An Open-label, Randomized, Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy Alone in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer
Phase: PHASE3
Conditions: Urothelial Cancer
Sponsor: Astellas Pharma Global Development, Inc.



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PROTOCOL SYNOPSIS 
Protocol Number 
SGN22E-003 
Version 
Amendment 09; 29-Sep-2023 
Phase 
3 
Product Name 
Enfortumab vedotin  
Sponsor 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
An open-label, randomized, controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab 
versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer 
Study Objectives 
Primary Objectives 
Corresponding Dual Primary Endpoints 
● To compare progression-free survival (PFS) 
between the experimental arm (enfortumab 
vedotin + pembrolizumab [Arm A]) and the 
control arm (gemcitabine + cisplatin or 
carboplatin [Arm B]) by blinded independent 
central review (BICR) 
● PFS per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 by BICR 
● To compare overall survival (OS) between the 
experimental arm (Arm A) and the control arm 
(Arm B) 
● OS 
Secondary Objectives 
Corresponding Secondary Endpoints 
● To compare the objective response rate (ORR) 
between the experimental arm (Arm A) and 
the control arm (Arm B) by BICR 
● ORR per RECIST v1.1 by BICR 
● To compare time to pain progression (TTPP) 
from the subject perspective between the 
experimental arm (Arm A) and the control arm 
(Arm B) 
● TTPP 
● To compare average change in pain from the 
subject perspective between the experimental 
arm (Arm A) and the control arm (Arm B) 
● Mean change from baseline in worst pain at Week 26 
● To evaluate PFS between the experimental arm 
(Arm A) and the control arm (Arm B) by 
investigator assessment 
● PFS per RECIST v1.1 by investigator assessment 
● To evaluate ORR between the experimental 
arm (Arm A) and the control arm (Arm B) by 
investigator assessment 
● ORR per RECIST v1.1 by investigator assessment 

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● To evaluate the duration of response (DOR) 
between the experimental arm (Arm A) and 
the control arm (Arm B) 
● DOR per RECIST v1.1 by BICR 
● DOR per RECIST v1.1 by investigator assessment 
● To evaluate the disease control rate (DCR) 
between the experimental arm (Arm A) and 
the control arm (Arm B) 
● DCR per RECIST v1.1 by BICR 
● DCR per RECIST v1.1 by investigator assessment 
● To evaluate the impact of study treatment on 
quality of life (QOL), functioning, and 
symptoms from the subject perspective 
● Mean scores and change from baseline of the European 
Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Core 30 (QLQ-C30), and EuroQOL 
5-dimensions (EQ-5D-5L) visual analogue scale (VAS), and 
utility scores 
● To evaluate the safety profile of each treatment 
regimen 
● Type, incidence, relatedness, severity and seriousness of 
adverse events (AEs) 
● Type, incidence and severity of laboratory abnormalities 
● Treatment discontinuation rate due to AEs 
Exploratory Objectives 
Corresponding Exploratory Endpoints 
● To assess PFS, ORR, and DOR per the 
modified RECIST v1.1 for immune-based 
therapeutics (iRECIST) in Arm A 
● PFS, ORR, and DOR per iRECIST by investigator 
assessment in Arm A 
● To assess subject reported health resource 
utilization (HRU)  
● Cumulative incidence of HRU as reported by subject 
● To assess the pharmacokinetics (PKs) of 
enfortumab vedotin and monomethyl 
auristatin E (MMAE)  
● To assess the development of anti-therapeutic 
antibody (ATA) to enfortumab vedotin  
● Plasma or serum concentrations of enfortumab vedotin 
and MMAE  
● Incidence of ATA to enfortumab vedotin  
● To assess biomarkers of biological activity, 
resistance, and predictive biomarkers of 
response 
● Exploratory biomarkers of clinical activity 
Study Population 
The population to be studied includes subjects with histologically documented, unresectable, previously untreated 
locally advanced or metastatic urothelial cancer (UC) and measurable disease according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1.  
Eligible subjects must be ≥18 years of age, and must have an anticipated life expectancy of ≥12 weeks as assessed 
by the investigator. Subjects must not have received prior systemic therapy with the exceptions of neoadjuvant or 
adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. Subjects 
must have an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1, or 2, with adequate 
baseline hematologic, hepatic, and renal function. In addition, subjects must be considered eligible to receive 
cisplatin- or carboplatin-based chemotherapy and pembrolizumab, in the investigator’s judgment. 
Subjects with locally advanced urothelial cancer (UC) that is resectable with curative intent are not eligible. 
Subjects must not have received previous treatment with enfortumab vedotin or other monomethyl auristatin E 
(MMAE)-based antibody-drug conjugates (ADCs), or a checkpoint inhibitor, defined as a programmed cell death 
protein-1 (PD-1) inhibitor or programmed cell death ligand-1 (PD-L1) inhibitor (including, but not limited to, 
atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). Subjects must not have ongoing sensory or 

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motor neuropathy (Grade 2 or higher) or active central nervous system (CNS) metastases. Subjects must not have a 
history of another malignancy within 3 years or any evidence of residual disease from a previously diagnosed 
malignancy. Subjects are also excluded if they are currently receiving systemic antimicrobial treatment for active 
infection or high dose steroids. Subjects 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. 
Number of Planned Subjects 
Approximately 860 subjects (approximately 430 subjects per arm) will be randomized in the global portion of this 
study. After enrollment of the global portion of the study is completed, the study may remain open to enrollment 
in China alone until approximately 130 subjects in China (including those randomized in the global portion and 
China portion) have been randomized. 
Study Design 
This is a phase 3 open-label, 2-arm randomized, controlled multicenter study to evaluate the combination of 
enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in 
subjects with previously untreated locally advanced or metastatic UC. The study is designed to assess the dual 
primary endpoints of progression-free survival (PFS) and overall survival (OS) of experimental Arm A (enfortumab 
vedotin + pembrolizumab) compared to control Arm B (gemcitabine + cisplatin or carboplatin). Subjects will be 
randomized in a 1:1 manner to one of the study arms with the following stratification factors: cisplatin eligibility 
(eligible or ineligible), PD-L1 expression (high or low), and liver metastases (present or absent).  
Subjects in Arm A will receive enfortumab vedotin at 1.25 mg/kg, administered as an intravenous (IV) infusion on 
Days 1 and 8 of every 3-week cycle, and pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle, 
after completion of the enfortumab vedotin infusion. 
Subjects in Arm B will receive gemcitabine at 1000 mg/m2 as an IV infusion on Days 1 and 8 of every 3-week cycle. 
Cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4.5, or AUC of 5 according to local guidelines) will 
be administered on Day 1 of every 3-week cycle, with adequate pre- and post-hydration, by IV infusion per 
institutional standards. 
Response will be assessed by computed tomography (CT) scans with contrast (unless contraindicated) every 
9 weeks (±1 week) timed from the randomization date. For subjects who cannot receive CT scans with contrast, 
other protocol-specified imaging methods may be used Appendix C). Brain scans should be repeated at this time 
point in subjects with a history of CNS metastasis or signs/symptoms of CNS metastasis. Bone imaging should also 
be repeated at this time point in subjects with a history of skeletal metastasis or suspicion of skeletal metastases 
based on imaging or symptoms. Objective responses will be confirmed per RECIST v1.1 with repeat scans done at 
the next scheduled response assessment per protocol after first documentation of response. Subsequent response 
assessments should be performed every 9 weeks (±1 week) until 18 months after randomization, then every 
12 weeks (±1 week). Tumor imaging should also be performed, and blinded independent central review (BICR) 
evaluation triggered, whenever disease progression is suspected. 
Subjects may continue on study treatment until progressive disease (BICR-confirmed or clinical progression [see 
Section 7.3]), an adverse event (AE), pregnancy, investigator decision, start of a subsequent anticancer therapy, 
subject decision (non-AE), study termination by the sponsor, completion of the maximum number of drug cycles 
allowed, or other reason unrelated to an AE (see Section 4.3). Treatment beyond disease progression per RECIST 
v1.1 may be considered in subjects in study Arm A (enfortumab vedotin [EV] + pembrolizumab) who are deriving 
clinical benefit as defined in Section 5.8. Subjects treated beyond disease progression per RECIST v1.1 may continue 
until confirmed disease progression per modified RECIST 1.1 for immune-based therapeutics (iRECIST) as assessed 
by the investigator (Seymour 2017) (Appendix K). Confirmatory scans must be performed 4 to 9 weeks after disease 
progression per RECIST v1.1 by BICR. Treatment with gemcitabine and treatment with platinum-containing 
chemotherapy may be given up to 6 cycles. Treatment with pembrolizumab will be discontinued once the subject 
has received a maximum of 35 administrations (approximately 2 years). There is no upper limit to the number of 
cycles of enfortumab vedotin permitted. Palliative radiotherapy on a nontarget bone lesion that is not progressing 

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is permitted and will not be considered a subsequent anticancer therapy; however, radiotherapy on any new or 
progressing lesion, per RECIST v1.1 as assessed by the investigator or after BICR-confirmed progression, will be 
considered a subsequent anticancer therapy and subjects will not be permitted to resume study treatment. Surgical 
resection for curative intent during study treatment may be permitted in subjects with favorable tumor response 
after discussion with the medical monitor.  
Subjects who discontinue treatment for reasons other than disease progression or consent withdrawal will 
continue to receive response assessments every 9 weeks (±1 week) for the first 18 months timed from the 
randomization date, and every 12 weeks (±1 week) thereafter, until the subject has radiologically-confirmed disease 
progression per RECIST v1.1 guidelines as determined by BICR, dies, withdraws consent, or the study closes, 
whichever occurs first. Subjects who initiate a subsequent anticancer therapy but do not have disease progression 
per BICR will continue to receive response assessments until radiologically-confirmed progression per BICR, death, 
consent withdrawal, or the study closes, whichever occurs first. After discontinuation of study treatment, all 
randomized subjects will be followed every 12 weeks (±1 week) to obtain information on subsequent anticancer 
therapy, and to assess survival status until death, study closure, lost to follow-up, or subject withdraws consent, 
whichever occurs first.  
Safety will be monitored over the course of the study by an Independent Data Monitoring Committee (IDMC). 
Investigational Product, Dose, and Mode of Administration 
Enfortumab vedotin (Arm A)  
Enfortumab vedotin 1.25 mg/kg will be administered as an IV infusion over approximately 30 minutes on Days 1 
and 8 of every 3-week cycle.  
Pembrolizumab (Arm A)  
Pembrolizumab 200 mg will be administered as an IV infusion after completion of the enfortumab vedotin Arm A. 
Infusion on Day 1 of every 3-week cycle.  
Cisplatin (Arm B)  
On Day 1 (or Day 2 if required per institutional guidelines) of each 3-week cycle, cisplatin 70 mg/m2 will be 
administered (with adequate pre- and post-hydration) as an IV infusion per institutional standards. The body 
surface area used to calculate cisplatin dose may be capped per institutional standards.  
Carboplatin (Arm B) 
On Day 1 of each 3-week cycle, carboplatin at AUC 4.5, or AUC of 5 according to local guidelines, will be 
administered (with adequate pre- and post-hydration) as an IV infusion per institutional standards. Body weight 
used to calculate carboplatin may be capped as per institutional standards. 
Gemcitabine (Arm B)  
On Days 1 and 8 of each 3-week cycle, gemcitabine at 1000 mg/m2 will be administered as an IV infusion. 
Duration of Treatment 
Subjects should continue on study treatment until one of the following protocol-defined reasons for treatment 
discontinuation occur: progressive disease (BICR-confirmed or clinical progression [see Section 7.3]), an AE, 
pregnancy, investigator decision, start of a subsequent anticancer therapy, subject decision(non-AE), study 
termination by the sponsor, completion of the maximum number of drug cycles allowed, or other reason unrelated 
to an AE.  
Pembrolizumab may be administered for up to a maximum of 35 cycles.  
Cisplatin, carboplatin, and/or gemcitabine may be administered for up to a maximum of 6 cycles. 

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Maintenance therapy (eg, avelumab) may be used following completion and/or discontinuation of 
platinum-containing therapy, if locally available, and provided the subject is deemed appropriate by the 
investigator (see Section 4.3.1).  
Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for 
treatment discontinuation occurs. In Arm A, subjects who experience an unacceptable AE that is attributable only 
to pembrolizumab may continue on enfortumab vedotin monotherapy until a protocol-defined reason for 
treatment discontinuation. Subjects who experience an unacceptable AE that is attributable only to enfortumab 
vedotin may continue on pembrolizumab monotherapy up to a maximum of 35 cycles.  
In Arm B, subjects who experience an unacceptable AE that is attributable only to platinum-containing 
chemotherapy may continue on gemcitabine monotherapy for up to 6 cycles. Subjects who experience an 
unacceptable AE that is attributable only to gemcitabine may continue on platinum-containing chemotherapy for 
up to 6 cycles. 
Efficacy Assessments 
Computed tomography scans with contrast (unless contraindicated), including chest, abdomen, and pelvis at the 
minimum, will be used to assess antitumor activity at protocol-specified time points. Subjects must receive the 
same imaging method throughout the study for response assessments. For subjects who cannot receive CT scans 
with contrast, other protocol-specified imaging methods may be used (see Appendix C). Bone imaging and/or brain 
scans should be repeated at disease assessment time points, and as clinically indicated throughout the study, in 
subjects with a history of skeletal metastasis or suspicion of skeletal metastasis based on imaging or symptoms, or 
a history of CNS metastasis or signs/symptoms of CNS metastasis. Objective responses will be confirmed per RECIST 
v1.1 by BICR with repeat scans done at the next scheduled scan per protocol, after first documentation of response.  
Pharmacokinetic and Immunogenicity Assessments 
Blood samples for pharmacokinetic (PK) and anti-therapeutic antibody (ATA) analyses will be collected for Arm A 
only, at specific time points. Validated or qualified assays will be used to measure the concentrations of enfortumab 
vedotin and MMAE in serum or plasma. A validated assay will be used to determine ATA for enfortumab vedotin in 
serum. Pharmacokinetic and ATA samples for pembrolizumab will be collected.  
Biomarker Assessments 
Biomarker assessments will be performed from archival or fresh tumor tissue, peripheral blood and urine. Subjects 
will be stratified by PD-L1 status, as determined by the Dako/Agilent PD-L1 immunohistochemistry (IHC) 22C3 
PharmDx on tumor biospecimens. Other biomarker assessments may include central assessment of Nectin-4 
expression by IHC, and Next Generation Sequencing for assessment of tumor subtyping and mutations associated 
with response to enfortumab vedotin in metastatic UC.  
Safety Assessments 
Safety assessments will include surveillance and recording of AEs, including serious adverse events (SAEs), 
concomitant medications, physical examination findings, vital signs, protocol-specified laboratory tests, ECOG 
status, electrocardiograms (ECGs), ophthalmologic examination findings and pregnancy testing. Safety will be 
monitored over the course of the study by the IDMC. 
Other Assessments 
Patient-reported outcome (PRO) assessments will include quality of life (QOL) measures, both general and oncology 
specific (EuroQOL 5-dimensions [EQ-5D-5L] and European Organisation for Research and Treatment of Cancer 
[EORTC] Quality of Life Core 30 [QLQ-C30] Questionnaire, respectively), as well as outcome specific PROs around 
pain (Brief Pain Inventory-Short Form [BPI-SF]). Impact on pain may also be correlated to pain medication use 
collected in the case report form (CRF). A health resource utilization (HRU) questionnaire will also aim to measure 
clinical burden outside of the clinical trial setting.  

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Statistical Methods 
Stratification 
Subject will be stratified based on the following variables: 
1. Cisplatin eligibility (eligible or ineligible) 
2. PD-L1 expression by IHC (High [combined positive score (CPS) ≥10] or Low [CPS <10]) 
3. Liver metastases (present or absent) 
Multiplicity 
The proposed 2-arm study will have dual primary endpoints of PFS and OS. The study can be considered positive if 
enfortumab vedotin plus pembrolizumab (Arm A) is superior to the control arm (Arm B) in either PFS or OS. A 
graphical approach with group sequential testing outlined in Maurer and Bretz (Maurer 2013) will be used to 
strongly control the family-wise type I error rate at a two-sided 5% level.  
The initial alpha allocation for the dual primary endpoints of PFS and OS are 0.5% and 4.5%, respectively. If only 
1 of the primary endpoints is statistically significant at the specified level, alpha recycling will be applied to evaluate 
the other primary endpoint at the 5% significance level. 
When the null hypotheses for PFS and OS are both rejected, selected secondary endpoints will be tested in the 
following order using a gatekeeping testing strategy: 
1. ORR by BICR 
2. Time to pain progression (TTPP) 
3. Mean change from baseline in worst pain at Week 26  
Each test will be at the 5% significance level (2-sided) as long as all preceding null hypotheses are rejected. These 
secondary endpoints will only be tested once at either the OS interim or final analysis after the null hypotheses for 
PFS and OS are both rejected, and the test statistics for inferential testing will be computed from the data at the 
time of OS interim analysis (IA). In the event that only the null hypothesis for PFS is rejected and the superiority 
boundary for OS has not been crossed at the time of OS IA, these secondary endpoints will not be tested and will 
only be analyzed descriptively. 
Sample Size Considerations 
Approximately 860 subjects will be randomized in a 1:1 ratio to one of the study arms.  
With 430 subjects per arm, the estimated number of OS events between Arm A and Arm B is 489, providing 93% 
power to demonstrate superiority at a two-sided alpha of 4.5% with 1 IA around 72.8% information fraction under 
the following assumptions: 
4. OS curves follow piecewise exponential distribution with a reduced hazard rate (50% of the initial rate) 
starting from 24 months 
5. hazard ratio (HR) of OS is 0.73 between the experimental and control arms  
6. median OS for the control arm is 15.3 months 
7. an enrollment period of 30 months  
8. a yearly dropout rate of 5%  
The number of PFS events between the 2 arms is estimated to be 526 events, providing 90% power to demonstrate 
superiority at a two-sided alpha of 0.5% with 430 subjects per arm based on the following assumptions:  

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1. PFS curves follow piecewise exponential distribution with a reduced hazard rate (20% of the initial 
rate) starting from 15 months  
2. HR of PFS is 0.70 between the experimental and the control arms  
3. median PFS for the control arm is 7 months  
4. an enrollment period of 30 months  
5. a yearly dropout rate of 5%  
To evaluate the consistency of efficacy and safety in a China subpopulation compared with the global population, 
after completion of enrollment in the global portion, subjects in China may continue to be randomized in a 1:1 ratio 
to either the experimental arm or the control arm until the planned sample size of approximately 130 subjects in 
China is reached, including those randomized in the global portion and China portion. Subjects in China randomized 
after completion of enrollment in the global portion will not be included in the analysis of the global portion. 
Timing of Analyses 
A single planned analysis (final analysis) for PFS will take place when approximately 526 PFS events or 356 OS 
events (72.8% information fraction) in the intent-to-treat (ITT) analysis set have occurred, whichever is later.  
Two analyses are planned for OS. OS IA is planned at the time of the final PFS analysis. At IA, the OS events in total 
will be approximately356 (about 72.8% of information). O’Brien-Fleming boundaries will be used to calculate the 
rejection boundaries based on the actual information fraction observed. The final OS analysis is planned when 
approximately 489 OS events have occurred in total. 
Analysis Methods 
Efficacy 
The ITT analysis set will be used for the primary analysis of OS and PFS. All subjects who are randomized will be 
included in the ITT analysis set. For primary endpoints of OS and PFS, a log-rank test stratified by randomization 
stratification factors will be used to compare the experimental arm to the control arm. The estimated HR and 
corresponding 95% confidence interval from the stratified Cox proportional hazards regression model will also be 
presented. The median survival time will be estimated using the Kaplan-Meier method and will be reported along 
with the corresponding 95% confidence interval by treatment arm. Similar estimation methods will be used for the 
other time-to-event endpoints. Duration of response (DOR) will be summarized descriptively by Kaplan-Meier 
methods for subjects with a confirmed response (complete response or partial response per RECIST v1.1). ORR, 
DCR, and DOR will be analyzed using the response evaluable set. 
Objective response rate and disease control rate will be estimated for each arm based on the response evaluable 
set. P-value comparing between experimental arm and the control arm using the Cochran Mantel-Haenszel test 
stratified by randomization stratification factors will be reported.  
Safety 
The frequency of AEs and SAEs will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class (SOC) and preferred term. In addition, summary statistics or listings will be provided for the 
following safety parameters: laboratory values, vital sign measurements, ECGs, and ECOG performance status. 
Pharmacokinetics 
Descriptive statistics will be provided for antibody drug-conjugate and unconjugated drug (MMAE) concentrations 
in Arm A and Arm C at each PK sampling time point. Any additional PK and PK/pharmacodynamic analyses may be 
described in a separate analysis plan and presented in a separate report. 
Pembrolizumab PK and immunogenicity analyses will be performed only if required. If pembrolizumab analysis are 
performed, the PK and immunogenicity results will be presented in a separate report. 
The incidence of ATA will be summarized.  

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Patient-Reported Outcomes 
Completion and compliance rates along with change from baseline for each domain of the PROs, including EQRTC 
QLQ-C30, EQ-5D-5L, and BPI-SF will be summarized. Cumulative incidence of HRU, including length of stay, 
hospitalizations, and emergency room (ER) visits will be summarized by treatment arm and by cycle. Additionally, 
TTPP and mean changes from baseline in worst pain at Week 26 will be evaluated. 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................................. 3 
LIST OF IN-TEXT TABLES ...................................................................................................................................... 15 
LIST OF IN-TEXT FIGURES .................................................................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................................. 16 
1. 
INTRODUCTION ................................................................................................................................ 20 
1.1. 
Urothelial Cancer .................................................................................................................................. 20 
1.1.1. 
Metastatic Urothelial Cancer ............................................................................................... 20 
1.2. 
Nectin-4 as a Target in Urothelial Cancer ............................................................................................ 21 
1.3. 
Enfortumab Vedotin ............................................................................................................................. 21 
1.3.1. 
Enfortumab Vedotin Monotherapy in Urothelial Cancer .................................................... 22 
1.4. 
Pembrolizumab ..................................................................................................................................... 24 
1.4.1. 
Pharmaceutical and Therapeutic Background ..................................................................... 25 
1.5. 
Enfortumab Vedotin and Pembrolizumab in Combination ................................................................... 25 
1.5.1. 
EV-103 (SGN22E-002) ....................................................................................................... 26 
1.6. 
Enfortumab Vedotin, Chemotherapy, and Pembrolizumab in Previously Untreated Locally 
Advanced or Metastatic Urothelial Carcinoma ..................................................................................... 28 
1.7. 
Assessment of Benefit-Risk .................................................................................................................. 29 
2. 
OBJECTIVES ....................................................................................................................................... 30 
3. 
INVESTIGATIONAL PLAN ............................................................................................................... 32 
3.1. 
Summary of Study Design .................................................................................................................... 32 
3.1.1. 
China Portion of the Study .................................................................................................. 34 
3.2. 
Discussion and Rationale for Study Design .......................................................................................... 34 
3.2.1. 
Rationale for Endpoints ....................................................................................................... 34 
3.2.2. 
Rationale for Study Population ............................................................................................ 35 
3.2.2.1. 
Rationale for Enrollment of a Biomarker-Unselected Population ............................ 35 
3.2.3. 
Rationale for Control Arm Selection and Stratification Factors .......................................... 36 
3.2.4. 
Method of Assigning Subjects to Treatment Groups ........................................................... 37 
3.2.5. 
Rationale for Selection of Doses ......................................................................................... 37 
3.2.6. 
Blinding and Unblinding ..................................................................................................... 38 
3.3. 
Overall End of Study ............................................................................................................................ 38 
4. 
STUDY POPULATION ....................................................................................................................... 38 
4.1. 
Inclusion Criteria .................................................................................................................................. 38 
4.2. 
Exclusion Criteria ................................................................................................................................. 41 
4.3. 
Removal of Subjects From Therapy or Assessment ............................................................................. 44 
4.3.1. 
Discontinuation of Study Treatment .................................................................................... 44 
4.3.2. 
Subject Discontinuation From Study ................................................................................... 45 
5. 
TREATMENTS .................................................................................................................................... 45 
5.1. 
Treatments Administered ...................................................................................................................... 45 
5.2. 
Investigational Product ......................................................................................................................... 46 
5.2.1. 
Description .......................................................................................................................... 46 
5.2.2. 
Method of Procurement ....................................................................................................... 46 
5.2.3. 
Dose and Administration ..................................................................................................... 46 
5.2.4. 
Dose Modifications.............................................................................................................. 47 
5.2.5. 
Storage and Handling .......................................................................................................... 52 
5.2.6. 
Packaging and Labeling ....................................................................................................... 52 
5.2.7. 
Preparation ........................................................................................................................... 52 
5.3. 
Pembrolizumab ..................................................................................................................................... 52 
5.3.1. 
Description .......................................................................................................................... 52 
5.3.2. 
Method of Procurement ....................................................................................................... 53 
5.3.3. 
Dose and Administration ..................................................................................................... 53 

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5.3.4. 
Dose Modifications.............................................................................................................. 53 
5.3.4.1. 
Dose Delays and Toxicity Management for Immune-related Adverse Events 
Associated with Pembrolizumab .............................................................................. 53 
5.3.4.2. 
Dose Delays and Toxicity Management of Infusion-reactions Related to 
Pembrolizumab ........................................................................................................ 56 
5.3.5. 
Storage and Handling .......................................................................................................... 57 
5.3.6. 
Packaging and Labeling ....................................................................................................... 57 
5.3.7. 
Preparation ........................................................................................................................... 57 
5.4. 
Other Allowed Dose Delays for Enfortumab Vedotin and Pembrolizumab ......................................... 57 
5.5. 
Cisplatin ................................................................................................................................................ 58 
5.5.1. 
Description .......................................................................................................................... 58 
5.5.2. 
Method of Procurement ....................................................................................................... 58 
5.5.3. 
Dose and Administration ..................................................................................................... 58 
5.5.3.1. 
Dosage with Renal Impairment ................................................................................ 59 
5.5.4. 
Storage and Handling .......................................................................................................... 59 
5.5.5. 
Packaging and Labeling ....................................................................................................... 59 
5.5.6. 
Preparation ........................................................................................................................... 59 
5.6. 
Carboplatin ........................................................................................................................................... 59 
5.6.1. 
Description .......................................................................................................................... 59 
5.6.2. 
Method of Procurement ....................................................................................................... 60 
5.6.3. 
Dose and Administration ..................................................................................................... 60 
5.6.3.1. 
Dosage for Renal Impairment .................................................................................. 61 
5.6.4. 
Storage and Handling .......................................................................................................... 61 
5.6.5. 
Packaging and Labeling ....................................................................................................... 61 
5.6.6. 
Preparation ........................................................................................................................... 61 
5.7. 
Gemcitabine .......................................................................................................................................... 61 
5.7.1. 
Description .......................................................................................................................... 61 
5.7.2. 
Method of Procurement ....................................................................................................... 62 
5.7.3. 
Dose and Administration ..................................................................................................... 62 
5.7.4. 
Dose Modifications.............................................................................................................. 62 
5.7.5. 
Storage and Handling .......................................................................................................... 62 
5.7.6. 
Packaging and Labeling ....................................................................................................... 62 
5.7.7. 
Preparation ........................................................................................................................... 62 
5.8. 
Treatment Duration ............................................................................................................................... 62 
5.9. 
Concomitant Therapy ........................................................................................................................... 63 
5.9.1. 
Required Concomitant Therapy ........................................................................................... 64 
5.9.2. 
Allowed Concomitant Therapy ............................................................................................ 64 
5.9.3. 
Prohibited Concomitant Therapy ......................................................................................... 65 
5.10. 
Management of Adverse Reactions ...................................................................................................... 65 
5.10.1. 
Overlapping Adverse Reactions .......................................................................................... 65 
5.10.2. 
Management of Infusion Reactions ..................................................................................... 66 
5.10.2.1. 
Enfortumab Vedotin ................................................................................................. 66 
5.10.2.2. 
Pembrolizumab ........................................................................................................ 66 
5.10.2.3. 
Infusion-related Reaction of Uncertain Cause ......................................................... 66 
5.10.3. 
Supportive Care Guidelines for Pembrolizumab ................................................................. 67 
5.10.4. 
Management of Hyperglycemia .......................................................................................... 67 
5.10.5. 
Management of Rash Related to Enfortumab Vedotin ........................................................ 68 
5.10.6. 
Management of Pneumonitis/ILD Related to Enfortumab Vedotin .................................... 68 
5.10.7. 
Management of Overdose .................................................................................................... 68 
5.10.7.1. 
Enfortumab Vedotin ................................................................................................. 68 
5.10.7.2. 
Pembrolizumab ........................................................................................................ 69 
5.10.7.3. 
Cisplatin ................................................................................................................... 69 
5.10.7.4. 
Carboplatin ............................................................................................................... 69 
5.10.7.5. 
Gemcitabine ............................................................................................................. 69 
5.11. 
Treatment Compliance .......................................................................................................................... 69 

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6. 
STUDY ACTIVITIES .......................................................................................................................... 69 
6.1. 
Schedule of Events ............................................................................................................................... 69 
6.2. 
Screening and Baseline Visits ............................................................................................................... 70 
6.2.1. 
Days –42 to Randomization................................................................................................. 70 
6.2.2. 
Days –28 to Randomization................................................................................................. 70 
6.2.3. 
Days –7 to Randomization................................................................................................... 71 
6.2.4. 
Days –3 to Day 1 ................................................................................................................. 71 
6.3. 
Treatment Period (Day 1 to Day 21) ..................................................................................................... 71 
6.3.1. 
Day 1 (±2 days beginning with Cycle 2) ............................................................................. 71 
6.3.2. 
Day 8 (–1 to +4 days) .......................................................................................................... 72 
6.3.3. 
Day 15 (±1 day) Cycles 1 and 2 only .................................................................................. 73 
6.3.4. 
Response Assessments ........................................................................................................ 73 
6.4. 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................... 74 
6.5. 
Follow-up (Every 9 Weeks [±1 week])................................................................................................. 74 
6.6. 
Survival Follow-up (Every 12 weeks [±1 week]) ................................................................................. 75 
6.7. 
Subject End of Study/End of Follow-up ............................................................................................... 75 
7. 
STUDY ASSESSMENTS .................................................................................................................... 75 
7.1. 
Screening/Baseline Assessments .......................................................................................................... 75 
7.2. 
Randomization ...................................................................................................................................... 75 
7.3. 
Response/Efficacy Assessments ........................................................................................................... 76 
7.4. 
Pharmacokinetic and Immunogenicity Assessments ............................................................................ 78 
7.5. 
Biomarker Studies ................................................................................................................................ 78 
7.6. 
Biospecimen Repository ....................................................................................................................... 80 
7.7. 
Electronic Patient-Reported Outcomes (ePRO) .................................................................................... 80 
7.7.1. 
EORTC Core Quality of Life (QLQ-C-30) Questionnaire .................................................. 81 
7.7.2. 
EuroQOL-5 Dimensions (EQ-5D-5L) ................................................................................. 81 
7.7.3. 
Brief Pain Inventory – Short Form (BPI-SF) ....................................................................... 81 
7.7.4. 
Health Resource Utilization ................................................................................................. 82 
7.8. 
Safety Assessments ............................................................................................................................... 82 
7.8.1. 
Adverse Events .................................................................................................................... 82 
7.8.1.1. 
Definitions ................................................................................................................ 82 
7.8.1.2. 
Procedures for Eliciting and Recording Adverse Events ......................................... 84 
7.8.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events ....................... 87 
7.8.1.4. 
Serious Adverse Events Require Immediate Reporting ........................................... 87 
7.8.1.5. 
Sponsor Reporting Requirements ............................................................................. 87 
7.8.1.6. 
Adverse Events of Special Interest ........................................................................... 88 
7.8.2. 
Physical Examination .......................................................................................................... 89 
7.8.3. 
Vital Signs ........................................................................................................................... 89 
7.8.4. 
Clinical Laboratory Tests .................................................................................................... 89 
7.8.5. 
ECOG Status ....................................................................................................................... 90 
7.8.6. 
Cardiac Monitoring.............................................................................................................. 90 
7.8.7. 
Ophthalmologic Examination .............................................................................................. 90 
7.8.8. 
Pregnancy Testing ............................................................................................................... 90 
7.9. 
Post-treatment Assessments .................................................................................................................. 90 
7.9.1. 
Follow-up Assessments ....................................................................................................... 90 
7.9.2. 
Survival Follow-up Assessments ......................................................................................... 91 
7.10. 
Appropriateness of Measurements ........................................................................................................ 91 
8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 92 
8.1. 
Site Training and Monitoring Procedures ............................................................................................. 92 
8.2. 
Data Management Procedures .............................................................................................................. 93 
8.3. 
Access to Source Data .......................................................................................................................... 93 
8.4. 
Accuracy and Reliability of Data .......................................................................................................... 93 
8.5. 
Quality Assurance Procedures .............................................................................................................. 93 
8.6. 
Data Handling and Record Keeping ..................................................................................................... 93 
8.6.1. 
Data Handling ...................................................................................................................... 93 

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8.6.2. 
Investigator Record Retention ............................................................................................. 94 
9. 
DATA ANALYSIS METHODS .......................................................................................................... 94 
9.1. 
Determination of Sample Size .............................................................................................................. 94 
9.1.1. 
China Portion of the Study .................................................................................................. 95 
9.2. 
Study Efficacy Endpoint Definitions .................................................................................................... 95 
9.2.1. 
Progression-Free Survival Per BICR ................................................................................... 95 
9.2.2. 
Overall Survival ................................................................................................................... 96 
9.2.3. 
Objective Response Rate ..................................................................................................... 96 
9.2.4. 
Disease Control Rate ........................................................................................................... 96 
9.2.5. 
Duration of Response .......................................................................................................... 96 
9.2.6. 
Progression-Free Survival Per Investigator Assessment ..................................................... 96 
9.3. 
Statistical and Analytical Plans ............................................................................................................. 96 
9.3.1. 
General Considerations ........................................................................................................ 97 
9.3.1.1. 
Randomization and Blinding .................................................................................... 97 
9.3.1.2. 
Adjustments for Covariates ...................................................................................... 97 
9.3.1.3. 
Handling of Dropouts and Missing Data .................................................................. 97 
9.3.1.4. 
Multicenter Studies .................................................................................................. 97 
9.3.1.5. 
Multiple Comparisons and Multiplicity ................................................................... 97 
9.3.1.6. 
Data Transformations and Derivations ..................................................................... 99 
9.3.1.7. 
Analysis Sets ............................................................................................................ 99 
9.3.1.8. 
Examination of Subgroups ....................................................................................... 99 
9.3.1.9. 
Interim Analysis ....................................................................................................... 99 
9.3.2. 
Subject Disposition ............................................................................................................ 100 
9.3.3. 
Subject Characteristics ...................................................................................................... 100 
9.3.4. 
Efficacy Analyses .............................................................................................................. 100 
9.3.5. 
Pharmacokinetic and Immunogenicity Analyses ............................................................... 101 
9.3.6. 
Biomarker Analyses .......................................................................................................... 101 
9.3.7. 
Patient-Reported Outcomes Analyses ............................................................................... 101 
9.3.7.1. 
Time to Pain Progression ....................................................................................... 101 
9.3.7.2. 
Mean Change from Baseline in Worst Pain at Week 26 ........................................ 102 
9.3.8. 
Safety Analyses ................................................................................................................. 102 
9.3.8.1. 
Extent of Exposure ................................................................................................. 102 
9.3.8.2. 
Adverse Events....................................................................................................... 102 
9.3.8.3. 
Deaths and Serious Adverse Events ....................................................................... 102 
9.3.8.4. 
Clinical Laboratory Results .................................................................................... 102 
9.3.8.5. 
Other Safety Analyses ............................................................................................ 102 
10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS .......................................................................................................................... 103 
10.1. 
Informed Consent ............................................................................................................................... 103 
10.2. 
Ethical Review .................................................................................................................................... 103 
10.3. 
Regulatory Considerations .................................................................................................................. 104 
10.3.1. 
Investigator Information .................................................................................................... 104 
10.3.2. 
Protocol Amendments and Study Termination .................................................................. 104 
10.4. 
Study Documentation, Privacy and Records Retention ...................................................................... 104 
10.5. 
Clinical Trial Agreement .................................................................................................................... 104 
11. 
REFERENCES ................................................................................................................................... 105 
APPENDIX A. 
SCHEDULE OF EVENTS ................................................................................................ 108 
APPENDIX B. 
PERFORMANCE STATUS SCALES CONVERSION ................................................... 111 
APPENDIX C. 
SCANNING AND CONTRAST OPTIONS ..................................................................... 112 
APPENDIX D. 
NEW YORK HEART ASSOCIATION CLASSIFICATION ........................................... 113 
APPENDIX E. 
LIVER SAFETY MONITORING AND ASSESSMENT* ............................................... 114 

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APPENDIX F. 
EORTC QLQ-C30 ............................................................................................................. 116 
APPENDIX G. 
EQ-5D-5L .......................................................................................................................... 118 
APPENDIX H. 
BPI-SF ............................................................................................................................... 120 
APPENDIX I. 
HEALTH RESOURCE UTILIZATION ........................................................................... 122 
APPENDIX J. 
RECIST CRITERIA VERSION 1.1 .................................................................................. 123 
APPENDIX K. 
IRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN TRIALS 
TESTING IMMUNOTHERAPEUTICS ............................................................................................ 125 
APPENDIX L. 
GUIDANCE ON CONTRACEPTION ............................................................................. 127 
APPENDIX M. 
MANAGEMENT OF EXISTING ARM C SUBJECTS (US ONLY) ............................... 128 
APPENDIX N. 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 129 
APPENDIX O. 
DOCUMENT HISTORY .................................................................................................. 130 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Summary of best overall response by investigator assessment per RECIST v1.1-full analysis 
set: 1L enfortumab vedotin 1.25 mg/kg + pembrolizumab ................................................................... 28 
Table 2: 
Objectives and corresponding endpoints .............................................................................................. 31 
Table 3: 
Baseline laboratory values .................................................................................................................... 40 
Table 4: 
Interventions and treatment arms .......................................................................................................... 46 
Table 5: 
Recommended dose modification for enfortumab vedotin-associated hematologic toxicity ................ 48 
Table 6: 
Recommended dose modifications for enfortumab vedotin-associated nonhematologic 
toxicity .................................................................................................................................................. 49 
Table 7: 
Guidelines for management of pembrolizumab immune-related adverse events ................................. 54 
Table 8: 
Pembrolizumab infusion reaction dose modifications and treatment guidelines .................................. 56 
Table 9: 
Dose modifications for cisplatin toxicity .............................................................................................. 59 
Table 10: 
Dose modification for carboplatin toxicity ........................................................................................... 61 
Table 11: 
Imaging and treatment after first radiologic evidence of progressive disease ...................................... 76 
Table 12: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points ............................... 79 
Table 13: 
Electronic Patient-Reported Outcomes Schedule of Events ................................................................. 80 
Table 14: 
Summary of timing of analyses and estimated rejection boundaries .................................................. 100 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study design ......................................................................................................................................... 34 
Figure 2: 
Initial graph of multiplicity adjustment (2-sided FWER=5%).............................................................. 98 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
1L 
first-line 
2L 
second-line 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin 
AST 
aspartate aminotransferase 
ATAs 
Anti-therapeutic antibodies 
AUC 
area under the curve 
β-hCG 
beta human chorionic gonadotropin  
BICR 
blinded independent central review 
BPI-SF 
Brief Pain Inventory – Short Form 
CBC 
complete blood count 
CD3ζ 
CD3 zeta 
CI 
confidence interval 
CNS 
central nervous system 
CPS 
combined positive score 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTA 
Clinical Trial Agreement 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 

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eCRF 
electronic case report form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of treatment 
ePROs 
electronic patient-reported outcomes 
EQ-5D-5L 
EuroQOL 5-dimensions 
EU 
European Union 
EV 
enfortumab vedotin 
FA 
final analysis 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
GFR 
glomerular filtration rate 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HR 
hazard ratio 
HRU 
health resource utilization 
IA 
interim analysis 
ICD 
immunogenic cell death 
ICH 
International Council for Harmonisation  
iCPD 
confirmed immune progressive disease 
IDMC 
Independent Data Monitor Committee 
IEC 
independent ethics committee 
Ig 
immunoglobulin  
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
imAE 
immune-mediated adverse events 
IND 
investigational new drug 
INR 
international normalized ratio 
iRECIST 
modified RECIST 1.1 for immune-based therapeutics 
IRB 
institutional review board 
IRR 
infusion related reaction 
IRT 
Interactive Response Technology 
ITT 
intent-to-treat 
iUPD 
unconfirmed immune progressive disease 
IV 
intravenous 

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LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MMRM 
mixed model for repeated measures 
mOS 
median overall survival 
mPFS 
median progression-free survival 
MRI 
magnetic resonance imaging 
mUC 
metastatic urothelial cancer 
MUGA 
multiple-gated acquisition 
MVAC 
methotrexate, vinblastine, doxorubicin, cisplatin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NLT 
new lesions-target 
NLNT 
new lesion-non-target 
NSAID 
nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death ligand-1 
PD-L2 
programmed cell death ligand-2 
Pembro 
pembrolizumab 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PKCθ 
protein kinase C-theta 
PN 
peripheral neuropathy 
PO 
by mouth 
PR 
partial response 
PRO 
patient-reported outcome 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QLQ-C30 
Quality of Life Core 30 
QOL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 

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SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SJS 
Stevens-Johnson Syndrome 
SmPC 
Summary of Product Characteristics 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
SSQ 
sponsor specified query 
SUSARs 
suspected unexpected serious adverse reactions 
T1DM 
type 1 diabetes mellitus 
TEAE 
treatment-emergent adverse events 
TEN 
toxic epidermal necrolysis 
TTPP 
time to pain progression 
UC 
urothelial cancer 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
Visual Analogue Scale 
VHP 
Voluntary Harmonization Procedure 
WHO 
World Health Organization 
ZAP70 
zeta-chain-associated protein kinase 

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1. 
INTRODUCTION 
1.1. 
Urothelial Cancer 
Bladder cancer, the most common form of urothelial cancer (UC), is estimated to kill nearly 
200,000 patients globally on an annual basis, including more than 65,000 in Europe and 18,000 
in the United States (US) (Bray 2018; Ferlay 2018; Siegel 2019). Annual diagnoses of new cases 
of bladder cancer are estimated to be more than 549,000 worldwide, including more than 
197,000 in Europe and 81,000 in the US (Bray 2018; Ferlay 2018; Siegel 2019). Those patients 
with metastatic UC represent a population with significant unmet medical need, as the 5-year 
mortality rate for this disease exceeds 85% (von der Maase 2005). 
1.1.1. 
Metastatic Urothelial Cancer 
First-line (1L) therapy for locally advanced and metastatic UC in patients with sufficient renal 
function consists of cisplatin-based combinations, like methotrexate, vinblastine, doxorubicin, 
and cisplatin (MVAC) or gemcitabine plus cisplatin, which demonstrate an objective response 
rate (ORR) of up to 55%, including approximately 12% complete responses (CRs) (von der 
Maase 2000). Despite initial chemosensitivity, most patients are not cured and the outcome of 
metastatic UC after these regimens is poor: median time to progression is 7 months and median 
overall survival (mOS) is 14 months. Long-term survival is poor (approximately 15%) and the 
prognosis is particularly grim for patients with visceral metastases, for whom the 5-year survival 
rate is 7% (von der Maase 2000; von der Maase 2005; Bellmunt 2011). 
Unfortunately, more than 50% of patients with UC are cisplatin-ineligible due to poor renal 
function, poor performance status, or co-morbidities (De Santis 2012). An even higher unmet 
need exists in this population. For these cisplatin-ineligible patients, carboplatin is the 
platinum-containing therapy of choice. Carboplatin is also an alkylating agent, similar to 
cisplatin, but with less nephrotoxicity, neurotoxicity, and ototoxicity (Dogliotti 2007). In 
first-line therapy for cisplatin-ineligible metastatic UC in patients, response rates to treatment 
with carboplatin monotherapy range from 8%–18% (Bamias 2006). In the European 
Organisation for Research and Treatment of Cancer (EORTC) 30986 trial, carboplatin combined 
with gemcitabine in a cisplatin-ineligible patient population resulted in a confirmed ORR of 
36.1%. Median progression-free survival (mPFS) was 5.8 months and median OS was 
9.3 months (De Santis 2012). The modest efficacy reported for available platinum-containing 
therapies highlights the need for additional treatment options for patients with metastatic UC. 
Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors 
have demonstrated a survival benefit compared to chemotherapy in the management of late-line 
metastatic UC. Randomized phase 3 trials have been reported for both atezolizumab (Tecentriq®) 
and pembrolizumab (Keytruda®) in the second-line (2L+) metastatic UC setting. In the 
IMvigor211 trial, median OS was not significantly different between the 2 arms (11.1 months vs. 
10.6 months, respectively) (Powles 2018). KEYNOTE-045 studied pembrolizumab vs. 
investigator's choice of chemotherapy in metastatic UC patients who had recurred or progressed 
following platinum-containing chemotherapy. This study demonstrated a statistically significant 
improvement in OS (10.3 months vs. 7.4 months) when comparing the pembrolizumab arm to 
the chemotherapy arm (Bellmunt 2017). 

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In the US, both atezolizumab (Tecentriq®) and pembrolizumab (Keytruda®) have also received 
accelerated approvals for first-line use in cisplatin-ineligible UC patients based on open-label, 
single-arm studies that showed ORRs of 24% and 29%, respectively (Tecentriq® Prescribing 
Information, Genentech, Apr 2017) (Keytruda® Prescribing Information,  May 2017). This was 
followed by European Union (EU) approval in September 2017. In May 2018, the Food and 
Drug Administration (FDA) issued an alert regarding decreased survival in patients with low 
expression of PD-L1 being treated in the first-line setting with pembrolizumab or atezolizumab 
monotherapy, compared with platinum-containing chemotherapy. Subsequent prescribing 
information for pembrolizumab and atezolizumab were revised to require high PD-L1 expression 
in first-line metastatic UC patients who are not eligible for cisplatin-containing chemotherapy. 
This development has further limited the options for metastatic UC patients with low expression 
of PD-L1. 
Avelumab (BAVENCIO®) received approval in the US as a maintenance treatment following 
first-line platinum-containing chemotherapy based on a randomized, open-label study. 
Improvement in mOS compared to best supportive care was shown in patients with stable disease 
(21.4 months vs 14.3 months, respectively) (BAVENCIO® US Prescribing Information, EMD 
Serono, Nov 2020). This study did not address patients that received fewer than 4 cycles of 
platinum-containing therapy and only evaluated patients with disease control. The study also 
randomized at the start of maintenance and did not evaluate avelumab maintenance treatment 
compared to use of a PD-1/PD-L1 inhibitor at progression (second-line). 
1.2. 
Nectin-4 as a Target in Urothelial Cancer 
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 three 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 from 25% to 30% in the ECD (Reymond 2001). 
The three 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 (Takai 2008b; Mandai 
2015). 
Nectin-4 was originally identified by bioinformatics and cloned from human trachea (Reymond 
2001). In humans, Nectin-4 is normally expressed in keratinocytes of the skin, sweat glands, hair 
follicles, transitional epithelium of the bladder, salivary gland ducts, esophagus, breast, and 
stomach (Challita-Eid 2016). Nectin-4 was identified as markedly upregulated in UC using 
suppression subtractive hybridization on a pool of UC specimens. Immunohistochemical 
characterization of expression in multiple tumor specimens demonstrated high levels of Nectin-4 
in bladder, breast, pancreatic, lung, ovarian and other cancers (Challita-Eid 2016). 
1.3. 
Enfortumab Vedotin 
Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) comprised of a fully human 
anti-Nectin-4 IgG1 kappa monoclonal antibody (mAb) conjugated to the small molecule 

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microtubule disrupting agent, monomethyl auristatin E (MMAE), via a protease cleavable 
maleimidocaproyl valine-citrulline linker. Conjugation takes place on cysteine residues that 
comprise the interchain disulfide bonds of the antibody to yield a product with a drug to antibody 
ratio of approximately 3.8. Nectin-4 is a 66 kDa type I transmembrane protein that belongs to the 
Nectin family of adhesion molecules. Nectins are thought to mediate Ca2+ independent cell-cell 
adhesion via both homophilic and heterophilic transinteractions at adherens junctions and 
support a wide range of biological functions, including cell movement, proliferation, 
polarization, survival and differentiation. Nectin-4 is expressed in multiple cancers, particularly 
urothelial, breast, lung, pancreatic, and ovarian cancers (Challita-Eid 2016). Higher levels of 
expression are associated with disease progression and/or poor prognosis in some cancers 
(Fabre-Lafay 2007). The high expression level of Nectin-4 on UC cells makes it an ideal 
therapeutic target.  
EV binds to the V domain of Nectin-4 protein (Challita-Eid 2016). In the presumed mechanism 
of action, the drug binds to the Nectin-4 protein on the cell surface and is internalized, causing 
proteolytic cleavage of the valine-citrulline linker and intracellular release of MMAE. Free 
MMAE subsequently disrupts tubulin polymerization and leads to mitotic arrest.  
Information about mode of action, chemical structure, and posology of enfortumab vedotin are 
provided in the Investigator’s Brochure.  
1.3.1. 
Enfortumab Vedotin Monotherapy in Urothelial Cancer 
EV monotherapy is being evaluated in multiple phase 1, phase 2, and phase 3 studies. Study 
EV-101 is a phase 1 study to evaluate the safety and pharmacokinetics (PKs) of escalating doses 
of enfortumab vedotin given as monotherapy in subjects with metastatic UC and other malignant 
solid tumors that express Nectin-4 (Rosenberg 2018). EV-101 identified 1.25 mg/kg of 
enfortumab vedotin as the recommended monotherapy dose in metastatic UC. Study EV-201 is 
an ongoing phase 2, single-arm, open-label, 2-cohort study to evaluate enfortumab vedotin 
monotherapy in subjects with locally advanced or metastatic UC who have previously received 
systemic therapy with a PD-1/PD-L1 inhibitor. Subjects in Cohort 1 have previously received 
platinum-containing chemotherapy, and subjects in Cohort 2 are platinum-naïve and are not 
eligible for cisplatin (Rosenberg 2018). Study EV-301 is an ongoing phase 3 randomized 
controlled trial comparing enfortumab vedotin monotherapy and chemotherapy in subjects with 
locally advanced or metastatic UC who previously received platinum-containing chemotherapy 
and a checkpoint inhibitor.  
The totality of EV monotherapy data to date demonstrate a manageable safety profile and 
significant activity in subjects with heavily pre-treated metastatic UC, where currently available 
therapies in the 2L setting achieve ORRs of approximately 10% with chemotherapy and 20% 
with anti-PD-1/PD-L1 antibodies (Bellmunt 2017).  
EV-101 (ASG-22CE-13-2) 
As of the 25 Oct 2018 data cutoff, 112 subjects with metastatic UC treated with enfortumab 
vedotin at 1.25 mg/kg (metastatic UC Total Analysis Set), ORR was 43% (95% confidence 
interval [CI]: 33.6, 52.5), with 5 subjects (4.5%) achieving CR, and a median duration of 
response (DOR) of 7.4 months (95% CI: 5.6, 9.6). The median OS was 12.3 months (95% CI: 
9.3, 15.3).  

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In the safety population of all subjects who received any amount of enfortumab vedotin (n=201), 
the most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (56%), 
nausea (45%), decreased appetite (43%), and alopecia (41%). The incidence of Grade 3 or higher 
TEAEs was 59%, and those reported in ≥5% of subjects included anemia (7%), hyperglycemia 
(7%), hyponatremia (6%), urinary tract infection (5%), and sepsis (5%). Serious adverse events 
(SAEs) were reported for 88 subjects (44%). The incidence of TEAEs leading to withdrawal of 
study drug was 24%, with 9% reported as possibly related to study drug. Twelve subjects (6%) 
died due to TEAEs; of these, 4 were reported as possibly related to study drug (diabetic 
ketoacidosis [DKA], multiple organ dysfunction syndrome, respiratory failure, and urinary tract 
obstruction). 
Adverse events (AEs) of special interest (AESI), which included peripheral neuropathy (PN), 
rash, hyperglycemia, and infusion-related reaction (IRR) were prespecified for analysis as 
composite terms (employing either Medical Dictionary for Regulatory Activities [MedDRA] 
SMQ or sponsor specified query [SSQ]). The incidence of events in the category of PN was 
45.8% and no SAEs were reported. In the category of rash, the incidence was 48%; of which 
94.5% were Grade 2 or lower. SAEs in the category of rash included dermatitis bullous, eczema, 
rash maculo-papular, and rash vesicular (1 subject each), and were all considered drug related. In 
the category of hyperglycemia, the incidence was 15%; of which 93.5% were Grade 2 or lower. 
Six subjects (3%) had hyperglycemia events considered SAEs. One subject (0.5%) had an SAE 
of diabetic ketoacidosis, which was considered by the investigator to be related to study drug and 
led to death. The category of IRR includes systemic and local site reactions. The IRR event 
incidence was 2.5%; 99.5% of which were Grade 2 or lower. The sole subject with a Grade 3 
event in this category experienced a serious event of infusion site extravasation. 
EV-201 (SGN22E-001) 
As of the data cutoff date of 01 Mar 2019, for subjects previously treated with a PD-1/PD-L1 
inhibitor and platinum-containing chemotherapy (Cohort 1), treatment with enfortumab vedotin 
resulted in an ORR per blinded independent central review (BICR) of 44% (95% CI: 35.1, 53.2), 
including a CR for 15 subjects (12%). Activity was observed in subjects with poor prognostic 
features such as liver metastases (ORR 38%; 95% CI: 24.7, 52.8) and prior PD-1/PD-L1 
non-response (ORR 41%; 95% CI: 31.3, 51.3). Responses to enfortumab vedotin were observed 
in subjects with both high (PD-L1 combined positive score [CPS] ≥10%) and low PD-L1 
expression, with an ORR 36% and 47%, respectively. Observed responses were durable, with 
median response duration of 7.6 months (95% CI: 6.34, not reached; range: 0.95 months, 
11.3+ months). Median progression-free survival (PFS) was 5.8 months (95% CI: 4.9 months, 
7.5 months) and median OS was 11.7 months (95% CI: 9.1 months, not reached). 
AEs (n=125) were consistent with those previously reported in the enfortumab vedotin clinical 
development program. The most common TEAEs of any grade in were fatigue (55%), decreased 
appetite (52%), alopecia (50%), nausea (45%), peripheral sensory neuropathy (43%), diarrhea 
(42%), and dysgeusia (42%). The incidence of Grade 3 or higher TEAEs was 73%, and those 
reported in >5% of subjects included anemia (14%), neutropenia (9%), hyperglycemia (7%), and 
fatigue and hyponatremia (6% each). SAEs were reported for 58 subjects (46%). The incidence 
of TEAEs leading to withdrawal of treatment was 16%, with peripheral sensory neuropathy as 
the most common reason for treatment withdrawal (6%). Seven subjects (6%) died due to 
TEAEs; none of these deaths were considered treatment-related. One subject died of interstitial 

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lung disease that was considered related to study treatment; the event did not meet the definition 
of a TEAE because it occurred >30 days after the last dose of enfortumab vedotin. This case was 
confounded by high dose steroid use and suspected Pneumocystis jiroveci pneumonia. 
The incidence of AESIs in the category of PN was 56%. The majority of subjects with 
treatment-emergent PN had events of Grade 2 or lower, irrespective of pre-existing PN. Most 
events were sensory and 6% of subjects discontinued due to AE of sensory neuropathy. Fourteen 
of 70 subjects (20%) had resolution of all events and an additional 19 subjects (27%) had 
resolution or improvement in at least some events at the time of last follow-up. In the category of 
treatment-emergent rash, there was a 51% incidence. The majority of subjects with rash (77%) 
had events of Grade 2 or lower. Serious events of rash occurred in 4 subjects, including 
1 reported event of Stevens-Johnson syndrome, which ultimately resolved. Overall, 72% of 
subjects with rash events had resolution of all events and 22% had resolution or improvement as 
of the last follow-up. In the category of treatment-emergent hyperglycemia, the incidence was 
16%, with 50% Grade 2 or lower. As of the last follow-up, 60% of subjects with hyperglycemia 
had resolution of all events and an additional 15% had resolution or improvement in some 
hyperglycemia events. In the category of treatment-emergent IRR, the incidence was 6%. Four 
subjects (3%) experienced systemic IRRs which were Grade 2 or lower. All subjects recovered 
and no IRR events resulted in treatment discontinuation. Local site reactions included 3 subjects 
with infusion site extravasation. Two of the infusion site extravasation events were SAEs. All of 
the events resolved.  
Cohort 2 is currently ongoing for subjects previously treated with a PD-1/PD-L1 inhibitor 
without platinum-containing chemotherapy and who are cisplatin-ineligible. 
These activity/efficacy data for enfortumab vedotin in a disease setting with high unmet need, 
together with acceptable safety, support a favorable benefit-risk assessment for enfortumab 
vedotin monotherapy in treatment of patients with locally advanced or metastatic UC.  
A complete summary of the clinical and nonclinical data relevant to the investigational product 
and its study in subjects is provided in the enfortumab vedotin Investigator’s Brochure. 
1.4. 
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 
receptor, thus inhibiting its interaction with PD-L1 and programmed cell death-ligand 2 (PD-L2). 
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies. Pembrolizumab 
has been approved for first-line treatment of patients with locally advanced or metastatic bladder 
cancer who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 
(CPS ≥10) as determined by an FDA-approved test (Dako/Agilent 22C3 PD-L1 PharmDx), or in 
patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 
status. 
It is also approved for the treatment of patients with locally advanced or metastatic UC who have 
disease progression during or following any platinum-containing chemotherapy, or within 
12 months of neoadjuvant or adjuvant treatment.  

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For more details on specific indications and background information, refer to the Investigator’s 
Brochure. 
1.4.1. 
Pharmaceutical and Therapeutic Background 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (Okazaki 2001; Greenwald 2005). 
The structure of murine PD-1 has been resolved (Zhang 2004). PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig-variable–type domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (Okazaki 2001; Chemnitz 2004; Sheppard 2004; Riley 2009). The mechanism 
by which PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins (Parry 2005; Francisco 
2010). As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in locally advanced or metastatic UC. 
1.5. 
Enfortumab Vedotin and Pembrolizumab in Combination 
PD-1/PD-L1 inhibitors unleash the antitumor activity of T-lymphocytes by targeting the T-cell 
inhibition pathway (Sonpavde 2017), and have shown effective antitumor activity as a single 
agent in locally advanced or metastatic UC. Although these agents are able to induce durable 
responses, most patients do not respond to PD-1/PD-L1 monotherapy. Combining PD-1/PD-L1 
inhibitors with a novel therapy, such as enfortumab vedotin, may be beneficial. Data from 
preclinical studies of brentuximab vedotin (a CD30-directed ADC comprising the same linker 
and MMAE payload as enfortumab vedotin), shows potential to induce immunogenic cell death 
(ICD), antigen presentation, and tumor immune infiltration (Gardai 2015). These results suggest 
that the effects are due to MMAE. Treatment with brentuximab vedotin in vitro and in preclinical 
models has been shown to induce hallmarks of ICD. ICD is characterized by induction of the 
endoplasmic reticulum stress response and subsequent surface presentation of danger-associated 
molecular patterns immune stimulatory molecules. These danger-associated molecular patterns 
induce innate immune migration and activation within the tumor microenvironment(Cao 2017; 
Cao 2018). 
Based on the potential enhancement of immune response, it is hypothesized that combining 
enfortumab vedotin with a PD-(L)-1 inhibitor will result in improved response leading to 

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prolonged progression-free survival (PFS) and OS in patients with locally advanced or metastatic 
UC. 
Common AEs associated with enfortumab vedotin are reviewed in Section 1.3. Pembrolizumab 
is generally well tolerated as a monotherapy. The most common adverse reactions reported for at 
least 20% of pembrolizumab-treated subjects in either of the 2 trials on which regular approval 
and accelerated approval were recently granted (KEYNOTE-045 and KEYNOTE-052) included 
fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and 
rash. Discontinuation of pembrolizumab secondary to adverse reactions occurred in 8% to 11% 
of subjects, dose interruptions occurred in approximately 20% of subjects, and serious adverse 
reactions occurred in approximately 40% of subjects. Immune-mediated adverse events (imAEs), 
including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in the trials and 
were managed according to guidelines now outlined in the label (Pembrolizumab Prescribing 
Information, 2019). Based on these safety data, it was hypothesized there may be minimal 
overlapping toxicity between enfortumab vedotin and pembrolizumab.  
1.5.1. 
EV-103 (SGN22E-002) 
Study EV-103 is an ongoing phase 1b study evaluating the safety and antitumor activity of the 
combination of enfortumab vedotin with pembrolizumab and/or chemotherapy in subjects with 
locally advanced or metastatic UC. The combination regimens are evaluated in separate cohorts 
in EV-103 to inform dosing and proposed experimental arms in the planned EV-302 study. The 
subject population enrolled in EV-103 approximates the planned study population of EV-302, 
with the exception that enfortumab vedotin + pembrolizumab cohorts in EV-103 were restricted 
to subjects who were ineligible for cisplatin chemotherapy. Separate cohorts evaluated 
enfortumab vedotin in doublet combinations with pembrolizumab, cisplatin, and carboplatin. An 
additional cohort is evaluating the triplet combination of enfortumab vedotin, pembrolizumab 
and platinum-containing (cisplatin or carboplatin) chemotherapy. The study also included a dose 
escalation phase to evaluate the safe dose of enfortumab vedotin when combined with the 
standard, approved dose of pembrolizumab.  
All cohorts received enfortumab vedotin dosed at 1.25 mg/kg on Days 1 and 8 of every 21-day 
cycle. Cohorts evaluating enfortumab vedotin plus cisplatin (n=7) or carboplatin chemotherapy 
(n=11, 10 of which were dose-limiting toxicity [DLT] evaluable) established the safety of 
enfortumab vedotin combined with cisplatin or carboplatin. The recommended dose of 
enfortumab vedotin in combination with pembrolizumab for the expansion parts was determined 
to be 1.25 mg/kg. An additional cohort enrolled a 1L metastatic UC population that received 
enfortumab vedotin 1.25 mg/kg in combination with pembrolizumab and either cisplatin or 
carboplatin, depending on the subject’s eligibility for cisplatin, as defined in the protocol. As of 
the data cut-off of 28 May 2020, a total of 55 subjects were enrolled in the cohort, and 51 
received treatment. Of the 51 subjects that were treated, 28 received enfortumab vedotin + 
cisplatin + pembrolizumab (median follow-up 6 months) and 23 received enfortumab vedotin + 
carboplatin + pembrolizumab (median follow-up 8 months). Given the limited follow-up time 
that is available, efficacy data for this cohort is still immature. However, the initial experience 
with enfortumab vedotin combined with platinum chemotherapy and pembrolizumab has 
demonstrated a manageable safety profile with no new safety signals identified.  

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Preliminary Safety (Enfortumab vedotin + Pembrolizumab) 
As of the data cut-off date of 13 Oct 2020, preliminary safety data in the first 45 subjects treated 
with enfortumab vedotin at 1.25 mg/kg in combination with pembrolizumab in the first-line 
setting showed that 43 subjects (96%) experienced at least 1 treatment-related AE. The most 
common treatment-related AEs (occurring in ≥20% of subjects overall) were peripheral sensory 
neuropathy (56%), fatigue (51%), alopecia (49%), diarrhea (47%), decreased appetite (40%), 
rash maculo-papular (36%), dysgeusia, pruritus (33% each), nausea (29%), decreased weight 
(24%), dry skin (22%), anemia, ALT increased, and AST increased (20% each). Increased lipase 
occurred in 18% of subjects overall. Of note, increase lipase events were all reported as 
non-clinically significant. A total of 29 subjects (64%) experienced at least one Grade 3 or higher 
treatment-related AE, the most common being increased lipase (18%), fatigue, rash 
maculo-papular (11% each), increased amylase, neutropenia, anemia, hyperglycemia (9% each), 
increased transaminases (7%), acute kidney injury, dehydration, dermatitis bullous, diarrhea, 
hypokalemia, hyponatremia, myositis, and peripheral sensory neuropathy (4% each). Seven 
(16%) subjects had treatment-related serious AEs and 11 (24%) discontinued study treatment due 
to treatment-related AEs. The most common reason for treatment-related discontinuation was 
peripheral sensory neuropathy for 4 subjects. There was 1 treatment-related death (multiple 
organ dysfunction syndrome) reported by investigator as possibly related to treatment with 
several confounding factors including concomitant acute onset of atrial fibrillation, 
corticosteroids, and amiodarone. Regarding the treatment-related AESIs assessed during the 
study, the rates of PN (62% of subjects), rash (67%), and hyperglycemia (11%) as well as the 
median time to first onset (respectively of 2.4 months [range: 0.66,12], 0.7 months [range: 
0.13,15.7], 0.5 months [range: 0.33,3.48]) were similar to that with enfortumab vedotin 
monotherapy in post-platinum, post-PD-1/PD-L1 inhibitor metastatic UC subjects (EV-201, 
Cohort 1 in (Rosenberg 2019b) 
The safety profile of enfortumab vedotin in combination with pembrolizumab to date appears 
tolerable and manageable. Among AEs of interest, identified risks as a composite term include 
PN, rash, and extravasation site reactions, all reported at similar rates and severity as that for 
enfortumab vedotin therapy alone.  
Combination of enfortumab vedotin with pembrolizumab did not notably alter the immune 
mediated toxicities known to be associated with pembrolizumab monotherapy.  
Preliminary Efficacy (Enfortumab vedotin + Pembrolizumab) 
The preliminary efficacy data of enfortumab vedotin 1.25 mg/kg in combination with 
pembrolizumab in the first-line setting are summarized in Table 1. As of the data cut-off of 
13 Oct 2020, of the 45 subjects in the full analysis set (FAS) who received enfortumab vedotin 
1.25 mg/kg in combination with pembrolizumab in the first-line setting, the confirmed ORR by 
investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was 
73.3% (95% CI: 58.1, 85.4), including 7 (16%) CRs and 26 (58%) partial responses (PRs). In 
addition, 9 subjects (20%) had the best overall response of stable disease (SD) and the disease 
control rate (DCR) (CR, PR, or SD) was 93% (95% CI: 81.7, 98.6). 

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Table 1: 
Summary of best overall response by investigator assessment per RECIST v1.1-full 
analysis set: 1L enfortumab vedotin 1.25 mg/kg + pembrolizumab 
1L EV 1.25 mg/kg + Pembro  
(N=45) 
Best Overall Responsea, n (%) 
      Complete Response (CR) 
7 (16) 
      Partial Response (PR) 
26 (58) 
      Stable Disease (SD) 
9 (20) 
      Progressive Disease (PD) 
1 (2) 
      Not Evaluable (NE) 
2 (4) 
Objective Response Rate (CR or PR), n (%) 
33 (73) 
95% CIb for ORR 
(58.1, 85.4) 
Disease Control Rate (CR, PR or SD), n (%) 
42 (93) 
95% CIb for DCR 
(81.7, 98.6) 
a Best overall response according to RECIST v1.1 
b Computed using the Clopper-Pearson method (Clopper 1934)  
Data cutoff: 13-Oct-2020 
The majority of subjects (93%) treated with the enfortumab vedotin and pembrolizumab 
combination had reduction in target lesion from baseline. The majority of responses per RECIST 
v1.1 occurred at the first tumor assessment (Week 9) and were confirmed in subsequent 
assessments. As of the data cut of 13-Oct-2020, responses sustained beyond 12 months have 
been observed. 
In first-line cisplatin-ineligible subjects with locally advanced or metastatic UC, enfortumab 
vedotin + pembrolizumab demonstrates encouraging efficacy with a tolerable and manageable 
safety profile. The confirmed ORR per investigator assessment for enfortumab vedotin + 
pembrolizumab observed to date in Study EV-103 suggests the potential for clinically 
meaningful efficacy relative to pembrolizumab alone (24% ORR on the KEYNOTE-052 trial, 
(Balar 2017)). Responses were achieved rapidly; the majority of responses occurred at the first 
tumor assessment (Week 9) and have remained durable based on available follow-up data. 
In summary, the initial experience with enfortumab vedotin in combination with pembrolizumab 
suggests that the safety profile is manageable and tolerable. Safety and efficacy data for this 
combination support a favorable benefit-risk assessment and support further exploration of 
enfortumab vedotin combinations with pembrolizumab and in conjunction with other active 
agents. 
1.6. 
Enfortumab Vedotin, Chemotherapy, and Pembrolizumab in Previously 
Untreated Locally Advanced or Metastatic Urothelial Carcinoma 
Platinum-containing agents, such as cisplatin and carboplatin, are a well-established component 
of the standard of care for many solid malignancies, including advanced urothelial carcinoma 
that is no longer amenable to local treatments, such as surgery and/or radiotherapy. Overall, 

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chemotherapy combinations have led to modest improvements in outcomes for patients with 
advanced UC (Loehrer 1992; von der Maase 2000; De Santis 2012). 
The established activity of platinum-containing chemotherapy along with the promising activity 
of the PD-(L)1-inhibitors in metastatic UC provide the rationale for combining enfortumab 
vedotin with pembrolizumab and chemotherapy to treat advanced UC. As previously described, 
enfortumab vedotin monotherapy has a distinct mechanism of action from pembrolizumab and 
the chemotherapeutic agents.  
Gemcitabine (2´2´-difluorodeoxycytidine) is a cytosine analog that has shown activity against 
many types of solid tumors, including metastatic UC. Gemcitabine in first-line metastatic UC has 
demonstrated activity when combined with platinum-containing agents, however its individual 
activity is modest. As monotherapy in first-line cisplatin-ineligible metastatic UC, a response 
rate of 43% was seen, however the responses were short-lived and median OS was only 
5.4 months (Culine 2011). Given this, replacing gemcitabine with enfortumab vedotin plus 
pembrolizumab in combination with platinum-containing drugs offers an opportunity for 
enhanced efficacy while maintaining tolerability. 
The combination chemotherapy agents (cisplatin, carboplatin, and gemcitabine) will be used at 
standard doses every 3 weeks given that the targeted populations of subjects are not considered 
heavily pretreated (first-line setting and/or clear pre-study requirements) and they are used in the 
current standard of care (GC combination treatment). A complete summary of the clinical and 
nonclinical data relevant to the investigational product and its study in human subjects is 
provided in the Investigator’s Brochure. 
The EV-103 study is evaluating the safety and preliminary anti-tumor activity of enfortumab 
vedotin plus pembrolizumab and platinum containing chemotherapy as outlined in Section 1.5.1. 
Preliminary data indicates similar efficacy to the enfortumab vedotin plus pembrolizumab 
combination.  
1.7. 
Assessment of Benefit-Risk 
Apart from cisplatin-containing regimens, no other treatment to date has demonstrated an OS 
advantage for first-line metastatic UC, leaving a substantial therapeutic gap for the majority of 
the population that is unable to receive cisplatin chemotherapy. Even for the patients that are able 
to receive cisplatin, long-term survival is limited to less than 15% of patients treated (von der 
Maase 2000; Rosenberg 2019a). Carboplatin-containing regimens are commonly used in 
cisplatin-ineligible patients. In first-line therapy for cisplatin-ineligible metastatic UC patients, 
response rates to treatment with carboplatin monotherapy range from 8%–18% (Bamias 2006). 
In the EORTC 30986 trial, carboplatin combined with gemcitabine in a cisplatin-ineligible 
patient population resulted in a confirmed ORR of 36.1%. Median PFS was 5.8 months and 
median OS was 9.3 months (De Santis 2012). Treatment with platinum-containing chemotherapy 
regimens is accompanied by significant toxicities and poor long-term outcomes.  
Although pembrolizumab and atezolizumab are approved for use in the first-line 
cisplatin-ineligible metastatic UC population, the use is restricted to those with high tumor 
PD-L1 expression. Patients with newly diagnosed or newly recurrent metastatic UC represent an 
area of unmet medical need. Novel therapies and combinations that demonstrate benefit in a 

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biomarker-unselected population are needed to improve outcomes in the first-line metastatic UC 
population. 
Two recent studies evaluated combinations of platinum-containing regimens with PD-1/PD-L1 
inhibitors in 1L metastatic UC. KEYNOTE-361 (platinum + gemcitabine + pembrolizumab) 
recently reported that despite a trend toward improved survival, the study did not show a 
statistically significant improvement in OS or PFS for subjects with mUC treated with 
pembrolizumab in combination with chemotherapy compared to chemotherapy alone (Powles 
2021). IMvigor130, which evaluated platinum + gemcitabine + atezolizumab versus 
platinum + gemcitabine + placebo, demonstrated a statistically significant improvement in PFS 
and a trend toward improvement in OS that did not meet significance at the interim OS analysis. 
The study showed a modest 1.9-month improvement in the median PFS and at the time of the OS 
interim analysis (IA), the median OS for the platinum + gemcitabine + atezolizumab arm was 
16 months compared to 13.4 months in the control arm (Galsky 2020).  
Preliminary clinical data from the EV-103 trial show the enfortumab vedotin + platinum + 
pembrolizumab combination to be manageable and tolerable. Preliminary data from efficacy 
evaluable subjects in the cohort suggest comparable response rates and tumor reduction to the 
enfortumab vedotin + pembrolizumab data. Overall, these data supported inclusion of the 
enfortumab vedotin + pembrolizumab + platinum arm within EV-302. Nevertheless, given the 
limited activity of the PD-1/PD-L1 and platinum combinations, and the increasingly promising 
efficacy and safety of enfortumab vedotin + pembrolizumab, the sponsor has elected not to 
further pursue the enfortumab vedotin + platinum + pembrolizumab combination within the 
EV-302 trial. The EV-302 trial will evaluate enfortumab vedotin + pembrolizumab versus 
platinum + gemcitabine in subjects with previously untreated, locally advanced or metastatic UC. 
Subjects randomized to the enfortumab vedotin + platinum + pembrolizumab combination in 
earlier versions of the protocol will be allowed to continue with the combination or to 
discontinue the platinum drug and continue with enfortumab vedotin + pembrolizumab (see 
Appendix M).  
The clinical data on the combination of enfortumab vedotin with pembrolizumab support a 
favorable benefit-risk ratio for patients with locally advanced or metastatic UC in the first-line 
setting. The EV-103 data show enfortumab vedotin and pembrolizumab to be tolerable, with 
manageable toxicities. Among AESIs, identified risks as a composite term include PN, rash, and 
extravasation site reactions, all reported at similar rates and severity as that for enfortumab 
vedotin therapy alone. Combination of enfortumab vedotin with pembrolizumab did not notably 
alter the immune mediated toxicities known to be associated with pembrolizumab monotherapy. 
The events reported in this combination appear to be consistent in type and severity. Clinical 
efficacy has been observed in the enfortumab vedotin plus pembrolizumab single-arm 
combination cohort and this doublet offers the potential to demonstrate improved 
progression-free and OS outcomes compared to the standard of care.  
2. 
OBJECTIVES 
This study will evaluate the efficacy, safety, and PK of enfortumab vedotin in combination with 
pembrolizumab versus standard of care gemcitabine plus platinum-containing chemotherapy in 
subjects with previously untreated locally advanced or metastatic UC. Specific objectives and 
corresponding endpoints for the study are summarized in Table 2. 

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Table 2: 
Objectives and corresponding endpoints 
Primary Objectives 
Corresponding Dual Primary Endpoints 
● To compare PFS between the experimental 
arm (enfortumab vedotin + pembrolizumab 
[Arm A]) and the control arm (gemcitabine + 
cisplatin or carboplatin [Arm B]) by blinded 
independent central review (BICR) 
● PFS per RECIST v1.1 by BICR 
● To compare overall survival (OS) between the 
experimental arm (Arm A) and the control arm 
(Arm B) 
● OS 
Secondary Objectives 
Corresponding Secondary Endpoints 
● To compare ORR between the experimental 
arm (Arm A) and the control arm (Arm B) by 
BICR 
● ORR per RECIST v1.1 by BICR 
● To compare time to pain progression (TTPP) 
from the subject perspective between the 
experimental arm (Arm A) and the control arm 
(Arm B) 
● TTPP 
● To compare average change in pain from the 
subject perspective between the experimental 
arm (Arm A) and the control arm (Arm B) 
● Mean change from baseline in worst pain at Week 26 
● To evaluate PFS between the experimental arm 
(Arm A) and the control arm (Arm B) by 
investigator assessment 
● PFS per RECIST v1.1 by investigator assessment 
● To evaluate ORR between the experimental 
arm (Arm A) and the control arm (Arm B) by 
investigator assessment 
● ORR per RECIST v1.1 by investigator assessment 
● To evaluate DOR) the experimental arm (Arm 
A) and the control arm (Arm B) 
● DOR per RECIST v1.1 by BICR 
● DOR per RECIST v1.1 by investigator assessment 
● To evaluate DCR between the experimental 
arm (Arm A) and the control arm (Arm B) 
● DCR per RECIST v1.1 by BICR 
● DCR per RECIST v1.1 by investigator assessment 
● To evaluate the impact of study treatment on 
quality of life (QOL), functioning, and 
symptoms from the subject perspective 
● Mean scores and change from baseline of the European 
Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Core 30 (QLQ-C30), and EuroQOL 
5-dimensions (EQ-5D-5L), visual analogue scale (VAS), 
and utility scores 
● To evaluate the safety profile of each 
treatment regimen 
● Type, incidence, relatedness, severity and seriousness of 
AEs 
● Type, incidence and severity of laboratory abnormalities 
● Treatment discontinuation rate due to AEs 
Exploratory Objectives 
Corresponding Exploratory Endpoints 

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● To assess PFS, ORR, and DOR per the modified 
RECIST v1.1 for immune-based therapeutics 
(iRECIST) in Arm A 
● PFS, ORR, and DOR per iRECIST by investigator 
assessment in Arm A  
● To assess subject reported health resource 
utilization (HRU) 
● Cumulative incidence of HRU as reported by subject 
● To assess the pharmacokinetics of enfortumab 
vedotin and MMAE 
● To assess the development of anti-therapeutic 
antibody (ATA) to enfortumab vedotin  
● Plasma or serum concentrations of enfortumab vedotin 
and MMAE  
● Incidence of ATA to enfortumab vedotin 
● To assess biomarkers of biological activity, 
resistance, and predictive biomarkers of 
response 
● Exploratory biomarkers of clinical activity 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a global phase 3 open-label, 2-arm randomized multicenter study to evaluate the 
combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + 
platinum-containing chemotherapy, in subjects with previously untreated locally advanced or 
metastatic UC. See Figure 1. 
Subjects will be enrolled regardless of PD-L1 expression status, however, PD-L1 status (high or 
low) will be a stratification factor for randomization. The study is designed to assess the dual 
primary endpoints of PFS and OS of experimental Arm A (enfortumab vedotin + 
pembrolizumab) compared to control Arm B (gemcitabine + cisplatin or carboplatin).  
A total of 860 subjects will be randomized in a 1:1 manner to one of the study arms with the 
following stratification factors: cisplatin eligibility (eligible or ineligible), PD-L1 expression 
(high or low), and liver metastases (present or absent). 
Subjects in Arm A will receive enfortumab vedotin at 1.25 mg/kg, administered as an IV 
infusion on Days 1 and 8 of every 3-week cycle, and pembrolizumab 200 mg as an IV infusion 
on Day 1 of every 3-week cycle, after completion of the enfortumab vedotin infusion.  
Subjects in Arm B will receive gemcitabine at 1000 mg/m2 as an IV infusion on Days 1 and 8 of 
every 3-week cycle, and either cisplatin (70 mg/m2) or carboplatin (area under the curve 
[AUC] 4.5, or AUC 5 according to local guidelines) on Day 1 of every 3-week cycle, with 
adequate pre- and post-hydration, by IV infusion per institutional standards. 
Response will be assessed by computed tomography (CT) scans with contrast (unless 
contraindicated) every 9 weeks (±1 week) timed from the randomization date. For subjects who 
cannot receive CT scans with contrast, other protocol-specified imaging methods may be used 
(Appendix C). Brain scans should be repeated at this time point in subjects with a history of 
central nervous system (CNS) metastasis or signs/symptoms of CNS metastasis. Bone imaging 
should also be repeated at this time point in subjects with a history of skeletal metastasis or 
suspicion of skeletal metastasis based on imaging or symptoms. Objective responses will be 
confirmed per RECIST v1.1 (Eisenhauer 2009) (Appendix J) with repeat scans at the next 
scheduled response assessment per protocol after first documentation of response. Subsequent 

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response assessments should be performed every 9 weeks (±1 week) until 18 months after 
randomization, then every 12 weeks (±1 week). Response assessment should also be performed, 
and BICR evaluation triggered, whenever disease progression is suspected. 
Subjects may continue on study treatment until progressive disease (BICR-confirmed or clinical 
progression [see Section 7.3]), an AE, pregnancy, investigator decision, start of a subsequent 
anticancer therapy, subject decision (non-AE), study termination by the sponsor, completion of 
the maximum number of drug cycles allowed, or other reason unrelated to an AE. Treatment 
beyond disease progression per RECIST v1.1 may be considered for subjects in study Arm A 
(EV + pembrolizumab) who are deriving clinical benefit as defined in Section 5.8. Subjects 
treated beyond disease progression per RECIST v1.1 may continue until confirmed disease 
progression per modified RECIST 1.1 for immune-based therapeutics (iRECIST) as assessed by 
the investigator (Seymour 2017) (Appendix K). Confirmatory scans must be performed 4 to 
9 weeks after disease progression per RECIST v1.1 by BICR. Treatment with gemcitabine and 
treatment with platinum-containing chemotherapy may be given up to 6 cycles. Treatment with 
pembrolizumab will be discontinued once the subject has received a maximum of 
35 administrations of pembrolizumab (approximately 2 years). There is no upper limit to the 
number of cycles of enfortumab vedotin permitted. To date in metastatic UC, enfortumab 
vedotin has been administered until disease progression or an unacceptable AE.  
Palliative radiotherapy on a nontarget bone lesion that is not progressing is permitted and will 
not be considered a subsequent anticancer therapy; however, radiotherapy on any new or 
progressing lesion, per RECIST v1.1 as assessed by the investigator or after BICR-confirmed 
progression, will be considered a subsequent anticancer therapy and subjects will not be 
permitted to resume study treatment. Surgical resection for curative intent during study treatment 
may be permitted in subjects with favorable tumor response after discussion with the medical 
monitor.  
Subjects who discontinue treatment for reasons other than disease progression or consent 
withdrawal will continue to receive response assessments every 9 weeks (±1 week) for the first 
18 months timed from the randomization date, and every 12 weeks (±1 week) thereafter, until the 
subject has radiologically-confirmed disease progression per RECIST v1.1 guidelines as 
determined by BICR, dies, withdraws consent, or the study closes, whichever occurs first. After 
discontinuation of study treatment, all randomized subjects will be followed every 12 weeks 
(±1 week) to obtain information on subsequent anticancer therapy, and to assess survival status 
until death, study closure, lost to follow-up, or subject withdraws consent, whichever occurs first.  
Crossover to the experimental arm of the trial (Arm A) will not be permitted for subjects in the 
control arm (Arm B). On a periodic basis, an Independent Data Monitoring Committee (IDMC) 
will monitor the safety of subjects participating in this trial. The IDMC will be responsible for 
evaluating the results of safety analyses and will make recommendations to the sponsor. 
Additional details will be described in a separate IDMC charter. 

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Figure 1: 
Study design 
 
3.1.1. 
China Portion of the Study 
After completion of enrollment in the global portion, subjects in China may continue to be 
randomized in a 1:1 ratio to either the experimental arm or the control arm until the planned 
sample size of approximately 130 subjects in China is reached.  
3.2. 
Discussion and Rationale for Study Design 
As outlined in Section 1, despite the availability of cisplatin-containing chemotherapy which 
offers a survival benefit in the first-line metastatic UC setting, the majority of patients receiving 
cisplatin chemotherapy do not achieve long-term disease-free survival and for patients ineligible 
for cisplatin, outcomes are even worse (De Santis 2012; Rosenberg 2019a). This global phase 3, 
randomized study evaluates enfortumab vedotin administered in combination with 
pembrolizumab versus chemotherapy alone in previously untreated locally advanced or 
metastatic UC. The study will enroll an all-comer first-line locally advanced or metastatic UC 
population without pre-selection based on a tissue biomarker.  
3.2.1. 
Rationale for Endpoints 
OS is a well-established endpoint for oncology drug approvals in metastatic UC. Both 
cisplatin-containing chemotherapy and pembrolizumab have demonstrated an OS benefit in 
metastatic UC (Loehrer 1992; von der Maase 2000; Bellmunt 2017). However, the OS endpoint 
may be impacted by subsequent therapies or non-cancer related causes of death (eg, accidents, 
comorbidities, and natural deaths in the elderly). The effect of later lines of treatments on the OS 
results are of concern for studies conducted in the earlier lines of treatment, as is the case for the 
EV-302 study in 1L metastatic UC. Multiple PD-1/PD-L1 inhibitors are approved in the post 

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platinum-containing setting, and enfortumab vedotin monotherapy is under development in later 
lines of therapy as well. OS also generally requires larger sample sizes and longer follow-up 
time, potentially delaying the time to availability of an active treatment to subjects. The 
sponsors, therefore, are planning to test for superiority in the PFS endpoint, in addition to the OS 
endpoint. PFS may better isolate effects of the study treatment without as much influence by 
external factors such as subsequent treatments and “cross-over” in the control arm. PFS can also 
be viewed as a measure of clinical benefit to patients, whereby prolonging the time to 
progression of cancer would have a direct impact on an individual patient’s sense of well-being, 
as well as delaying the need for subsequent treatments with the associated side-effects. Of note, 
quality of life (QOL) data and patient-reported outcomes (PROs) will also be collected in this 
study to better understand the impact of improved PFS on subjects’ daily lives. 
With these considerations in mind, the sponsors have designated both PFS and OS as dual 
primary endpoints in the EV-302 study design, providing the opportunity to robustly evaluate the 
clinical benefit of enfortumab vedotin and pembrolizumab over the standard of care.  
3.2.2. 
Rationale for Study Population 
3.2.2.1. 
Rationale for Enrollment of a Biomarker-Unselected Population 
The current trial will enroll an all-comer population with no preselection for tumor-specific 
biomarkers, including Nectin-4 and PD-L1 expression. The rationale for this approach is 
supported by data from the phase 1 and phase 2 trials of enfortumab vedotin, which showed no 
evidence to support an expression-response relationship between either Nectin-4 or PD-L1 and 
enfortumab vedotin therapy.  
Subjects in the ongoing EV-201 and EV-301 studies investigating EV monotherapy in 
second-line and third-line metastatic UC, as well as study EV-103 investigating EV 
combinations in first-line metastatic UC, are all enrolled in an unselected manner with regard to 
the biomarkers Nectin-4 and PD-L1.  
In the EV-101 (ASG 22CE-13-2) phase 1 study, more than 97% of archival tumor samples from 
screened subjects expressed Nectin-4 using a immunohistochemistry (IHC) assay with a median 
H-score of 280 out of a maximum of 300 (Petrylak 2017). Based upon the observed prevalence 
of high Nectin-4 expression, the protocol for phase 1 study EV-101 was amended to eliminate 
the enrollment requirement for H-score ≥150 in metastatic UC subjects.  
In the EV-201 trial, there was no pre-selection by Nectin-4 expression and Nectin-4 expression 
was detectable by IHC in tumor biopsies from all treated subjects who had adequate tumor tissue 
for testing. The vast majority of subjects had high Nectin-4 expression levels, with a median 
H-score of 290 out of 300 (Rosenberg 2019b).  
In the EV-201 study, PD-L1 levels at baseline were assessed by a validated 22C3 PD-L1 IHC 
assay. Of the 120 subjects, previously treated with both platinum-containing chemotherapy and a 
PD-1/PD-L1 inhibitor (Cohort 1), who had evaluable PD-L1 expression data, 65% had a CPS 
<10 and 35% had a CPS ≥10. Responses to enfortumab vedotin were observed in subjects with 
both high and low PD-L1 expression, with an ORR of 36% and 47%, respectively (Petrylak 
2019). In the EV-201 trial, responses were observed regardless of PD-L1 expression level.  

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In the ongoing study EV-103 in 1L metastatic UC, subjects are enrolled regardless of PD-L1 
expression. As of the data cut-off date of 08 Oct 2019, an ORR of 73.3% has been observed, 
which further supports enrollment of a PD-L1-unselected first-line metastatic UC population. 
Forty-two percent (42%) of subjects had low PD-L1 expression (CPS <10), 31% had high PD-L1 
expression (CPS ≥10), and 27% were not evaluable. Responses were observed regardless of 
expression level.  
Given the current understanding that PD-L1 expression is important for the use of 
pembrolizumab monotherapy in 1L metastatic UC, and of uncertain relevance when 
pembrolizumab is used in combination with cytotoxic agents, PD-L1 expression (high [CPS ≥10] 
versus low [CPS <10] as determined by the Dako/Agilent PD-L1 IHC 22C3 PharmDx assay) 
will be included as a stratification factor in the EV-302 study. Baseline tumor PD-L1 expression 
will be assessed in all subjects prior to randomization to evaluate any predictive or prognostic 
role for PD-L1 expression in this study. 
3.2.3. 
Rationale for Control Arm Selection and Stratification Factors 
Gemcitabine plus cisplatin is a preferred first-line regimen for patients with locally advanced or 
metastatic UC who are cisplatin eligible (von der Maase 2000). For patients who are cisplatin 
ineligible, gemcitabine plus carboplatin is a preferred regimen (De Santis 2012). Contemporary 
phase 3 trials conducted by the EORTC cooperative group with gemcitabine plus 
platinum-containing chemotherapy control arms include EORTC 30987 using gemcitabine plus 
cisplatin (Bellmunt 2012) and EORTC 30986 using gemcitabine plus carboplatin (De Santis 
2012). More recently, the CALGB cooperative group presented data from the 90601 trial, 
including gemcitabine plus cisplatin control arm (Rosenberg 2019a). Several additional recent 
and ongoing phase 3 studies use gemcitabine plus platinum-containing chemotherapy in control 
arms, including the DANUBE study (NCT02516241), NILE (NCT03682068), KEYNOTE-361 
(NCT02853305), IMvigor130 (NCT02807636), and CheckMate901 (NCT03036098).  
Together, these data support the use of gemcitabine plus cisplatin or carboplatin, the current 
standard of care for 1L treatment of subjects with locally advanced or metastatic UC, as the 
control arm for the current study.  
Stratification Factors 
Given the different outcomes observed between the cisplatin-eligible and the cisplatin-ineligible 
1L metastatic UC populations, cisplatin eligibility will be included as a stratification factor to 
ensure balance across treatment arms. Investigators will determine a subject’s cisplatin-eligibility 
at the time of enrollment, per protocol. A subject may be considered cisplatin-ineligible provided 
they meet at least one of the following criteria: glomerular filtration rate (GFR) <60 mL/min, 
Eastern Cooperative Oncology Group (ECOG) or World Health Organization (WHO) 
performance status of 2, National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Grade ≥2 audiometric hearing loss, or New York Heart Association 
(NYHA) Class III heart failure. Subjects will be stratified by cisplatin eligibility for 
randomization, with the intent to support approval for both cisplatin-eligible and 
cisplatin-ineligible (carboplatin-eligible) subject populations. Subjects will be stratified by 
PD-L1 expression into either PD-L1 high (CPS ≥10) or PD-L1 low (CPS <10) categories 
according to the Dako/Agilent PD-L1 IHC 22C3 PharmDx. Additional stratification factors 

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include presence or absence of liver metastases at randomization, which is an established 
prognostic factor in patients with metastatic UC (Bajorin 1999) (Sonpavde 2016).  
3.2.4. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1 manner to 1 of the 2 treatment arms based on the following 
stratification factors: cisplatin eligibility (eligible or ineligible), PD-L1 expression (high or low), 
and liver metastases (present or absent). Interactive Response Technology (IRT) will be used for 
randomization. 
3.2.5. 
Rationale for Selection of Doses 
Enfortumab vedotin administered at 1.25 mg/kg on Days 1, 8, and 15 of every 28-day cycle is 
the approved dose and schedule for locally advanced or metastatic UC in second-line subjects 
who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy 
(PADCEV® Prescribing Information, Seagen, December 2019). Based on PK data from previous 
studies, the half-life of enfortumab vedotin is approximately 3 to 4 days. No notable intra-cycle 
accumulation (<30%) of ADC was observed with this monotherapy dosing regimen at any dose 
level. Minimal intra-cycle accumulation (<50%) of MMAE was observed.  
In this combination study, additional drugs in the regimen (pembrolizumab, gemcitabine and 
platinum-containing chemotherapy) are administered in a 21-day cycle. Enfortumab vedotin is 
administered on Days 1 and 8 of a 21-day cycle. When comparing the same dose level, the 
average weekly total exposure of enfortumab vedotin following administration on Days 1 and 8 
of each 21-day cycle is predicted to be similar to that observed for dosing on Days 1, 8, and 15 of 
a 28-day cycle. Thus, it is anticipated that the dosing schedule in the current combination study 
will achieve ADC exposures over each 3-week cycle that may lead to a favorable balance of 
antitumor activity and safety similar to that observed in the phase 1 Study EV-101. Similar to the 
monotherapy dosing regimen, no to minimal accumulation of ADC and MMAE, respectively, is 
expected on the 21-day cycle.  
Enfortumab vedotin will be administered at a dose of 1.25 mg/kg as an IV infusion over 
approximately 30 minutes on Days 1 and 8 of each 3-week cycle.  
The dose of pembrolizumab for this study will be 200 mg administered on Day 1 of each 21-day 
cycle in combination with enfortumab vedotin. This is the approved dose and schedule for 
pembrolizumab for urothelial cancer in both first-line cisplatin-ineligible patients and 
second-line patients (Keytruda Prescribing Information, June 2019).  
The safety and antitumor activity of enfortumab vedotin 1.25 mg/kg administered on Days 1 and 
8 of every 21-day cycle in combination with pembrolizumab is currently being evaluated in the 
ongoing EV-103 trial outlined in Section 1.5. Early safety data shows the combination to be 
tolerable and consistent with the AE profiles for each individual agent.  
Gemcitabine 1000 mg/m2 will be administered on Days 1 and 8 of each 21-day cycle. Either 
cisplatin 70 mg/m2 or carboplatin AUC=4.5 (or AUC=5 according to local guidelines) will be 
administered on Day 1 of each 21-day cycle. Cisplatin and gemcitabine at these doses have been 
tested in both 21-day and 28-day cycles with similar efficacy outcomes (von der Maase 2000; 
Rosenberg 2019a). The 21-day cycle has been a preferred schedule when tested in combination 
with other agents administered on a 21-day schedule (Rosenberg 2019a); (KEYNOTE-361 

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NCT02853305). The carboplatin and gemcitabine regimen at this dose and schedule was 
established as a standard of care for the cisplatin-ineligible population (De Santis 2012). 
3.2.6. 
Blinding and Unblinding 
This trial evaluates the experimental arm (enfortumab vedotin plus pembrolizumab) compared to 
the standard-of-care control arm (platinum-containing chemotherapy plus gemcitabine). As the 
control arm contains agents not contained in the experimental arm, blinding with placebo-control 
would be difficult and could complicate the ability to assess attribution of overlapping toxicities. 
Given this, the study will be conducted in an open-label fashion. Although this is an open-label 
study, to maintain trial integrity, until database lock and study unblinding for the pre-planned 
analyses, analyses or summaries by treatment assignment are only planned for the purpose of the 
IDMC monitoring and will be conducted by an external vendor. The primary endpoint of PFS 
along with response-based secondary endpoints will be assessed by BICR. Additional details will 
be provided in a separate document.  
3.3. 
Overall End of Study 
The study will end 5 years after enrollment of the last subject, or when no subjects remain in 
survival follow-up. Additionally, the sponsor may terminate the study at any time. 
4. 
STUDY POPULATION 
Subjects with previously untreated locally advanced or metastatic UC. Subjects must meet all of 
the enrollment criteria to be eligible for this study. Eligibility criteria may not be waived 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. Subjects must have histologically documented, unresectable locally advanced or 
metastatic urothelial carcinoma (ie, cancer of the bladder, renal pelvis, ureter, or urethra). 
Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible. 
2. Subjects must have measurable disease by investigator assessment according to 
RECIST v1.1 (Appendix J).  
a. Subjects with prior definitive radiation therapy must have measurable disease per 
RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal 
progression since completion of radiation therapy 
3. Subjects must not have received prior systemic therapy for locally advanced or metastatic 
urothelial carcinoma with the following exceptions: 
a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from 
completion of therapy are permitted 
b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence 
>12 months from completion of therapy are permitted 
4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing 
chemotherapy, in the investigator’s judgment. 

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a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they 
meet at least one of the following criteria: 
i. 
GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault 
formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine) 
• Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility 
criteria may be considered cisplatin-eligible based on the investigator’s 
clinical judgment 
ii. 
ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional 
criteria for ECOG 2 subjects) 
iii. 
NCI CTCAE Grade ≥2 audiometric hearing loss 
iv. 
NYHA Class III heart failure 
5. Subjects must be age 18 years or older. 
6. Archival tumor tissue comprising muscle-invasive urothelial carcinoma, or a biopsy of 
metastatic urothelial carcinoma must be provided for PD-L1 testing prior to 
randomization. If adequate archival tumor sample is not available, or evaluable, a new 
biopsy sample may be performed (see Section 7.5).  
7. Subjects must have an ECOG Performance Status score of 0, 1, or 2 (see Appendix B for 
conversion of performance status using Karnofsky, if applicable).  
a. Subjects with ECOG performance status of 2 must additionally meet the following 
criteria:  
i. 
Hemoglobin ≥10 g/dL  
ii. 
GFR ≥50 mL/min  
iii. 
May not have NYHA Class III heart failure 
8. Subjects must have adequate hematologic and organ function as defined by the baseline 
laboratory values in Table 3.  

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Table 3: 
Baseline laboratory values 
System 
Laboratory Value 
Hematological 
 
     ANC 
≥1500/µL 
     Platelets 
≥100,000/µL 
     Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/L 
Renal 
 
      Measured or calculateda creatinine clearance    
     (CrCl) 
    (GFR can also be used in place of creatinine or   
     CrCl) 
≥30 mL/min 
Hepatic 
 
     Total bilirubin 
≤1.5× ULN OR direct bilirubin ≤ ULN for subjects 
with total bilirubin levels >1.5× ULN 
≤3× ULN for subjects with Gilbert’s disease 
     AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for subjects with liver 
metastases 
Coagulation 
     International normalized ratio (INR) OR 
     prothrombin time (PT) 
    Activated partial thromboplastin (aPTT) 
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic 
range of intended use of anticoagulation 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 
a Creatinine clearance should be calculated via either Cockcroft-Gault, Modification of Diet in Renal Disease 
(MDRD) equations or 24h urine, per institutional standard. The same method should be used consistently for a 
subject over the course of the study with the exception of carboplatin dose calculation where Cockcroft-Gault 
method should be used in all subjects. 
9. A female subject of childbearing potential is anyone born female who has experienced 
menarche and who has not undergone surgical sterilization (eg, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is 
defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of 
other biological, physiological, or pharmacological causes. Female subjects of 
childbearing potential must meet the following conditions:  
• Agree not to try to become pregnant during the study and for at least 6 months after 
the final dose of study drug. 
• Must have a negative urine or serum pregnancy test (minimum sensitivity of 
25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) 
within 1 day prior to administration of study drug. Female subjects with false positive 
results and documented verification of negative pregnancy status are eligible for 
participation. 

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• If heterosexually active, must consistently use highly effective methods of birth 
control, with a failure rate of less than 1% (as described in Appendix L) starting at 
screening, throughout the study period, and for at least 6 months after the final dose 
of study drug. 
• Female subjects 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 dose of study 
drug. 
10. A male subject who can father children is anyone born male who has testes and who has 
not undergone surgical sterilization (eg, vasectomy followed by a clinical test proving 
that the procedure was effective). Male subjects who can father children, must meet the 
following conditions: 
• Must not donate sperm starting at screening and throughout the study period, and for 
at least 6 months after the final dose of study drug. Male subjects will be informed 
about the negative risk to reproductive function and fertility from the study treatment. 
Prior to treatment male subjects should be advised to seek information on fertility 
preservation and sperm cryoconservation.  
• Must consistently use highly effective methods of birth control, with a failure rate of 
less than 1% (as described in Appendix L) starting at screening and continue 
throughout study period and for at least 6 months after the final dose of study drug.  
• Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 
2 contraception options for preventing secondary exposure to seminal fluid (as 
described in Appendix L) for the duration of the pregnancy or time partner is 
breastfeeding throughout the study period and for at least 6 months after the final 
dose of study drug. 
11. Subjects must provide written informed consent. 
4.2. 
Exclusion Criteria 
1. Subjects who have previously received enfortumab vedotin or other MMAE-based 
ADCs.  
2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any 
malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor 
(including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or 
avelumab).  
3. Subjects who have previously received any prior treatment with an agent directed to 
another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 
agonists, CTLA-4 inhibitors, or OX-40 agonists). 
4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, or 
investigational agents not otherwise prohibited by exclusion criteria 1–3 that is not 
completed 4 weeks prior to first dose of study treatment (ongoing 
hormonal/anti hormonal treatment, eg, for breast cancer, is allowed, provided that the 
subject is eligible per exclusion criterion 14).  

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5. Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c 
(HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or 
polydipsia) that are not otherwise explained. 
6. Subjects with an estimated life expectancy <12 weeks 
7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.  
8. Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted 
on study if all of the following are true: a) CNS metastases have been clinically stable for 
at least 4 weeks prior to screening and baseline scans show no evidence of new or 
enlarged metastasis; b) the subject is on a stable dose of ≤10 mg/day of prednisone or 
equivalent for at least 2 weeks (if requiring steroid treatment); c) subject does not have 
leptomeningeal disease.  
9. Subjects with ongoing clinically significant toxicity associated with prior treatment 
(including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to 
baseline. 
10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, 
or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.  
11. Subjects who have known active hepatitis B (defined as HBsAg reactive) or known 
active hepatitis C virus (defined as HCV RNA [qualitative] detected) infection, testing 
for hepatitis B and hepatitis C is required if mandated by country health authority. 
Subjects who have been curatively treated for hepatitis C infection are permitted if they 
have documented sustained virologic response of 12 weeks. 
12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not 
required unless mandated by the local health authority. 
13. Subjects with conditions requiring high doses of steroids (>10 mg/day of prednisone or 
equivalent) or other immunosuppressive medications are excluded. Inhaled or topical 
steroids are permitted in the absence of active autoimmune disease. Physiologic 
replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency. 
14. Subjects with a history of another invasive malignancy within 3 years before the first 
dose of study drug, or any evidence of residual disease from a previously diagnosed 
malignancy. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type (if 
complete resection was performed) are allowed. 
a. A history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with 
definitive intent (surgically or with radiation therapy) at least 1 year prior to study 
entry is acceptable, provided that the subject is considered prostate cancer-free and 
the following criteria are met: 
i. 
Participants who have undergone radical prostatectomy must have 
undetectable PSA for >1 year and at screening. 
ii. 
Participants who have had radiation must have a PSA doubling time >1 year 
(based on at least 3 values determined >1 month apart) and a total PSA value 
that does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL 
above nadir). 

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b. Participants with untreated low-risk prostate cancer (Gleason score ≤6) on active 
surveillance with PSA doubling time >1 year (based on at least 3 values determined 
>1 month apart) are also eligible. 
15. Subjects with a documented history of a cerebral vascular event (stroke or transient 
ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent 
with NYHA Class IV within 6 months prior to randomization (Appendix D). 
16. Subjects who have received radiotherapy within 2 weeks prior to randomization. Subject 
must have recovered adequately from the toxicity from the intervention prior to starting 
study treatment. 
17. Subjects who have received major surgery within 4 weeks prior to randomization. 
Subject must have recovered adequately from complications from the intervention prior 
to starting study treatment. 
18. Subjects with known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin 
excipient contained in the drug formulation of enfortumab vedotin (including histidine, 
trehalose dihydrate, and polysorbate 20). Subjects with known severe (≥ Grade 3) 
hypersensitivity to any pembrolizumab excipient contained in the drug formulations of 
pembrolizumab. Subjects with known severe (≥ Grade 3) hypersensitivity to the platinum 
agent selected by the investigator for study treatment. Subjects with known severe 
(≥ Grade 3) hypersensitivity to the gemcitabine. 
19. Subjects with active keratitis or corneal ulcerations. Subjects with superficial punctate 
keratitis are allowed if the disorder is being adequately treated in the opinion of the 
investigator. 
20. History of autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed. 
b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered 
standard of care. 
c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved 
childhood asthma/atopy will not be excluded. 
d. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections will not be excluded. 
e. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's 
syndrome will not be excluded. 
21. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan.  
22. Subjects who have received a prior allogeneic stem cell or solid organ transplant. 

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23. Subjects who have received a live attenuated vaccine within 30 days prior to 
randomization. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed. 
24. Subjects with active tuberculosis 
25. Subjects with another underlying medical condition that, in the opinion of the 
investigator, would impair the ability of the subject to receive or tolerate the planned 
treatment and follow-up; any known psychiatric or substance abuse disorders that would 
interfere with cooperating with the requirements of the study. 
4.3. 
Removal of Subjects From Therapy or Assessment 
4.3.1. 
Discontinuation of Study Treatment 
A subject’s study treatment will be discontinued for any of the following reasons: 
• Progressive disease (BICR-confirmed or clinical progression [see Section 7.3]) 
o Confirmed progressive disease per iRECIST (Appendix K) as assessed by 
investigator in subjects in study Arm A treated beyond BICR-confirmed 
disease progression (see criteria in Section 5.8) 
• AE 
• Pregnancy 
• Investigator decision 
• Start of a subsequent anticancer therapy 
• Subject decision, non-AE  
• Study termination by sponsor 
• Completion of study treatment  
• Other, non-AE 
Subjects who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 
Pembrolizumab may be administered for up to a total of 35 cycles (approximately 2 years). 
Cisplatin, carboplatin, and gemcitabine may be administered for up to a total of 6 cycles. 
Maintenance therapy (eg, avelumab) may be used following completion and/or discontinuation 
of platinum-containing therapy, if locally available, and provided the subject is deemed 
appropriate by the investigator. Avelumab must be used in accordance with the latest version of 
the Summary of Product Characteristics (SmPC) currently available. The following conditions 
should also be met: 
• Completion of end of treatment (EOT) visit 

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• All study-related procedures occurring post-EOT, including all disease assessments 
until BICR-confirmed disease progression occurs, should be continued per the 
Schedule of Assessments (see Appendix A). 
4.3.2. 
Subject Discontinuation From Study 
Any subject may be discontinued from the study for any of the following reasons: 
• Subject withdrawal of consent 
• Study termination by sponsor 
• Lost to follow-up 
• Death 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
For subjects randomized to enfortumab vedotin + cisplatin or carboplatin + pembrolizumab 
(Arm C) in a previous protocol version, please follow cisplatin and carboplatin dosing and 
treatment administration guidelines below. See Appendix M for additional details specific to 
Arm C. 
Enfortumab vedotin (Arm A) 
Enfortumab vedotin 1.25 mg/kg, the investigational product under study, will be administered as 
an IV infusion over approximately 30 minutes on Days 1 and 8 of every 3-week cycle. 
Pembrolizumab (Arm A)  
Pembrolizumab 200 mg will be administered as an IV infusion approximately 30 minutes after 
completion of enfortumab vedotin (Arm A) on Cycle 1 Day 1. A delay of 15 minutes may be 
used for subsequent infusions if the previous infusion was well tolerated.  
Gemcitabine (Arm B)  
Gemcitabine 1000 mg/m2 will be administered as an IV infusion on Days 1 and 8 of each 3-week 
cycle. 
Cisplatin (Arm B)  
On Day 1 (or Day 2 if required per institutional guidelines) of each 3-week cycle, cisplatin 
70 mg/m2 will be administered (with adequate pre- and post-hydration) as an IV infusion per 
institutional standards (Arm B). The body surface area used to calculate cisplatin dose may be 
capped per institutional standards. 
Carboplatin (Arm B) 
On Day 1 of each 3-week cycle, carboplatin at AUC 4.5, or AUC of 5 according to local 
guidelines, will be administered (with adequate pre- and post-hydration) as an IV infusion per 
institutional standards (Arm B). Body weight used to calculate carboplatin may be capped as per 
institutional standards.  

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Table 4: 
Interventions and treatment arms 
Agent (IV) 
Arm A 
(EV+Pembro) 
Arm Ba 
(Gemcitabine + 
Cisplatin/Carboplatin) 
Enfortumab vedotin 
1.25 mg/kg over 30 min on Days 1 
and 8 
 
Pembrolizumab 
200 mg over 30 min on Day 1 
 
Gemcitabine 
 
1000 mg/m2 on Days 1 and 8 
Cisplatinb 
 
70 mg/m2 on Day 1 over 1 hour, or 
per local label or institutional 
standards 
Carboplatinc 
 
AUC 4.5 on Day 1 over 1 hour, or 
per local label or institutional 
standards 
a Subjects will receive either cisplatin or carboplatin. 
b Can be given on Day 2 if required per institutional standards. 
c A starting dose of AUC 5 can be given according to local guidelines. 
5.2. 
Investigational Product 
Detailed information describing the preparation, administration, and storage of enfortumab 
vedotin is located in the Pharmacy Instructions. 
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. 
5.2.2. 
Method of Procurement 
The investigational study drug (enfortumab vedotin) will be provided by the sponsor. 
5.2.3. 
Dose and Administration 
Enfortumab vedotin will be administered on Days 1 and 8 of every 3-week cycle by IV infusion 
given over approximately 30 minutes. In the absence of IRRs, the infusion rate for all subjects 
should be calculated in order to achieve a 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. 
Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol 
defined reason for treatment discontinuation occurs (see Section 5.8). 
Weight-based dosing is based on the subject’s actual body weight. Doses must be adjusted for 
subjects who experience a ≥10% change in weight from baseline or previous cycle. Subject 
weight must be measured during all relevant assessment windows as described in the schedule of 

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events as well as per institutional standards, if applicable. Other dose adjustments for changes in 
body weight <10% are permitted per institutional standard. An exception to weight-based 
dosing of enfortumab vedotin is made for subjects weighing greater than 100 kg; doses will 
be based on 100 kg for these individuals. The maximum dose permitted on study is 125 mg. 
The subject should be observed during enfortumab vedotin administration and for at least 
60 minutes following the infusion during the first 3 cycles. All supportive measures consistent 
with optimal patient care should be given throughout the study according to institutional 
standards. 
The infusion site should be monitored closely for redness, swelling, pain, and infection during 
and at any time after administration. Subjects should be advised to report redness or discomfort 
promptly at the time of administration or after infusion. For subjects with difficult peripheral 
venous access or who are at risk for extravasation (ie, limited vein selection, small or fragile 
veins, local neuropathies, or lymphedema), placement of a central venous port or catheter should 
be considered. Institutional guidelines will be followed for the administration of chemotherapy 
agents and precautions taken to prevent extravasation per institutional standards and as described 
in (Polovich 2014) and (Perez Fidalgo 2012). In case of enfortumab vedotin extravasation, the 
combination drug(s) should be held until consultation and further discussion with the medical 
monitor/sponsor. 
5.2.4. 
Dose Modifications 
Dose modification recommendations for enfortumab vedotin associated toxicity (hematologic 
and non-hematologic, by CTCAE v4.03 grade) are presented in Table 5 and Table 6. 
Dose reduction or delay for other enfortumab vedotin-associated toxicity is permitted at the 
discretion of the site investigator. Dose reduction from 1.25 mg/kg to 1 mg/kg or to 0.75 mg/kg 
will be allowed depending on the type and severity of toxicity. Subjects requiring a dose 
reduction may be re-escalated by 1 dose level (ie, subjects reduced to 0.75 mg/kg may only be 
re-escalated to 1 mg/kg) provided the toxicity does not require study drug discontinuation and 
has returned to baseline or ≤ Grade 1. If the toxicity recurs, re-escalation will not be permitted. 
Subjects with ≥ Grade 2 corneal AEs will not be permitted to dose re-escalate. 
The Day 8 dose of enfortumab vedotin must be given within 4 days of the planned dose (Day 8 + 
4 days). If the Day 8 dose cannot be administered within this timeframe, the dose should be held 
until Day 1 of the next treatment cycle. Dose delay for other EV associated toxicity is permitted 
at the discretion of the site investigator. A dose delay may last up to 6 weeks (2 cycles). Dose 
delays for subjects who are deriving clinical benefit from treatment may be extended beyond 
6 weeks, if the subject’s toxicity does not otherwise require permanent discontinuation. If there is 
a dose delay, the schedule for response assessments will not be adjusted. 
Enfortumab vedotin may be delayed for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Subjects should resume 
study therapy as soon as clinically safe as assessed by the investigator. For delays longer than 
6 weeks, the medical monitor should be consulted before resuming study therapy. The reason for 
delay should be documented in the subject's case report form (CRF). 
For subjects in the enfortumab vedotin plus pembrolizumab treatment arm who develop a rash or 
a skin reaction that is determined by the investigator to be related to study treatment, initial 

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management actions (ie, to withhold or discontinue study treatment) should apply to both study 
treatments, and the investigator should follow the most conservative dose modification 
recommendations described below in Table 6 for enfortumab vedotin or in Section 5.3.4 (Table 
7) for pembrolizumab. However, for Grade 2 skin reactions that are stable (not worsening and in 
the absence of fever) with supportive measures and not limiting the subject’s activities of daily 
living, continued dosing of enfortumab vedotin may be considered following consultation with 
the sponsor. Neither enfortumab vedotin nor pembrolizumab should be administered in the 
setting of a Grade ≥3 skin reaction. 
Table 5: 
Recommended dose modification for enfortumab vedotin-associated hematologic 
toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same dose 
level. 
Continue at same dose 
level. 
 
For Grade 2 
thrombocytopenia, 
withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then resume treatment at 
the same dose level. 
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then resume treatment at 
the same dose level or 
consider dose reduction 
by 1 dose level.  
 
Transfusions or growth 
factors may be used as 
indicated per institutional 
guidelines. 
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then reduce dose by 
1 dose level and resume 
treatment or discontinue 
at the discretion of the 
investigator. Transfusions 
or growth factors may be 
used as indicated per 
institutional guidelines. 
 
For anemia, treatment 
discontinuation should be 
strongly considered. 
Note: Hematologic toxicity refers to anemia, thrombocytopenia, neutropenia, and febrile neutropenia. 

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Table 6: 
Recommended dose modifications for enfortumab vedotin-associated 
nonhematologic toxicity 
Toxicity 
Grade 
Skin reactions 
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 
For Grade 1 rash 
or skin reactions, 
may continue at 
same dose level. 
See also 
Section 5.10.5 for 
recommended 
management of 
rash. 
Continue at same 
dose level. 
For worsening rash 
or skin reactions or 
skin reactions with 
concomitant fever, 
withhold 
enfortumab 
vedotin until 
toxicity is 
≤ Grade 1 or has 
returned to 
baseline, 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 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 confirmed SJS or 
TEN, or Grade 4 
rash, permanently 
discontinue 
treatment. 
 

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Ocular 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
 
If ocular symptoms 
and/or changes in 
vision are 
identified, the 
subject should be 
evaluated by an 
optometrist or 
ophthalmologist. 
For Grade 2 
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 corneal 
AEs, withhold 
dose until toxicity 
is ≤ Grade 1, then 
reduce the dose by 
1 dose level and 
resume treatment. 
 
If ocular symptoms 
and/or changes in 
vision are 
identified, the 
subject should be 
evaluated by an 
optometrist or 
ophthalmologist. 
For Grade 3 corneal 
AEs, discontinue 
treatment at the 
discretion of the 
investigator. 
 
If ocular symptoms 
and/or changes in 
vision are identified, 
the subject should be 
evaluated by an 
optometrist or 
ophthalmologist. 
For Grade 4 AEs, 
discontinue 
treatment. 
Neuropathy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
For Grade 2 
neuropathy 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 
withhold dose until 
toxicity is ≤ Grade 
1, then reduce the 
dose by 1 dose 
level and resume 
treatment. 
For Grade 3 
neuropathy AEs, 
discontinue treatment 
at the discretion of 
the investigator. 
For Grade 4 AEs, 
discontinue 
treatment. 

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Gastrointestinal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
Continue at same 
dose level. 
Withhold dose until 
toxicity is ≤ Grade 1 
or has returned to 
baseline, then resume 
treatment at the same 
dose level or consider 
dose reduction by 1 
dose level. 
For Grade 4 AEs, 
discontinue 
treatment. 
 
Grade 4 vomiting 
and/or diarrhea that 
improves to 
≤ Grade 2 within 
72 hours with 
supportive 
management does not 
require 
discontinuation. 
Hyperglycemia 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
Continue at same 
dose level. 
For Grade 3 
hyperglycemia/elevat
ed blood glucose, 
withhold enfortumab 
vedotin treatment. 
Resume treatment 
once 
hyperglycemia/elevat
ed blood glucose has 
improved to ≤ Grade 
2 and subject is 
clinically and 
metabolically stable. 
See also 
pembrolizumab dose 
modification 
recommendations for 
hyperglycemia in 
Table 7. 
For Grade 4 
hyperglycemia/elevat
ed blood glucose 
withhold enfortumab 
vedotin treatment and 
undertake a full 
evaluation of the 
hyperglycemia to 
determine the 
underlying diagnosis. 
Once blood glucose 
returns to ≤ Grade 2, 
drug dosing may 
resume with close 
monitoring after 
consultation with the 
medical monitor. See 
also pembrolizumab 
dose modification 
recommendations for 
hyperglycemia in 
Table 7. 
Pneumonitis/ILD 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
Withhold dose 
until ≤ Grade 1, 
then resume at the 
same dose level or 
consider dose 
reduction by 1 
dose level. 
Permanently 
discontinue 
treatment. 
Permanently 
discontinue 
treatment. 
All Other  
(not previously 
mentioned) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Continue at same 
dose level. 
Continue at same 
dose level. 
Withhold dose until 
toxicity is ≤ Grade 1 
or has returned to 
baseline, then resume 
treatment at the same 
For Grade 4 AEs, 
discontinue 
treatment.* 

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dose level or consider 
dose reduction by 1 
dose level.* 
* Grade 3/4 electrolyte imbalances/laboratory abnormalities, except hyperglycemia, that are not associated with 
clinical sequelae or are corrected with supplementation/appropriate management within 72 h of their onset do not 
require discontinuation (eg, Grade 4 hypouricemia). Grade 3 or 4 elevations of amylase or lipase, if asymptomatic 
do not require treatment delay. 
5.2.5. 
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. 
Vials of enfortumab vedotin lyophilized powder, reconstituted drug product and/or dosing 
solutions should be protected from direct sunlight. 
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. Drug accountability procedures are provided in 
the Pharmacy Binder. 
5.2.6. 
Packaging and Labeling 
Refer to the Pharmacy Binder for information regarding packaging and labeling. 
5.2.7. 
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. 
Pembrolizumab 
5.3.1. 
Description 
Pembrolizumab is a humanized mAb that blocks the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa Ig with an approximate molecular weight 
of 149 kDa.  
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water 
for Injection, United States Pharmacopeia (USP). 

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5.3.2. 
Method of Procurement 
Pembrolizumab will be provided to all study sites by the sponsor. In countries outside the US, 
pembrolizumab will also be relabeled by the sponsor, to meet country-specific regulatory 
requirements. 
5.3.3. 
Dose and Administration 
Pembrolizumab will be administered at a dose of 200 mg on Day 1 of every 3-week cycle by IV 
infusion given over approximately 30 minutes.  
Pembrolizumab may be administered for a maximum of 35 cycles. 
5.3.4. 
Dose Modifications 
5.3.4.1. 
Dose Delays and Toxicity Management for Immune-related Adverse 
Events Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
imAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. The dose of 
pembrolizumab should not be reduced. Based on existing clinical study data, most imAEs were 
reversible and could be managed with a delay of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected imAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, and/or skin biopsy may be included as part of the evaluation. Based on the severity 
of imAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
Dose delay and toxicity management guidelines for imAEs associated with pembrolizumab are 
provided in Table 7 and are also detailed in the pembrolizumab package insert. 

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Table 7: 
Guidelines for management of pembrolizumab immune-related adverse events 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening imAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if imAEs cannot be controlled by 
corticosteroids. 
 
Immune-mediated 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE 
v4.03) 
Action Taken to 
Pembrolizumab 
imAE Management 
with Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids (initial 
dose of 1–2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor subjects for signs 
and symptoms of 
pneumonitis 
Evaluate subjects with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
Add prophylactic antibiotics 
for opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids (initial 
dose of 1–2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor subjects for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus) 
Subjects with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis 
Subjects with diarrhea/colitis 
should be advised to drink 
liberal quantities of clear 
fluids. If sufficient oral fluid 
intake is not feasible, fluid 
and electrolytes should be 
substituted via IV infusion 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 

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Immune-mediated 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE 
v4.03) 
Action Taken to 
Pembrolizumab 
imAE Management 
with Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-up 
AST/ALT 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 0.5–1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable) 
Grade 3 or 4 
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1–2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withholda
Initiate insulin 
replacement therapy 
for subjects with 
T1DM 
Administer 
anti-hyperglycemic in 
subjects with 
hyperglycemia  
Monitor subjects for 
hyperglycemia or other signs 
and symptoms of diabetes 
See also enfortumab vedotin 
dose modification 
recommendations and 
management for 
hyperglycemia in Table 6 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4 
Withhold or 
permanently 
discontinuea 
Hyperthyroidism 
Grade 2 
Continue 
Treat with 
non-selective 
beta-blockers (eg, 
propranolol) or 
thioamides as 
appropriate  
Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinuea 
Hypothyroidism 
Grade 2–4 
Continue 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold 
Administer 
corticosteroids 
(prednisone 1–
2 mg/kg or 
equivalent) followed 
by taper. 
Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
Footnotes

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Immune-mediated 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE 
v4.03) 
Action Taken to 
Pembrolizumab 
imAE Management 
with Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-up 
All other 
immune-mediated 
AEs 
Persistent 
Grade 2 
Withhold 
Based on severity of 
AE administer 
corticosteroids  
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 
Withhold or 
discontinueb.  
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
Note: Non-immune related (ir)AE will be managed as appropriate, following clinical practice recommendations. 
a The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed.  
b Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Drug 
Rash with Eosinophilia and Systemic Symptom (DRESS), Stevens-Johnson Syndrome, toxic epidermal necrolysis, 
myelitis, and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
5.3.4.2. 
Dose Delays and Toxicity Management of Infusion-reactions Related to 
Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 h of completion of infusion. Dose delay and 
treatment guidelines on pembrolizumab associated infusion reaction are provided in Table 8. 
Table 8: 
Pembrolizumab infusion reaction dose modifications and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (eg, from 100 mL/hr to 
50 mL/hr). Otherwise dosing will be held until 
Subject may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of study intervention 
with: 
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500–1000 mg 
PO (or equivalent dose of 
analgesic). 

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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug intervention. 
Grade 3 or 4 
Grade 3 
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) 
 
Grade 4 
Life-threatening; pressor 
or ventilator support 
indicated 
 
 
 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: Epinephrine**, IV 
fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics, oxygen, pressors, and corticosteroids. 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
 
 
 
 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from further 
pembrolizumab treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. For further information, please refer to the CTCAE v4.03. 
5.3.5. 
Storage and Handling 
Refer to the Pharmacy Binder for storage and handling instructions. 
5.3.6. 
Packaging and Labeling 
Drug product vials may be labeled as pembrolizumab, the United States Adopted Name and 
International Nonproprietary Name. 
5.3.7. 
Preparation 
The pharmacy manual contains specific instructions for the preparation of the pembrolizumab 
solution. 
5.4. 
Other Allowed Dose Delays for Enfortumab Vedotin and Pembrolizumab 
Enfortumab vedotin and/or pembrolizumab may be delayed for situations other than 
treatment-related AEs such as medical/surgical events or logistical reasons not related to study 
therapy. Subjects should resume study therapy as soon as clinically safe as assessed by the 
investigator. For delays longer than 6 weeks, the medical monitor should be consulted before 
resuming study therapy. The reason for delay should be documented in the subject's CRF.  

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5.5. 
Cisplatin 
5.5.1. 
Description 
Alone or in combination with other anticancer agents, cis-diamminedichloroplatinum (II) 
(cisplatin) is used in the management of many solid malignancies, including for advanced UC 
that is no longer amenable to local treatments, such as surgery and/or radiotherapy. Cisplatin is a 
platinum-containing anticancer agent classified as a direct DNA-interacting agent.  
Cisplatin is a yellow to orange crystalline powder with the molecular formula PtCl2H6N2, and a 
molecular weight of 300.1. Cisplatin is a heavy metal complex containing a central atom of 
platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is 
soluble in water or saline at 1 mg/mL.  
Cisplatin injection infusion concentrate is a clear, colorless, sterile aqueous solution available in 
amber vials. Each 50, 100, or 200 mL amber vial of infusion concentrate contains 1 mg/mL 
cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and sodium hydroxide to approximate pH 
of 4.0, and water for injection to a final volume of 50, 100, or 200 mL, respectively. Cisplatin 
Injection infusion concentrate must be further diluted prior to administration. 
5.5.2. 
Method of Procurement 
Cisplatin is commercially available and details regarding sourcing of cisplatin may vary by site 
and/or region as outlined in other documents such as Clinical Trial Agreements (CTA). 
5.5.3. 
Dose and Administration 
Subjects that are determined to be cisplatin-eligible per protocol should receive cisplatin.  
Cisplatin will be administered with adequate pre- and post-hydration at a dose of 70 mg/m2 on 
Day 1 (or Day 2 if required by institutional guidelines) of each 3-week cycle as an IV infusion 
per institutional standards (Arm B). Cisplatin may be administered for a maximum of 6 cycles. 
Weight-based dosing of cisplatin is based on the subject’s actual body weight. Doses must be 
adjusted for subjects who experience a ≥10% change in weight from baseline or previous cycle. 
Subject weight must be measured during all relevant assessment windows as described in the 
schedule of events as well as per institutional standards, if applicable. Other dose adjustments for 
changes in body weight <10% are permitted per institutional standard. 
The body surface area used to calculate cisplatin dose may be capped per institutional standards. 
Split dosing of cisplatin is not allowed. See the cisplatin package insert for detailed instructions. 
Cisplatin dose modifications are shown below in Table 9. Additional details can be found in the 
package insert. 
 

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Table 9: 
Dose modifications for cisplatin toxicity 
Worst Toxicity in Previous Cycle 
Cisplatin Dose for Next Cyclea 
Grade 4 platelets ≥5 days, Grade 4 ANC ≥5 daysb, 
thrombocytopenic bleeding, or febrile neutropenia 
Decrease dose by 25% 
Grade 2 neurotoxicity or ototoxicity 
Decrease dose by 25% or discontinue depending on 
risk-benefit 
Grade 3 or 4 neurotoxicity or ototoxicity 
Discontinue 
Other Grade 3 non-hematologic/organ toxicity 
Decrease dose by 25% 
Other Grade 4 non-hematologic/organ toxicity 
Discontinue 
a Do not retreat until platelets ≥100,000/µL, ANC ≥1500/µL, and toxicity has recovered to ≤ Grade 2 (Grade 1 for  
neurotoxicity). 
b Growth factor support is allowed per institutional standards. 
5.5.3.1. 
Dosage with Renal Impairment 
Renal function should return to baseline before subjects are retreated. Cisplatin dosing should be 
discontinued if creatinine clearance (CrCl) is <30 mL/min. The same method to determine CrCl 
should be used consistently for a subject over the course of the study with the exception of 
carboplatin dose calculation where Cockcroft-Gault method should be used in all subjects. 
If a subject develops acute kidney injury that fails to resolve during treatment with 
cisplatin-containing therapy, a one-time switch from cisplatin to carboplatin for the remaining 
cycles will be permitted if deemed appropriate by the investigator. In the event that kidney 
function improves, switching back to cisplatin will not be permitted. Switching due to lack of 
response or disease progression is not permitted. 
5.5.4. 
Storage and Handling 
Refer to the cisplatin package insert in the Pharmacy Binder for storage and handling 
instructions. 
5.5.5. 
Packaging and Labeling 
Refer to the cisplatin package insert in the Pharmacy Binder for packaging and labeling 
information. 
5.5.6. 
Preparation 
Refer to the cisplatin package insert in the Pharmacy Binder for preparation instructions. 
5.6. 
Carboplatin 
5.6.1. 
Description 
Alone or in combination with other anticancer agents, cis-Diammine 
(cyclobutane-1,1-dicarboxylato)platinum (carboplatin) is used in the management of many solid 
malignancies, including for advanced UC which is no longer amenable to local treatments, such 
as surgery and/or radiotherapy, and which is not eligible for treatment with cisplatin as defined 

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by a consensus working group (Galsky 2011). Carboplatin is a platinum-containing anticancer 
agent classified as a cisplatin analog, with similar actions and uses. 
Carboplatin is a crystalline powder with the molecular formula C6H12N2O4Pt and a molecular 
weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% 
solution is 5 to 7. 
Carboplatin injection is supplied as a sterile, pyrogen-free, aqueous solution of carboplatin, USP. 
Each 50, 150, 450, or 600 mg multidose vial of solution contains 10 mg/mL carboplatin. 
5.6.2. 
Method of Procurement 
Carboplatin is commercially available and details regarding sourcing of carboplatin may vary by 
site and/or region as outlined in other documents such as CTAs. 
5.6.3. 
Dose and Administration 
Subjects that are determined to be cisplatin-ineligible per protocol should receive carboplatin. 
Carboplatin will be administered with adequate pre- and post-hydration at a dose of AUC 4.5, or 
AUC of 5 according to local guidelines, on Day 1 of each 3-week cycle as an IV infusion per 
institutional standards (Arm B).  
Carboplatin may be administered for a maximum of 6 cycles. 
The recommended dose of carboplatin is for a targeted AUC of 4.5 mg/mL per minute calculated 
based on the Calvert formula; carboplatin dose in mg=AUC × (CrCl + 25) administered (with 
adequate pre- and post-administration hydration) as an IV infusion. The IDMC and/or the 
sponsor may recommend using a targeted AUC of 5 mg/mL per minute based on the totality of 
the data available at that time (adjusted carboplatin dose in mg=AUC × [CrCl + 25]). Hydration 
may be administered during gemcitabine infusions (Arm B). CrCl (mL/min) is estimated by the 
Cockcroft-Gault formula (CrCl [mL/min] = [((140-age) × weight in kgs)/(72 × serum creatinine 
in mg/dL)] x 0.85 [if female]). The estimated CrCl for calculating carboplatin dose should not 
exceed 125 mL/min. Body weight may be capped per institutional standards. See the carboplatin 
package insert for detailed instructions. 
Dosing of carboplatin is based on the subject’s actual body weight and estimated CrCl on Day 1 
of each treatment cycle.  
If the performance status or renal function of a subject improves during treatment with 
carboplatin-containing therapy such that the subject is deemed eligible for cisplatin therapy, a 
one-time switch from carboplatin to cisplatin for the remaining cycles will be permitted if 
deemed appropriate by the investigator. If the subject experiences a subsequent AE to cisplatin 
that prevents further treatment, switching back to carboplatin will not be permitted and 
platinum-containing chemotherapy must be discontinued. Switching due to lack of response or 
disease progression is not permitted. 
Carboplatin dose modifications are shown below in Table 10. Additional details can be found in 
the package insert. 
 

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Table 10: 
Dose modification for carboplatin toxicity 
Worst Toxicity in Previous Cycle 
Carboplatin Dose for Next Cycle* 
Grade ≥3 platelets and/or thrombocytopenic bleeding, 
Grade 4 ANC ≥5 days and/or febrile neutropenia 
Decrease dose by 25% 
Grade 2 neurotoxicity  
Hold dose until event resolves to Grade 0 or 1 or 
discontinue depending on risk-benefit 
Grade 3 or 4 neurotoxicity 
Discontinue 
Other Grade 3 non-hematologic/organ toxicity 
Decrease dose by 25% 
Other Grade 4 non-hematologic/organ toxicity 
Discontinue 
* Do not retreat until platelets ≥100,000/µL, ANC ≥1500/µL, and toxicity has recovered to ≤Grade 2 (Grade 1 for 
neurotoxicity). 
5.6.3.1. 
Dosage for Renal Impairment 
Renal function should return to baseline before subjects are retreated. Carboplatin dosing should 
be discontinued if CrCl is <30 mL/min per the Cockcroft-Gault formula. 
5.6.4. 
Storage and Handling 
Refer to the carboplatin package insert in the Pharmacy Binder for storage and handling 
instructions. 
5.6.5. 
Packaging and Labeling 
Refer to the carboplatin package insert in the Pharmacy Binder for packaging and labeling 
instructions. 
5.6.6. 
Preparation 
Refer to the carboplatin package insert in the Pharmacy Binder for preparation information. 
5.7. 
Gemcitabine 
5.7.1. 
Description 
Alone or in combination with other anticancer agents, 
4-Amino-1-(2-deoxy-2,2-difluoro-β-D-ribofuranosyl)pyrimidin-2(1H)-one hydrochloride; 
2'-Deoxy-2',2'-difluorocytidine hydrochloride (gemcitabine) is a pyrimidine antimetabolite that is 
structurally similar to cytarabine and has demonstrated antitumor activity in several 
malignancies. In advanced UC, it is commonly used as a combination product, or in patients that 
are not eligible for treatment with platinum-containing therapy.  
Gemcitabine is a white or almost white powder with a molecular formula C9H11F2N3O4 • HCl 
and a molecular weight of 299.66. A 1% solution in water has a pH of 2.0 to 3.0. 
Gemcitabine injection is a clear and colorless to light straw-colored solution available in sterile 
single-use vials containing gemcitabine: 200 mg, 1 g, and 2 g. Each mL contains equivalent of 
38 mg of gemcitabine in water for injection, USP. 

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5.7.2. 
Method of Procurement 
Gemcitabine is commercially available and details regarding sourcing of gemcitabine may vary 
by site and/or region as outlined in other documents such as CTAs. 
5.7.3. 
Dose and Administration 
Gemcitabine will be administered at a dose of 1000 mg/m2 on Days 1 and 8 of every 3-week 
cycle as an IV infusion. BSA may be capped per institutional standards. 
Weight-based dosing of gemcitabine is based on the subject’s actual body weight. Doses must be 
adjusted for subjects who experience a ≥10% change in weight from baseline or previous cycle. 
Subject weight must be measured during all relevant assessment windows as described in the 
schedule of events as well as per institutional standards, if applicable. Other dose adjustments for 
changes in body weight <10% are permitted per institutional standard. 
Gemcitabine may be administered for a maximum of 6 cycles. 
5.7.4. 
Dose Modifications 
Dose modifications of gemcitabine are allowed per the local label or institutional standards. See 
the local label for further information. 
The Day 8 dose of gemcitabine must be given within 4 days of the planned dose (Day 8 [–1 to + 
4 days]). If the Day 8 dose cannot be administered within this timeframe, the dose should be held 
until Day 1 of the next treatment cycle. 
5.7.5. 
Storage and Handling 
Refer to the gemcitabine package insert in the Pharmacy Binder for storage and handling 
instructions. 
5.7.6. 
Packaging and Labeling 
Refer to the gemcitabine package insert in the Pharmacy Binder for packaging and labeling 
information. 
5.7.7. 
Preparation 
Refer to the gemcitabine package insert in the Pharmacy Binder for preparation instructions. 
5.8. 
Treatment Duration 
Enfortumab vedotin may be administered for an unlimited number of cycles until a 
protocol-defined reason for treatment discontinuation occurs. Pembrolizumab may be 
administered for a maximum of 35 cycles or a protocol-defined reason for treatment 
discontinuation occurs, whichever is first. Cisplatin, carboplatin, and/or gemcitabine may be 
administered for a maximum of 6 cycles or a protocol-defined reason for treatment 
discontinuation occurs, whichever is first.  
Subjects may continue on study treatment until one of the following protocol-defined reasons for 
treatment discontinuation occurs:  
• Progressive disease (BICR-confirmed or clinical progression [see Section 7.3]) 

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o Confirmed progressive disease per iRECIST (Appendix K) as assessed by 
investigator in subjects in study Arm A treated beyond BICR-confirmed 
disease progression (see criteria below) 
• AE 
• Pregnancy 
• Investigator decision  
• Start of a subsequent anticancer therapy 
• Subject decision, non-AE  
• Study termination by the sponsor.  
• Completion of study treatment  
• Other, non-AE 
In Arm A, subjects who experience an unacceptable AE that is attributable only to 
pembrolizumab may continue on enfortumab vedotin monotherapy until a protocol-defined 
reason for treatment discontinuation. Subjects who experience toxicity that is attributable only to 
enfortumab vedotin may continue on pembrolizumab monotherapy up to a maximum of 
35 cycles.  
In Arm B, subjects who experience an unacceptable AE that is attributable only to 
platinum-containing chemotherapy may continue on gemcitabine for up to 6 cycles. Subjects 
who experience an unacceptable AE that is attributable only to gemcitabine may continue on 
platinum-containing chemotherapy for up to 6 cycles. 
Subjects in Arm A may be treated beyond disease progression per RECIST v1.1 provided they 
are deriving clinical benefit, as defined by all of the following: 
• Improvement in clinical symptoms or functional status as assessed by the investigator 
• No decline in WHO or ECOG performance status attributable to disease progression 
• Absence of symptoms or signs (including worsening laboratory values) of 
unequivocal disease progression  
• Absence of disease progression at critical anatomic sites (eg, CNS, spinal cord 
compression) 
The subject should additionally be informed of other available treatment options. If, in the 
opinion of the investigator, all of the above criteria have been met, the subject may be treated 
beyond disease progression per RECIST v1.1. Protocol treatment must be discontinued upon 
confirmed disease progression by iRECIST per investigator (see Appendix K). 
Study drug that is discontinued cannot be subsequently restarted. 
5.9. 
Concomitant Therapy 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care except for those medications identified as prohibited (see Section 5.9.3).  

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All concomitant medications and blood products administered will be recorded from Day 1 
(predose) through 30 days after the last study treatment, or 90 days after the last study treatment 
for SAEs related to pembrolizumab (see Section 7.8.1.3 and Section 7.8.1.6). Any concomitant 
medication given for a study protocol-related AE should be recorded from the time of informed 
consent. 
5.9.1. 
Required Concomitant Therapy 
There are no required concomitant therapies. 
5.9.2. 
Allowed Concomitant Therapy 
During study treatment, palliative radiotherapy on a stable (not growing), symptomatic nontarget 
bone lesion is allowed and will not be considered a subsequent anticancer therapy. Study 
treatment should be held for at least 7 days prior to and 14 days following administration of 
radiation.  
Surgical resection for curative intent, including TUR for papillary lesions, during study treatment 
may be permitted in subjects with favorable tumor response after discussion with the medical 
monitor.  
The use of anti-emetics is permitted. For subjects randomized to the platinum-containing 
treatment arm, substance P/neurokinin 1 inhibitors (eg, Aprepitant), 5-HT3 antagonists (eg, 
Ondansetron), and short courses (≤1 week) of corticosteroids (eg, Dexamethasone) may be 
administered per local label and/or institutional guidelines for platinum-related nausea 
prevention.  
Granulocyte stimulating growth factors (eg, Filgrastim) may be administered on or after Day 9 of 
each treatment cycle for neutropenia prevention/treatment according to local guidelines.  
The use of insulin is permitted as part of standard of care. Pre-medications for IRRs per Section 
5.10.2 are permitted; however, prophylactic premedication prior to combination treatment on 
Cycle 1 Day 1 for prevention of IRRs may not be administered. 
Therapy to manage enfortumab vedotin-associated toxicity as recommended in Section 5.2.4 is 
permitted, including hematopoietic growth factors and transfusions. 
Subjects who are receiving strong CYP3A4 inhibitors or P-glycoprotein inhibitors concomitantly 
with enfortumab vedotin should be monitored for adverse reactions. 
Routine prophylaxis with vaccines is permitted; however, subjects may not be treated with a live, 
attenuated vaccine during the study and for 90 days after the last dose of study treatment. 
Antimicrobial prophylaxis or ongoing treatment of resolving and/or controlled infection is 
permitted during the study. 
The following applies to subjects receiving pembrolizumab (Arm A):  
With approval from the medical monitor, concomitant chronic prednisone (or equivalent) may be 
used at a dose of ≤10 mg/day to manage pre-existing conditions. Higher doses of prednisone (or 
equivalent) are permitted for limited duration to treat acute conditions that arise during the study 
as medically indicated. The medical monitor should be notified of subjects requiring systemic 
steroids (≥10 mg prednisone or equivalent) for longer than 24 hours for management of a 

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treatment-related AE. Chronic use of inhaled or topical steroids are permitted in the absence of 
active autoimmune disease. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
5.9.3. 
Prohibited Concomitant Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the course of study treatment. If there is a clinical indication for any medication or 
vaccination specifically prohibited during study treatment, discontinuation of study treatment 
may be required. The investigator should discuss any questions regarding this with the medical 
monitor. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician. However, the decision to continue the subject on study 
treatment requires the mutual agreement of the investigator, the sponsor, and the subject. 
Listed below are specific restrictions for concomitant therapy or vaccination during the course of 
study treatment: 
• Systemic antineoplastic therapy with the exception of adjuvant hormonal therapy for 
localized breast or prostate cancer that has undergone definitive treatment  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab or enfortumab vedotin  
• Radiation therapy  
Note: Radiation therapy to a stable (not growing) symptomatic nontarget bone lesion is permitted 
at the investigator’s discretion (see Section 5.9.2).  
• Live vaccines within 30 days prior to the first dose of study treatment, while 
participating in the study, and for 90 days after the last dose of study treatment. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated 
vaccines and are not allowed.  
Subjects who, in the assessment of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from study treatment.  
5.10. 
Management of Adverse Reactions 
5.10.1. 
Overlapping Adverse Reactions 
The Investigator’s Brochures for enfortumab vedotin and pembrolizumab and package inserts for 
cisplatin, carboplatin, and gemcitabine individually describe AEs commonly observed relative to 
individual study treatments, as well as less common serious findings. The respective 

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Investigator’s Brochures and package inserts should be referenced when attributing causality; 
however, the final decision regarding causality is at the discretion of the investigator.  
Some AEs, including rash or skin reactions or pneumonitis/interstitial lung disease (ILD), may 
represent overlapping toxicities for enfortumab vedotin and pembrolizumab, and attribution to an 
individual study treatment may be difficult. For overlapping AEs of skin reaction or 
pneumonitis/ILD, the management actions (ie, to withhold or discontinue study treatment) 
should apply to both enfortumab vedotin and pembrolizumab, and the investigator should follow 
the most conservative dose modification guidelines as described in Section 5.2.4 (Table 6) and 
Section 5.3.4 (Table 7). However, for Grade 2 skin reactions that are stable (not worsening and 
in the absence of fever) with supportive measures and not limiting the subject’s activities of daily 
living, continued dosing of enfortumab vedotin may be considered following consultation with 
the sponsor. 
5.10.2. 
Management of Infusion Reactions 
5.10.2.1. Enfortumab Vedotin 
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. 
Pre-medications for IRRs are permitted as described below; however, prophylactic 
premedication prior to combination treatment on Cycle 1 Day 1 for prevention of IRRs may not 
be administered. Subjects who have experienced an IRR may be premedicated for subsequent 
infusions. Premedication may include pain medication (eg, acetaminophen or equivalent), an 
antihistamine (eg, diphenhydramine hydrochloride), and a corticosteroid administered 
approximately 30–60 minutes prior to each enfortumab vedotin infusion or according to 
institutional standards. Should a subject experience IRRs in the setting of premedication, 
continued treatment must be discussed with the medical monitor prior to the next planned dose. 
If anaphylaxis occurs, study treatment administration should be immediately and permanently 
discontinued.  
5.10.2.2. Pembrolizumab 
Please refer to the recommendations in Table 8. 
5.10.2.3. Infusion-related Reaction of Uncertain Cause 
Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of 
administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate 
symptoms.  
Anaphylactic-like reactions to cisplatin have been reported. Facial edema, bronchoconstriction, 
tachycardia, and hypotension may occur within minutes of cisplatin administration. Epinephrine, 
corticosteroids, and antihistamines have been effectively employed to alleviate symptoms. 
If anaphylaxis occurs, administration of the implicated drug should be immediately and 
permanently discontinued.  

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If a subject experiences an IRR after receiving study treatments and a single cause of the IRR 
cannot be determined, appropriate sets of guidelines for IRRs must be followed. For 
chemotherapy combinations, institutional guidelines should be followed. 
5.10.3. 
Supportive Care Guidelines for Pembrolizumab 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.3.4, and Table 7. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 7 in Section 5.3.4 for 
guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
5.10.4. 
Management of Hyperglycemia 
Investigators should monitor blood glucose levels and are advised to perform additional 
assessments if any symptoms of hyperglycemia are observed, including a thorough evaluation 
for infection. In addition, if steroids are used to treat any other condition, blood glucose levels 
may require additional monitoring. If elevated blood glucose levels are observed, subjects should 
be treated according to local standard of care and referral to endocrinology may be considered. 
Subjects, especially those with a history of or ongoing diabetes mellitus or hyperglycemia, 
should be advised to immediately notify their physician if their glucose level becomes difficult to 
control or if they experience symptoms suggestive of hyperglycemia such as frequent urination, 
increased thirst, blurred vision, fatigue, and headache. 
Subjects who enter the study with an elevated HbA1c (≥6.5%) at baseline should be referred to 
an appropriate provider during Cycle 1 for glucose management. Blood glucose should be 
checked prior to each dosing and dose should be withheld for blood glucose >250 mg/dL (Grade 
3 or higher). Dosing may continue once the subject’s blood glucose has improved to ≤ Grade 2 
and subject is clinically and metabolically stable. The use of insulin is permitted as part of 
standard of care. Blood glucose >500 mg/dL (Grade 4) considered related to enfortumab vedotin 
requires drug interruption and a full evaluation of the hyperglycemia to determine the underlying 
diagnosis. Once hyperglycemia/elevated blood glucose has improved to ≤ Grade 2, drug dosing 
may resume with close monitoring after consultation with medical monitor. 

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5.10.5. 
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, SAEs of severe cutaneous 
adverse reactions were reported in 11 of 749 subjects (1.5%) and included dermatitis bullous 
(0.4%), drug eruption (0.4%), blister (0.1%), conjunctivitis (0.1%), SJS (0.1%), stomatitis 
(0.1%), and toxic skin eruption (0.1%).  
Subjects should be informed that rash and severe skin reactions have occurred after 
administration of enfortumab vedotin and to contact the Investigator immediately if they have 
signs and symptoms of skin reactions, oral mucosal and ocular abnormalities including mucositis 
or conjunctivitis. Starting in the first cycle and throughout treatment, closely monitor subjects for 
skin reactions. For mild to moderate skin reactions, consider appropriate treatment, such as 
topical corticosteroids and antihistamines as clinically indicated. For recommendations regarding 
dose modifications for skin reactions due to enfortumab vedotin, refer to Section 5.2.4. 
5.10.6. 
Management of Pneumonitis/ILD Related to Enfortumab Vedotin 
Severe, life-threatening or fatal pneumonitis/ILD have occurred in subjects receiving enfortumab 
vedotin. Monitor subjects for signs and symptoms indicative of pneumonitis/ILD such as 
hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. For all subjects, including 
subjects with asymptomatic/Grade 1 pneumonitis/ILD, clinical monitoring and supportive 
measures consistent with local medical guidelines should be followed as appropriate throughout 
the study. Medical intervention per standard of care should be considered for Grade ≥2 events 
(eg, corticosteroids initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper). 
For recommendations regarding dose modifications for pneumonitis/ILD due to enfortumab 
vedotin, refer to Section 5.2.4.  
5.10.7. 
Management of Overdose 
5.10.7.1. Enfortumab Vedotin 
Weight-based dosing for enfortumab vedotin is based on the subject’s actual body weight, with 
the exception of subjects weighing greater than 100 kg; doses will be based on 100 kg for these 
individuals. The maximum dose calculated per cycle in this study is 125 mg. 

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In the event of an overdose of enfortumab vedotin >10%, study personnel should: 
• Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of enfortumab vedotin. 
• Notify the Medical Monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (eg, exact amount of enfortumab vedotin administered, subject 
weight) and AEs, if any. 
5.10.7.2. Pembrolizumab 
For this study, an overdose of pembrolizumab will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of an overdose, the site should notify the sponsor as soon as they 
are aware of the overdose. The subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
5.10.7.3. Cisplatin 
For cisplatin, the maximum dose calculated per cycle in this study is 70 mg/m2. In the event 
of an overdose (≥10% of the calculated dose) of cisplatin, the event should be managed 
according to the product label and/or institutional standard of care, and promptly reported to the 
sponsor. 
5.10.7.4. Carboplatin 
For carboplatin, the maximum dose calculated per cycle in this study is calculated using an 
AUC=5. In the event of an overdose (≥10% of the calculated dose) of carboplatin, the event 
should be managed according to the product label and/or institutional standard of care, and 
promptly reported to the sponsor. 
5.10.7.5. Gemcitabine 
For gemcitabine, the maximum dose calculated per cycle in this study is 1000 mg/m2. In the 
event of an overdose (≥10% of the calculated dose) of gemcitabine, the event should be managed 
according to the product label and/or institutional standard of care, and promptly reported to the 
sponsor. 
5.11. 
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 
AEs and concomitant medications (see Section 5.9) will be recorded from Day 1 (predose) 
through the safety reporting period (see Section 7.8.1.3). Any study protocol-related AE (defined 

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in Section 7.8.1.1) as well as any concomitant medications given for treatment of the AE, should 
be recorded from the time of informed consent. 
Clinical laboratory assessments (serum chemistry panel, complete blood count [CBC] with 
differential [manual differential if clinically indicated, see Section 7.8.4], physical exam, weight, 
and performance status) may be performed within 1 day prior to administration of study drug. 
The results from all relevant clinical laboratory assessments must be reviewed prior to dosing by 
qualified site medical personnel. 
Initial QOL, pain and health resource utilization (HRU) assessments will be completed within 
24 hours of Cycle 1 Day 1 at the clinic using an electronic patient-reported outcome (ePRO) 
device. Subsequent assessments will be completed at home by the subject between clinic visits 
using the ePRO device (see Section 7.7 and Table 13). 
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. 
6.2. 
Screening and Baseline Visits 
6.2.1. 
Days –42 to Randomization 
• Informed consent 
• Initiate collection of archival tumor tissue or a new tumor biopsy sample (see 
Section 7.5) 
• Transthoracic echocardiogram or multiple-gated acquisition (MUGA) scan with left 
ventricular ejection fraction is required for subjects with NYHA Class III Heart 
Failure or a history of coronary heart disease, arrhythmia or other significant heart 
disease (see Section 7.8.6) 
6.2.2. 
Days –28 to Randomization 
• Study eligibility per inclusion/exclusion criteria 
• Medical history (see Section 7.1) 
• Complete ophthalmologic examination, (see Section 7.8.7) 
• Brain scan (magnetic resonance imaging [MRI] with gadolinium preferred; if 
contraindicated, see Appendix C), will be conducted at screening/baseline in subjects 
with a history of CNS metastasis or signs/symptoms of CNS metastasis 
• Bone scan will be conducted at screening/baseline in subjects with a history of 
skeletal metastasis or suspicion of skeletal metastasis based on imaging or symptoms 
• CT scan with contrast (preferred; if contraindicated, see Appendix C), including 
chest, abdomen, and pelvis. Other regions should be scanned if the subject has known 
disease in that region (see Section 7.3) 
• International normalized ration (INR)/prothrombin time (PT) and partial 
thromboplastin time (PTT) 

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• HbA1c. If HbA1c is elevated (≥6.5%), refer subject to appropriate provider during 
Cycle 1 for glucose management 
• Urinalysis (with reflexive microscopy, if abnormal) 
• Amylase 
• Lipase 
• Thyroid function tests (see Section 7.8.4) 
6.2.3. 
Days –7 to Randomization 
• Height and weight  
• Vital signs (see Section 7.8.3) 
• Electrocardiogram (ECG) (see Section 7.8.6) 
• Pregnancy test for subjects of childbearing potential (see Section 7.8.8 and 
Appendix A) 
• Physical exam (see Section 7.8.2) 
• ECOG performance status (see Section 7.8.5) 
• Serum chemistry panel (see Section 7.8.4) 
• CBC with differential (see Section 7.8.4) 
• CrCl (see Section 7.8.4) 
6.2.4. 
Days –3 to Day 1 
• Randomization 
6.3. 
Treatment Period (Day 1 to Day 21) 
6.3.1. 
Day 1 (±2 days beginning with Cycle 2) 
• Results from clinical laboratory assessments must be reviewed and must confirm 
eligibility to receive study drug prior to administration 
• The following activities will occur prior to study drug dosing: 
o Physical exam (including weight) (not required if performed within 1 day 
prior to administration of study drug; see Section 7.8.2 and Appendix A) 
o Vital signs 
o ECOG performance status (not required if performed within 1 day prior to 
administration of study drug; see Section 7.8.5 and Appendix A) 
o Serum chemistry panel (not required if performed within 1 day prior to 
administration of study drug; see Section 7.8.4 and Appendix A) 
o Verify blood glucose is <250 mg/dL prior to dosing (see 
Section 5.10.4). Subjects with diabetes must be tested in the clinic and 

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blood glucose must be <250 mg/dL prior to dosing. Use of insulin is 
permitted as part of the standard of care. 
o CBC with differential (not required if performed within 1 day prior to 
administration of study drug; see Section 7.8.4 and Appendix A) 
o Thyroid function test  
o Arm A: Cycle 2 and every even cycle thereafter 
o Arm B: If clinically indicated 
o Pregnancy test for subjects of childbearing potential (not required if 
performed within 1 day prior to administration of study drug; see Section 
7.8.8 and Appendix A) 
o QOL, pain, and HRU assessments (administer before any study procedures 
within 24 hours of Cycle 1 Day 1; see Section 7.7) 
o Blood samples for PK and biomarker assessments (see Section 7.4, Section 
7.5, and Table 12) 
o Urine sample for biomarker assessments (Cycles 1, 3 and 5 only; see Section 
7.5, and Table 12) 
• If Baseline Visit activities occur within 1 day prior to Cycle 1, Day 1, the following 
assessments do not need to be repeated: physical exam (including weight), ECOG 
performance status, serum chemistry panel, CBC with differential, thyroid function 
test, and pregnancy test. 
• Arm A 
o Enfortumab vedotin administration (see Section 5.2.3) 
o Pembrolizumab administration (see Section 5.3.3) 
• Arm B 
o Cisplatin (see Section 5.5.3) or carboplatin (see Section 5.6.3) administration  
o Gemcitabine administration (see Section 5.7.3) 
• The following activities will occur postdose: 
o Blood samples for PK assessments (Cycles 1 and 2 only; see Section 7.4, and 
Table 12) 
6.3.2. 
Day 8 (–1 to +4 days) 
• The following activities will occur prior to study drug dosing: 
o Vital signs 
o Serum chemistry panel 
o Verify blood glucose is <250 mg/dL prior to dosing (see 
Section 5.10.4). Subjects with diabetes must be tested in the clinic and 

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blood glucose must be <250 mg/dL prior to dosing. Use of insulin is 
permitted as part of the standard of care 
o CBC with differential 
o Blood samples for PK assessments (Cycles 1 and 2 only; see Section 7.4, and 
Table 12) 
• Arm A 
o Enfortumab vedotin administration (see Section 5.2.3) 
• Arm B 
o Gemcitabine administration (see Section 5.7.3) 
• The following activities will occur postdose: 
o Blood samples for PK assessment (Cycles 1 and 2 only; see Section 7.4, 
Section 7.5, and Table 12) 
6.3.3. 
Day 15 (±1 day) Cycles 1 and 2 only 
The following activities will occur: 
• Serum chemistry panel (Cycles 1 and 2 only, unless clinically indicated) 
• CBC with differential (Cycles 1 and 2 only, unless clinically indicated) 
6.3.4. 
Response Assessments 
Scans should be conducted on the following schedule until progressive disease (BICR-confirmed 
progressive disease), consent withdrawal, death, or study closure.  
• CT scans with contrast (unless contraindicated; see Section 7.3 and Appendix C) 
every 9 weeks (±1 week) timed from randomization until 18 months after 
randomization, then every 12 weeks (±1 week) thereafter.  
Objective responses will be confirmed per RECIST v1.1 (Appendix J) with repeat 
scans done at the next scheduled response assessment per protocol after first 
documentation of response. Subsequent response assessments should be performed 
every 9 weeks (±1 week) until 18 months after randomization, regardless of dose 
interruptions, then every 12 weeks (±1 week) thereafter. Tumor imaging should also 
be performed, and BICR evaluation triggered, whenever disease progression is 
suspected. 
• Brain scan (MRI with gadolinium preferred; if contraindicated, see Appendix C), will 
be conducted every 9 weeks (±1 week) timed from randomization until 18 months 
after randomization, then every 12 weeks (±1 week) thereafter, and as clinically 
indicated in subjects with a history of CNS metastasis or signs/symptoms of CNS 
metastasis 
• Bone scan will be conducted 9 weeks (±1 week), timed from randomization until 
18 months after randomization, then every 12 weeks (±1 week) thereafter, and as 

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clinically indicated in subjects with a history of skeletal metastasis or suspicion of 
skeletal metastasis based on imaging or symptoms. 
6.4. 
End of Treatment Visit (30 to 37 days after last dose of study drug) 
End of treatment 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. If EOT evaluations are completed before 30 days after the last study treatment, the 
subject will be contacted 30 to 37 days following the last treatment to assess for AEs.  
• Physical examination (including weight) 
• ECOG performance status (Appendix B) 
• Serum chemistry panel 
• CBC with differential 
• Serum or urine β-hCG pregnancy test (only subjects of childbearing potential) 
• CT scan with contrast (unless contraindicated; see Section 7.3 and Appendix C). Not 
required if previous scan conducted <4 weeks prior to EOT 
• Brain scan (in subjects with a history of CNS metastasis or signs/symptoms of CNS 
metastasis. MRI with gadolinium, unless contraindicated; see Appendix C) 
• Bone imaging (in subjects with a history of skeletal metastasis or suspicion of skeletal 
metastasis based on imaging or symptoms) 
• Blood samples for PK and immunogenicity anti-therapeutic antibodies (ATAs) 
assessments (see Section 7.4, and Table 12) 
• Blood samples for biomarker assessments (see Section 7.5) 
• Urine samples for biomarker assessments (see Section 7.5) 
6.5. 
Follow-up (Every 9 Weeks [±1 week]) 
The assessments listed below will be done every 9 weeks (±1 week) from the date of 
randomization until 18 months after randomization, then every 12 weeks (±1 week) until 
BICR-confirmed progressive disease per RECIST v1.1 (Appendix J), subject death, study 
closure, or withdrawal of consent, whichever occurs first.  
• Physical exam – may be discontinued at initiation of subsequent anticancer therapy 
• ECOG performance status (Appendix B) – may be discontinued at initiation of 
subsequent anticancer therapy 
• CT scan with contrast preferred (if contraindicated, see Section 7.3 and Appendix C). 
Repeat scans at the next scheduled response assessment per protocol after first 
documentation of response. For confirmation of disease progression, repeat scans at 
4 to 9 weeks.  

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• Brain scans (MRI with gadolinium preferred; if contraindicated, see Appendix C) 
should be conducted in subjects with a history of CNS metastasis or signs/symptoms 
of CNS metastasis.  
• Bone imaging should also be repeated at this time point in subjects with a history of 
skeletal metastasis or suspicion of skeletal metastasis based on imaging or symptoms. 
• QOL, pain, and HRU assessments will be conducted according to the schedule in 
Table 13. 
6.6. 
Survival Follow-up (Every 12 weeks [±1 week]) 
All randomized subjects will be contacted every 12 weeks (±1 week) after EOT or 12 weeks 
(±1 week) from last study visit, whichever is later, for survival status and collection of 
subsequent anticancer therapy information until death, study closure, lost to follow-up, or 
withdrawal of consent, whichever occurs first. QOL, pain, and HRU assessments will be 
conducted according to the schedule in Table 13  
6.7. 
Subject End of Study/End of Follow-up 
All randomized subjects will remain on study until death, study closure, lost to follow-up, or 
withdrawal of consent, whichever occurs first. The date the subject met criteria for study 
discontinuation and the reason for study discontinuation will be recorded. For subjects who are 
lost to follow-up or withdraw consent from study participation, data for OS will be collected 
from public records as allowed per local regulations. 
7. 
STUDY ASSESSMENTS 
7.1. 
Screening/Baseline Assessments 
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study.  
Subject medical history includes a thorough review of significant past medical history, current 
conditions, any treatment for prior malignancies and response to prior treatment, and any 
concomitant medications. 
Acquisition of a new tumor biopsy tissue or collection of an archived tumor specimen, an 
ophthalmologic examination (see Appendix A), brain scan (MRI with gadolinium contrast 
preferred; see Appendix C for preferred imaging methods), bone scan, CT scan with contrast 
(preferred; see Appendix C for preferred imaging methods) for baseline tumor imaging, 
INR/PT/PTT, urinalysis (with reflexive microscopy, if abnormal), HbA1c, amylase, lipase, and 
thyroid function tests are required for all subjects at screening. A pregnancy test (either urine or 
serum, for females of childbearing potential), physical examination (including weight), 
collection of height, vital signs, CBC with differential, serum chemistry panel, CrCl (see 
Section 7.8.4), ECOG performance status assessment, and ECG are required at baseline.  
7.2. 
Randomization 
Randomization will occur at Day –3 to 1, prior to the first dose of study drug. 

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7.3. 
Response/Efficacy Assessments 
CT scans with contrast (unless contraindicated), including chest, abdomen, and pelvis at the 
minimum, will be used to assess antitumor activity at protocol-specified time points. Subjects 
must receive the same imaging method throughout the study for response assessments. For 
subjects who cannot receive CT scans with contrast, MRI may be used as long as it will continue 
to be used for all disease assessments. Bone imaging and/or brain scans should be repeated at 
disease assessment time points, and as clinically indicated throughout the study, in subjects with 
a history of skeletal metastasis or suspicion of skeletal metastasis based on imaging or 
symptoms, or a history of CNS metastasis or signs/symptoms of CNS metastasis. Other regions 
should be scanned if the subject has known disease or new symptoms suggestive of disease in 
that region.  
Objective responses will be assessed according to RECIST v1.1 (Eisenhauer 2009) (Appendix J) 
by BICR. Response assessments should be performed every 9 weeks (±1 week) timed from the 
randomization date until 18 months after randomization, then every 12 weeks (±1 week) 
thereafter. Tumor imaging should also be performed, and BICR evaluation triggered, whenever 
disease progression is suspected. Objective responses will also be assessed according to 
iRECIST per investigator assessment for all subjects in Arm A. 
Treatment beyond disease progression per RECIST v1.1 may be considered for subjects in study 
Arm A who are deriving clinical benefit as defined in Section 5.8. Subjects treated beyond 
disease progression per RECIST v1.1 may continue until confirmed disease progression per 
iRECIST (Seymour 2017) (Appendix K) as assessed by the investigator. Confirmatory scans 
must be performed 4 to 9 weeks after disease progression per RECIST v1.1 by BICR (see Table 
11). 
Table 11: 
Imaging and treatment after first radiologic evidence of progressive disease 
 
Clinically Stable 
Imaging 
Treatment 
First radiologic evidence of PD by 
RECIST v1.1 per BICR 
Repeat imaging at 4 to 
9 weeks to confirm PD. 
May continue study intervention 
after the subject’s consent and at 
the investigator’s discretion while 
awaiting confirmed PD by 
iRECIST per investigator 
assessment. 
Repeat tumor imaging confirms PD 
(iCPD) by iRECIST per investigator 
assessment. 
No additional imaging 
required. 
Discontinue treatment  

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Repeat tumor imaging shows iUPD by 
iRECIST per investigator assessment. 
Repeat imaging at next 
regularly scheduled imaging 
visit. If this scan is within 
4 weeks of the next scheduled 
timepoint, it can be used to 
satisfy both imaging 
timepoints. 
Continue study intervention at the 
investigator’s discretion. 
Repeat tumor imaging shows iSD, iPR, 
or iCR by iRECIST per investigator 
assessment. 
Continue regularly scheduled 
imaging assessments. 
Continue study intervention at the 
investigator’s discretion. 
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iPR=iRECIST partial response; 
iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; 
iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease 
Note: If progression has been centrally verified, further management is by the site, based on iRECIST. Any further 
imaging should still be submitted to the CRO, but no expedited review will occur.  
In the event disease progression is suspected by the investigator, the images must be transferred 
to the Imaging Contract Research Organization (CRO) for expedited BICR. The investigator 
seeking an expedited review should indicate this request to the Imaging CRO on a designated 
form. In all instances, the process at the Imaging CRO will ensure that the BICR remains blinded 
to the results of the local assessment and to the nature of the review. The result of the BICR will 
be communicated directly to the trial site.  
Every effort should be made to continue the subject on study treatment during the BICR period, 
as long as it is clinically acceptable. If the BICR verifies disease progression, the subject must 
permanently discontinue study treatment unless they are eligible per the criteria in Section 5.8 
for treatment beyond disease progression per iRECIST. 
If the BICR does not verify disease progression, every effort must be made to continue study 
treatment, as long as it is clinically acceptable. Subjects should continue on-trial radiological 
evaluation.  
Subjects who discontinue study treatment for reasons other than radiographically-confirmed 
disease progression per BICR or consent withdrawal will continue to receive CT scans with 
contrast (unless contraindicated) every 9 weeks (±1 week) for the first 18 months timed from the 
randomization date, then every 12 weeks (±1 week) until the subject has BICR-confirmed 
disease progression per RECIST v1.1, dies, the study closes, or the subject withdraws consent, 
whichever occurs first. For subjects that initiate subsequent anticancer therapy prior to disease 
progression per BICR, response assessment should be continued and submitted until BICR 
confirmed disease progression. Sites should contact the medical monitor prior to discontinuing 
study disease assessments and/or initiating subsequent anti-cancer therapy. 
Survival status and information on subsequent anticancer therapy will be updated every 
12 weeks (±1 week) until death, withdrawal of consent, lost to follow-up, or study closure, 
whichever occurs first. 
Subjects’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee), upon request. 

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7.4. 
Pharmacokinetic and Immunogenicity Assessments 
Blood samples for PK and ATA will be collected for Arm A only, per the sample collection 
schedule provided in Table 12. Validated or qualified assays will be used to measure the 
concentrations of enfortumab vedotin and MMAE in serum or plasma. A validated assay will be 
used to determine the levels of ATA for enfortumab vedotin in serum. PK and ATA samples for 
pembrolizumab will be collected. Determination of serum levels for pembrolizumab 
concentrations and pembrolizumab ATA will be performed only if required. 
If at some point prospective PK blood sample collection is no longer required, sites will be 
notified. Refer to the Central Laboratory Manual for information on collection, processing, 
storage, and shipment of samples. 
7.5. 
Biomarker Studies 
To identify markers of sensitivity, resistance, and possible AEs, samples for biomarker analyses 
will be collected at protocol-specified time points (see Table 12). All subjects must provide 
pre-treatment tumor non-decalcified tissue collected by core needle biopsy or excision for 
biomarker analysis (fine needle aspirate is not acceptable). Archived tumor tissue, not previously 
irradiated, should be collected after completion of the most recent prior systemic therapy, ideally 
within 12 months prior to enrollment, if possible. If adequate archival tumor samples are not 
available, a fresh biopsy may be performed. A formalin-fixed, paraffin embedded (FFPE) tumor 
block is preferred.  
To understand the relationship between the biological characteristics of tumors before treatment 
and subject outcomes, tumor tissue from pre-treatment biopsies will be examined. Subjects will 
be stratified prior to randomization according to PD-L1 status (PD-L1 high: CPS ≥10 and PD-L1 
low: CPS <10 based on Dako/Agilent PD-L1 IHC 22C3 PharmDx). Exploratory biomarker 
assessments on pre-treatment tumor tissue may include, but are not limited to, Nectin-4 
expression, assessment of tumor subtyping, tumor microenvironment, and mutations associated 
with response to enfortumab vedotin in metastatic UC. Biomarkers from serially collected 
peripheral blood and urine may include, but are not limited to, cell -free tumor DNA, cytokines, 
and T-cell clonality analyses as markers of tumor response or resistance. Methods of analysis 
may include, but are not limited to, IHC, next-generation sequencing of DNA and RNA, and 
immunoassays. These assessments will be compared to similar assessments conducted in 
enfortumab vedotin monotherapy trials and may provide insight into treatment-related changes.  
Refer to the Central Laboratory Manual for information on collection, processing, storage, and 
shipment of samples. 

 
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Table 12: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points 
 
Study 
Day 
Time 
Window 
Relative Time 
Pharmacokinetics and Immunogenicity 
(Arm A only) 
Blood Biomarkers 
(All arms) 
Urine 
Biomarkers 
(All arms) 
Tissue 
Biomarkers 
(All arms) 
EV 
PK 
Pembro 
PK 
ATA 
EV 
ATA 
Pembro  
Serum 
Plasma 
Urine 
Tumor Tissue  
Screening 
Days  
–42 to 
RND 
N/A 
N/A 
N/A 
 
 
 
 
 
 
 
X  
Cycles 1 and 2 
Day 1 
Predose 
Within 
4 h 
Start of EV, 
gemcitabine or 
platinum 
infusion 
X 
XA 
X 
X 
X 
X 
XA 
 
End of EV 
IV infusion 
Within 
15 min 
End of EV 
infusion 
X 
 
 
 
 
 
 
 
End of 
Pembro IV 
infusion 
Within 
15 min 
End of Pembro 
infusion 
 
XA 
 
 
 
 
 
 
Day 8 
Predose 
Within  
4 h 
Start of EV 
infusion 
X 
 
 
 
 
 
 
 
 End of EV 
IV infusion 
 Within 
15 min 
End of EV 
infusion 
X 
 
 
 
 
 
 
 
Cycle 3 and 
every 
odd-numbered 
cycle thereafter 
Day 1 
Predose 
Within 24 h  
Start of EV, 
gemcitabine or 
platinum 
infusion 
XC 
XC 
XC 
XC 
XB 
XB 
 XB 
 
End of Treatment (within 30–37 days of last dose) 
N/A 
X 
X 
X 
X 
X 
X 
X 
 
RND=randomization. 
A Cycle 1 only. 
B Cycle 3 and 5. 
C Up to Cycle 9 only. 

 
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7.6. 
Biospecimen Repository 
In the US only, for subjects who provide additional consent, remaining de-identified unused 
blood and/or tissue and/or urine will be retained by Seagen 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 of ADCs. 
Blood, urine, 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 after the study has been completed and all applicable regulatory obligations have been 
met. 
7.7. 
Electronic Patient-Reported Outcomes (ePRO) 
Electronic PRO assessments will include the EuroQOL 5-dimensions (EQ-5D-5L), EORTC 
Quality of Life Core 30 (QLQ-C30), Brief Pain Inventory – Short Form (BPI-SF), and HRU 
questionnaires. Electronic PROs will be administered per the schedule outlined in Table 13.  
Table 13: 
Electronic Patient-Reported Outcomes Schedule of Events 
Questionnairesa 
ePRO Assessment Timepoints 
Week 0 
Week 1  
Weeks 2b to 12  
Week 14 
Week 17+ 
Time Interval 
Day 1 
+3 to 4 days 
from Week 0 
Weekly 
Once 
Every 
3 weeksc 
EuroQOL 5-dimensions  
X 
X 
X 
X 
X 
 Brief Pain Inventory –  
Short Form 
X 
X 
X 
X 
X 
 EORTC Quality of 
Life Core 30 
X 
X 
X 
X 
X 
Healthcare Resource 
Utilization  
X 
X 
X 
X 
X 
EORTC=European Organisation for Research and Treatment of Cancer; ePRO=electronic patient-reported outcome; 
QOL=quality of life. 
a If study procedures/assessments are performed on ePRO completion day, questionnaires should be done first. 
b Week 2 questionnaires are completed on Days 11 to 12. 
c Through disease progression and survival follow-up. 
Questionnaires will be completed by the subject on an electronic device. On Cycle 1 Day 1, 
subjects will complete the questionnaires in the clinic up to 24 hours prior to the first dose of 
study treatment and before any study procedures/assessments are conducted. After Cycle 1 Day 
1, questionnaires will be completed at home several days prior to a clinic visit. Subjects will be 
provided with digital support (eg, instruction) to fill in the questionnaires at home in between 
clinic visits, with the exception of Cycle 1 Day 1. The ePRO device will notify subjects to 
complete the questionnaires at the appropriate time points. This will ensure that data are 
collected in between study treatments.  
The information completed by the subject on the electronic device will be automatically 
uploaded into a central website. The investigator or site designee will closely monitor the 
questionnaire data on the website for each subject during study treatment and the follow up 

 
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period and address any compliance issues that may arise. If a subject does not complete the 
questionnaires per protocol, the investigator or site designee should document the event as a 
protocol deviation.  
The investigator or site designee, and site personnel will be trained on how to provide support to 
each subject on the use of the ePRO device. Refer to the ePRO site user guide for additional 
information on the questionnaire schedule and ePRO device operation. 
7.7.1. 
EORTC Core Quality of Life (QLQ-C-30) Questionnaire 
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 symptoms scales (fatigue, pain, nausea and vomiting) 
• Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease, and 
• 2 global items (health, overall QOL) 
Each domain is scored from 0 to 100. For the global health status/QOL and functional domain 
scores, higher scores represent better QOL and functioning, respectively. For symptom scales, 
higher scores represent greater symptomatology (see Appendix F). 
7.7.2. 
EuroQOL-5 Dimensions (EQ-5D-5L) 
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. Responses to the 5 items are then converted to a weighted health state 
index (utility score) based on values derived from general population samples (Herdman 2011). 
The health utility score is between 0 and 1, where 0 is death and 1 is perfect health. In addition to 
the utility score, this questionnaire also records the respondent’s self-rated health status on a 
vertical graduated (0 to 100) visual analogue scale (VAS) (See Appendix G). 
7.7.3. 
Brief Pain Inventory – Short Form (BPI-SF) 
The BPI-SF is a validated PRO designed to assess the severity of pain and its impact on 
functioning specifically in the clinical trial setting (Cleeland 1994; Atkinson 2011). The BPI-SF 
measures worst, least, and average pain experienced in the last 24 hours, the location of the pain 
and the medications used for treatment of the pain. Additionally, it also asks questions about the 
interference due to pain in general activity, mood, walking, normal work, relationships, sleep and 
enjoyment of life. The pain severity and interference questions are answered on a 10-point Likert 

 
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scale and scoring is calculated using arithmetic mean of the four severity items to provide 
measurement of the pain severity and the arithmetic mean of the seven interference items to 
measure of pain interference. Individual scores for each severity item as well as each interference 
item can also be done. Higher scores are associated with higher pain levels (Cleeland 2009) 
(Appendix H).  
7.7.4. 
Health Resource Utilization 
HRU information will be collected using a questionnaire designed to collect data from the 
subject perspective summarizing unplanned use of health resources outside of the clinical trial 
(Appendix I). 
7.8. 
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, vital signs, protocol-specified laboratory tests, 
ECOG status, ECGs, ophthalmologic examination findings and pregnancy testing.  
Safety will be monitored over the course of the study by an IDMC. 
7.8.1. 
Adverse Events 
7.8.1.1. 
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 312.32, Investigational 
New Drug (IND) Safety Reporting, an AE is any untoward medical occurrence in a subject 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: 
• 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 (during and post-dose) through the end of the safety reporting period (see 
Section 7.8.1.3). Complications that occur in association with any procedure 
(eg, 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. 

 
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• 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 (eg, 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 subject 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. Hospitalizations or prolonged hospitalizations for 
scheduled therapy of the underlying cancer or study target disease need not be 
captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or substantial disruption 
of the subject’s ability to conduct normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a subject 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 subject 
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. Potential drug-induced liver injury (DILI) also is considered a 
medically significant event (see Section 7.8.1.2 for the definition of potential DILI.) 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 4.03.  
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). 
 

 
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Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to enfortumab vedotin, pembrolizumab, and/or cisplatin or 
carboplatin, and gemcitabine and cisplatin or carboplatin 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 (eg, 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 (eg, 
tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (eg, 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 
7.8.1.2. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during subject 
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 
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 AE. 

 
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Important exceptions for this study are adverse reactions associated with the infusion of study 
drug. For this study, adverse reactions associated with the infusion of study drugs must be 
recorded as a NCI CTCAE term, which includes IRR, or a more specific diagnosis if appropriate 
(ie, ‘cytokine release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity 
reaction’). Each sign or symptom that occurs within a given infusion-related event (ie, chills, 
fever, rash) must also be recorded. Level of severity for both the overall IRR term and the 
individual signs and symptoms should be recorded. 
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 Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it should 
not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of Disease”, or 
“Malignant disease progression” and other similar terms should not be used to describe an AE or 
SAE. However, clinical symptoms of progression may be reported as AEs or SAEs if the 
symptom cannot be determined as exclusively due to progression of the underlying malignancy 
or does not fit the expected pattern of progression for the disease under study. In addition, 
complications from progression of the underlying malignancy should be reported as AEs or 
SAEs. 
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 study subject who is able to father a child. Only report pregnancies that occur 
in a subject’s partner if the estimated date of conception is after the subject’s first study drug 
dose. Email or fax to the sponsor’s Drug Safety Department within 48 hours of becoming aware 
of a pregnancy. As part of the study all pregnancies will be monitored for the full duration and 
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 CRF. 

 
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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 7.8.1.1) should be reported as SAEs. 
Corneal Adverse Events 
Corneal ulcer or keratitis AEs ≥ Grade 2 should be graded within their respective NCI CTCAE 
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. 
Diabetes and Hyperglycemia 
Grading for diabetes should be based on the NCI CTCAE v4.03 event term of glucose 
intolerance. Grading for hyperglycemia should be based on the NCI CTCAE v4.03 event term of 
hyperglycemia.  
Potential Drug-Induced Liver Injury 
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity. 
The absence of hepatotoxicity in clinical trials provides a limited predictive value for potential 
hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law case in 
clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe DILI. 
Definition 
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (alanine aminotransferase [ALT] and/or aspartate aminotransferase 
[AST]) elevation >3x upper limit of normal (ULN) 
AND 
2. Total bilirubin >2x ULN, without initial findings of cholestasis (ie, elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements 
Any potential Hy’s Law case should be handled as a serious adverse reaction associated 
with the use of the drug and reported promptly to the Sponsor on an SAE form. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary data. 

 
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Follow-up for Abnormal Laboratory Results Suggesting Potential DILI 
In general, an increase of serum ALT or AST to >3x ULN should be followed by repeat testing 
within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, to confirm 
the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding factors 
and alternative causes of hepatotoxicity. During this investigation, consider withholding study 
drug. 
7.8.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs (except SAEs related to pembrolizumab) 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. The reporting period 
for SAEs related to pembrolizumab is from study Day 1 (predose) through 90 days after the last 
study treatment, or 30 days following cessation of study treatment if the subject initiates a new 
anticancer therapy. 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 
subject dies or withdraws consent. All non-serious AEs will be followed through the safety 
reporting period. Certain non-serious AEs of interest may be followed until resolution, return to 
baseline, or study closure (see Section 7.8.1.6). 
7.8.1.4. 
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. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a minimum, 
the following should be included: 
• Subject number 
• Date of event onset 
• Description of the event 
• Investigator’s causality assessment 
• Study treatment, if known 
The completed SAE forms are to be emailed or faxed to the sponsor’s Drug Safety Department 
within 24 hours (see email or fax number specified on the SAE report form), unless otherwise 
instructed on the Sponsor’s SAE form.  
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes available. 
7.8.1.5. 
Sponsor Reporting Requirements 
The sponsor will handle and report suspected unexpected serious adverse reactions (SUSARs) 
according to relevant local legislation or regulation. 

 
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7.8.1.6. 
Adverse Events of Special Interest 
Certain non-serious AESIs may be followed (including collection of relevant concomitant 
medications) until resolution, return to baseline, subject withdrawal, study closure, or the events 
become chronic to the extent that they are adequately characterized. 
AESIs related to enfortumab vedotin or enfortumab vedotin in combination with pembrolizumab 
for this purpose include those events in the list below (*denotes that event must be Grade ≥2 or 
any grade resulting in a dose modification to be considered an AESI): 
• Skin reactions 
• Neuropathy (PN, Guillain-Barre) 
• Corneal event or uveitis 
• Hyperglycemia or Type 1 diabetes 
• IRR 
• Pneumonitis*  
• Diarrhea* or colitis* 
• Hepatitis* or AST/ALT increased* or bilirubin increased* 
• Endocrinopathy* (defined as hypophysitis, adrenal insufficiency, hypothyroidism, 
hyperthyroidism) 
• Nephritis or acute renal failure 
• Myocarditis 
• Pancreatitis 
• Myasthenia gravis or syndrome 
• Vasculitis 
• Sclerosing cholangitis 
AESIs should be promptly reported by electronic data capture (EDC). If an event is medically 
significant or meets serious criteria it should be reported as a serious event within 24 hours (see 
Section 7.8.1.4). 
Adverse Events of Special Interest Requiring Immediate Reporting 
For the time period beginning at Cycle 1, Day 1 through 30 days following the last study drug 
dose, any AESI listed below, or follow-up to an AESI, whether or not related to the sponsor’s 
product, must be reported within 24 hours to the sponsor, either by electronic media or by paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. 
AESIs for this purpose include: 
• An overdose of sponsor's product, as defined in Section 5.10.7.1 (enfortumab 
vedotin) and Section 5.10.7.2 (pembrolizumab) that is not associated with clinical 
symptoms or abnormal laboratory results. 

 
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• Increased LFTs not otherwise explained by an underlying liver condition as defined 
in Appendix E. Additional recommendations for liver safety monitoring and 
assessment are also included in Appendix E. 
7.8.2. 
Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Height will only be collected at 
the Baseline visit. Weight will be collected at specified time points (see Appendix A) and 
additionally per institutional standards, if applicable, but does not need to be collected at visits 
following EOT. 
7.8.3. 
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 AE or 
pre-existing condition. 
7.8.4. 
Clinical Laboratory Tests 
Samples will be drawn for local laboratory testing. Local lab results will be sent to a local 
laboratory data repository. 
Local laboratory testing will include institutional standard tests for evaluating study eligibility, 
safety and making clinical decisions. If local laboratory testing for bicarbonate is not available, a 
central laboratory will perform the test. The following laboratory assessments will be performed 
by the local lab to evaluate safety at scheduled timepoints (see Appendix A) during the course of 
the study: 
• The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
ALT, AST, bicarbonate, blood urea nitrogen, calcium, creatinine, chloride, lactate 
dehydrogenase, phosphorus, potassium, sodium, non-fasting glucose, and total 
bilirubin.  
• Amylase and lipase  
• 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.  
• CrCl at baseline should be calculated via either Cockcroft-Gault, MDRD or 24-hour 
urine, per institutional standard. The same method to determine CrCl should be used 
consistently for a subject over the course of the study with the exception of 
carboplatin dose calculation where Cockcroft-Gault method should be used in all 
subjects.  
• Thyroid function tests, including:  
o Triiodothyronine or free triiodothyronine 
o Free thyroxine 

 
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o Thyroid-stimulating hormone 
• Standard urinalysis (with reflexive microscopy, if abnormal) 
• INR/PT/PTT (at baseline and as clinically indicated thereafter) 
• A serum or urine β-hCG pregnancy test for females of childbearing potential  
• HbA1c. If HbA1c is elevated (≥6.5%), refer subject to appropriate provider during 
Cycle 1 for glucose management. 
7.8.5. 
ECOG Status 
ECOG performance status (Appendix B) will be evaluated at protocol-specified time points (see 
Appendix A). 
7.8.6. 
Cardiac Monitoring 
ECGs will be conducted at baseline. Routine 12-lead ECGs will be performed after the subject 
has been in a supine position for at least 5 minutes. For subjects with NYHA Class III Heart 
Failure (see Appendix D) or a history of coronary heart disease, arrhythmia or other significant 
heart disease, a transthoracic ECHO or MUGA scan with left ventricular ejection fraction is 
required.  
7.8.7. 
Ophthalmologic Examination 
Subjects will have a complete ophthalmologic examination at screening including, but not 
limited to, visual acuity, slit lamp, tonometry examination and dilated fundus examination. 
Subsequent ophthalmology assessments should be performed as clinically indicated throughout 
the study. EOT slit lamp examinations are required for subjects who experience corneal AEs 
during the study and must be performed ≥4 weeks from the last dose. 
7.8.8. 
Pregnancy Testing 
For subjects of childbearing potential, a serum or urine β-hCG pregnancy test with sensitivity of 
at least 25 mIU/mL will be performed at baseline, on Day 1 of every cycle, and at the EOT visit. 
A negative pregnancy result is required before the subject may receive study drug on Day 1 of 
each cycle. The pregnancy test may be performed within 1 day prior to administration of study 
drug. Pregnancy tests may also be repeated as requested per Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) or if required by local regulations. 
7.9. 
Post-treatment Assessments 
7.9.1. 
Follow-up Assessments 
Subjects who discontinue study treatment will receive physical exams and ECOG assessment. 
Physical exams and ECOG assessments may be discontinued for subjects that start a new 
anticancer therapy. Response assessments every 9 weeks (±1 week) for the first 18 months timed 
from the randomization date, and every 12 weeks (±1 week) thereafter. ePRO questionnaires 
(QLQ-C30, EQ-5D-5L, BPI-SF, HRU) will continue to be completed per the schedule outlined 
in Table 13 Scans are to be done until BICR confirmed progressive disease per RECIST v1.1 
(Appendix J), subject death, study closure, or withdrawal of consent, whichever occurs first.  

 
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During study treatment, palliative radiotherapy on a nontarget bone lesion that is not progressing 
will not be considered a subsequent anticancer therapy; however, radiotherapy on any new or 
progressing lesion, per RECIST v1.1 as assessed by the investigator or after BICR-confirmed 
progression, will be considered a subsequent anticancer therapy and subjects will not be 
permitted to resume study treatment. Surgical resection for curative intent during study treatment 
may be permitted in subjects with favorable tumor response after discussion with the medical 
monitor. 
7.9.2. 
Survival Follow-up Assessments 
After discontinuation of study treatment, all randomized subjects will be contacted every 
12 weeks (±1 week) to obtain information on subsequent anticancer therapy and survival status. 
ePRO questionnaires (QLQ-C30, EQ–5D-5L, BPI-SF, HRU) will continue to be completed per 
the schedule outlined in Table 13. Survival follow-up will continue until subject death, study 
closure, lost to follow-up, or withdrawal of consent, whichever occurs first. 
7.10. 
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 BICR-confirmed 
radiographically-confirmed objective response assessments as defined by RECIST v1.1 
(Eisenhauer 2009) (Appendix J). Treatment decisions by the investigator will be based on 
investigator-assessed disease progression per RECIST v1.1 with BICR confirmation. RECIST 
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. iRECIST 
guidelines are newly published criteria that will be applied as exploratory criteria for this study 
in cohorts that utilize pembrolizumab. These guidelines allow consideration that 
immunotherapeutics, such as pembrolizumab, may result in infiltration of immune cells leading 
to transient increase in the size in malignant lesions, or undetectable lesions becoming 
detectable. The guidelines are identical to those of RECIST v1.1 in many respects but have been 
adapted to account for instances where an increase in tumor burden, or the appearance of new 
lesions, does not reflect true tumor progression (Seymour 2017) (Appendix K). 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be performed 
to detect the possible presence of specific antibodies to enfortumab vedotin. 
PK assessments are also common in clinical studies to help characterize dose-exposure-response 
relationships. 
Exploratory biomarker measurements in peripheral blood samples enable correlation with PK 
assessments and are common in clinical studies. Assessments conducted on pre-treatment tumor 
tissue are similarly common. Peripheral blood, urine and tissue biomarker samples will be 
assessed using commonly employed, standard tests.  

 
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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 subjects 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/package insert 
• Recording and reporting AEs and SAEs 
• Enrollment goals and study timelines 
• The CRF completion process and source documentation requirements 
• Use of the ePRO device 
• Monitoring requirements 
• 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 
• Subject coding and randomization  
• Study samples/specimen collection, handling and shipping 
• Protocol compliance 
• Clinical study 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 will typically review 
regulatory documentation, CRFs, source documentation, and investigational product storage, 
preparation, and accountability. The CRFs will be reviewed for completeness, 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 subjects 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 
and by quality assurance auditors, or representatives of regulatory authorities. 

 
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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 subject confidentiality are to be employed during 
monitoring. The CRFs and related source documents will typically 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 the 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 during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5. 
Quality Assurance Procedures 
The Research and Development Quality group or its designee may conduct audits at the clinical 
site or other study-related facilities and organizations. Audit reports will be retained by the 
Research and Development Quality group 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. 

 
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Any change or correction to a CRF will be maintained in an audit trail within the EDC 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 subject 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 to Seagen. 
9. 
DATA ANALYSIS METHODS 
9.1. 
Determination of Sample Size 
Approximately 860 subjects will be randomized in a 1:1 ratio to one of the study arms. Control 
arm assumptions are based on recent trials: EORTC 30987, which tested gemcitabine + cisplatin 
(Bellmunt 2012), EORTC 30986, which tested gemcitabine + carboplatin (De Santis 2012), 
CALGB 90601 which included gemcitabine + cisplatin + placebo (Rosenberg 2019a) and 
IMvigor130 which included gemcitabine + cisplatin or carboplatin + placebo (Galsky 2020). 
Median PFS for the EORTC trials gemcitabine + platinum-containing control arms was 7.6 and 
5.8 months, respectively, and corresponding median OS was 12.7 months and 9.3 months. In the 
CALGB 90601 trial, the gemcitabine + cisplatin reference arm achieved a median PFS of 
6.6 months and median OS of 14.3 months. In IMvigor130, median PFS for the control arm was 
6.3 months and median OS was 13.4 months. Notably, the proportion of carboplatin-treated 
subjects approached 70% due to an initial study design which only enrolled cisplatin-ineligible 
subjects. In the JAVELIN Bladder 100 trial, median OS was 21.4 months for the avelumab arm 
and 14.3 months for the control arm (best supportive care alone) (BAVENCIO® US Prescribing 
Information, EMD Serono, Nov 2020).  
PFS and OS assumptions for the control arm for the currently proposed trial were calculated 
utilizing a weighted average (anticipating 60% cisplatin-eligible/40% carboplatin-eligible 
enrollment). Thus, median OS and PFS assumptions for the control arm of the current trial were 
adjusted for expected improvement in survival outcomes in the contemporary era; the current 
trial assumes a control arm median PFS of 7 months and median OS of 15.3 months accounting 
for subjects receiving maintenance therapy.  
This sample size of 430 subjects per arm is determined by providing a sufficient power in OS 
superiority test between Arms A and B. More specifically, with 430 subjects per arm, 
approximately 489 OS events are required to provide 93% power to demonstrate superiority at a 
two-sided alpha of 4.5% without alpha roll-over with 1 IA around 72.8% information fraction 
under the following assumptions:  
1. OS curves follow piecewise exponential distribution with a reduced hazard rate (50% of 
the initial rate) starting from 24 months;  

 
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2. hazard ratio (HR) of OS is 0.73 between the experimental and control arms;  
3. median OS for the control arm is 15.3 months;  
4. an enrollment period of 30 months; 
5. a yearly dropout rate of 5%.  
 
With 430 subjects per arm, the number of PFS events in total is estimated to be 526 events, 
providing 90% power to demonstrate superiority at a two-sided alpha of 0.5% without alpha 
roll-over based on the following assumptions:  
1. PFS curves follow piecewise exponential distribution with a reduced hazard rate (20% of 
the initial rate) starting from 15 months;  
2. HR of PFS is 0.70 between the experimental and control arms;  
3. median PFS for the control arm is 7 months;  
4. an enrollment period of 30 months;  
5. a yearly dropout rate of 5%. 
9.1.1. 
China Portion of the Study 
To evaluate the consistency of efficacy and safety in a China subpopulation compared with the 
global population, after completion of enrollment in the global portion, subjects in China may 
continue to be randomized in a 1:1 ratio to either the experimental arm or the control arm until 
the planned sample size of approximately 130 subjects in China is reached, including those 
randomized in the global portion and China portion. Subjects in China randomized after 
completion of enrollment in the global portion will not be included in the analysis of the global 
portion. Subjects enrolled in China will be analyzed separately for efficacy and safety (Section 
9.3.1.7). Details of analysis of the China portion of the study will be provided in the statistical 
analysis plan (SAP).  
9.2. 
Study Efficacy Endpoint Definitions 
PFS per BICR and OS are the dual primary endpoints for the study. See Section 2 for a complete 
list of endpoints. 
9.2.1. 
Progression-Free Survival Per BICR 
PFS per BICR is defined as the time from randomization to first documentation of disease 
progression per RECIST v1.1 by BICR, or to death due to any cause, whichever comes first.  
If a subject has neither progressed nor died, the subject will be censored at the date of last 
radiological assessment. Subjects who receive new anticancer therapy (excluding maintenance 
therapy [eg, avelumab] following first-line platinum-containing chemotherapy) for locally 
advanced or metastatic UC before disease progression will be censored at the date of the last 
radiological assessment before the anticancer therapy started. Subjects lacking radiological 
assessment data beyond the day of randomization will be censored at the day of randomization.  
Details of the censoring scheme for the primary analysis of PFS are described in the SAP. 

 
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9.2.2. 
Overall Survival 
OS is defined as the time from date of randomization to date of death due to any cause. In the 
absence of confirmation of death, survival time will be censored at the last date the subject is 
known to be alive.  
9.2.3. 
Objective Response Rate 
ORR is defined as the proportion of subjects with confirmed CR or PR according to RECIST 
v1.1 (Eisenhauer 2009) (Appendix J). Subjects who do not have at least 2 (initial response and 
confirmation scan) post-baseline response assessments will be counted as non-responders for the 
primary analysis of ORR. The definition of confirmed CR and PR will be specified in the SAP. 
ORR per investigator and per BICR will be analyzed. 
9.2.4. 
Disease Control Rate 
DCR is defined as the proportion of subjects with confirmed CR, PR, or SD according to 
RECIST v1.1 (Eisenhauer 2009) (Appendix J). The definition of confirmed CR and PR will be 
specified in the SAP. DCR per investigator and per BICR will be analyzed. 
9.2.5. 
Duration of Response 
DOR is defined as the time from first documented response of CR or PR (that is subsequently 
confirmed) to the first documented disease progression per RECIST v1.1 (Eisenhauer 2009) 
(Appendix J), or to death due to any cause, whichever comes first. DOR will only be calculated 
for the subjects achieving a confirmed CR or PR. DOR per investigator and per BICR will be 
analyzed. 
9.2.6. 
Progression-Free Survival Per Investigator Assessment 
PFS, per investigator assessment, is defined as the time from randomization to first 
documentation of disease progression per RECIST v1.1 (Eisenhauer 2009) (Appendix J), or to 
death due to any cause, whichever comes first.  
The same censoring rules outlined in Section 9.2.1 for PFS per BICR will be applied to PFS per 
investigator.  
9.3. 
Statistical and Analytical Plans 
The statistical and analytical plans are presented below. Additional analysis details of the global 
portion and China population will be provided in the SAP. A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct 
(eg, adding baseline assessments to define a subgroup). Changes in the SAP related to primary or 
secondary endpoints after the study has begun, but prior to database lock for primary analysis 
will be documented in a SAP amendment and will be described and justified in the clinical study 
report.  

 
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9.3.1. 
General Considerations 
Overall, descriptive statistics will be used to summarize continuous data (eg, number of subjects, 
mean, standard deviation, median, minimum and maximum). Categorical data will be 
summarized using frequency and percentage. 
Tabular summaries will be presented by treatment arm unless otherwise specified. 
9.3.1.1. 
Randomization and Blinding 
Subjects will be randomized in a 1:1 ratio to one of the treatment arms based on the following 
stratification factors: cisplatin eligibility (eligible or ineligible), PD-L1 expression (high or low), 
and liver metastases (present or absent).  
Although this is an open-label study, to maintain trial integrity, until database lock and study 
unblinding for the pre-planned analyses, analyses or summaries by treatment assignment are only 
planned for the purpose of the IDMC monitoring and will be conducted by an external vendor. In 
addition, the primary endpoint of PFS by BICR will be based on assessment of radiological scans 
by BICR without knowledge of treatment assignment. Additional details will be provided in a 
separate document. 
9.3.1.2. 
Adjustments for Covariates 
The randomization scheme will include the following stratification factors: Cisplatin eligibility 
(eligible or ineligible), PD-L1 expression (high or low), and Liver metastases (present or absent). 
These stratification factors used for randomization will be included in both the stratified log-rank 
test and the stratified Cox proportional hazards model for the analyses of the primary endpoints 
of PFS and OS. 
9.3.1.3. 
Handling of Dropouts and Missing Data 
With the exception of censoring for time-to-event endpoints, no imputation will be conducted for 
missing data unless otherwise specified in the SAP.  
9.3.1.4. 
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. 
9.3.1.5. 
Multiple Comparisons and Multiplicity 
The proposed 2-arm study will have dual primary endpoints of PFS and OS. The study can be 
considered positive if enfortumab vedotin plus pembrolizumab (Arm A) is superior to the control 
arm (Arm B) in either PFS or OS. A graphical approach with group sequential testing outlined in 
Maurer and Bretz (Maurer 2013) will be used to strongly control the family-wise type I error rate 
at a two-sided 5% level.  
The initial alpha allocation for each test with lines connecting between hypotheses: 4.5% and 
0.5% two-sided alpha for comparisons between Arm A and Arm B in OS and PFS, respectively, 
as shown in Figure 2. These are also the alpha values used for sample size and power planning. 
The updated graph and rejection boundaries will be derived using the algorithm outlined in 
Maurer and Bretz (Maurer 2013). O’Brien-Fleming boundaries will be used to calculate the 

 
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rejection boundaries based on the actual information fraction observed for OS data. As an 
example, if the null hypothesis for PFS is rejected, the 0.5% alpha of PFS will be passed to OS. 
Thus, OS can be re-tested using a 2-sided alpha of 5%. The rejection boundaries of OS IA and 
final analysis (FA) will be re-calculated based on 5% alpha and actual information fraction using 
the O’Brien-Fleming function.  
Figure 2: 
Initial graph of multiplicity adjustment (2-sided FWER=5%) 
 
ε is a positive number close to zero, indicating the potential to pass alpha to ORR only if both PFS and OS are 
statistically significant. 
FWER=family-wise error rate  
 
When the null hypotheses for PFS and OS are both rejected, selected secondary endpoints will be 
tested in the following order using a gatekeeping testing strategy: 
1. ORR by BICR 
2. Time to pain progression (TTPP) 
3. Mean change from baseline in worst pain at Week 26  
Each test will be at the 5% significance level (2-sided) as long as all preceding null hypotheses 
are rejected. These secondary endpoints will only be tested once at either the OS interim or final 
analysis after the null hypotheses for PFS and OS are both rejected, and the test statistics for 
inferential testing will be computed from the data at the time of OS IA. In the event that only the 
null hypothesis for PFS is rejected and the superiority boundary for OS has not been crossed at 
the time of OS IA, these secondary endpoints will not be tested and will only be analyzed 
descriptively. 

 
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9.3.1.6. 
Data Transformations and Derivations 
Time variables based on 2 dates (eg, start date and end date) will be calculated as (end date – 
start date +1 [in days]) unless otherwise specified. 
Baseline values used in all statistical analyses will be the most recent non-missing measurement 
prior to the first dose of study drug unless otherwise specified. 
9.3.1.7. 
Analysis Sets 
All subjects who are randomized will be included in the intent-to-treat (ITT) analysis set. 
Subjects will be included in the treatment group assigned at randomization regardless of the 
actual treatment received. The primary analysis of the efficacy endpoints of OS and PFS will be 
based on the ITT analysis set. Demographic and baseline characteristics will be summarized for 
the ITT analysis set.  
The response evaluable set will include all randomized subjects who have measurable disease 
per RECIST v1.1 at baseline. Subjects will be analyzed according to the treatment arm assigned 
at randomization regardless of the actual treatment received. The response evaluable set will be 
used for primary analysis of response related endpoints, eg, ORR, DCR, and DOR. 
The safety analysis set will include all randomized subjects who received at least 1 dose of 
investigational product (or any component of combination therapy). Subjects will be evaluated 
by the treatment actually received. Treatment exposure and AE will be summarized in the safety 
analysis set. 
The PRO FAS will include all randomized subjects who have received at least 1 dose of 
investigational product (or any component of combination therapy) and have completed at least 1 
PRO assessment at baseline. Subjects will be analyzed according to the treatment arm assigned 
at randomization. The PRO FAS will be used for PRO analyses, unless otherwise specified. 
Subjects in China who are randomized in the China portion will not be included in the analysis 
population for the global portion. The China ITT population, including all subjects in China 
randomized in both the global portion and the China portion, will be analyzed in the 
China-specific efficacy analyses. The China safety analysis set, including all randomized 
subjects in China (from both the global portion and the China portion) who receive at least 
1 dose of investigational product (or any component of combination therapy) will be analyzed in 
the China-specific safety analyses.  
Additional analysis sets of subjects may be defined in the SAP. 
9.3.1.8. 
Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. Subgroup 
analyses will include an analysis of OS, PFS, and ORR by PD-L1 status at baseline (low or 
high). Detailed methodology for all subgroups analyses will be provided in the SAP. 
9.3.1.9. 
Interim Analysis 
A single planned analysis (FA) for PFS will take place when approximately 526 PFS events or 
356 OS events (72.8% information fraction) in the ITT analysis set have occurred, whichever is 
later.  

 
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Two analyses are planned for OS. OS IA is planned at the time of the final PFS analysis. At IA, 
the OS events in total will be approximately 356 (about 72.8% of information). O’Brien-Fleming 
boundaries will be used to calculate the rejection boundaries based on the actual information 
fraction observed. 
 
 
Estimated analyses timing and the rejection boundaries at the planned PFS and OS analyses are 
presented in Table 14. The results are based on the initial alpha allocated to each hypothesis 
before any alpha recycling. O’Brien-Fleming boundaries will be used to calculate the rejection 
boundaries for the interim and final OS analyses based on the actual number of deaths observed 
in the study. 
Table 14: 
Summary of timing of analyses and estimated rejection boundaries 
Analysis 
2-sided αd 
Est. Time after 
Enrollment 
Completion 
Planned # of 
Events 
p-value 
(2-sided) at 
Boundary 
Approx. Obs. HR 
at Boundary 
Planned 
Power 
Analysis 
Time 1a 
FA: PFS 
0.5% 
7 months 
526 
0.005 
0.783 
90% 
IA: OS 
1.5% 
7 months 
356 
(72.8% info.) 
0.015 
0.773 
70%b 
Analysis 
Time 2 
FA: OS 
 
 
 
 
 
 
a Analysis Time 1 is triggered by the planned number of PFS events in total (526 events) or 356 OS events (72.8% information 
fraction), whichever is later.  
b Probability to cross the efficacy boundary at the interim analysis 
c Overall power at the final OS analysis 
d Cumulative alpha assigned for each test without alpha roll-over. For OS IA, 1.5% is the estimated alpha spent at IA. 
9.3.2. 
Subject Disposition 
Subject enrollment and disposition will be summarized by each treatment arm and also by total. 
The number and percentage of subjects who discontinue study treatment and subjects who 
withdraw from the study will be summarized with reason for discontinuation or withdrawal. The 
number of subjects who signed informed consent and the number of subjects in each analysis set 
will be summarized by treatment group and total. 
9.3.3. 
Subject Characteristics 
Demographics and other baseline characteristics will be summarized by treatment arm and by 
total with counts and percentages for categorical variables and with summary statistics for 
continuous variable. Details will be provided in the SAP. 
9.3.4. 
Efficacy Analyses 
The primary analysis of efficacy endpoints of OS and PFS will be analyzed using the ITT 
analysis set. ORR, DCR, and DOR will be analyzed using the response evaluable set. 
For the primary endpoints of OS and PFS, a log-rank test stratified by randomization 
stratification factors will be used to compare the experimental arm to the control arm. The 
estimated HR and corresponding 95% CI from the stratified Cox proportional hazards regression 
model will also be presented. The median survival will be estimated using the Kaplan-Meier 

 
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(KM) method and will be reported along with estimated KM curves and the corresponding 95% 
CI by treatment arm. Similar estimation methods will be used for the other time-to-event 
endpoints. DOR will be summarized descriptively by Kaplan-Meier methods for subjects with a 
confirmed response (complete response or partial response per RECIST v1.1 [Appendix J]).  
ORR and disease control rate will be estimated for each treatment arm based on the response 
evaluable set based on the response evaluable set. Additionally, p-value between treatment arms 
using the Cochran Mantel-Haenszel test, controlling for randomization stratification factors will 
be provided.  
Due to the limited sample size of subjects receiving enfortumab vedotin + platinum + 
pembrolizumab, only a listing of efficacy data will be provided for subjects randomized to this 
treatment arm. Additional sensitivity analyses for the efficacy endpoints and the exploratory 
analysis per iRECIST (Appendix K) will be specified in the SAP. 
9.3.5. 
Pharmacokinetic and Immunogenicity Analyses 
Descriptive statistics will be provided for antibody drug-conjugate and unconjugated drug 
(MMAE) concentrations in the experimental arm at each PK sampling time point. Any additional 
PK and PK/pharmacodynamic analyses may be described in a separate analysis plan and 
presented in a separate report. The incidence of ATA will be summarized. 
Pembrolizumab PK and immunogenicity analysis will be performed only if required. If 
pembrolizumab analysis are performed, the PK and immunogenicity results will be presented in 
a separate report. 
9.3.6. 
Biomarker Analyses 
Relationships of biomarker parameters (eg, baseline values, absolute and relative changes from 
baseline) to efficacy, safety, and PK may be explored. Relationships and associated data that are 
determined to be of interest will be summarized. Details will be described separately. 
9.3.7. 
Patient-Reported Outcomes Analyses 
Descriptive analyses for EORTC QLQ-C30, EQ-5D-5L, and BPI-SF will be performed on the 
PRO FAS. Compliance and completion rate will be summarized for each scheduled assessment 
by treatment arm using the ITT analysis set for Arm A and Arm B.  
PRO-based secondary endpoints TTPP and mean change from baseline in worst pain at Week 26 
will be hierarchically tested when OS, PFS, and ORR are all statistically significant. Additional 
PRO analyses of remaining BPI-SF, EORTC QLQ-C30, and EQ-5D-5L questionnaires will be 
described in the supplemental PRO SAP.  
9.3.7.1. 
Time to Pain Progression 
TTPP is defined as the time from randomization to the first date a subject experiences a pain 
progression. Pain progression is defined as either an increase of 2 or more points from baseline 
on question 3 of the BPI-SF or initiation of new opioid pain medication.  
TTPP will be compared between the experimental and control arms using a stratified log-rank 
test. Kaplan-Meier curves and the median TTPP with 95% CI will be presented. Further details 
on the TTPP analysis, will be provided in the SAP.  

 
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9.3.7.2. 
Mean Change from Baseline in Worst Pain at Week 26 
Using the BPI-SF question 3, mean change from baseline in worst pain will be calculated for 
each postbaseline assessment timepoint for Arm A and Arm B. A mixed model for repeated 
measures (MMRM) will be used to estimate marginal mean change scores and differences 
between Arm A and Arm B. The difference in mean change from baseline between treatment 
arms at Week 26 will be evaluated for statistical significance. 
9.3.8. 
Safety Analyses 
The safety analysis set will be used to summarize all safety endpoints. 
9.3.8.1. 
Extent of Exposure 
Duration of treatment will be summarized and listed. 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized by 
treatment arm. Details will be provided in the SAP. 
9.3.8.2. 
Adverse Events 
An overview of TEAEs will provide a tabulation of the number and incidence of TEAEs, 
treatment-related TEAEs, Grade 3 and higher TEAEs, serious TEAEs, treatment-related serious 
TEAEs, TEAE leading to deaths, and TEAEs leading to study treatment discontinuation. AEs 
will be defined as treatment-emergent if they are newly occurring or worsen after the first dose 
of study treatment through 30 days after the last dose of the study drug or through 90 days after 
the last dose of study treatment for SAE in Arms A and C. 
AEs will be listed and summarized by MedDRA, system organ class (SOC), preferred term, 
severity, and relationship to study drug. In the event of multiple occurrences of the same AE with 
the same preferred term in one subject, the AE will be counted once as the occurrence. The 
incidence of TEAEs will be tabulated by preferred term and treatment group. TEAEs leading to 
premature discontinuation of study drug will be summarized and listed in the same manner. 
9.3.8.3. 
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. 
9.3.8.4. 
Clinical Laboratory Results 
For laboratory values (eg, chemistry and hematology), summary statistics of actual values and 
change from baseline may be presented as appropriate by scheduled visit. Laboratory shift tables 
will also be provided by treatment group. Laboratory values will also be listed with grade per 
NCI CTCAE v4.03 and flagged when values are outside the normal reference range. Details will 
be provided in the SAP. 
9.3.8.5. 
Other Safety Analyses 
Vital Signs 
Vital signs will be listed by subject and scheduled visit.  

 
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ECOG Status 
Shifts from baseline to the best and worst post-baseline score may be tabulated. 
ECG 
A by-subject listing will be generated. 
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 (R2); 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 presenting the risks and benefits of study participation to the 
subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring subjects 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 subject, 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. 
For phase 1 studies, it is preferable for a subject to provide consent themselves. If informed 
consent is obtained from a legally acceptable representative for a subject who is unable to 
provide informed consent at study entry (if applicable), but the subject is later able to provide 
informed consent, the investigator must obtain written informed consent from the subject. 
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 (eg, quarterly, annual) re-approval of the protocol. 

 
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• 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. 
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 sub investigators 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 subject) must be approved by the sponsor prior to seeking approval 
from the IRB/IEC, and prior to implementing. The investigator is responsible for enrolling 
subjects 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 subject medical 
records in the subject 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 subject medical information must be handled in accordance with local and 
national laws, rules, and regulations and consistent with the terms of the subject 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 subject 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 CTA. 

 
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APPENDIX A. 
SCHEDULE OF EVENTS 
Day 
Screening/ Baseline 
Every 3-week Cycle 
EOT 
Follow-up 
Survival 
Follow-up 
D –42 
to 
RND 
D –28 to 
RND 
D –7 to 
RND 
D1A 
D8A 
D15 
Within 30  
to 37 d of 
last doseB 
Every 
9 weeksG 
Every 
12 weeks 
Visit windowW 
±2 dU 
–1 to
+4 d
±1 d 
±7 d 
±7 d 
Screening/Baseline 
Assessments  
Inclusion/Exclusion, medical history 
X 
Informed consent 
X 
Acquire and submit archival or fresh tumor biopsy 
tissueC  
X 
Ophthalmologic examinationD 
X 
Brain scan (if indicated) 
XE 
XR 
XR 
XR 
Bone scan 
XE 
XR 
XR 
XR 
INR/PT/PTT 
X 
HbA1cN 
X 
Urinalysis (with reflexive microscopy, if abnormal) 
X 
Pregnancy test (urine or serum; only for females of 
childbearing potential) 
XQ 
X 
X 
RandomizationY 
X 
Safety Assessments 
Physical exam (including weight) 
X 
XF,T 
X  
XG 
Height 
X 
Vital signs 
X 
XT 
X T 
X 
CBC with differentialO 
X 
XF,T 
X T 
XZ 
X 
Serum chemistry panelO 
X 
XF,S,T 
XS,T 
XZ 
X 
Amylase 
X 
Lipase 
X 
CrClBB 
X 
Footnotes

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Day 
Screening/ Baseline 
Every 3-week Cycle 
EOT 
Follow-up 
Survival 
Follow-up 
D –42 
to 
RND 
D –28 to 
RND 
D –7 to 
RND 
D1A 
D8A 
D15 
Within 30  
to 37 d of 
last doseB 
Every 
9 weeksG 
Every 
12 weeks 
Visit windowW 
±2 dU 
–1 to
+4 d
±1 d 
±7 d 
±7 d 
Thyroid function testsX 
X 
XF 
ECOG performance status 
X 
XF,T 
X 
XG 
ECG 
X 
Transthoracic ECHO or MUGAAA 
X 
Concomitant medications 
Related to study 
proceduresH 
Collect from Day 1 (predose) through 30 days 
(AEs/SAEs) post last dose, or 90 days (SAEs 
related to pembrolizumab) post last dose 
(30 days post last dose if new anticancer 
therapy is started). For AESIs, AEs and 
concomitant medications may be followed until 
AE resolution, return to baseline, subject 
withdrawal, study closure, or the event becomes 
chronic. 
Adverse event collection 
Patient-Reported 
Outcome Assessments 
Quality of Life (QOL) and Pain Assessment 
See Electronic Patient-Reported Outcomes Schedule of Events table 
for assessment detailsV 
Healthcare Resource Utilization (HRU) 
Treatment 
Enfortumab vedotin administrationP 
X 
X 
Pembrolizumab administrationI 
X 
Gemcitabine administrationI 
X 
X 
Cisplatin administrationI  
X 
Carboplatin administrationI 
X 
PK/Imunogenicity/ 
Biomarker 
Blood, urine and tissue sample collection 
See PK, Immunogenicity, and Biomarker table for 
sample collection detailsA 
Response Assessment 
CT/MRI scan with contrastJ 
X 
XK 
XL 
XK 
Survival status 
XM 
RND=Randomization 
A 
See Table 12 for PK, immunogenicity, and biomarker sampling. 
B 
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study treatment, conduct a phone screen 30–
37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
Footnotes

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C 
Archival tumor tissue must be available for participation in the study. Archived tumor tissue, not previously irradiated, should be collected after completion of the most recent prior systemic 
therapy, ideally within 12 months prior to enrollment, if possible. If adequate archival tumor sample is not available, a new biopsy may be performed. Tumor FFPE block is preferred. Core needle 
biopsy or excision of non-decalcified tissue is required (fine needle aspirate is not acceptable). 
D 
A complete ophthalmologic examination will include, but is not limited to, visual acuity, slit lamp, tonometry examination and dilated fundus examination. Subsequent ophthalmology 
assessments should be performed as clinically indicated. End of treatment slit lamp examinations are required for subjects who experience corneal AEs during the study and must be performed 
≥4 weeks from last dose. 
E 
Brain scans will be conducted at screening/baseline in subjects with a history of CNS metastasis or signs/symptoms of CNS metastasis. Bone scans will be conducted at screening/baseline in 
subjects with a history of skeletal metastasis or suspicion of skeletal metastasis based on imaging or symptoms. See Appendix C for preferred imaging methods.  
F 
Clinical laboratory assessments, physical exam, weight, and ECOG performance status are not required if performed within 1 day prior to administration of study drug. 
G 
Subjects who discontinue study treatment for reasons other than BICR-confirmed radiographically-confirmed disease progression by RECIST v1.1 guidelines or consent withdrawal will have 
physical exams, ECOG, and disease assessments every 9 weeks (±1 week) for the first 18 months timed from the randomization date, then every 12 weeks (±1 week) until the subject has 
BICR-confirmed radiologically-confirmed disease progression (per RECIST v1.1), subject death, study closure, or withdrawal of consent, whichever occurs first. ECOG status and physical exams 
may be discontinued at start of subsequent anticancer therapy. Palliative radiotherapy on a nontarget lesion that is not progressing will not be considered a subsequent anticancer therapy; however, 
radiotherapy on any new or progressing target lesion will be a subsequent anticancer therapy.  
H 
From time of informed consent. 
I 
On Day 1 of each cycle, pembrolizumab should be administered approximately 30 minutes after completion of enfortumab vedotin administration (Arm A). On Day 1, or Day 2 if required per 
institutional standards for cisplatin, of each cycle, cisplatin or carboplatin and gemcitabine should be administered per institutional standard (Arm B).  
J 
Computed tomography (CT) scan with contrast, including chest, abdomen, and pelvis. Other regions should be scanned if the subject has known disease or new symptoms suggestive of disease in 
that region. Response assessment will be evaluated using RECIST v1.1. 
K 
Response assessment will be performed every 9 weeks (±1 week) from the randomization date. Objective responses will be confirmed per RECIST v1.1 with repeat scans done at the next 
scheduled scan per protocol. Subsequent scans are to be performed every 9 weeks ((±1 week) until 18 months after randomization, then every 12 weeks (±1 week). Tumor imaging should also be 
performed whenever disease progression is suspected. 
L 
Not required if conducted <4 weeks prior to EOT.  
M 
Contact subject for survival status and collection of subsequent anticancer treatment information every 12 weeks (±1 week) after BICR-confirmed radiologically-confirmed progressive disease per 
RECIST v1.1 guidelines until death, study closure, lost to follow-up, or subject withdraws consent, whichever occurs first. Additional follow-up contacts may be required per sponsor request for 
analysis purposes. 
N 
If HbA1c is elevated (≥6.5%), refer subject to appropriate provider during Cycle 1 for glucose management.  
O 
Safety labs may be collected 1 day prior to dosing. 
P 
At least 6 days must elapse between doses of enfortumab vedotin 
Q 
Either serum or urine pregnancy test. May be performed within 1 day prior to administration of study drug.  
R 
Brain scans should be repeated every 9 weeks (± 1 week) for the first 18 months timed from the randomization date, then every 12 weeks (±1 week) thereafter, and as clinically indicated in 
subjects with a history of CNS metastasis or signs/symptoms of CNS metastasis. Bone imaging should be repeated every 9 weeks (± 1 week) for the first 18 months timed from the randomization 
date, then every 12 weeks (±1 week) thereafter, and as clinically indicated in subjects with a history of skeletal metastasis or suspicion of skeletal metastasis based on imaging or symptoms. See 
Appendix C for preferred imaging methods. 
S 
Verify blood glucose is <250 mg/dL prior to dosing. Subjects with diabetes must be tested in the clinic and blood glucose must be <250 mg/dL prior to dosing. Use of insulin is permitted as part 
of the standard of care. 
T 
Procedures should be conducted pre-dose.  
U 
Window applies to Cycle 2+ 
V 
The EQ-5D-5L, BPI-SF, EORTC QLQ-C30, and HRU questionnaires will be completed in clinic at Cycle 1 Day 1 before any study procedures/assessments. Questionnaires will be completed by 
the subject at home in between clinic visits on the ePRO device beginning with Cycle 1 Day 4 or 5, once weekly for the first 12 weeks, on Week 14 and once every 3 weeks for the remainder of 
the study through disease progression and survival follow-up. See Section 7.7; Table 13.  
W 
Visit windows do not apply to QOL, Pain, or HRU assessments. 
X 
Thyroid function tests (see Section 7.8.4) should be conducted for all subjects at screening/baseline. Subjects in Arm A should be tested at Cycle 2, and every even cycle thereafter. Subjects in 
Arm B should be tested as clinically indicated.  
Y 
All screening/baseline procedures should occur prior to randomization. Randomization will be allowed at Day –3 to 1 and must occur prior to the first dose of study drug.  
Z 
Cycles 1 and 2 only, unless clinically indicated. 
AA 
A transthoracic echocardiogram or multiple-gated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) is required for subjects with NYHA Class III Heart Failure or a history 
of coronary heart disease, arrhythmia, or other significant heart disease.  
BB 
The same method to determine CrCl should be used consistently for a subject over the course of the study with the exception of carboplatin dose calculation, where the Cockcroft-Gault method 
should be used in all subjects. 

 
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APPENDIX B. 
PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky  
 
ECOG 
Percent 
Description 
 
Score 
Description 
100 
Normal, no complaints, 
no evidence of disease. 
 
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. 
 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
 
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. 
 
60 
Requires occasional 
assistance but is able to 
care for most of his/her 
needs. 
 
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. 
 
40 
Disabled, requires special 
care and assistance. 
 
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. 
 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
 
4 
100% bedridden. Completely disabled. Cannot carry on 
any self-care. Totally confined to bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
 
0 
Dead. 
 
5 
Dead. 
 
 

 
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APPENDIX C. 
SCANNING AND CONTRAST OPTIONS 
In decreasing order of preference 
Brain Scan 
1. Brain magnetic resonance imaging (MRI) with gadolinium 
If gadolinium is medically contraindicated: 
2. Brain MRI without gadolinium 
3. Brain computed tomography (CT) with intravenous (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 
5. Radio opaque agents (eg, iodine and barium based agents) 
6. 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 D. 
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_30
6328_Article.jsp 
 
 

 
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APPENDIX E. 
LIVER SAFETY MONITORING AND ASSESSMENT* 
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease, or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study treatment. The investigator may determine that it is not in the 
subject’s best interest to continue study treatment. Discontinuation of treatment should be 
considered if any of the severe liver abnormalities listed below should occur. 
Any subject with an increase of serum aminotransferases to >3× 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). 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 
(eg, 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. 
* 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. 
** 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 subjects 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. Subjects 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 subject is asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology, 
may be considered an important medical event and may be reported as a SAE. The sponsor 
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory 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 subjects 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 subject’s history, other testing may be appropriate including: 
o Acute viral hepatitis (A, B, C, D, E or other infectious agents), 
o Ultrasound or other imaging to assess biliary tract disease, 
o Other laboratory tests including INR, direct bilirubin. 
• Consider gastroenterology or hepatology consultations. 
Conduct additional testing as determined by the investigator to further evaluate possible etiology. 
 
 

 
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APPENDIX F. 
EORTC QLQ-C30 
 

 
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APPENDIX G. 
EQ-5D-5L 
 
 
 

 
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APPENDIX H. 
BPI-SF 
 

 
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APPENDIX I. 
HEALTH RESOURCE UTILIZATION 
 
 
 
 

 
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APPENDIX J. 
RECIST CRITERIA VERSION 1.1 
 
 

 
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Reproduced from (Eisenhauer 2009) 
 
 

 
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APPENDIX K. 
IRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN 
TRIALS TESTING IMMUNOTHERAPEUTICS  
Response will also be assessed using modified RECIST v1.1 for immune-based therapeutics 
(iRECIST) guidelines (Seymour 2017). Immunotherapeutics may result in infiltration of immune 
cells leading to transient increase in the size in malignant lesions, or undetectable lesions 
becoming detectable. The criteria are identical to those of RECIST v1.1 in many respects but 
have been adapted to account for instances where an increase in tumor burden, or the appearance 
of new lesions, does not reflect true tumor progression. 
Key differences are described below. All responses defined using iRECIST guidelines are 
designated with a prefix. iRECIST time point and best responses will be recorded separately. 
Confirming Disease Progression 
Unlike RECIST v1.1, the iRECIST guidelines require the confirmation of progression and uses 
the terms unconfirmed immune progressive disease (iUPD) and confirmed immune progressive 
disease (iCPD). Confirmatory scans should be performed at least 4 weeks, but no longer than 
9 weeks after iUPD. 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen 
as evidenced by 1 or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST v1.1 definitions of 
progression had been met (from nadir) in target, nontarget disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in nontarget disease with an increase in 
tumor burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
• RECIST v1.1 criteria are met in lesions types (target or nontarget or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or immune stable disease [iSD], immune 
partial response [iPR] or immune complete response [iCR] if those criteria are met compared to 
baseline). 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST v1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short 
axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target 
(NLNT) to allow clear differentiation from baseline target and nontarget lesions. 

 
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New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline. Rather, these measurements will be collected separately in 
the case report form. 
 
 

 
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APPENDIX M. 
MANAGEMENT OF EXISTING ARM C SUBJECTS (US ONLY) 
For subjects randomized to enfortumab vedotin + pembrolizumab + cisplatin or carboplatin 
(Arm C) on the original protocol and Protocol Amendment 1, investigators should discuss the 
updated study design, removal of Arm C, and the subject should be re-consented to Protocol 
Amendment 2. Upon re-consenting, and after discussion with the principal or treating 
investigator, subjects may be given the option to continue and complete platinum chemotherapy 
per the previous protocol versions or discontinue platinum chemotherapy and continue with 
enfortumab vedotin and pembrolizumab therapy. Subjects that continue platinum chemotherapy 
should follow the chemotherapy dosing guidelines, including dose modifications and 
concomitant medications, as outlined in Section 5 of this protocol for cisplatin and carboplatin. 
Arm C Treatments Administered 
Enfortumab vedotin 
Enfortumab vedotin 1.25 mg/kg, the investigational product under study, will be administered as 
an IV infusion over approximately 30 minutes on Days 1 and 8 of every 3-week cycle. 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as an IV infusion approximately 30 minutes after 
completion of platinum-containing chemotherapy, on Day 1 of every 3-week cycle. 
Pembrolizumab may be administered during post chemotherapy hydration. 
Cisplatin  
On Day 1 (or Day 2 if required per institutional guidelines) of each 3-week cycle, cisplatin 
70 mg/m2 will be administered (with adequate pre- and post-hydration) as an IV infusion per 
institutional standards after completion of enfortumab vedotin administration. The body surface 
area used to calculate cisplatin dose may be capped per institutional standards. 
Carboplatin 
On Day 1 of each 3-week cycle, carboplatin at AUC 4.5, or AUC of 5 according to local 
guidelines, will be administered (with adequate pre- and post-hydration) as an IV infusion per 
institutional standards after completion of enfortumab vedotin administration. Body weight used 
to calculate carboplatin may be capped as per institutional standards. 
 

 
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APPENDIX N. 
INVESTIGATOR SIGNATURE PAGE 
Investigator Statement and Signature 
I have read the attached protocol entitled “An open-label, randomized, controlled phase 3 study 
of enfortumab vedotin in combination with pembrolizumab versus chemotherapy alone in 
previously untreated locally advanced or metastatic urothelial cancer” 
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 O. 
DOCUMENT HISTORY 
Version 
Date 
Original 
03-Dec-2019 
Amendment 1 
25-Jun-2020 
Amendment 2 
12-Aug-2020 
Amendment 3 
10-Feb-2021 
Amendment 4 
11-Nov-2021 
Amendment 5 
29-Mar-2022 
Amendment 6 
12-Apr-2022 
Amendment 7 
30-Nov-2022 
Amendment 8 
15-Feb-2023 
Amendment 9 
29-Sep-2023 

 
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Section(s) 
Change 
Rationale 
 
 
 

 
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Summary of Changes in Amendment 07 
Section(s) 
Change 
Rationale 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Summary of Changes in Amendment 09 
Section(s) 
Change 
Rationale 
Title Page 
Updated medical monitor information. Updated 
address. Added EU CT number. 
Administrative change 
5.6.1 
Each 50, 150, 450, or 600 mLg multidose vial of 
solution contains 10 mg/mL carboplatin. 
Correction 
5.10.6 
5.10.6. Management of Pneumonitis/ILD Related 
to Enfortumab Vedotin 
Severe, life-threatening or fatal pneumonitis/ILD have 
occurred in subjects receiving enfortumab vedotin. 
Monitor subjects for signs and symptoms indicative of 
pneumonitis/ILD such as hypoxia, cough, dyspnea or 
interstitial infiltrates on radiologic exams. For all 
subjects, including subjects with asymptomatic/Grade 
1 pneumonitis/ILD, clinical monitoring and 
supportive measures consistent with local medical 
guidelines should be followed as appropriate 
throughout the study. Medical intervention per 
standard of care should be considered for Grade ≥2 
events (eg, corticosteroids initial dose of 
1-2 mg/kg/day prednisone or equivalent followed by a 
taper). For recommendations regarding dose 
modifications for pneumonitis/ILD due to enfortumab 
vedotin, refer to Section 5.2.4. 
Additional instructions were added to the protocol 
to clarify recommended steps for management of 
subjects who develop pneumonitis/ILD due to 
enfortumab vedotin. 
7.5 
To understand the relationship between the biological 
characteristics of tumors before treatment and subject 
outcomes, tumor tissue from pre-treatment biopsies 
will be examined. Tumor tissue  
from any standard of care biopsies may also be 
collected to assess the on-treatment effects of  
enfortumab vedotin. Subjects will be stratified prior 
to randomization according to PD-L1 status (PD-L1 
high: CPS ≥10 and PD-L1 low: CPS <10 based on 
Dako/Agilent PD-L1 IHC 22C3 PharmDx). 
On-treatment biopsy samples are not collected as 
part of the study. The stricken text was included in 
the protocol inadvertently and is being removed 
for consistency with study procedures 
 

 
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Section(s) 
Change 
Rationale 
7.8.1.1 
AE severity should be graded using the NCI CTCAE, 
version 4.03. These criteria are provided in the study 
manual. 
Correction