Patients who enter the study with an elevated HbA1c 
(≥6.5%) at baseline should be referred to an appropriate 
provider during Cycle 1 for glucose management. Blood 
glucose should be checked prior to each dosing and dose 
should be withheld for blood glucose >250 ml/dL (Grade 
3 or higher). Dosing may continue once the patient’s 
blood glucose has improved to ≤ Grade 2 and patient is 
clinically and metabolically stable.  
 
6.2, 7.1, 7.7.2, and 
Appendix A 
Added assessment at screening: 
 
HbA1c: If HbA1c is elevated (≥6.5%), refer patient to 
appropriate provider during Cycle 1 for glucose 
management. 
Adds HbA1c at screening, with guidelines for glucose 
management if elevated. 
 


 
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Summary of Changes in Amendment 2  
 
Section(s) 
Change 
Rationale 
3.1, 6.3.6, 7.7.7, 9.1, and 
Appendix A 
Added Cycle 6 (±1 week) slit lamp examinations for at 
least the first 60 enrolled patients.  
 
Clarified that end of treatment (EOT) slit lamp exams 
will be performed for all patients who experience a 
corneal adverse event on study.  
 
Added per Food and Drug Administration (FDA) request 
 
 
Clarification 
5.4.2 
Revised the text as follows: 
 
 Blood glucose >250 mLmg/dL 
Error correction 


 
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Summary of Changes in Amendment 3  
 
Section(s) 
Change 
Rationale 
1.6 
Updated section with 2-Oct-2017 data cut-off date for 
ASG-22CE-13-2.  
 
Added text to explicitly state benefit-risk statement as 
follows:  
 
Clinical data to date support a favorable benefit-risk ratio 
for enfortumab vedotin in patients with locally advanced 
or metastatic urothelial carcinoma who previously 
received CPI therapy. To assure an ongoing favorable 
benefit-risk assessment for subjects enrolled into the 
study, an Independent Data Monitoring Committee 
(IDMC) will be utilized to monitor safety data and may 
request interim efficacy data, if needed. 
Updates section to match current Investigator’s Brochure 
edition data cut. Adds benefit-risk statement per regulatory 
agency request under the Voluntary Harmonisation Procedure 
(VHP).  
4.2 
Added text to exclusion criteria 3 as follows: 
 
Patients with immunotherapy related myocarditis, colitis, 
uveitis, or pneumonitis are excluded. 
Excludes patients with immunotherapy related myocarditits per 
regulatory agency request under VHP. 
Synopsis, 3.1, 4.3.1 
Added pregnancy to list of reasons for treatment 
discontinuation. 
Per regulatory agency request under VHP 
5.2.2 
Added text regarding drug administration setting as 
follows: 
 
The patient should be observed during administration of 
enfortumab vedotin and for at least 60 minutes following 
the infusion during the first 3 cycles. All supportive 
measures consistent with optimal subject care should be 
given throughout the study according to institutional 
standards. 
Adds administration monitoring per regulatory agency request 
under VHP. 
6.5 and Appendix A 
Added a pregnancy test monthly (±1 week) for 6 months 
after end of treatment (EOT) for patients of childbearing 
potential  
Per regulatory agency request under VHP. 
 


 
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Summary of Changes in Amendment 4  
 
Section(s) 
Change 
Rationale 
1.2 
Updated the second-line therapy options for metastatic 
urothelial cancer. 
To provide current regulatory approvals and data for the 
various treatment options for urothelial cancer. 
 
Synopsis and 2.1 
Revised primary objective as follows: 
• 
To determine the antitumor activity of single-
agent enfortumab vedotin as measured by 
confirmed objective response rate (ORR) in 
patients with locally advanced or metastatic 
urothelial cancer who tohave previously 
received systemic therapy with a CPI and either 
previously received platinum-containing 
chemotherapy or are platinum-naïve and 
cisplatin-ineligible 
 
To align with revisions to the inclusion criteria that further 
differentiate patients who received prior platinum-containing 
chemotherapy from those who are platinum-naïve and 
cisplatin-ineligible. 
Synopsis and 3.1 
Revised summary of the study design and the study 
schema to reflect changes in other sections.  
To align with revisions to the inclusion criteria, efficacy 
assessments (methods and timing), and cohorts from which the 
corneal events will be evaluated. 
 
3.2 
Added efficacy data from a recent study of patients 
treated with docetaxel after platinum and CPI therapy. 
 
To provide additional support for rationale for the current 
study design. 
3.2.2 
Updated section with 2-Oct-2017 data cut-off date for 
ASG-22CE-13-2. 
 
Updates section to match current IB edition data cut. 
Synopsis and 4.1 
Revised inclusion criterion 1 as follows: 
1. Patients must have histologically or cytologically 
documented locally advanced or metastatic urothelial 
(previously known as transitional cell) carcinoma of the 
urothelium (i.e., cancer of the bladder, renal pelvis, 
ureter, or urethra).  
 
To align with current disease terminology. 
Synopsis and 4.1 
Revised inclusion criterion 2 as follows: 
2. Patient must have received prior treatment with a CPI 
in the locally advanced or metastatic urothelial cancer 
setting. Patients who received CPI therapy in the 
neoadjuvant/adjuvant setting and had recurrent or 
To clarify the eligibility requirements for prior CPI therapy. 


 
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Section(s) 
Change 
Rationale 
progressive disease either during therapy or within 3 
months of therapy completion are eligible. A CPI is 
defined as a PD-1 inhibitor or PD-L1 inhibitor (including, 
but not limited to: atezolizumab, pembrolizumab, 
durvalumab, avelumab, and nivolumab). 
 
Synopsis and 4.1 
Revised inclusion criterion 3 as follows: 
3. Patients must either have be one of the following: 
 
a.Platinum-treated (Cohort 1): Patients who received 
prior treatment with platinum-containing chemotherapy 
or be defined as those who received platinum in the 
adjuvant/neoadjuvant setting and had recurrent or 
progressive disease within 12 months of completion OR 
received treatment with platinum in the locally advanced 
(defined as unresectable with curative intent) or 
metastatic setting; 
 
OR 
  
b. Platinum-naïve and cisplatin ineligible (Cohort 2): 
Patients who have not received prior treatment with 
platinum-containing or other chemotherapy in the locally 
advanced or metastatic setting and are ineligible for 
treatment with cisplatin at time of enrollment due to one 
of the following: impaired renal function (defined as 
creatinine clearance [CrCl] ≥30 and <60 mL/min), or a 
hearing loss of 25 decibels (dB) at two contiguous 
frequencies. If Patients who received platinum was 
administered in the adjuvant/neoadjuvant setting patient 
must have progressed and did not progress within 12 
months of completion will be considered platinum-naïve. 
 
To further differentiate patients who received prior platinum-
containing chemotherapy from those who are platinum-naïve 
and cisplatin-ineligible. 
4.1 and 7.7.2 
Revised inclusion criterion 9 by adding that CrCl could 
be measured by 24-hour urine collection. 
 
To allow flexibility in the method for measuring CrCl. 
Synopsis and 4.2 
Revised exclusion criterion 4 as follows: 
To ensure no crossover of patients between enfortumab vedotin 
studies. 


 
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Section(s) 
Change 
Rationale 
4. Prior treatment with enrollment in an enfortumab 
vedotin study or prior treatment with other MMAE-based 
ADCs. 
4.2 
Revised exclusion criterion 13 as follows: 
13.  Patients with active keratitis or corneal ulcerations. 
Patients with superficial punctate keratitis are allowed if 
the disorder is being adequately treated in the opinion of 
the investigator. 
 
To allow patients on study with superficial punctate keratitis 
whose disorder is being adequately treated in the opinion of the 
investigator. 
Synopsis and 4.2 
Added exclusion criterion 16 as follows: 
16.  Uncontrolled tumor-related bone pain or impending 
spinal cord compression. Patients requiring pain 
medication must be on a stable regimen at the time of 
enrollment (a minimum of 2 weeks). 
 
To exclude patients with uncontrolled tumor-related bone pain 
or impending spinal cord compression and to ensure that those 
who have pain being controlled pain medication have been on 
a stable regimen for a minimum of 2 weeks at the time of 
enrollment. 
Synopsis and 4.3.1 
Added pregnancy to list of reasons for discontinuation of 
study treatment 
Updates to align with other enfortumab vedotin studies, based 
on regulatory feedback and for patient safety 
5.2.2 
Added the following language to the dose and 
administration instructions: 
The injection site should be monitored closely for 
redness, swelling, pain, and infection during and at any 
time after administration. Patients should be advised to 
report redness or discomfort promptly at the time of 
administration or after infusion. Institutional guidelines 
will be followed for the administration of chemotherapy 
agents and precautions taken to prevent extravasation per 
institutional standards and as described in 
“Chemotherapy and Biotherapy Guidelines and 
Recommendations for Practice” (Polovich 2014) and 
“Management of Chemotherapy Extravasation:  ESMO-
EONS Clinical Practice Guidelines” (Perez Fidalgo 
2012). 
 
To ensure that injection sites are monitored for potential 
adverse reactions and provide guidelines for managing 
extravasation if it occurs. 
5.2.3 
Revised dose modifications by adding dose re-escalation 
parameters for patients who are dose reduced, adding that 
enfortumab vedotin should not be administered to 
patients with CrCl < 30 mL/min (if known), and adding 
parameters for dose delays and eliminations depending 
To ensure patient safety. 


 
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Section(s) 
Change 
Rationale 
on the timing of toxicities relative to dosing days. 
Clarified that dose reduction or delay for other 
enfortumab vedotin-associated toxicity does not need 
medical monitor involvement, but can be done at the 
discretion of the site investigator. Also clarified that dose 
delays for any patient may be extended beyond 8 weeks 
without the approval of the medical monitor if the 
toxicity does not require permanent discontinuation. 
Added an exception to allow patients to receive palliative 
radiotherapy during a dose delay.  
 
5.2.3, Table 1 
Revised recommended dose modifications for 
enfortumab vedotin-associated hematologic toxicity to 
allow discontinuations at the discretion of the investigator 
for Grade 4 hematologic toxicity rather than requiring 
discussion with the sponsor. Also clarified that 
discontinuation is strongly recommended for Grade 4 
anemia. 
 
To ensure patient safety. 
5.2.3, Table 2 
Revised recommended dose modifications for 
enfortumab vedotin-associated nonhematologic toxicity 
to ensure that treatment is discontinued for any Grade 4 
nonhematologic adverse event except for Grade 4 
vomiting and/or diarrhea that improves to ≤ Grade 2 
within 72 hours with supportive management. Clarified 
that for Grade 3 neuropathy or corneal AEs, treatment 
should be discontinued regardless of investigator 
discetion or sponsor approval. Added that if ocular 
symptoms and/or changes in vision are identified (Grades 
1 – 3), the patient should be evaluated by a qualified 
optometrist or ophthalmologist. Also clarified the 
following: Grade 3/4 electrolyte imbalances/laboratory 
abnormalities, except hyperglycemia, that are not 
associated with clinical sequelae and are corrected with 
supplementation/ appropriate management within 72 
hours of their onset do not require discontinuation (e.g., 
Grade 4 hyponatremia). Grade 3 rash that is not limiting 
self-care activities of daily living or associated with 
infection requiring systemic antibiotics does not require 
To ensure patient safety. 


 
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Section(s) 
Change 
Rationale 
treatment interruption, provided symptoms are not severe 
and can be managed with supportive treatment. In 
addition, patients with Grade 4 nausea and/or diarrhea 
resolved within 72 hours with supportive management do 
not require discontinuation. 
 
Synopsis and 5.2.3, 6.3.6, 
6.4, 6.6, and 7.2 
Clarified throughout the protocol that response 
assessments will not be adjusted for dose delays or other 
changes in timing of study activities and will all be timed 
from Cycle 1 Day 1 during treatment. 
 
To ensure that the timing of response assessments is consistent 
across patients and applicable to the course of the disease 
under study. 
5.3.2, 5.3.3, and 9.2.2 
Added allowed concomitant therapy with palliative 
radiotherapy for a non-target bone lesion. 
 
To provide an option for additional disease management that 
will not interfere with measurement of the investigational 
agent’s activity. 
 
5.3.3 
Clarified that patients who receive prohibited 
concomitant therapy must be discontinued from the 
study. 
 
To ensure that patients who receive prohibited concomitant 
therapy do not continue on study. 
5.4.2 
Added additional instructions for the management of 
hyperglycemia as follows: 
Blood glucose >500 mg/dL (Grade 4) considered related 
to enfortumab vedotin requires treatment discontinuation. 
If a patient experiences new onset diabetes mellitus, 
evaluate patients with a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide to assess for 
new onset type 1 diabetes in the setting of prior CPI. 
 
To ensure patient safety. 
5.4.3 
Added management of rash as follows: 
In the phase 1 study (Study ASG-22CE-13-2), rash and 
similar dermatologic AEs were common among patients 
treated with enfortumab vedotin, and were seen more 
frequently at the highest dose. Although the exact 
etiology of dermatologic toxicities associated with 
enfortumab vedotin is unclear at this time, due to the 
expression of Nectin-4 in the skin, rash maybe an on-
target toxicity. The most common dermatological AEs 
reported in ASG 22CE-13-2 were drug eruption, rash, 
skin exfoliation, skin pigmentation disorder, and rash 
To ensure patient safety. 


 
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Section(s) 
Change 
Rationale 
maculo-papular. Most occurred during Cycle 1, and some 
were associated with pruritus. Almost all were mild, with 
the exception of two events of rash reported as Grade 3 in 
the 1 mg/kg dose group. None required discontinuation of 
study drug and one event of Grade 1 papular rash at 1.25 
mg/kg required a dose reduction. Mild rash related to 
enfortumab vedotin should be treated using local 
supportive care as needed. Topical corticosteroids have 
been used along with antihistamines for pruritus as 
needed. Grade 3 rash that is not limiting self-care 
activities of daily living or associated with infection 
requiring systemic antibiotics does not require treatment 
interruption, provided symptoms are not severe and can 
be managed with supportive treatment. 
 
Synopsis, 6.2, 6.3.6, 6.4, 
6.6, 7.1, and 7.2, and 
Appendix A 
Clarified that brain scans are to be performed using an 
MRI with gadolinium unless contraindicated and that CT 
scans with contrast are to be done for other parts of the 
body unless contrast is contraindicated. For patients for 
whom contrast is contraindicated, additional guidelines 
for scanning have been provided in Appendix F. Also 
clarified that brain scans will be performed if metastases 
were identified at baseline or if metastasis is suspected.  
 
To ensure consistent methodologies used in performing disease 
assessments and to provide alternatives for patients for whom 
contrast is contraindicated. 
6.2 
Clarified that serology for antihepatitis C antibody is to 
be done during screening and that if positive, follow up 
with PCR testing. 
 
Clarification. 
6.3.1, 6.3.3, and 6.3.4, and 
Appendix A 
Clarified that on Days 1, 8, and 15 of each treatment 
period CBC with differential and the serum chemistry 
panel may be collected the day prior to dosing. 
 
Clarification. 
6.6 and 6.7 
Moved duration of the study from Section 6.6 Long-term 
Follow-up to Section 6.7 End of Study/End of Follow-up 
 
To place duration of the study in the appropriate section of the 
protocol 
Synopsis and 7.2 
Replaced ‘protocol-specified timepoints’ with the actual 
timing of the response assessments:  Measures of 
anticancer activity will be assessed by CT scans with 
contrast approximately every 8 weeks (±1 week). After 1 
To ensure clarity of the timing of the response assessments and 
to align with other protocol sections 


 
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Section(s) 
Change 
Rationale 
year on study, response assessments will be reduced to 
every 12 weeks (±1 week). 
 
7.3 
Added example of possible analysis on archived samples: 
other enfortumab vedotin related species, such as 
circulating metabolites of MMAE. 
Clarification 
Synopsis and 7.4 
Changed enzyme-linked immunosorbent assay (ELISA) 
to immunoassays. 
 
Because other immunoassays may be used rather than just 
ELISA. 
Synopsis and 7.4.1 
Added circulating tumor DNA (ctDNA) to the biomarker 
assessments. 
 
To allow testing of ctDNA. 
7.4.2 
Removed examples of messenger ribonucleic acid 
(mRNA) expression (e.g., Nectin-4) and examples of 
markers of the tumor immune microenvironment (e.g., 
PD-L1, CD4, CD8). Also added tumor mutational burden 
to the biomarker assessments. 
 
Because other mRNA may be tested rather than only Nectin-4 
and because other markers of the tumor immune 
microenvironment may be tested rather than only PD-L1, CD4, 
and CD8. Added tumor mutational burden to allow testing of 
that biomarker. 
7.7.2 
Added the following local laboratory assessment: 
serology for hepatitis B surface antigen and antihepatitis 
B core antibody 
To allow testing for hepatitis B. 
7.7.7 
Added that eye examinations may be performed by a 
qualified optometrist and clarified that uncorrected, 
corrected and best correct visual acuity are to be 
examined. 
Clarification. 
7.7.7 and 9.1, and 
Appendix A 
Added the cohorts from which the corneal events will be 
evaluated. 
Clarification. 
Synopsis and 9.1, 9.3.1.9, 
and 9.3.10 
Increased enrollment from 120 to 200 patients and 
defined Cohort 1 as patients who received prior platinum-
containing chemotherapy (100 or more patients), and 
Cohort 2 as patients who are platinum-naïve and 
cisplatin-ineligible (up to approximately 100 patients). 
Based on the increased sample size and addition of 
separate cohorts of patients, statistical analysis details 
were updated as well as the timepoints at which analyses 
will be performed. 
 
To ensure collection of sufficient efficacy and safety data and 
to ensure that a sufficient number of patients are analyzed. 


 
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Section(s) 
Change 
Rationale 
Synopsis and 9.3.1 and 
9.3.5.1 
Based on the addition of separate cohorts of patients, 
summaries and analyses will be provided by cohort (i.e., 
platinum-treated and platinum-naïve and cisplatin-
ineligible). Summaries and analyses may also be 
provided overall. 
 
To clarify that all analyses will now be performed by cohort 
and may be performed overall. 
9.3.1.7 
Clarified that the intent-to-treat (ITT) analysis set will 
include all patients who are enrolled and receive any 
amount of enfortumab vedotin in the study. 
 
Clarification. 
9.3.1.8 
Added from the statistical analysis plan (SAP) to the 
protocol the important subgroup of metastatic sites at 
baseline: lymph node only, liver. Also updated subgroups 
based on revisions to eligibility criteria. 
 
Also added best response achieved to prior CPI therapy 
for urothelial cancer (e.g., patients with PD), which will 
also be added to the SAP 
  
To add one of the previously defined subgroups from the SAP 
to the protocol and to align subgroups with the other revisions 
made in this amendment for eligibility. To also add the new 
subgroup analysis for response to prior CPI therapy to further 
characterize the patient population. 
Appendix A 
Revised based on revisions made in this amendment 
To align with changes made for this amendment 
Appendix D 
Added to the definition of measurable lesions that a 
lymph node that must be ≥15 mm in short axis when 
assessed by CT scan to be considered measurable. 
 
To align with the published RECIST Version 1.1. 
Appendix F 
Added Scanning and Contrast Guidelines. 
To provide protocol-specified options for scanning for all 
patients and options for those for whom contrast is 
contraindicated. 
 
 


 
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Summary of Changes in Amendment 5  
Section(s) 
Change 
Rationale 
Title page 
Replaced
with 
as Medical 
Monitor 
Administrative change 
Synopsis, 4.1 
Revised Study Population to allow ECOG performance 
status 2 patients into the study in Cohort 2.  
 
Revised Inclusion Criterion #8 as follows: 
 
An ECOG Performance Status score of ≤0 or 1 for 
Cohort 1, or ≤2 for Cohort 2. 
Revises population of Cohort 2 to allow ECOG performance 
status 2 patients 
Synopsis, 4.1 
Revised Study Population to require an anticipated life 
expectancy of ≥3 months.  
 
Add new Inclusion Criterion #16: 
 
Patients must have an anticipated life expectancy of ≥3 
months as assessed by the investigator. 
Revises inclusion criteria to require that all patients must have 
a life expectancy of ≥3 months as assessed by the investigator 
Synopsis, 7.3, 9.3.6 
Revised text on PK assessments to add measurement of 
total antibody (TAb) 
Error correction 
Synopsis, 9.1, 9.3.1.9, 
9.3.10 
Revised Statistical Methods section as follows: 
 
Analysis for Cohort 2 will occur at 3 timepoints: 1) at the 
time of analysis of Cohort 1, 2) when approximately 50 
patients in Cohort 2 have been had the opportunity to be 
followed for at least 6 months, and 3) when all patients in 
Cohort 2 have been had the opportunity to be followed 
for at least 6 months, or have discontinued from study, or 
had 30 days safety follow-up after PD.  
 
Revised Statistical Methods section as follows: 
 
The confirmed ORR and 95% exact CI in Cohort 2 will 
be summarized at 3 timepoints: 1) at the time of analysis 
of Cohort 1, 2) when approximately 50 patients in Cohort 
2 have been had the opportunity to be followed for at 
least 6 months, and 3) when all patients treated in Cohort 
2 have been had the opportunity to be followed for at 
Clarifies timing of and description for Cohort 2 analyses 
PPD
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Section(s) 
Change 
Rationale 
least 6 months, or have discontinued from study, or had 
30 days safety follow-up after PD. 
2.4 
Corrected definitions for ORR and DOR as follows: 
 
ORR (confirmed CR andor PR per Response Evaluation 
Criteria in Solid Tumors [RECIST] Version 1.1) 
 
DOR (confirmed CR andor PR) 
Clarification that either a confirmed CR or confirmed PR 
would qualify toward the analysis of ORR and DOR 
2.4.2 
Added total antibody to secondary endpoint regarding PK 
Error correction 
4.1 
Revised definition of cisplatin-ineligible in Inclusion 
Criterion #3b as follows: 
 
…ineligible for treatment with cisplatin at time of 
enrollment due to one of the following: ECOG 
performance status score of 2; impaired renal function 
(defined as creatinine clearance [CrCl] ≥30 and <60 
mL/min), or a ≥ Grade 2 hearing loss of 25 decibels (dB) 
at two contiguous frequencies. 
Revises cisplatin-ineligibility definition to include ECOG 
peformance status 2 patients 
 
Revises cisplatin-ineligibility definition regarding hearing loss 
4.2 
Revised Exclusion Criterion #3 as follows: 
 
Patients with ≤ Grade 2 hypothyroidism or 
panhypopituitarism related to treatment with PD-1 and 
PD-L1 inhibitors may be enrolled. Patients on hormone 
replacement therapy may be enrolled if on a stable dose. 
Patients with ≥ Grade 3 immunotherapy-related 
hypothyroidism or panhypopituitarism are excluded. 
Clarifies the conditions under which patients with 
immunotherapy related hypothyroidism and 
panhypopituitarism may be enrolled on or excluded from the 
study  
5.2.3 
Deleted the following text from the Table 2 footnote: 
 
In addition, patients with Grade 4 nausea and/or diarrhea 
resolved within 72 hours with supportive management do 
not require discontinuation. 
Removes potentially redundant and incorrect footnote 
5.3.2 
Revised P-pg to P-glycoprotein (P-gp) 
Error correction 
5.4.2 
Revised the text as follows: 
 
Blood glucose should be checked prior to each dosing 
and dose should be withheld for blood glucose 
>250 mg/dL (Grade 3 or higher), regardless of 
relatedness to enfortumab vedotin. Dosing may continue 
once the patient’s blood glucose has improved to ≤250 
Clarifies hyperglycemia conditions under which dosing should 
be held, and under which treatment should be discontinued 


 
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Section(s) 
Change 
Rationale 
mg/dL (≤ Grade 2) and the patient is clinically and 
metabolically stable. Patients with blood glucose 
>500 mg/dL (Grade 4) considered unrelated to 
enfortumab vedotin may continue dosing once the 
patient’s blood glucose has improved to ≤250 mg/dL 
(≤ Grade 2) and the patient is clinically and metabolically 
stable. Blood glucose >500 mg/dL (Grade 4) considered 
related to enfortumab vedotin requires treatment 
discontinuation. 
6.3.1, Appendix A 
Revised Day 1 procedures as follows: 
 
Physical exam (including weight; may be conducted the 
day prior to dosing) 
 
ECOG performance status (may be conducted the day 
prior to dosing) 
Allows additional flexibility for conducting the physical exam 
and ECOG performance status the day before Day 1 dosing.  
7.7.1.3 
Revised the definition of Adverse Events of Clinical 
Interest as follows: 
 
Certain non-serious AEs of clinical interest may be 
followed (including collection of relevant concomitant 
medications) until resolution, return to baseline, orstudy 
closure, or the events become chronic to the extent that 
they are adequately characterized. 
Allows for the collection of concomitant medications for 
Adverse Events of Clinical Interest. Limits the requirement to 
follow these events if the AE stabilizes. 
9.2.2 
Added the following text to the definition of duration of 
response:  
 
(per RECIST Version 1.1) 
Clarifies that progressive disease per RECIST v1.1 is 
considered an event in the calculation of duration of response 
9.2.4 
Removed the following text: 
 
For patients who are enrolled but fail to receive study 
treatment, the enrollment date will be used as the starting 
point in the calculation in PFS. 
Removes irrelevant language; these patients will not be 
considered part of the full analysis set 
9.2.5 
Removed the following text: 
 
For patients who are enrolled but fail to receive study 
treatment, the enrollment dates will be used as the 
starting point in the calculation in OS. 
 
Removes irrelevant language; these patients will not be 
considered part of the full analysis set 
 
 
 
 


 
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Section(s) 
Change 
Rationale 
Revised the following text: 
 
In the absence of confirmation of death, OS will be 
censored at the last date the patient is known to be alive.  
Updates for accuracy 
 
 
 
9.3.1.7, 9.3.2, 9.3.3, 9.3.5, 
9.3.7 
Revised the name of the intent to treat analysis set to the 
full analysis set.  
Revises the analysis set name to be consistent with ICH E9 
guidance 
9.3.1.7, 9.3.5 
Removed the per protocol analysis set.  
 
Revised the PK analysis set as follows: 
 
The PK analysis set will include all patients who received 
enfortumab vedotin and from whom at least one blood 
sample was collected and assayed for enfortumab 
vedotin, MMAE, or TAb concentration. Corresponding 
records of the time of dosing and sample collection must 
also be available for all enfortumab vedotin, MMAE, and 
TAb concentration data. Enrolled patients with sufficient 
administered dose and plasma concentration data to 
reliably estimate PK parameters as determined by a 
clinical pharmacologist. The PK analysis set will be used 
for PK analyses. 
Removes irrelevant language; sensitivity analyses will not be 
performed, and the per protocol analysis set is not needed 
 
 
Updates PK analysis set with currently planned analyses 
 
 
 
 
9.3.1.8 
Revised the planned subgroup analyses as follows: 
 
Number of prior systemic therapies (e.g., number, CPI 
type, PD-1 vs. PD-L1) 
 
Best response achived to prior CPI therapy for urothelial 
cancer (e.g., patients with PD) 
 
Liver Visceral metastases vs non-visceral metastases 
metastasis at baseline 
 
Metastatic sites at baseline: lymph node only, liver 
 
Nectin-4 expression 
Simplifies the planned subgroup analyses 
9.3.10 
Removed the following text: 
 
No formal interim analyses are planned. 
Updates for accuracy 
 


 
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Summary of Changes in Amendment 6  
 
Section(s) 
Change 
Rationale 
Title page 
Replaced
with 
as 
Medical Monitor 
Administrative change 
Synopsis  
Added text as follows:  
 
The primary analysis of efficacy endpoints will be based 
on the full analysis set, including all patients who 
enrolled and received any amount of enfortumab vedotin.  
Updates the synopsis to better reflect the statistical 
methodology presented in the body of the protocol. 
Synopsis, 9.3.1.7, 9.3.5 
Defined the ‘efficacy-evaluable set’ to include all patients 
who started treatment with enfortumab vedotin at least 8 
months before the analysis data cutoff. 
 
Specified in the protocol that at the time of Cohort 2 
interim analysis, additional analyses of the efficacy 
endpoints will be performed based on the efficacy-
evaluable set to allow adequate follow up for a stable 
estimate of ORR and DOR. 
Defines a population that allows adequate follow up for 
response endpoints at the time of the interim analysis 
Synopsis, 9.1, 9.3.1.9, 
9.3.10 
Revised the timing of Cohort 2 interim analysis and final 
analysis to when patients have had the opportunity to be  
followed for approximately 8 months from the first dose 
of enfortumab vedotin. 
 
Added additional interim analysis for Cohort 2 after 
approximately 70 subjects have been followed for 
approximately 8 months from the first dose of enfortumab 
vedotin. 
 
Added a row for this interim analysis in the synopsis 
table for the expected 95% confidence interval: N=70 
20% - 42% 
Clarifies the timing of Cohort 2 analyses to allow adequate 
follow up for response endpoints 
PPD
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Synopsis, 9.3.5.1 
Removed the following text: 
 
The primary efficacy analysis will be performed by 
testing the null hypothesis of ORR being less than or 
equal to 10% against the alternative hypothesis that ORR 
is greater than 10% at overall 1-sided 2.5% level of 
significance, i.e., H0: P≤0.10 vs Ha: P>0.10. 
Within each cohort, the study will be considered 
successful if the lower bound of the 2-sided 95% exact 
Clopper-Pearson CI for ORR is greater than 10%, so that 
the null hypothesis that the ORR is less than or equal to 
10% can be rejected. 
Updated to reflect current feedback from the FDA.  
3.1, 6.3.6, 7.7.7, 
Appendix A 
Removed Cycle 2 Day 22 and Cycle 6 Day 22 slit lamp 
exams from study activities and the Schedule of Events. 
Slit lamp exams are no longer required per IDMC 
recommendation as of Jul 2018 and Aug 2019. This revision 
clarifies that these exams are no longer required. 
3.2 
Revised the text as follows: 
 
Given that patients enrolled in the current study have a 
poor prognosis and represent an area of unmet medical 
need, the lower bound of the exact 95% confidence 
interval (CI) for ORR that excludes a historical response 
rate of 10% an ORR of greater than 10% as measured by 
the lower bound of the 95% confidence interval (CI) is 
considered to be a meaningful improvement over 
currently available therapies with the proposed 
enrollment of approximately 100 patients. 
Clarification. 
5.3, 6.1, 7.7.1.3, 
Appendix A 
Revised the safety reporting period from: 
 
The safety reporting period for all AEs and SAEs is from 
study Day 1 (predose) through the EOT visit or 30 days 
after the last study treatment, whichever is later. 
 
To:  
 
The safety reporting period for all AEs and SAEs is from 
study Day 1 (predose) through 30 days after the last study 
treatment. 
Provides a definitive safety reporting period for the study, 
eliminating ambiguity around subjects who have no EOT visit. 


 
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5.3.2 
Added the following text: 
 
Patients with a positive hepatitis B surface antigen and/or 
antihepatitis B core antibody and a negative PCR assay at 
baseline should receive appropriate antiviral prophylaxis 
or regular surveillance monitoring as per local or 
institutional guidelines.  
Adds that antiviral prophylaxis for hepatis B virus (HBV) is 
permitted, and clarifies that local or institutional guidelines in 
treatment or surveillance monitoring of PCR negative HBV 
may be followed. 
6.1, 7.7.2 and Appendix A 
Added the following text: 
 
Local laboratory testing should be performed on all 
dosing days. All local laboratory results must be 
reviewed prior to study drug administration in order to 
determine whether to proceed with dosing or whether 
dose modification is required. 
Clarifies that local labs are required for each dosing day, and 
that lab results should be available before dosing, for patient 
safety. 
 
 
 


 
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Summary of Changes in Amendment 7  
 
Section(s) 
Change 
Rationale 
Title page and throughout 
protocol 
Revised Sponsor name from Seattle Genetics, Inc or 
Seattle Genetics to Seagen Inc or Seagen 
Administrative change 
Title page 
Updated study medical monitor 
Administrative change 
Section 5.2.3 
Added the following text to Table 2: 
 
Grade 1: For Grade 1 rash or skin reactions, may 
continue at same dose level. See also Section 5.4.3 for 
recommended management of rash. 
 
Grade 2: For worsening rash or skin reactions, consider 
withholding enfortumab vedotin until toxicity is ≤ Grade 
1 or has returned to baseline, then resume treatment at the 
same dose level or consider dose reduction by 1 level. 
See also Section 5.4.3 for recommended management of 
rash. 
 
Grade 3: For Grade 3 rash or skin reactions withhold 
enfortumab vedotin until toxicity is ≤ Grade 1 or has 
returned to baseline, then resume treatment at the same 
dose level or consider dose reduction by 1 level. See also 
Section 5.4.3 for recommended management of rash. 
 
For suspected Stevens-Johnson Syndrome (SJS) or 
suspected toxic epidermal necrolysis (TEN) withhold 
enfortumab vedotin. 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. 
 
Grade 4: For confirmed SJS or TEN, or Grade 4 rash, 
permanently discontinue treatment. 
 
 
 
Removed the following table footnote text: 
Safety update addressing severe cutaneous adverse reactions 


 
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a . Grade 3/4 electrolyte imbalances/laboratory 
abnormalities, except hyperglycemia, that are not 
associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 
hours of their onset do not require discontinuation (e.g., 
Grade 4 hyponatremia). Grade 3 rash that is not limiting 
self-care activities of daily living or associated with 
infection requiring systemic antibiotics does not require 
treatment interruption, provided symptoms are not severe 
and can be managed with supportive treatment. 
Section 5.4.3 
Renamed Section as follows:  
 
Management of Rash Related to Enfortumab Vedotin 
 
Added text as follows: 
 
Enfortumab vedotin is a Nectin-4 directed antibody drug 
conjugate. Nectin-4 is a cell adhesion molecule that is 
highly expressed in urothelial carcinoma. Low to 
moderate levels of Nectin-4 are also expressed on normal 
tissues, including skin keratinocytes, sweat glands and 
hair follicles; thus, skin reactions are anticipated events. 
As such, skin reactions are adverse events of interest in 
all clinical studies with enfortumab vedotin.  
 
A cumulative review of post-marketing safety data from 
18 Dec 2019 (the approval date of enfortumab vedotin in 
the US) through 22 Oct 2020 identified reports of severe 
cutaneous adverse reactions in 15 patients receiving 
enfortumab vedotin, some of whom had fatal outcomes. 
These reactions occurred predominantly during the first 
cycle of treatment. Adverse events reported in these cases 
included SJS (5 cases), blister (3 cases), dermatitis 
bullous (3 cases), symmetrical drug-related intertriginous 
and flexural exanthema (SDRIFE; 2 cases), and 1 case 
each of dermatitis exfoliative, exfoliative rash, epidermal 
necrosis, oropharyngeal blistering, stomatitis, and TEN.  
 
Safety update addressing severe cutaneous adverse reactions 


 
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In enfortumab vedotin monotherapy studies of urothelial 
carcinoma, serious adverse events of severe cutaneous 
adverse reactions were reported in 11 of 749 subjects 
(1.5%) and included dermatitis bullous (0.4%), drug 
eruption (0.4%), blister (0.1%), conjunctivitis (0.1%), 
SJS (0.1%), stomatitis (0.1%), and toxic skin eruption 
(0.1%).  
 
Subjects should be advised 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 worsening Grade 2 rash or skin reactions, consider 
withholding enfortumab vedotin. For severe (Grade 3) 
rash or skin reactions or suspected SJS or TEN, withhold 
enfortumab vedotin and consider referral for specialized 
care. Permanently discontinue enfortumab vedotin in 
patients with confirmed SJS or TEN, or Grade 4 or 
recurrent Grade 3 skin reactions. 
 
 
Deleted the following text: 
 
In the phase 1 study (Study ASG-22CE-13-2), rash and 
similar dermatologic AEs were common among patients 
treated with enfortumab vedotin, and were seen more 
frequently at the highest dose. Although the exact 
etiology of dermatologic toxicities associated with 
enfortumab vedotin is unclear at this time, due to the 
expression of Nectin-4 in the skin, rash may be an on-
target toxicity. The most common dermatological AEs 
reported in ASG 22CE 13-2 were drug eruption, rash, 
skin exfoliation, skin pigmentation disorder, and rash 
maculo-papular. Most occurred during Cycle 1, and some 
were associated with pruritus. Almost all were mild, with 
the exception of two events of rash reported as Grade 3 in 


 
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the 1 mg/kg dose group. None required discontinuation of 
study drug and one event of Grade 1 papular rash at 1.25 
mg/kg required a dose reduction. Mild rash related to 
enfortumab vedotin should be treated using local 
supportive care as needed. Topical corticosteroids have 
been used along with antihistamines for pruritus as 
needed. Grade 3 rash that is not limiting self-care 
activities of daily living or associated with infection 
requiring systemic antibiotics does not require treatment 
interruption, provided symptoms are not severe and can 
be managed with supportive treatment. 
 


 
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Summary of Changes in Amendment 08  
Sections 
Change  
Rationale 
5.2.3 (Table 2) 
Dose modification recommendations for skin reactions 
related to enfortumab vedotin were modified as shown 
below, with additional formatting changes to 
accommodate the updated recommendations: 
Any Grade:  
For suspected Stevens-Johnson syndrome (SJS), 
suspected toxic epidermal necrolysis (TEN), or bullous 
lesions, immediately withhold enfortumab vedotin and 
refer the subject to a dermatologist/specialist for 
diagnosis and specialized care. 
For confirmed SJS or TEN, permanently discontinue 
treatment. 
If SJS or TEN is ruled out, see recommendations 
provided below for skin reactions. 
Grade 2: 
For worsening rash or skin reactions or skin reactions 
with concomitant fever, consider withholding enfortumab 
vedotin until toxicity is ≤ Grade 1 or has returned to 
baseline, 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.See also Section 5.10.5 for 
recommended management of rash. 
Grade 3: 
For Grade 3 rash or skin reactions withhold enfortumab 
vedotin until toxicity is ≤ Grade 1 or has returned to 
baseline, 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.See also Section 5.2.3 for recommended 
management of rash. 
For suspected Stevens-Johnson Syndrome (SJS) or 
suspected toxic epidermal necrolysis (TEN) withhold 
enfortumab vedotin. Consider referral of the subject to a 
dermatologist/specialist for diagnosis and specialized 
care. 
Guidance modified to clarify dose modification 
recommendations for bullous lesions and certain Grade 2 skin 
reactions. 
 


 
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Subjects who have confirmed SJS or recurrent Grade 3 
rash events should have therapy permanently 
discontinued. 
5.4.3 
Subjects should be informed that rash and severe skin 
reactions have occurred after administration of 
enfortumab vedotin and advised 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 enfortumab 
vedotin, refer to Section 5.2.3.For worsening Grade 2 
rash or skin reactions, consider withholding enfortumab 
vedotin. For severe (Grade 3) rash or skin reactions or 
suspected SJS or TEN, withhold enfortumab vedotin and 
consider referral for specialized care. Permanently 
discontinue enfortumab vedotin in patients with 
confirmed SJS or TEN, or Grade 4 or recurrent Grade 3 
skin reactions. 
For clarity, the section on management of rash was updated to 
refer directly to dose modification recommendations in Section 
5.2.3, rather than repeat the same information in this section. 
 
 


 
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Summary of Changes in Amendment 09 
Sections 
Change  
Rationale 
5.2.3 (Table 2) 
Dose modification recommendations for pneumonitis/ILD 
related to enfortumab vedotin were added as shown below, with 
additional formatting changes to accommodate the updated 
recommendations: 
 
Grade 2: 
Continue at same dose level, except in the event of Grade 2 
neuropathy, corneal AEs, or pneumonitis/ILD. 
 
For Grade 2 pneumonitis/ILD, withhold dose until ≤ Grade 1, 
then resume at the same dose level or consider dose reduction 
by 1 dose level. 
 
Grade 3: 
For Grade 3 pneumonitis/ILD, permanently discontinue 
treatment. 
 
Grade 4: 
For Grade 4 pneumonitis/ILD, permanently discontinue 
treatment. 
Severe, life-threatening, or fatal pneumonitis/interstitial lung disease 
has occurred in patients receiving enfortumab vedotin and 
recommendations regarding management of and dose modifications 
for pneumonitis/interstitial lung disease due to enfortumab vedotin 
were added to the protocol.  
 
5.4.4 
Added new Section 5.4.4 for management of pneumonitis/ILD 
related to enfortumab vedotin as shown below: 
 
5.4.4 Management of Pneumonitis/ILD Related to 
Enfortumab Vedotin 
Severe, life-threatening or fatal pneumonitis/interstitial lung 
disease (ILD) have occurred in patients receiving enfortumab 
vedotin. Monitor patients for signs and symptoms indicative of 
pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial 
infiltrates on radiologic exams. For recommendations regarding 
dose modifications for pneumonitis/ILD due to enfortumab 
vedotin, refer to Section 5.2.3.  
The section on management of adverse reactions was updated to 
include new section on management of pneumonitis/ILD. 
 

SAP_001.pdf: 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc.
STATISTICAL ANALYSIS PLAN
Protocol Number:
SGN22E-001
Version:
Version 4 17-Sep-2020
Protocol Title:
A single-arm, open-label, multicenter study of enfortumab 
vedotin (ASG-22CE) for treatment of patients with locally 
advanced or metastatic urothelial cancer who previously 
received immune checkpoint inhibitor (CPI) therapy
Study Sponsor:
Seattle Genetics, Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
IND Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way.
Northbrook, IL 60062, USA
DocuSign Envelope ID: 0549668D-83D8-46B5-964F-0AF698FD2718


Study SGN22E-001
Statistical Analysis Plan
Version 4 17-SEP-2020 
Enfortumab vedotin (ASG-22CE)
Seattle Genetics, Inc. - Confidential
Page 2 of 34
APPROVAL SIGNATURES
Product:
Enfortumab vedotin (ASG-22CE)
Protocol Number/Amendment:
SGN22E-001 / Amendment 6
SAP Version:
Version 4
Version Date:
17-Sep-2020
The individuals signing below have reviewed and approve this statistical analysis plan.
Date
Date
Date
Date
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17-Sep-2020
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Study SGN22E-001
Statistical Analysis Plan
Version 4 17-SEP-2020 
Enfortumab vedotin (ASG-22CE)
Seattle Genetics, Inc. - Confidential
Page 3 of 34
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ................................................................................................................................5 
1 
INTRODUCTION...........................................................................................................................................6 
2 
STUDY OBJECTIVES ...................................................................................................................................6 
2.1 
Primary Objectives................................................................................................................................6 
2.2 
Secondary Objectives............................................................................................................................6 
2.3 
Additional Objectives............................................................................................................................6 
3 
STUDY ENDPOINTS ....................................................................................................................................7 
3.1 
Primary Endpoint ..................................................................................................................................7 
3.2 
Secondary Endpoints.............................................................................................................................7 
3.3 
Additional Endpoints.............................................................................................................................7 
4 
STUDY DESIGN............................................................................................................................................7 
5 
ANALYSIS SETS...........................................................................................................................................9 
5.1 
Full Analysis Set ...................................................................................................................................9 
5.2 
Safety Analysis Set................................................................................................................................9 
5.3 
Efficacy Evaluable Set ..........................................................................................................................9 
5.4 
Pharmacokinetics (PK) Analysis Set...................................................................................................10 
6 
STATISTICAL CONSIDERATIONS ..........................................................................................................10 
6.1 
General Principles ...............................................................................................................................10 
6.2 
Determination of Sample Size.............................................................................................................10 
6.3 
Randomization and Blinding...............................................................................................................12 
6.4 
Data Transformations and Derivations................................................................................................12 
6.4.1 
General ...................................................................................................................................12 
6.4.2 
Best Overall Response............................................................................................................12 
6.4.3 
Response Assessment Dates...................................................................................................13 
6.4.4 
Adequate Response Assessment.............................................................................................13 
6.4.5 
Action Taken with Study Treatment of Adverse Events ........................................................13 
6.5 
Handling of Dropouts and Missing Data.............................................................................................13 
6.6 
Multicenter Studies .............................................................................................................................14 
6.7 
Multiple Comparison/Multiplicity.......................................................................................................14 
6.8 
Examination of Subgroups..................................................................................................................14 
6.9 
Covariates............................................................................................................................................15 
6.10 Timing of Analyses .............................................................................................................................15 
7 
PLANNED ANALYSES ..............................................................................................................................15 
7.1 
Disposition ..........................................................................................................................................15 
7.2 
Demographic and Baseline Characteristics .........................................................................................16 
7.3 
Protocol Deviations.............................................................................................................................16 
7.4 
Treatment Administration ...................................................................................................................16 
7.5 
Efficacy Analyses................................................................................................................................17 
7.5.1 
Primary Efficacy Endpoint - Objective Response Rate (ORR) per IRF.................................17 
7.5.2 
Objective Response Rate (ORR) per investigator ..................................................................17 
7.5.3 
Duration of Response .............................................................................................................18 
7.5.4 
Disease Control Rate at Week 16 (DCR16) ............................................................................18 
7.5.5 
Progression-free Survival (PFS).............................................................................................19 
7.5.6 
Overall Survival (OS).............................................................................................................19 
7.6 
Safety Analyses...................................................................................................................................19 
7.6.1 
Adverse Events.......................................................................................................................20 
7.6.2 
Clinical Laboratory Parameters..............................................................................................22 
7.6.3 
Electrocardiogram ..................................................................................................................22 
7.6.4 
Vital Signs..............................................................................................................................23 
7.6.5 
Concomitant Medications.......................................................................................................23 
7.7 
Additional Analyses ............................................................................................................................23 
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Study SGN22E-001
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7.7.1 
Patient Reported Outcomes ....................................................................................................23 
7.7.2 
Subsequent Cancer-Related Therapy......................................................................................23 
7.7.3 
Pharmacokinetics....................................................................................................................24 
7.7.4 
Antitherapeutic Antibody (ATA) ...........................................................................................24 
7.7.5 
Pharmacodynamic and Pre-treatment Biomarkers .................................................................24 
8 
INTERIM ANALYSIS..................................................................................................................................24 
9 
CHANGES FROM PLANNED ANALYSES ..............................................................................................24 
9.1 
Changes from the Original Protocol....................................................................................................24 
9.2 
Changes from the Original SAP..........................................................................................................24 
9.2.1 
Version 2 Changes..................................................................................................................24 
9.2.2 
Version 3 Changes..................................................................................................................25 
9.2.3 
Version 4 Changes..................................................................................................................26 
10 REFERENCES..............................................................................................................................................27 
APPENDIX A: IMPUTATION OF PARTIAL MISSING ADVERSE EVENT DATES ...................................28 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ......................................................................................................................................31 
APPENDIX C: IMPUTATION OF PARTIAL MISSING PRIOR THERAPY DATES.....................................33 
APPENDIX D: IMPUTATION OF PARTIAL MISSING SUBSEQUENT ANTICANCER THERAPY START 
DATE............................................................................................................................................................34 
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Study SGN22E-001
Statistical Analysis Plan
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Enfortumab vedotin (ASG-22CE)
Seattle Genetics, Inc. - Confidential
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LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ATA
antitherapeutic antibodies
CDISC
clinical data interchange standards consortium
CI
confidence interval
CPI
checkpoint inhibitor
CR
complete response
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
EOS
end of study
EOT
end of treatment
EQ-5D
EuroQol five dimensions
IDMC
independent data monitoring committee
IRF
independent review facility
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Affairs
MMAE
monomethyl auristatin E
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic
PP
per protocol
PR
partial response
PRO
patient reported outcome
PT
preferred term
QLQ-C30
EORTC Quality of Life Questionnaire
QoL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
statistical analysis plan
SAE
serious adverse event
SMQ
standard MedDRA query
TEAE
treatment emergent adverse event
SD
stable disease
SOC
system organ class
SSQ
sponsor specified query
VAS
visual analog scale
WHO
World Health Organization
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Study SGN22E-001
Statistical Analysis Plan
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Enfortumab vedotin (ASG-22CE)
Seattle Genetics, Inc. - Confidential
Page 6 of 34
1
INTRODUCTION
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN22E-001, entitled “A single-arm, open-label, multicenter study of enfortumab 
vedotin (ASG-22CE) for treatment of patients with locally advanced or metastatic urothelial 
cancer who previously received immune checkpoint inhibitor (CPI) therapy”. Results of the 
proposed analyses will become the basis of the clinical study report (CSR) for this protocol.
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final CSR. Any changes will either be reflected in amendments to this plan before the 
database lock or specifically documented in the CSR.
2
STUDY OBJECTIVES
2.1
Primary Objectives
●
To determine the antitumor activity of single-agent enfortumab vedotin as measured by 
confirmed objective response rate (ORR) in patients with locally advanced or metastatic 
urothelial cancer who have previously received systemic therapy with a CPI and either 
received platinum-containing chemotherapy or are platinum-naïve and cisplatin-ineligible
2.2
Secondary Objectives
●
To assess duration of response (DOR)
●
To assess disease control rate (DCR)
●
To assess progression-free survival (PFS)
●
To assess overall survival (OS)
●
To assess the safety and tolerability of enfortumab vedotin 
●
To assess the pharmacokinetics (PK) of enfortumab vedotin
●
To assess the incidence of antitherapeutic antibodies (ATA) 
2.3
Additional Objectives
●
To explore potential correlations between biomarkers and clinical outcomes 
●
To evaluate the treatment effect of enfortumab vedotin on quality of life (QoL)
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Study SGN22E-001
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3
STUDY ENDPOINTS
3.1
Primary Endpoint 
The primary efficacy endpoint of this study is ORR (confirmed complete response [CR] or 
partial response [PR] per Response Evaluation Criteria in Solid Tumors [RECIST] Version 
1.1) as determined by an independent review facility (IRF)
3.2
Secondary Endpoints
●
DOR (confirmed CR or PR) per IRF
●
DCR16 (DCR [CR, PR or stable disease (SD)] at 16 weeks) per IRF
●
PFS per IRF
●
ORR per investigator assessment
●
DOR per investigator assessment
●
DCR16 per investigator assessment
●
PFS per investigator assessment
●
OS
●
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs)
●
Laboratory abnormalities 
●
Selected plasma or serum PK parameters of enfortumab vedotin and monomethyl 
auristatin E (MMAE)
●
Incidence of ATA to enfortumab vedotin
3.3
Additional Endpoints
●
Biomarkers of biological and clinical activity, including Nectin-4 expression
●
Patient reported outcomes (PRO) per the EORTC Quality of Life Questionnaire (QLQ-
C30)
●
PRO per EuroQol 5-dimensions (EQ-5D), including health utility values, and visual 
analog scale
4
STUDY DESIGN
This is a single-arm, open-label, multicenter trial designed to assess the efficacy and safety of 
enfortumab vedotin as a single agent in locally advanced or metastatic urothelial cancer 
subjects who have previously received systemic therapy with a CPI. Subjects must also either 
have received prior treatment with platinum-containing chemotherapy (Cohort 1) or received 
no prior platinum-containing or other chemotherapy and are ineligible for treatment with 
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cisplatin (Cohort 2). Subjects must have progressive disease (PD) during or following their 
most recent therapy. There are no limits for prior lines of therapy, including taxanes. 
Enfortumab vedotin at a dose of 1.25 mg/kg will be administered as an intravenous infusion 
on Days 1, 8, and 15 of each 28-day cycle. Subjects will continue to receive study treatment 
until disease progression, unacceptable toxicity, investigator decision, consent withdrawal, 
start of subsequent anticancer therapy, pregnancy, or study termination by the sponsor.  
Subjects who discontinue study treatment for reasons other than disease progression per 
RECIST v1.1 or start of subsequent anticancer therapy will continue to have response 
assessments, Eastern Cooperative Oncology Group (ECOG) performance status, and physical 
exams every 8 weeks (±1 week). After 1 year on study, the frequency of follow-up exams 
including response assessments will be reduced to every 12 weeks (±1 week). Subjects who 
have progressed or begun subsequent anticancer therapy will be contacted every 8 weeks 
(±1 week) up to 1 year on study, and every 12 weeks (±1 week) thereafter to obtain 
information on subsequent anticancer therapy, and survival status until death, study closure,
withdrawal of consent, or subject is lost to follow-up, whichever occurs first (see Figure 1). 
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.
Measures of anticancer activity will be assessed by radiographic tumor imaging at protocol-
specified timepoints. Tumor response will be assessed locally and centrally by an IRF
according to RECIST v1.1 (Eisenhauer 2009). Clinical response of CR, PR, SD, or PD will 
be determined at each assessment. Responses (CR or PR) will be confirmed with repeat scans 
at least 4 weeks after first documentation of response. Tumor assessments will continue until 
the subject has radiologically-confirmed disease progression per RECIST v1.1 by the 
investigator, initiates a new anticancer therapy, dies, withdraws consent, or the study closes, 
whichever comes first. 
Safety assessments will be based on the information collected through the safety surveillance 
process and will include the data from recorded AEs including serious adverse events 
(SAEs), recording of concomitant medication, medical history, physical examination 
findings, and laboratory tests.
Approximately 200 subjects will be enrolled in this study, including approximately 100 or 
more platinum-treated subjects (Cohort 1) and up to approximately 100 platinum-naïve and 
cisplatin-ineligible subjects (Cohort 2).
On a periodic basis, approximately every 3 months until all treated subjects in Cohort 1 have 
had the opportunity to be followed for at least 6 months and at a frequency considered 
adequate based on the rate of enrollment to Cohort 2 thereafter, an independent data 
monitoring committee (IDMC) will monitor the safety of subjects participating in this trial. 
The IDMC will be guided by an independent charter and will be responsible for evaluating 
the results of safety analyses and will make recommendations to the sponsor. The IDMC may 
also request efficacy data, if needed, to evaluate risk/benefit before making 
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recommendations. The IDMC will make recommendations to either continue the study 
unchanged, modify the study, or discontinue the study. The final decision to act on the IDMC 
recommendations will be made by the sponsor.
An ongoing real-time review of subject safety and SAEs will also be conducted by the 
sponsor’s Drug Safety Department.
Figure 1 Study Schema
Pre-study
End of Treatment
Follow-up
Response 
assessments every 
8 weeksb (±1 week)
30-37 days 
post last 
dose of 
study 
treatment
Until progression or 
subsequent anticancer 
therapy
Each 28-day cycle
enfortumab vedotin 
1.25 mg/kg IV on Day 1, 8, 15 
Response assessments every 
8 weeksb (±1 week), with 
confirmatory repeat scans 4 
weeks (+1 week) after first 
documentation of response
Screening
Enrollmenta
Until patient 
death, study 
closure, 
withdrawal of 
consent, or 
patient is lost 
to follow-up
Long-term 
Follow-up
Survival and 
subsequent 
anticancer 
therapies
a There are 2 cohorts of CPI-treated patients in the study: Cohort 1) platinum-treated patients, and Cohort 2) platinum-
naïve/cisplatin-ineligible patients.
b After 1 year on study, the frequency of response assessments will be reduced to every 12 weeks (±1 week). 
A detailed study assessment schedule can be found in the protocol.
5
ANALYSIS SETS
5.1
Full Analysis Set
The full analysis set will include all subjects who are enrolled in the study and receive any 
amount of enfortumab vedotin.
The full analysis set will be used as the primary analysis set for efficacy endpoints. Subject 
demographics and baseline disease characteristics will be summarized based on the full 
analysis set.
5.2
Safety Analysis Set
The safety analysis set will include all subjects who receive any amount of enfortumab 
vedotin, and thus is equivalent to the full analysis set defined in this protocol. The safety
analysis set will be used for all safety analyses.
5.3
Efficacy Evaluable Set
The efficacy evaluable set will include all subjects in the full analysis set who started 
treatment with enfortumab vedotin at least 8 months before the analysis data cutoff. The 
efficacy evaluable set will be used for the additional analyses of efficacy endpoints at the 
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time of the Cohort 2 interim analyses to allow adequate follow up for a stable estimate of 
ORR and DOR.
5.4
Pharmacokinetics (PK) Analysis Set
The PK analysis set will include all subjects who received enfortumab vedotin and from 
whom at least one blood sample was collected and assayed for enfortumab vedotin, MMAE 
or TAb concentration. Corresponding records of the time of dosing and sample collection 
must also be available for all enfortumab vedotin, MMAE and TAb concentration data. The 
PK analysis set will be used for PK analyses.
6
STATISTICAL CONSIDERATIONS
6.1
General Principles
In general, all analyses will be performed separately for each cohort and the 2 cohorts 
combined, unless otherwise specified. Descriptive statistics will be presented that include the 
number of observations, mean, median, standard deviation, minimum and maximum for 
continuous variables, and  the number and percentages (of non-missing) per category for
categorical variables.
Unless otherwise specified, confidence intervals (CIs) will be calculated at two-sided 95% 
level.
The two-sided 95% exact CI using the Clopper-Pearson method will be calculated for the 
response rates where applicable (e.g., ORR) (Clopper 1934).
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994).
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the CSR as a post hoc analysis.
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets. To facilitate data review for the study report, only 
pertinent data listings will be created and attached to Section 16 of the study report.
All statistical Tables, Listings and Figures will be produced using SAS®, version 9.3 or 
higher. Sample size calculations were performed using EAST®, version 6.0. Other statistical 
software, if used, will be described in the CSR.
6.2
Determination of Sample Size
The study is designed to estimate the confirmed ORR in the full analysis set and to detect an 
improvement in the ORR compared with a historical 10% response rate. 
The primary efficacy hypothesis is
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H0: ORR ≤10% vs. Ha: ORR >10%
Approximately 200 subjects will be enrolled to ensure collection of sufficient efficacy and 
safety data, including approximately 100 or more platinum-treated subjects (Cohort 1) and up 
to approximately 100 platinum-naïve and cisplatin-ineligible subjects (Cohort 2). Using the 
estimate of approximately 100 subjects in Cohort 1, the study will have 98% power to detect 
a 15% increase in ORR from 10% to 25%, and 81% power to detect a 10% increase in ORR 
from 10% to 20%, at one-sided significance level of 0.025, based on exact methods using 
EAST®, Version 6.0, by Cytel Inc.
The confirmed ORR and 95% exact CI for subjects in Cohort 2 will be summarized at 4
timepoints: 
1) at the time of the primary analysis of Cohort 1 (i.e., after all subjects in Cohort 1 have 
had the opportunity to be followed for at least 6 months),
2) when approximately 50 subjects in Cohort 2 have had the opportunity to be followed 
for approximately 8 months from the first dose of enfortumab vedotin,
3) when approximately 70 subjects in Cohort 2 have had the opportunity to be followed 
for approximately 8 months from the first dose of enfortumab vedotin, and 
4) when all subjects in Cohort 2 have had the opportunity to be followed for 
approximately 8 months from the first dose of enfortumab vedotin.
For illustration purpose, assuming the observed ORR in Cohort 2 is 30%, the 95% exact CIs 
of ORR based on the expected number of subjects at each analysis timepoint are summarized 
below: 
Number of Subjects
95% Exact CI
N=20
(12%, 54%)
N=50
(18%, 45%)
N=70
(20%, 42%)
N=100
(21%, 40%)
Sample Size for IDMC Assessment of Slit Lamp Examination
Slit lamp examinations will be conducted on at least the first 60 enrolled subjects (from 
Cohorts 1 and/or 2) on Cycle 2 Day 22 (±1 week) and Cycle 6 Day 22 (±1 week). If 
treatment-emergent corneal events are observed in <15% of the first 60 enrolled subjects and 
if the events are generally low grade or asymptomatic, the IDMC may make a 
recommendation to cease Cycle 2 Day 22 and/or Cycle 6 Day 22 slit lamp exams for the 
remaining subjects if warranted based on review of the cumulative ocular safety data. Based 
on the results from the Phase 1 study (Study ASG-22CE-13-2), as of the data cutoff date of 
14 November 2016, there were 3 subjects who reported experiencing corneal adverse events 
out of 33 subjects (9%) on 1.25 kg/mg of enfortumab vedotin. Assuming an event rate of 9%, 
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with a sample size of 60, the probability of observing >3 events (5%) is 80.0% and the 
probability of observing <9 events (15%) is 91.2%. If the event rate is higher, the probability 
of observing <9 events is decreased. For example, if the event rate is 20%, the probability of 
observing <9 events is decreased to 12.7%.
6.3
Randomization and Blinding
This is a single-arm, open-label study. No randomization or blinding will be used.
6.4
Data Transformations and Derivations
6.4.1 General
Reported age in years will be used; if not available, age at informed consent in years will be 
calculated with the SAS® INTCK function (with method specified as “continuous”) using 
informed consent date and birth date.
Study Day will be calculated as (Date – First Dose Date + 1) for dates on or after the first 
dose date. The date of first dose will be Study Day 1. For dates prior to the first dose date, 
Study Day will be calculated as (Date – First Dose Date). For example, the date before the 
first dose date will be Study Day -1.
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section.
The following unit conversion will be implemented unless otherwise specified:
Months=Days/30.4375
Years=Days/365.25
Unless otherwise specified, baseline values used in all analyses will be the most recent non-
missing measurement prior to the first dose of study drug.
6.4.2 Best Overall Response
The subject’s best overall response per IRF will be the best demonstrated response to date 
that has been confirmed, when confirmation is required (i.e. for PR and CR). Response after 
the start of subsequent anticancer therapy will not be included in the derivation of best 
overall response. The subject’s best overall response will be used in determining the ORR 
per IRF. 
A response (CR or PR) will be considered confirmed if the subsequent response assessment 
(at least 4 weeks after the initial response) still shows response (CR or PR). A subject will 
have a best response of SD if there is at least one SD assessment (or better) ≥6 weeks after 
the start of treatment and the subject does not qualify for confirmed CR or PR. RECIST v1.1 
outlines scenarios for best overall responses when confirmation of CR and PR is required. 
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6.4.3 Response Assessment Dates
At each response assessment time point, scans to evaluate target and non-target lesions can 
be performed on multiple dates. If the time point response is CR or PR, then the latest date of 
all radiologic scans at the given response assessment visit will be the date of response. If the 
time point response is SD, then the earliest date of all radiologic scans at the given response 
assessment visit will be the date of SD. If the time point response is PD, then the earliest date 
that PD has been documented will be the date of PD, i.e. the earliest of:
x
Date of target lesion assessments when the target lesion response is PD
x
Date of non-target lesion assessments when the lesion status is unequivocal 
progression
x
Date of documenting new lesions
For subjects whose best overall response is a confirmed CR or PR, the date of objective 
response will be the date of initial documentation of response (i.e., CR or PR that is 
subsequently confirmed).
6.4.4 Adequate Response Assessment
An adequate tumor assessment must include a radiologic scan with the overall disease 
response of CR, PR, SD, or PD.
6.4.5 Action Taken with Study Treatment of Adverse Events
Action taken with study treatment of each adverse event (AE) will be mapped to the Clinical 
Data Interchange Standards Consortium (CDISC) controlled terminology as listed below: 
1. dose not changed
2. dose reduced
3. drug interrupted
4. drug withdrawn
Drug interruption includes dose elimination, dose delay, infusion interruption with full dose 
received, and infusion stop early without full dose received, as collected on the case report 
form (CRF). If more than one action is associated to an AE, the action taken that is the end 
result will be selected.
6.5
Handling of Dropouts and Missing Data
Missing data will not be imputed unless otherwise specified.
For time-to-event endpoints (e.g., duration of response, PFS, and OS), subjects who have no 
specified event will be censored as specified for each respective endpoint in Section 7.5.
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Subjects who do not have at least two (initial response and confirmation scan) post-baseline 
response assessments will be counted as non-responders for the analysis of primary endpoint.
Missing AE dates will be imputed for the purpose of calculating duration of events and 
treatment-emergent status (see Appendix A for imputation details and Appendix B for 
treatment-emergent definition).  
Missing prior therapy dates will be imputed for the purpose of calculating the time from prior 
therapy to first dose of study drug (see Appendix C for details).
Missing subsequent anticancer therapy start date will be imputed for the purpose of deriving 
the time-to-event endpoints as applicable (see Appendix D for details).
Unless otherwise specified, if the numeric value of a laboratory test is not available because 
it is below the lower limit of quantification (LLOQ), the result will be analyzed as equal to 
the LLOQ when a numeric value is required (e.g., calculating the mean) and be listed as 
“< LLOQ” in the listings.
6.6
Multicenter Studies
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough subjects to warrant an analysis by center.
6.7
Multiple Comparison/Multiplicity
No multiple comparisons are planned and no alpha adjustment is needed because only one 
primary endpoint will be tested in this single-arm study.
6.8
Examination of Subgroups
As exploratory analyses, subgroup analyses will be conducted for selected endpoints. 
Subgroup analyses to be conducted are:
●
Age (<65, ≥65 years old)
●
Age (<75, ≥75 years old)
●
Sex (female, male)
●
Race (white, non-white)
●
ECOG performance score at baseline (0, 1-2)
●
Bellmunt risk score (0-1, ≥2) (Bellmunt 2010)
●
Baseline weight (≤100, >100 kg)
●
Primary tumor sites (upper tract, bladder/other)
●
Liver metastasis (yes, no)
●
Number of prior systemic therapy in locally advanced or metastatic setting (1-2, ≥3)
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●
Best response to prior CPI (responder, non-responder)  
●
PD-L1 CPS (<10, ≥10)
A subgroup analysis may not be performed if the number of subjects in the subgroup is not 
sufficiently large (i.e., <10% of the full analysis set for a given cohort). At the time of the 
primary analysis of Cohort 1, subgroup analysis will be performed for Cohort 1 only, without 
including Cohort 2 subjects.
6.9
Covariates
No adjustment for covariates is planned in the analyses.
6.10 Timing of Analyses
The primary analysis of Cohort 1 (platinum-treated subjects) will be conducted when 
enrollment is completed in Cohort 1 and all subjects in this cohort have been followed for at 
least 6 months, discontinued from study, or had 30 days safety follow up after PD, whichever 
comes first. 
Analysis for Cohort 2 will occur at 4 timepoints; 
1) at the time of the primary analysis of Cohort 1, 
2) when approximately 50 subjects in Cohort 2 have had the opportunity to be followed 
for approximately 8 months from the first dose of enfortumab vedotin,
3) when approximately 70 subjects in Cohort 2 have had the opportunity to be followed 
for approximately 8 months from the first dose of enfortumab vedotin, and 
4) when all subjects in Cohort 2 have had the opportunity to be followed for 
approximately 8 months from the first dose of enfortumab vedotin.
Additional cutoff dates may be defined and corresponding database locks may occur to allow 
for more precise estimates of time-to-event endpoints.
7
PLANNED ANALYSES
7.1
Disposition
Subject disposition will be summarized for all enrolled subjects with descriptive statistics. 
Subjects who discontinue study treatment and subjects who withdraw from the study will be 
summarized along with the reason for discontinuation or withdrawal. 
The number of subjects who signed informed consent, number of screen failures, and the 
reason for screen fail will be summarized for all screened subjects. The number of subjects 
enrolled at each site will be summarized. 
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7.2
Demographic and Baseline Characteristics
Demographics and baseline characteristics, including age at consent, sex, ethnicity, race, 
baseline height, weight, body mass index, ECOG performance status, estimated creatinine 
clearance, hemoglobin A1c, smoking status, and Bellmunt risk factors will be listed and 
summarized with descriptive statistics for the full analysis set. 
Disease specific characteristics, including time from diagnosis of locally advanced/metastatic 
disease to enrollment, histology, current extent of disease, disease stage, primary tumor 
location, and metastases sites will be listed and summarized for the full analysis set.
Summary of prior cancer-related therapies, including number of prior therapies, therapy type, 
setting of prior therapies, best response to prior therapies, time from most recent prior 
therapy to first dose of study drug, and prior cystectomy and nephrectomy, will be presented 
for the full analysis set.
In addition, the pre-existing conditions that are ongoing at baseline will be summarized.
7.3
Protocol Deviations
Important protocol deviations are a subset of protocol deviations that may represent a 
divergence from the protocol that could have a significant effect on the integrity of the study 
data, or on the subject’s rights, safety, or welfare. Important protocol deviations also include 
exemptions to the study inclusion/exclusion criteria and will be summarized by category. A 
list of subjects with important protocol deviations will be presented.
7.4
Treatment Administration
Treatment administration will be summarized for the safety analysis set. Summary statistics 
for duration of treatment (weeks), number of cycles, and the number and percentage of 
subjects who were treated at each cycle will be presented. In addition, number of infusions 
per subject, cumulative dose administered, absolute dose intensity (ADI), and relative dose 
intensity (RDI) will be described. The number and percentage of subjects whose dose was 
ever modified will be summarized.
Duration of treatment is defined as time from the first study dose to the earliest of the 
following:
x
Day 28 of the last treatment cycle
x
Date of death
x
Analysis cutoff date if the subject is still on treatment at the time of the analysis
x
Start of subsequent anticancer therapy 
Intended dose intensity (IDI) is defined as the intended dose of study drug per unit of time 
according to the protocol (i.e., 3.75 mg/kg/4-wk cycle).
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ADI is defined as the actual dose of study drug per unit of time that a subject received over 
the entire treatment period. For the purpose of calculating ADI, treatment period is defined as 
time from the first dose of study drug to Day 28 of the last treatment cycle, regardless if 
death occurs before the end of the cycle.
RDI is defined as the ADI over the IDI (i.e., RDI = ADI/IDI * 100%).
7.5
Efficacy Analyses
The primary analysis of efficacy endpoints will be performed using the full analysis set.
Sensitivity analysis of the primary efficacy endpoint will be presented using the efficacy 
evaluable set.
7.5.1 Primary Efficacy Endpoint - Objective Response Rate (ORR) per IRF
The primary endpoint of this study is the confirmed ORR per IRF. ORR is defined as the 
proportion of subjects whose best overall response is a confirmed CR or PR according to 
RECIST v1.1 (Eisenhauer 2009). Subjects who do not have at least two (initial response and 
confirmation scan) post-baseline response assessment will be considered non-responders.
The primary efficacy hypothesis is outlined in Section 6.2.
The ORR per IRF and its exact two-sided 95% CI will be calculated for the full analysis set. 
In addition, the ORR per IRF will be summarized and presented graphically by the subgroups 
defined in Section 6.8.
The maximum percent reduction from baseline in the sum of diameters per IRF will be 
calculated for each subject and presented graphically with a waterfall plot.
Time to response per IRF 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). 
Time to response per IRF will be summarized for the responders only. Subgroup analysis of 
time to response will be performed for subjects who responded to the prior CPI therapy
versus those who did not respond to the prior CPI therapy.
7.5.2 Objective Response Rate (ORR) per investigator
The ORR per investigator and its two-sided 95% exact CI will be calculated for the full 
analysis set.  
The ORR per investigator in the subgroups will be presented graphically. The maximum 
percent reduction from baseline in sum of diameters per investigator will be calculated for 
each subject and presented graphically with a waterfall plot. 
Time to response per investigator will be analyzed in the same way as the time to response 
per IRF.
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7.5.2.1 Concordance between Investigator and IRF Assessment
A summary of the concordance between investigator and IRF assessment will be provided. 
The percent agreement will be calculated as the proportion of subjects whose best overall 
response per IRF match the best overall response per investigator.
Percent agreement = (Number of matched responders + Number of matched non-responders) 
/ Total number of subjects assessed.
7.5.3 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 v1.1 or death due to 
any cause, whichever comes first.  
DOR will be censored as described below:
●
Subjects who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the last adequate response assessment documenting absence of 
PD
●
Subjects who have started a new anticancer treatment (with the exception of palliative 
radiotherapy on a non-target lesion that is not progressing) prior to documentation of 
PD will be censored at the date of the last adequate response assessment prior to start 
of new treatment
●
Subjects who discontinue from the study prior to documentation of PD will be 
censored at the date of the last adequate response assessment documenting absence of 
PD.
DOR per IRF will only be calculated for subjects achieving a confirmed CR or PR per IRF. 
DOR will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided. The median DOR and its two-sided 95% CI will be calculated. In addition, the 
DOR at 6 and 12 months will be summarized.
Sensitivity Analysis
The following sensitivity analysis will be performed for the DOR per IRF:
1. A sensitivity analysis to censor subjects who progressed or died after an extended loss 
to follow up (i.e., ≥2 consecutive missed response assessments) at the date of the last 
adequate response assessment prior to the missed visits.
DOR per investigator will be analyzed in the same way as the DOR per IRF. 
7.5.4 Disease Control Rate at Week 16 (DCR16)
DCR16 per IRF is defined as the proportion of subjects with CR, PR, or SD at Week 16
(±1 week) based on IRF assessment. Responses do not need to be confirmed for the purpose 
of determining DCR16. Subjects whose disease status cannot be assessed or have a missing 
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assessment at Week 16 will be considered not having disease control at Week 16. The only 
exception is for subjects who have a CR, PR, or SD at the visits subsequent to Week 16; 
these subjects will be considered to have disease control at Week 16 although the Week 16 
assessment is missing or not evaluable.
DCR16 per IRF will be summarized for the full analysis set. The exact two-sided 95% CI will 
be calculated.
DCR16 per investigator will be analyzed in the same way as the DCR16 per IRF.
7.5.5 Progression-free Survival (PFS) 
PFS is defined as the time from start of study treatment to first documentation of PD per 
RECIST v1.1 or death due to any cause, whichever comes first. 
The same censoring rules as outlined in Section 7.5.3 for DOR will be applied to PFS. In 
addition, subjects who are not known to have died and do not have any post-baseline 
response assessment will be censored at the date of first dose. 
PFS per IRF will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will 
be provided. The median PFS and its two-sided 95% CI will be calculated. In addition, the 6-
and 12-month PFS rates will be summarized.
Sensitivity Analysis
The following sensitivity analysis will be performed for the PFS per IRF:
1. A sensitivity analysis to censor subjects who progressed or died after an extended loss 
to follow up (i.e., ≥2 consecutive missed response assessments) at the date of the last 
adequate response assessment prior to the missed visits.
PFS per investigator will be analyzed in the same way as the PFS per IRF.
7.5.6 Overall Survival (OS)
OS is defined as the time from start of study treatment to date of death due to any cause. In 
the absence of death, OS will be censored at the date the subject is last known to be alive or 
at the analysis cutoff date, whichever is earlier. Subjects who died after the analysis cutoff 
date will be censored at the analysis cutoff date. Subject lacking data beyond start of study 
treatment will have their survival time censored on the date of first dose.
OS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided. The median OS and its two-sided 95% CI will be calculated. In addition, the 6- and 
12-month OS rates will be summarized.
7.6
Safety Analyses
The safety analysis set will be used to summarize all safety endpoints.
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Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 20.0 or higher).
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher).
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary (version: June 2016 or more recent).
7.6.1 Adverse Events
Adverse events (AEs) will be summarized by MedDRA preferred term (PT) in descending 
frequency of occurrence unless otherwise specified. For incidence reporting, if a subject 
reports more than one AE that was coded to the same system organ class (SOC) or PT, the 
subject will be counted only once for that specific SOC or PT.
A treatment-emergent adverse event (TEAE) is defined as a newly occurring or worsening 
AE after the first dose of study treatment. See Appendix B for details regarding treatment-
emergent classification.  
An overall summary of TEAEs will be provided. Summaries of TEAEs by MedDRA 
classification will also be provided for the following:
●
TEAEs 
●
Grade 3 or higher TEAEs
●
Serious TEAEs
●
TEAEs leading to dose interruption
●
TEAEs leading to dose reduction
●
TEAEs leading to treatment discontinuation
●
TEAEs leading to death
●
Treatment-related TEAEs
●
Treatment-related grade 3 or higher TEAEs
●
Treatment-related serious TEAEs
●
Treatment-related TEAEs leading to dose interruption
●
Treatment-related TEAEs leading to dose reduction
●
Treatment-related TEAEs leading to treatment discontinuation
●
Treatment-related TEAEs leading to death
●
TEAEs by SOC, PT and maximum severity. At each SOC or PT, multiple occurrences 
of events within a subject are counted only once at the highest severity
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●
TEAEs by SOC and PT
All TEAEs, grade 3 or higher TEAEs, serious TEAEs, TEAEs leading to treatment 
discontinuation, and TEAEs leading to death will be listed.
7.6.1.1 Adverse Events of Special Interest
Peripheral neuropathy, corneal events, hyperglycemia, dermatological reactions, and infusion 
related reactions (IRR) are considered adverse events of special interest (AESI) for 
enfortumab vedotin. These are medical concepts of composite terms based on the search 
criteria (standard MedDRA query [SMQ] or sponsor specified query [SSQ]). Other AEs may 
be added to AESI as necessary. The search criteria for AESI will be maintained in a separate 
document and finalized prior to final database lock.
Treatment-emergent AESI will be summarized by PT and maximum severity. In addition, 
serious AESI, treatment-emergent AESI that are related to study drug, leading to dose 
modification and study treatment discontinuation will be summarized.
For selected AESI, time to onset, improvement, or resolution will be analyzed as appropriate. 
Time to onset of a specific AESI will be calculated as time from the first dose of study drug 
to the start of first treatment-emergent event that meets the respective search criteria. In the 
analysis of time to onset of AE of a specific grade (e.g., grade 3 or higher), episode of events 
that are improved from a previous higher grade will not be included.
Resolution is defined as event outcome of ‘recovered/resolved’ or ‘recovered/resolved with 
sequelae’, or returning to baseline grade as of the latest assessment for conditions that are 
ongoing at baseline. For events with an outcome of ‘recovered/resolved’ or 
‘recovered/resolved with sequelae’, time to resolution will be calculated as time from the 
event start date to end date. For events that return to baseline grade, time to resolution will be 
calculated as time from the start of treatment-emergent event to the date the event was last 
assessed.
For events that are not resolved, improvement is defined as decrease by at least one grade 
from the worst grade as of the latest assessment. For events that meet the definition of 
‘improvement’, time to improvement will be calculated as time from the worst grade of the 
event to the date the event was last assessed.
Time to onset will be summarized at the subject level. Time to resolution and improvement 
will be summarized at the event level.
7.6.1.2 Eye examination and Corneal AEs
The data for eye examination (complete eye examination and slit lamp examinations) at 
baseline and post-baseline visits will be listed. Structural corneal abnormality will be 
reported by the investigators and corneal events will be identified by the corneal disorders 
SMQ (narrow scope).
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The number and percentage of subjects with slit lamp examination performed at the protocol 
specified timepoints, the number and percentage of subjects with corneal events at baseline, 
and the number and percentage of subjects with treatment-emergent corneal events at Cycle 2 
Day 22 and Cycle 6 Day 22 will be summarized. In addition, treatment-emergent corneal 
events will be summarized separately for subjects with and without corneal event at baseline.
7.6.2 Clinical Laboratory Parameters
All laboratory results (hematology and serum chemistry) up to the end of treatment visit will 
be presented in standardized units. Both observed value and changes from baseline will be 
summarized with descriptive statistics for each scheduled visit. Shift from baseline to
maximum post-baseline NCI CTCAE grade will be summarized for each lab test. Treatment-
emergent laboratory abnormalities will also be summarized.
Laboratory results and NCI CTCAE grades for hematology and serum chemistry will be 
presented in data listings. Normal ranges will be documented and out-of-range values will be 
flagged. A separate listing of laboratory results with CTCAE grade 3 or higher will be 
presented.
7.6.2.1 Liver Safety Assessment
The liver safety assessment will be summarized based on the measurements of alkaline 
phosphatase (ALP), alanine transaminase (ALT), total bilirubin, aspartate transaminase 
(AST), and their combination as defined below. The number and percentage of subjects 
meeting the criteria post-baseline will be summarized.
x
ALT: > 3xULN, > 5xULN, > 10xULN, > 20xULN
x
AST: > 3xULN, > 5xULN, > 10xULN, > 20xULN
x
ALT or AST: > 3xULN, > 5xULN, > 10xULN, > 20xULN
x
ALP: > 1.5xULN
x
Total bilirubin: > 2xULN
x
(ALT or AST > 3xULN) and Total bilirubin > 2xULN*
x
(ALT or AST > 3xULN) and Total bilirubin > 2xULN and ALP < 2xULN*
*Combination of values measured on the same day or within 1 day apart.
In addition, subjects with the post-baseline liver function test results that are consistent with 
the Hy’s law criteria will be listed.
7.6.3 Electrocardiogram
ECG variables will be summarized with descriptive statistics for each scheduled visit. The 
number and percentage of subjects with normal and abnormal results for the overall 
interpretation will be tabulated.
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7.6.4 Vital Signs
Vital sign measurements, including heart rate, diastolic and systolic blood pressure, and 
temperature, will be listed by subject and visit. 
7.6.5 Concomitant Medications
Concomitant medications will be summarized by the WHO Drug ATC class and preferred 
name. The number and percentage of subjects who take concomitant medications will be 
tabulated. Concomitant medications will be listed by subject. In addition, concomitant 
medications for treatment of peripheral neuropathy, corneal events, hyperglycemia, rash and 
IRR will be presented in separate listings.
7.7
Additional Analyses
7.7.1 Patient Reported Outcomes
7.7.1.1 EORTC QLQ-C30
For each QLQ-C30 scale, score will be calculated and missing data will be accounted for 
according to the EORTC QLQ-C30 scoring manual. Descriptive summary of actual value 
and change from baseline will be presented by visit using the full analysis set.
The number and percentage of subjects with an improvement of ≥10 points from baseline in
global health status/QoL scale will be summarized by visit.
The compliance and completion rate of EORTC QLQ-C30 will be summarized for each visit. 
Compliance rate is defined as the proportion of subjects who completed the instrument 
among those who are expected to complete at a given visit. Completion rate is defined as the 
proportion of subjects who completed the instrument among the full analysis set.
7.7.1.2 EuroQol-5D
The EQ-5D health state dimension scores will be converted into a health state index using the 
time trade-off valuation method and the US-based value set (Shaw 2005). Change from 
baseline in EQ-5D health state index and visual analogue scale (VAS) will be summarized 
with descriptive statistics by visit using the full analysis set.  
The compliance and completion rate of EQ-5D will be summarized for each visit.
7.7.2 Subsequent Cancer-Related Therapy
The number and percentage of subjects who receive subsequent cancer-related therapies, 
including palliative radiotherapy, systemic therapy for disease progression, maintenance, and 
systemic therapy for secondary malignancy, will be summarized for the full analysis set. In 
addition, time from last dose of study treatment to the first subsequent anticancer therapy and 
time from last dose of study treatment to the first subsequent systemic therapy for disease 
progression will be summarized.
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7.7.3 Pharmacokinetics
Concentrations of ADC, MMAE, and TAb will be summarized using descriptive statistics 
(including geometric mean and coefficient of variation) at each PK sampling time point for 
the PK analysis set. PK parameters will be summarized using descriptive statistics.
Geometric mean estimates of selected PK parameters will be compared as a ratio of drug 
product manufacturing process (Process B to Process A).
Additional PK and PK/pharmacodynamic analyses may be performed and be presented in a 
separate report. Data from this study may be combined with data from previous studies for 
population PK and PK/pharmacodynamic analyses. If performed, these analyses will be 
described in a separate analysis plan and the results will be reported separately from the CSR. 
7.7.4 Antitherapeutic Antibody (ATA) 
The ATA incidence rate is defined as the proportion of subjects that develop ATA at any 
time during the study.
ATA incidence will be summarized by visit and overall using the safety analysis set. 
7.7.5 Pharmacodynamic and Pre-treatment Biomarkers
The H-score of Nectin-4 expression at baseline will be summarized with descriptive 
statistics. Baseline H-score will be displayed in a boxplot by BOR. The number and 
percentage of subjects with baseline PD-L1 CPS <1 vs. ≥1, and <10 vs. ≥10 will be 
summarized. The TCGA subtype at baseline will be summarized. Additional analyses for 
pharmacodynamic biomarkers and for pre-treatment biomarkers that are potentially 
predictive of subject outcomes may be described in a separate analysis plan and the results 
may be reported separately from the CSR.
8
INTERIM ANALYSIS
Data from Cohort 2 will be analyzed at the timepoints as specified in Sect 6.10. 
An IDMC will periodically monitor the trial for safety. The IDMC will review expedited 
SAEs as they are received. Further details will be provided in the IDMC Charter.
9
CHANGES FROM PLANNED ANALYSES
9.1
Changes from the Original Protocol
Not Applicable.
9.2
Changes from the Original SAP
9.2.1 Version 2 Changes
The SAP was updated to reflect changes in protocol amendments 3, 4 and 5, and add 
additional details to the analysis. Changes from version 1 are summarized below:
x
Sec 2.1, 4, 5, 6.1, 6.2 and 6.10: update per protocol amendments 3, 4 and 5
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x
Sec 5.3: add efficacy evaluable set for sensitivity analysis of the primary efficacy 
endpoint
x
Sec 6.4.3: update response assessment date algorithm following Paules 2011
x
Sec 6.4.5: add data handling rule for action taken with study treatment of AE
x
Sec 6.5 and Appendix C and D: add missing data handling rules for prior therapy and 
subsequent anticancer therapy dates 
x
Sec 6.8: update subgroup analysis to those based on important prognostic factors, and 
clarify subgroup analysis will not be performed for Cohort 2 at the time of the 
primary analysis of Cohort 1 
x
Sec 7.2: add summary of pre-existing conditions
x
Sec 7.4: update algorithm for duration of treatment 
x
Sec 7.5.1 and 7.5.2: add definition for time to response; add waterfall plot for 
maximum percent reduction in sum of diameters
x
Sec 7.5.2.1: add analysis to evaluate the concordance between investigator and IRF 
assessments
x
Sec 7.6.1: update AE summary to base on treatment-emergent events only
x
Sec 7.6.1.1: add additional details to the analysis of AESI
x
Sec 7.6.1.2: add analysis for slit lamp examinations
x
Sec 7.6.2: add summary of treatment-emergent laboratory abnormalities
x
Sec 7.6.2.1: add liver safety assessment
x
Sec 7.6.3: add summary of ECG parameters
x
Sec 7.7: move Patient Reported Outcomes, Pharmacokinetics, ATA, and Biomarkers 
endpoints to ‘Additional Analyses’ section 
x
Sec 7.7.3: add summary of geometric mean ratio of drug product manufacturing 
process for selected PK parameters
x
Sec 7.7.5: add summary of PD-L1 CPS and TCGA subtype
x
Appendix B: update TEAE algorithm to better reflect the definition of TEAEs
9.2.2 Version 3 Changes
The SAP was updated to reflect changes in protocol amendment 6. Changes from version 2 
are summarized below:
x
Sec 5.3: updated the definition of ‘efficacy-evaluable set’ to allow adequate follow up 
for response related endpoints at the time of interim analyses
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x
Sec 6.2 and 6.10: clarified the timing of Cohort 2 analyses and added additional 
interim analysis for Cohort 2 after approximately 70 subjects have been followed for 
approximately 8 months from the first dose of study drug
9.2.3 Version 4 Changes
Changes from version 3 are summarized below:
x
Corrected section numbing for 6.4.3, 6.4.4, and 6.4.5
x
Sec 6.8: clarified the number of subjects required in a subgroup to enable the 
subgroup analysis  
x
Sec 10: removed the references that were not cited in the SAP
x
Appendix B: added additional details to the TEAE definition to account for changes 
in seriousness or relatedness for events that continue from the baseline conditions
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10 REFERENCES
Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, Culine S, von der Maase H, Vaughn DJ 
and Rosenberg JE (2010). Prognostic factors in patients with advanced transitional cell carcinoma of 
the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol 28: 
1850-5.
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413.
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. London, 
Chapman & Hall: 237-251.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D and Verweij J (2009). New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 
228-47.
Paules M, Casey M, Williams G, Swann RS, Murphy PS, Salazar VM, Foose D, Bailey B, and Therasse P 
(2011). Recommendations for capture, validation and summarization of data from studies using 
RECIST. Eur J Cancer 47: 697-7.
Shaw JW, Johnson JA and Coons SJ (2005). US valuation of the EQ-5D health states: development and testing 
of the D1 valuation model. Med Care 43: 203-20.
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APPENDIX A: IMPUTATION OF PARTIAL MISSING ADVERSE EVENT DATES
The algorithm below should be used to impute pre-existing condition and adverse event (AE) 
start dates for which only partial information is known. For ease of reading, both pre-existing 
conditions and AEs will be referred to as AE for the remainder of this document. The 
algorithm should be applied to every AE record on a record by record basis. AE start dates 
should be imputed before imputation of AE condition end date in all cases. The AE condition 
end date should only be used in the imputation of the AE start date if it is a complete, known 
date.
AE day and month are missing
●
If the year is the same as the year of first dose of study treatment  and the onset period 
and/or onset time indicate that the start of the AE was pre-dose:
○
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of study treatment)
●
If the year is the same as the year of first dose of study treatment  and the onset period 
and/or onset time indicate that the start of the AE was post-dose:
○
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of study treatment)
●
If the year is before the year of first dose of study treatment:
○
AE start date will be imputed as the minimum of (AE condition end date*, 
December 31st see example 2 below)
●
If the year is after the year of first dose of study treatment:
○
AE start date will be imputed as the minimum of (AE condition end date*, 
January 31st see example 2 below)
AE month only is missing
●
Treat day as missing and replace both month and day according to the above 
procedure
AE day only is missing
●
If the month/year is the same as the month/year of first dose of study treatment and 
the onset period and/or onset time indicate that the start of the AE was pre-dose:
○
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of study treatment)
●
If the month/year is the same as the month/year of first dose of study treatment and 
the onset period and/or onset time indicate that the start of the AE was post-dose:
○
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of study treatment)
●
If the month/year is before the month/year of first dose of study treatment:
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○
AE start date will be imputed as the minimum of (AE condition end date*, last 
day of the month)
●
If the month/year is after the month/year of first dose of study treatment:
○
AE start date will be imputed as the minimum of (AE condition end date*, last day 
of the month)
* Only use condition end date if known and complete end date is available.
The following algorithm should be used to impute AE condition end dates. The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month. Repeat as necessary. 
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates:
For all records excluding the last chronological record for a condition/event
●
AE condition end date will be imputed as the start date of the subsequent record
For the last chronological record for a condition/event
●
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal” 
apply the following:
○
If only year is provided for the end date and year is equal to the year of the last 
dose date:
■
AE condition end date will be imputed as the minimum of (last dose date+30, 
death date, data extraction date, December 31st of the end date year)
○
If only year is provided for the end date and year is not equal to the year of the 
last dose date:
■
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, December 31st of the end date year)
○
If month and year are provided for the end date:
■
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, last day of the end date month/year)
●
If outcome is “recovering/resolving”, “not recovered/resolved”, “unknown”, or blank:
○
AE condition end date will not be imputed.
Example 1
AESPID 1: Condition/Event HEADACHE
First dose date 01JAN2012
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Prior to imputation
Start date
Condition end date
Severity
Outcome
Onset
UNUNK2011
15APR2012
1
not recovered/resolved
pre-ICF
15APR2012
UNMAY2012
2
recovering/resolving
post 1st dose
UNMAY2012
UNJUN2012
1
not recovered/resolved
post 1st dose
UNJUN2012
UNJUN2012
3
recovering/resolving
post 1st dose
UNJUN2012
10JUL2012
2
recovering/resolving
post 1st dose
10JUL2012
--
1
not recovered/resolved
post 1st dose
Post imputation
Start date
Condition end date
Severity
Outcome
31DEC2011
15APR2012
1
not recovered/resolved
15APR2012
31MAY2012
2
recovering/resolving
31MAY2012
30JUN2012
1
not recovered/resolved
30JUN2012
30JUN2012
3
recovering/resolving
30JUN2012
10JUL2012
2
recovering/resolving
10JUL2012
--
1
not recovered/resolved
Example 2 (highlights choice of last day of the month as opposed to the 1st or the 15th)
AESPID 4: Condition/Event NAUSEA
First dose date 01APR2012
Prior to imputation
Start date
Condition end date
Severity
Outcome
Onset
UNUNK2011
25APR2012
1
not recovered/resolved
pre-ICF
25APR2012
UNAPR2012
2
recovering/resolving
post 1st dose
UNAPR2012
04MAY2012
1
recovered/resolved
post 1st dose
Post imputation
Start date
Condition end date
Severity
Outcome
31DEC2011
25APR2012
1
not recovered/resolved
25APR2012
31APR2012
2
recovering/resolving
31APR2012
04MAY2012
1
recovered/resolved
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APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH 
RESPECT TO AE CLASSIFICATION
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE). A TEAE is defined as any AE which is 
newly occurring or worsening in severity, where newly occurring means that the AE was not 
present at baseline. For ease of reading, both pre-existing conditions and AEs will be referred 
to as AEs for the remainder of this document. AE dates should be imputed in accordance 
with the algorithm detailed in Appendix A prior to determination of TEAE classification. 
Details of the TEAE classification are as follows:
¾ For each subject, determine the first dose date, which is the earliest date the subject 
receives any amount of study drug.
¾ Baseline AEs: classify an AE record as baseline AE if it satisfies both criteria a and b 
below:
a
AE onset satisfies either of i, ii or iii below:
i.
Onset date is prior to the first dose date
ii.
Onset date is the same as the first dose date, and Onset Period is “started after 
consent but before the first dose of any study treatment” or Onset Time Relative 
to Study Treatment is “started before first infusion or before infusion on any 
dosing day”
iii.
Onset Period is “started before the signing of consent” or “started after consent 
but before the first dose of any study treatment”
b
AE end date satisfies either of i or ii below:
i.
End date is the same as or after the first dose date 
ii.
End date is missing with outcome equal to 
●
recovering/resolving, or
●
not recovered/not resolved, or 
●
unknown or missing
¾ Post-baseline AEs: classify an AE record as post-baseline AE if it meets either of criteria 
a, b or c below:
a
Onset date is after the first dose date
b
Onset date is the same as the first dose date, and Onset Period is “started after the first 
dose of any study treatment” or Onset Time Relative to Study Treatment is not 
“started before first infusion or before infusion on any dosing day”
c
Onset Period is “started after the first dose of any study treatment” 
Note: at interim timepoint, if an AE is classified as both ‘baseline AE’ and ‘post-
baseline AE’ due to data issues, the AE is to be considered ‘post-baseline AE’ in the 
derivation of TEAE flag.
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¾ TEAE flag will be derived as follows:
a.
For all AE records that have an end date prior to the first dose date, assign TEAE flag 
to ‘N’
b. For all baseline AEs, assign TEAE flag to ‘N’
c.
For post-baseline AEs where onset date is ≤30 days after last dose of study drug:
x
If the post-baseline AE is a continuing event of a baseline AE (i.e., events with 
the same AE identifier, where AE identifier is the number before the colon in 
SDTM AE.AESPID), then compare the CTCAE grade of the post-baseline AE to 
the CTCAE grade of the most recent baseline AE with the same AE identifier:
o
If the post-baseline AE has a higher CTCAE grade, then assign TEAE flag 
to ‘Y’. All subsequent episodes of the same AE should have TEAE flag = 
‘Y’ regardless of the CTCAE grade. If the CTCAE grade of the baseline 
AE is missing, then assign TEAE flag to ‘Y’.
o
Else if the relationship to study drug changes from ‘unrelated’ to ‘related’
post-baseline, then assign TEAE flag to ‘Y’.
o
Else if the seriousness of the AE changes from ‘No’ to ‘Yes’ post-
baseline, then assign TEAE flag to ‘Y’.
o
Otherwise, assign TEAE flag to ‘N’
x
If the post-baseline AE is not a continuing event of a baseline AE, then assign 
TEAE flag to ’Y’
NOTE:
¾ For summaries which include only treatment emergent AEs include all AEs which 
are classified as TEAEs as well as those AEs for which TEAE status could not be 
determined (e.g., the value of the TEAE variable may be missing if the event cannot 
be identified as baseline or post-baseline - missing information on the AE CRF 
should be queried). Only exclude those AEs which were determined to not be 
treatment emergent.
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APPENDIX C: IMPUTATION OF PARTIAL MISSING PRIOR THERAPY DATES
Prior therapy dates will be imputed if both month and year are present and only day is 
missing.
x
For prior therapy start date, impute the first day of the month. 
x
For prior therapy end date, impute the last day of the month or 14 days before the first 
dose of study drug, whichever is earlier. 
x
For date of progression on prior therapy, impute the last day of the month or the day 
before study enrollment, whichever is earlier.
After imputation rules are applied, use the following algorithm to determine if a prior therapy 
is to be included in the analysis:
x
For CPI:
o
Include all therapies in locally advanced/metastatic setting.
o
Include all therapies in neo-adjuvant/adjuvant setting that reason off therapy 
is PD or the best response to the therapy is PD.
o
Include all therapies in neo-adjuvant/adjuvant setting that date of progression 
or date of locally advanced/metastatic disease is within 3 months after 
therapy completion.
x
For platinum-based therapy:
o
Include all therapies in locally advanced/metastatic setting.
o
Include all therapies in neo-adjuvant/adjuvant setting that reason off therapy 
is PD or the best response to the therapy is PD.
o
Include all therapies in neo-adjuvant/adjuvant setting that date of progression 
or date of locally advanced/metastatic disease is within 12 months after 
therapy completion.

If month is missing for either prior therapy end date or PD date but 
year is the same for both dates, include the therapy in the analysis.
x
For non-CPI/non-platinum based therapy:
o
Include all therapies indicated as given in locally advanced/metastatic setting 
with the exception of intravesical treatment.
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APPENDIX D: IMPUTATION OF PARTIAL MISSING SUBSEQUENT 
ANTICANCER THERAPY START DATE
Subsequent anticancer therapy start date will be imputed if both month and year are present 
and only day is missing.
x
If the year of the subsequent anticancer therapy start date is the same as the year of 
the EOT date,
o
If the month of subsequent anticancer therapy start date is the same as the 
month of the EOT date, then the subsequent anticancer therapy start date will 
be imputed as the EOT date.
o
If the month of the subsequent anticancer therapy start date is later than the 
month of the EOT date, then the subsequent anticancer therapy start date will 
be imputed as the first day of the month.
o
If the month of the subsequent anticancer therapy start date is earlier than the 
month of the EOT date, then the subsequent anticancer therapy start date will 
be imputed as the last day of the month.
x
If the year of the subsequent anticancer therapy start date is later than the year of the 
EOT date, then the subsequent anticancer therapy start date will be imputed as the 
first day of the month.
If the EOT date is missing, then the EOT date will be the end-of-study (EOS) date or 30 days 
after the last dose of any study drug, whichever is earlier.
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