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

• ClinicalTrials.gov Identifier: NCT03288545
• Recruitment Status: Active, not recruiting
• First Posted: September 20, 2017
• Last Update Posted: October 18, 2023
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Merck Sharp & Dohme LLC; Seagen Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information

• First Submitted Date: September 18, 2017
• First Posted Date: September 20, 2017
• Last Update Posted Date: October 18, 2023
• Actual Study Start Date: October 11, 2017
• Estimated Primary Completion Date: December 31, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 12, 2021)

• Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only) [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
  Descriptive statistics will be used to summarize results.
• Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only) [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
  Descriptive statistics will be used to summarize results.
• 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) [ Time Frame: Up to 3 years ]
  The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1
• Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only) [ Time Frame: Up to approximately 5 months ]
  The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Original Primary Outcome Measures (submitted: September 18, 2017)

• Incidence of dose-limiting toxicity (DLT) [ Time Frame: 21 days ]
  Incidence of DLTs that are considered related to enfortumab vedotin and/or enfortumab vedotin + CPI, and are not attributed to CPI alone
• Type, incidence, severity, seriousness, and relatedness of adverse events [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to 22 months ]
  Descriptive statistics will be used to summarize results
• Type, incidence, and severity of laboratory abnormalities [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to 22 months ]
  Descriptive statistics will be used to summarize results

Current Secondary Outcome Measures (submitted: March 24, 2023)

• Incidence of dose-limiting toxicity (DLT) [ Time Frame: 21 days ]
  Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).
• Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [ Time Frame: Up to 3 years ]
  The proportion of patients with confirmed CR or PR according to RECIST 1.1.
• Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only) [ Time Frame: Up to 3 years ]
  The proportion of patients with confirmed CR or PR according to RECIST 1.1
• 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) [ Time Frame: Up to 3 years ]
  The proportion of patients with confirmed CR or PR according to iRECIST.
• Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [ Time Frame: Up to 5 years ]
  Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.
• DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [ Time Frame: Up to 3 years ]
  Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1
• DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only) [ Time Frame: Up to 3 years ]
  Proportion of patients with CR, PR, or SD according to iRECIST.
• Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [ Time Frame: Up to 5 years ]
  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.
• DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [ Time Frame: Up to 5 years ]
  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
• DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only) [ Time Frame: Up to 5 years ]
  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.
• Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [ Time Frame: Up to 5 years ]
  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.
• PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [ Time Frame: Up to 5 years ]
  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
• PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only) [ Time Frame: Up to 5 years ]
  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.
• Event-free (EFS) on study therapy by BICR (Cohort L only) [ Time Frame: Up to 3 years ]
  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.
• Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only) [ Time Frame: Up to 3 years ]
  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.
• Overall survival (OS) (all cohorts) [ Time Frame: Up to 5 years ]
  The time from start of study treatment to date of death due to any cause.
• Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Cmax will be derived from the PK blood samples collected.
• PK parameter for monomethyl auristatin E (MMAE): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Cmax will be derived from the PK blood samples collected.
• PK parameter for total antibody (Tab): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Cmax will be derived from the PK blood samples collected.
• Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
  Blood samples for ATA analysis will be collected.
• PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Tmax will be derived from the PK blood samples collected.
• PK parameter for MMAE: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Tmax will be derived from the PK blood samples collected.
• PK parameter for Tab: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Tmax will be derived from the PK blood samples collected.
• 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) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  AUC will be derived from the PK blood samples collected.
• PK parameter for MMAE: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  AUC will be derived from the PK blood samples collected.
• PK parameter for Tab: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  AUC will be derived from the PK blood samples collected.
• Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only) [ Time Frame: Up to approximately 5 months ]
  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).
• Disease-free survival (DFS) by investigator assessment (MIBC cohorts only) [ Time Frame: Up to approximately 5 years ]
  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.
• DFS by BICR (Cohort L only) [ Time Frame: Up to 3 years ]
  DFS is defined as the time from RC to the time of first occurrence of a DFS event
• Type, incidence, severity, seriousness, and relatedness of AEs (Randomized Cohort K and MIBC cohorts only) [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years ]
  Descriptive statistics will be used to summarize results.
• Type, incidence, and severity of laboratory abnormalities (Randomized Cohort K and MIBC cohorts only) [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years ]
  Descriptive statistics will be used to summarize results.
• Percentage of planned radical cystectomy and pelvic lymph node dissections (RC+PLND) delayed due to treatment-related AEs (MIBC cohorts only) [ Time Frame: Up to approximately 5 months ]
  Delayed is defined as greater than 12 weeks after the last dose of treatment.

Original Secondary Outcome Measures (submitted: September 18, 2017)

• Objective response rate (ORR) by investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: Up to 34 months ]
  The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1
• Disease control rate (DCR) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 34 months ]
  Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1
• Duration of response (DOR) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 34 months ]
  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
• Progression free survival (PFS) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 34 months ]
  The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1), or to death due to any cause, whichever comes first
• Overall survival (OS) [ Time Frame: Up to 34 months ]
  The time from start of study treatment to date of death due to any cause
• Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Cmax will be derived from the PK blood samples collected
• PK parameter for monomethyl auristatin E (MMAE): Cmax [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Cmax will be derived from the PK blood samples collected
• PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Tmax will be derived from the PK blood samples collected
• PK parameter for MMAE: Tmax [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  Tmax will be derived from the PK blood samples collected
• PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  AUC will be derived from the PK blood samples collected
• PK parameter for MMAE: AUC [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  AUC will be derived from the PK blood samples collected
• PK parameter for enfortumab vedotin: Half-life (t1/2) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  t1/2 will be derived from the PK blood samples collected
• PK parameter for MMAE: t1/2 [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
  t1/2 will be derived from the PK blood samples collected
• Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to 22 months ]
  Blood samples for ATA analysis will be collected

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer
• Official Title: A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer
• Brief 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.

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
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

multi-cohort, open-label, multicenter study, global

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

• Drug: enfortumab vedotin (EV)
  Intravenous (IV) infusion on days 1 and 8 every 21 days
  Other Names:

  • ASG-22CE
  • ASG-22ME
  • PADCEV
• Drug: pembrolizumab
  IV infusion on day 1 every 21 days
  Other Name: Keytruda
• Drug: cisplatin
  IV infusion on day 1 every 21 days
• Drug: carboplatin
  IV infusion on day 1 every 21 days
• Drug: gemcitabine
  IV infusion on days 1 and 8 every 21 days

Study Arms

• 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
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
• Experimental: Cohort A: EV + Pembrolizumab in cisplatin-ineligible 1L
  Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
• Experimental: Optional Cohort B: Enfortumab Vedotin + Pembrolizumab in 2L
  Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
• Experimental: Cohort D: Enfortumab Vedotin + Cisplatin in 1L
  Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: cisplatin
• Experimental: Cohort E: Enfortumab Vedotin + Carboplatin in 1L
  Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: carboplatin
• Experimental: Optional Cohort F: Enfortumab Vedotin+Gemcitabine in 1L and 2L
  Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: gemcitabine
• 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
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
  • Drug: cisplatin
  • Drug: carboplatin
• Experimental: Cohort H: Enfortumab vedotin in MIBC neoadjuvant setting
  Enfortumab vedotin on days 1 and 8 every 21 days
  Intervention: Drug: enfortumab vedotin (EV)
• 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
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
• Experimental: Randomized Cohort K: Enfortumab Vedotin Monotherapy
  Enfortumab vedotin on days 1 and 8 every 21 days
  Intervention: Drug: enfortumab vedotin (EV)
• Experimental: Randomized Cohort K: Enfortumab Vedotin + Pembrolizumab
  Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  Interventions:

  • Drug: enfortumab vedotin (EV)
  • Drug: pembrolizumab
• Experimental: Cohort L: Enfortumab vedotin in MIBC in perioperative setting
  Enfortumab vedotin on days 1 and 8 and every 21 days
  Intervention: Drug: enfortumab vedotin (EV)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 19, 2022): 348
• Original Estimated Enrollment (submitted: September 18, 2017): 85
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: December 31, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Italy, Puerto Rico, Spain, United States

Administrative Information

• NCT Number: NCT03288545
• Other Study ID Numbers: SGN22E-002; MK-3475-869 ( Other Identifier: Merck ); KEYNOTE KN-869 ( Other Identifier: Merck )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Astellas Pharma Global Development, Inc.
• Original Study Sponsor: Same as current

Collaborators

• Merck Sharp & Dohme LLC
• Seagen Inc.

Investigators

• Study Director: Changting Meng, MD; Seagen Inc.
• Study Director: Jason Lukas, MD, PhD; Seagen Inc.

• PRS Account: Astellas Pharma Inc
• Verification Date: October 2023