A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer

Urinary Bladder Neoplasms Clinical Trial

— EV-103  

Official title:

A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03288545
• Other study ID #: SGN22E-002
• Secondary ID: MK-3475-869KEYNO
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: October 11, 2017
• Est. completion date: December 31, 2026

Study information

• Verified date: October 2023
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra. Some parts of the study will look at locally advanced or metastatic urothelial cancer (la/mUC), which means the cancer has spread to nearby tissues or to other areas of the body. Other parts of the study will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that has spread into the muscle wall of the bladder. This study will look at the side effects of enfortumab vedotin alone and with other anticancer therapies. A side effect is a response to a drug that is not part of the treatment effect. This study will also test if the cancer shrinks with the different treatment combinations.

Description:

This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts:

Locally advanced or metastatic urothelial cancer:

• Dose escalation

• Expansion

• Part 1: Cohorts A and Optional B

• Part 2: Cohorts D, E, and Optional F

• Part 3: Cohort G.

• Randomized Cohort K

• EV Monotherapy Arm

• EV Combination Arm

Muscle invasive bladder cancer:

• Cohort H

• Optional Cohort J

• Cohort L

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 348
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K.

• Histologically documented la/mUC, including squamous differentiation or mixed cell types.

• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin =10 g/dL, GFR =50 mL/min, may not have NYHA Class III heart failure.

• Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).

• Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment.

• Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.

• Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.

• Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.

• Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.

• Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.

• Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.

• Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and =30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade =2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.

• Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.

• Histologically confirmed MIBC with predominant >50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible.

• Must be cisplatin-ineligible.

• Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab.

• ECOG performance status of 0, 1, or 2.

• Anticipated life expectancy of =3 months.

• Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis.

• Participants must be deemed eligible for RC+PLND.

Exclusion Criteria:

• la/mUC - Cohorts A, B, D, E, F, G, and K

• Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.

• Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).

• Ongoing sensory or motor neuropathy Grade 2 or higher.

• Active central nervous system (CNS) metastases.

• Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).

• Conditions requiring high doses of steroids or other immunosuppressive medications.

• Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).

• Uncontrolled diabetes mellitus.

• MIBC - Cohorts H, J, and L

• Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.

• Received any prior treatment with a CPI.

• Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.

• For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, =N2 nodal disease on imaging.

• Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.

• Ongoing sensory or motor neuropathy Grade 2 or higher.

• Conditions requiring high doses of steroids or other immunosuppressive medications.

• Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.

• Participants with a history of another invasive malignancy within 3 years before first dose of study drug.

Related Conditions & MeSH terms

• Carcinoma, Transitional Cell
• Neoplasms
• Pelvic Neoplasms
• Renal Pelvis Neoplasms
• Ureteral Neoplasms
• Urethral Neoplasms
• Urinary Bladder Neoplasms
• Urologic Neoplasms
• Urothelial Cancer

Intervention

Drug:
• enfortumab vedotin (EV)
Intravenous (IV) infusion on days 1 and 8 every 21 days
• pembrolizumab
IV infusion on day 1 every 21 days
• cisplatin
IV infusion on day 1 every 21 days
• carboplatin
IV infusion on day 1 every 21 days
• gemcitabine
IV infusion on days 1 and 8 every 21 days

Locations

Country	Name	City	State
Canada	Site CA11008	East Brampton	Ontario
Canada	Site CA11011	Kingston	Ontario
Canada	Site CA11005	Montreal	Quebec
Canada	Site CA11013	Montreal	Quebec
Canada	Site CA11002	Sherbrooke	Quebec
Canada	Site CA11001	Toronto	Ontario
France	Site FR33008	Bordeaux
France	Site FR33005	Dijon
France	Site FR33003	Lyon
France	Site FR33004	Marseilles
France	Site FR33010	Moselle
France	Site FR33002	Nice Cedex
France	Site FR33006	Pierre-Benite
France	Site FR33001	Strasbourg
Italy	Site IT39002	Terni
Puerto Rico	Site PR78701	Rio Piedras
Spain	Site ES34006	Barcelona
Spain	Site ES34001	Madrid
Spain	Site ES34008	Madrid
Spain	Site ES34012	Madrid
Spain	Site ES34007	Pamplona
Spain	Site ES34005	Sabadell
Spain	Site ES34004	Santander
United States	New York Oncology Hematology, P.C.	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Alaska Urological Institute	Anchorage	Alaska
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Piedmont Cancer Institute	Atlanta	Georgia
United States	Winship Cancer Institute / Emory University School of Medicine	Atlanta	Georgia
United States	Rocky Mountain Cancer Centers - Aurora	Aurora	Colorado
United States	University of Colorado Hospital / University of Colorado	Aurora	Colorado
United States	Memorial Sloan Kettering Cancer Center - Basking Ridge	Basking Ridge	New Jersey
United States	Tower Hematology Oncology Medical Group	Beverly Hills	California
United States	Boca Raton Regional Hospital / Lynn Cancer Institute	Boca Raton	Florida
United States	CMOH Broomall	Broomall	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Gabrail Cancer Center Research, LLC	Canton	Ohio
United States	UNC Lineberger Comprehensive Cancer Center / University of North Carolina	Chapel Hill	North Carolina
United States	Medical University of South Carolina/Hollings Cancer Center	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Sarah Cannon Research Institute	Chattanooga	Tennessee
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Case Western Reserve University / University Hospitals Case Medical Center	Cleveland	Ohio
United States	Memorial Sloan Kettering Cancer Center - Commack	Commack	New York
United States	Decatur Memorial Hospital - Illinois	Decatur	Illinois
United States	Northwestern Medicine Cancer Center - Kishwaukee / Kishwaukee Cancer Center	DeKalb	Illinois
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Southcoast Centers for Cancer Care - Fairhaven Site	Fairhaven	Massachusetts
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center	Fort Lauderdale	Florida
United States	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Saint Francis Hospital Cancer Center	Greenville	South Carolina
United States	Vidant Medical Center	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Sloan Kettering Cancer Center - Westchester	Harrison	New York
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	UC San Diego / Moores Cancer Center	La Jolla	California
United States	Northwell Cancer Center / Monter Cancer Center	Lake Success	New York
United States	McLaren Greater Lansing Hospital	Lansing	Michigan
United States	OptumCare Cancer Center	Las Vegas	Nevada
United States	Nebraska Hematology Oncology P.C.	Lincoln	Nebraska
United States	Cardinal Bernardin Cancer Center / Loyola University Medical Center	Maywood	Illinois
United States	University of Miami	Miami	Florida
United States	Memorial Sloan Kettering Cancer Center - Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin (Milwaukee)	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center - Bergen	Montvale	New Jersey
United States	Carolina Urologic Research Center	Myrtle Beach	South Carolina
United States	Tennessee Oncology / Sarah Cannon Research Institute	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Tulane University Hospital and Clinic	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York University (NYU) Cancer Institute	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Virginia Oncology Associates - Norfolk	Norfolk	Virginia
United States	Eastern CT Hematology and Oncology Associates	Norwich	Connecticut
United States	University of California Irvine - Newport	Orange	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California, Davis Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine - Siteman Cancer Center	Saint Louis	Missouri
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California at San Francisco	San Francisco	California
United States	Saint Joseph Heritage Medical Group	Santa Rosa	California
United States	Maryland Oncology Hematology, P.A.	Silver Spring	Maryland
United States	Medical Oncology Associates	Spokane	Washington
United States	Stanford Cancer Center / Blood & Marrow Transplant Program	Stanford	California
United States	Toledo Clinic Cancer Center	Toledo	Ohio
United States	Arizona Oncology Associates, PC - HOPE	Tucson	Arizona
United States	Texas Oncology - Tyler	Tyler	Texas
United States	Memorial Sloan Kettering Cancer Center - Nassau	Uniondale	New York
United States	Northwestern Medicine Cancer Center - Warrenville / Central DuPage Hospital - Cancer Care	Warrenville	Illinois
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	University of Kansas Cancer Center	Westwood	Kansas
United States	Kaiser Permanente Southern California	Woodland Hills	California

Sponsors (3)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.	Merck Sharp & Dohme LLC, Seagen Inc.

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy,  Puerto Rico,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only)	Descriptive statistics will be used to summarize results.	Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
Primary	Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only)	Descriptive statistics will be used to summarize results.	Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
Primary	Confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR) (Cohort K only)	The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1	Up to 3 years
Primary	Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only)	The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.	Up to approximately 5 months
Secondary	Incidence of dose-limiting toxicity (DLT)	Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).	21 days
Secondary	Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)	The proportion of patients with confirmed CR or PR according to RECIST 1.1.	Up to 3 years
Secondary	Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only)	The proportion of patients with confirmed CR or PR according to RECIST 1.1	Up to 3 years
Secondary	Confirmed ORR by investigator assessment per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Dose escalation and Part 1-3 cohorts with pembrolizumab only)	The proportion of patients with confirmed CR or PR according to iRECIST.	Up to 3 years
Secondary	Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)	Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.	Up to 5 years
Secondary	DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)	Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1	Up to 3 years
Secondary	DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only)	Proportion of patients with CR, PR, or SD according to iRECIST.	Up to 3 years
Secondary	Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)	The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first.	Up to 5 years
Secondary	DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)	The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first	Up to 5 years
Secondary	DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)	The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per iRECIST or to death due to any cause, whichever comes first.	Up to 5 years
Secondary	Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)	The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first.	Up to 5 years
Secondary	PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)	The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first	Up to 5 years
Secondary	PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)	The time from start of study treatment to first documentation of objective tumor progression (PD per iRECIST) on or following study therapy, or to death due to any cause, whichever comes first.	Up to 5 years
Secondary	Event-free (EFS) on study therapy by BICR (Cohort L only)	The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.	Up to 3 years
Secondary	Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only)	The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.	Up to 3 years
Secondary	Overall survival (OS) (all cohorts)	The time from start of study treatment to date of death due to any cause.	Up to 5 years
Secondary	Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Cmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for monomethyl auristatin E (MMAE): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Cmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for total antibody (Tab): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Cmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Blood samples for ATA analysis will be collected.	Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
Secondary	PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Tmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for MMAE: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Tmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for Tab: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	Tmax will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	AUC will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for MMAE: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	AUC will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	PK parameter for Tab: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)	AUC will be derived from the PK blood samples collected.	Through 2 cycles of treatment, up to 42 days
Secondary	Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only)	The pDS rate is defined as patients with tumors	Up to approximately 5 months
Secondary	Disease-free survival (DFS) by investigator assessment (MIBC cohorts only)	DFS is defined as the time from RC to the time of first occurrence of a DFS event, including local recurrence of urothelial cancer (UC), urinary tract recurrence of UC, distant metastasis of UC, or death from any cause.	Up to approximately 5 years
Secondary	DFS by BICR (Cohort L only)	DFS is defined as the time from RC to the time of first occurrence of a DFS event	Up to 3 years
Secondary	Type, incidence, severity, seriousness, and relatedness of AEs (Randomized Cohort K and MIBC cohorts only)	Descriptive statistics will be used to summarize results.	Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years
Secondary	Type, incidence, and severity of laboratory abnormalities (Randomized Cohort K and MIBC cohorts only)	Descriptive statistics will be used to summarize results.	Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years
Secondary	Percentage of planned radical cystectomy and pelvic lymph node dissections (RC+PLND) delayed due to treatment-related AEs (MIBC cohorts only)	Delayed is defined as greater than 12 weeks after the last dose of treatment.	Up to approximately 5 months