A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Urologic Neoplasms; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Ureteral Neoplasms; Urothelial Cancer; Urethral Neoplasms; Renal Pelvis Neoplasms
• Intervention / Treatment: Drug: enfortumab vedotin (EV); Drug: pembrolizumab; Drug: cisplatin; Drug: carboplatin; Drug: gemcitabine

Detailed 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

• Study Type: Interventional
• Enrollment (Actual): 348
• Phase: Phase 2; Phase 1

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • East Brampton, Ontario, Canada, L6R 3J7
      • Site CA11008
    • Kingston, Ontario, Canada, K7L 2V7
      • Site CA11011
    • Toronto, Ontario, Canada, M5G 2M9
      • Site CA11001
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Site CA11005
    • Montreal, Quebec, Canada, H4A3J1
      • Site CA11013
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Site CA11002
• France
  • Bordeaux, France, 33000
    • Site FR33008
  • Dijon, France, 21000
    • Site FR33005
  • Lyon, France, 69008
    • Site FR33003
  • Marseilles, France, 13273
    • Site FR33004
  • Moselle, France, 54519
    • Site FR33010
  • Nice Cedex, France, 06189
    • Site FR33002
  • Pierre-Benite, France, 69310
    • Site FR33006
  • Strasbourg, France, 67200
    • Site FR33001
• Italy
  • Terni, Italy, 05100
    • Site IT39002
• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • Site PR78701
• Spain
  • Barcelona, Spain, 08041
    • Site ES34006
  • Madrid, Spain, 28033
    • Site ES34008
  • Madrid, Spain, 28034
    • Site ES34001
  • Madrid, Spain, 28041
    • Site ES34012
  • Pamplona, Spain, 31008
    • Site ES34007
  • Sabadell, Spain, 08208
    • Site ES34005
  • Santander, Spain, 39008
    • Site ES34004
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Alaska Urological Institute
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85710
      • Arizona Oncology Associates, PC - HOPE
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • California
    • Beverly Hills, California, United States, 90211
      • Tower Hematology Oncology Medical Group
    • La Jolla, California, United States, 92093
      • UC San Diego / Moores Cancer Center
    • Orange, California, United States, 92868
      • University of California Irvine - Newport
    • Sacramento, California, United States, 95817
      • University of California, Davis Comprehensive Cancer Center
    • San Francisco, California, United States, 94134
      • University of California at San Francisco
    • Santa Rosa, California, United States, 95403
      • Saint Joseph Heritage Medical Group
    • Stanford, California, United States, 94305
      • Stanford Cancer Center / Blood & Marrow Transplant Program
    • Woodland Hills, California, United States, 91367
      • Kaiser Permanente Southern California
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
    • Aurora, Colorado, United States, 80045-0510
      • University of Colorado Hospital / University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
    • Norwich, Connecticut, United States, 06360
      • Eastern CT Hematology and Oncology Associates
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Boca Raton Regional Hospital / Lynn Cancer Institute
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute / Emory University School of Medicine
    • Atlanta, Georgia, United States, 30309
      • Piedmont Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Medical Center
    • DeKalb, Illinois, United States, 60115
      • Northwestern Medicine Cancer Center - Kishwaukee / Kishwaukee Cancer Center
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital - Illinois
    • Geneva, Illinois, United States, 60134
      • Northwestern Medicine Cancer Center Delnor
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center / Loyola University Medical Center
    • Warrenville, Illinois, United States, 60555
      • Northwestern Medicine Cancer Center - Warrenville / Central DuPage Hospital - Cancer Care
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Hospital and Clinic
  • Maryland
    • Silver Spring, Maryland, United States, 20904
      • Maryland Oncology Hematology, P.A.
  • Massachusetts
    • Fairhaven, Massachusetts, United States, 02719
      • Southcoast Centers for Cancer Care - Fairhaven Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Lansing, Michigan, United States, 48910
      • McLaren Greater Lansing Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Mississippi
    • Jackson, Mississippi, United States, 39213
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine - Siteman Cancer Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Nebraska Hematology Oncology P.C.
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • OptumCare Cancer Center
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Cancer Center - Basking Ridge
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Cancer Center - MONMOUTH
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering Cancer Center - BERGEN
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12206
      • New York Oncology Hematology, P.C.
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Cancer Center - Commack
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Cancer Center - Westchester
    • Lake Success, New York, United States, 11042
      • Northwell Cancer Center / Monter Cancer Center
    • Mineola, New York, United States, 11501
      • NYU Winthrop Hospital
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • New York University (NYU) Cancer Institute
    • New York, New York, United States, 10087-9049
      • Memorial Sloan Kettering Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Cancer Center - NASSAU
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center / University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • Vidant Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research, LLC
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University / University Hospitals Case Medical Center
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center
  • Pennsylvania
    • Broomall, Pennsylvania, United States, 19008
      • CMOH Broomall
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina/Hollings Cancer Center
    • Greenville, South Carolina, United States, 29607
      • Saint Francis Hospital Cancer Center
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology / Sarah Cannon Research Institute
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology - Fort Worth Cancer Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • Tyler, Texas, United States, 75702
      • Texas Oncology - Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University Of Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates - Norfolk
  • Washington
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin (Milwaukee)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EV + Pembrolizumab in cisplatin-ineligible 1L and in 2L; Dose Escalation: Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda
Experimental: Cohort A: EV + Pembrolizumab in cisplatin-ineligible 1L; Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda
Experimental: Optional Cohort B: Enfortumab Vedotin + Pembrolizumab in 2L; Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda
Experimental: Cohort D: Enfortumab Vedotin + Cisplatin in 1L; Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: cisplatin; IV infusion on day 1 every 21 days
Experimental: Cohort E: Enfortumab Vedotin + Carboplatin in 1L; Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: carboplatin; IV infusion on day 1 every 21 days
Experimental: Optional Cohort F: Enfortumab Vedotin+Gemcitabine in 1L and 2L; Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: gemcitabine; IV infusion on days 1 and 8 every 21 days
Experimental: Cohort G: Enfortumab Vedotin + Platinum + Pembrolizumab in 1L; Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda; Drug: cisplatin; IV infusion on day 1 every 21 days; Drug: carboplatin; IV infusion on day 1 every 21 days
Experimental: Cohort H: Enfortumab vedotin in MIBC neoadjuvant setting; Enfortumab vedotin on days 1 and 8 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME
Experimental: Optional Cohort J:EV+Pembrolizumab in MIBC neoadjuvant setting; Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda
Experimental: Randomized Cohort K: Enfortumab Vedotin Monotherapy; Enfortumab vedotin on days 1 and 8 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME
Experimental: Randomized Cohort K: Enfortumab Vedotin + Pembrolizumab; Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME; Drug: pembrolizumab; IV infusion on day 1 every 21 days; Other Names: Keytruda
Experimental: Cohort L: Enfortumab vedotin in MIBC in perioperative setting; Enfortumab vedotin on days 1 and 8 and every 21 days	Drug: enfortumab vedotin (EV); Intravenous (IV) infusion on days 1 and 8 every 21 days; Other Names: ASG-22CE; PADCEV; ASG-22ME

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
Overall survival (OS) (all cohorts)	The time from start of study treatment to date of death due to any cause.	Up to 5 years
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
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.
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
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
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
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
Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only)	The pDS rate is defined as patients with tumors <pT2 and N0 in examined tissue from radical cystectomy (RC) and pelvic lymph node dissection (PLND).	Up to approximately 5 months
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Merck Sharp & Dohme LLC; Seagen Inc.
• Investigators: Study Director: Jason Lukas, MD, PhD, Seagen Inc.; Study Director: Changting Meng, MD, Seagen Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2017
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: September 18, 2017
• First Submitted That Met QC Criteria: September 18, 2017
• First Posted (Actual): September 20, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Gemcitabine; Drug therapy; Cisplatin; Pembrolizumab; Carboplatin; Enfortumab vedotin; PD-1 inhibitor; ASG-22CE; Antineoplastic agents; Muscle invasive bladder cancer; Nectin-4; CPI; MIBC; ASG-22ME; Antibody-drug conjugate; Checkpoint Inhibitors; Locally advanced urothelial cancer; Metastatic urothelial cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Ureteral Diseases; Urethral Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms; Urinary Bladder Neoplasms; Pelvic Neoplasms; Urologic Neoplasms; Carcinoma, Transitional Cell; Ureteral Neoplasms; Urethral Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Carboplatin; Pembrolizumab; Gemcitabine
• Other Study ID Numbers: SGN22E-002; MK-3475-869 (Other Identifier: Merck); KEYNOTE KN-869 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No