A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103)
Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Urologic Neoplasms
About this trial
This is an interventional treatment trial for Carcinoma, Transitional Cell focused on measuring ASG-22ME, ASG-22CE, Antibody-drug conjugate, Antineoplastic agents, CPI, Enfortumab vedotin, MIBC, Locally advanced urothelial cancer, Cisplatin, Drug therapy, Carboplatin, Metastatic urothelial cancer, Nectin-4, Gemcitabine, Muscle invasive bladder cancer, Checkpoint Inhibitors, Pembrolizumab, PD-1 inhibitor
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.
Sites / Locations
- Alaska Urological Institute
- Banner MD Anderson Cancer Center
- Mayo Clinic Arizona
- Arizona Oncology Associates, PC - HOPE
- Highlands Oncology Group
- Tower Hematology Oncology Medical Group
- UC San Diego / Moores Cancer Center
- University of California Irvine - Newport
- University of California, Davis Comprehensive Cancer Center
- University of California at San Francisco
- Saint Joseph Heritage Medical Group
- Stanford Cancer Center / Blood & Marrow Transplant Program
- Kaiser Permanente Southern California
- Rocky Mountain Cancer Centers - Aurora
- University of Colorado Hospital / University of Colorado
- Yale Cancer Center
- Eastern CT Hematology and Oncology Associates
- Georgetown University Medical Center
- Boca Raton Regional Hospital / Lynn Cancer Institute
- Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center
- Mayo Clinic Florida
- University of Miami
- Piedmont Cancer Institute
- Winship Cancer Institute / Emory University School of Medicine
- University of Chicago Medical Center
- Decatur Memorial Hospital - Illinois
- Northwestern Medicine Cancer Center - Kishwaukee / Kishwaukee Cancer Center
- Northwestern Medicine Cancer Center Delnor
- Cardinal Bernardin Cancer Center / Loyola University Medical Center
- Northwestern Medicine Cancer Center - Warrenville / Central DuPage Hospital - Cancer Care
- University of Kansas Cancer Center
- Tulane University Hospital and Clinic
- Ochsner Clinic Foundation
- Maryland Oncology Hematology, P.A.
- Southcoast Centers for Cancer Care - Fairhaven Site
- University of Michigan Comprehensive Cancer Center
- Henry Ford Health System
- McLaren Greater Lansing Hospital
- University of Minnesota
- University of Mississippi Medical Center
- Washington University School of Medicine - Siteman Cancer Center
- Nebraska Hematology Oncology P.C.
- OptumCare Cancer Center
- Memorial Sloan Kettering Cancer Center - Basking Ridge
- Hackensack University Medical Center
- Memorial Sloan Kettering Cancer Center - Monmouth
- Memorial Sloan Kettering Cancer Center - Bergen
- University of New Mexico Cancer Center
- New York Oncology Hematology, P.C.
- Roswell Park Cancer Institute
- Memorial Sloan Kettering Cancer Center - Commack
- Memorial Sloan Kettering Cancer Center - Westchester
- Northwell Cancer Center / Monter Cancer Center
- NYU Winthrop Hospital
- New York University (NYU) Cancer Institute
- Weill Cornell Medical College
- Memorial Sloan Kettering Cancer Center
- University of Rochester Medical Center
- Memorial Sloan Kettering Cancer Center - Nassau
- UNC Lineberger Comprehensive Cancer Center / University of North Carolina
- Levine Cancer Institute
- Duke University Medical Center
- Vidant Medical Center
- Gabrail Cancer Center Research, LLC
- Case Western Reserve University / University Hospitals Case Medical Center
- Toledo Clinic Cancer Center
- CMOH Broomall
- Penn State Milton S. Hershey Medical Center
- Fox Chase Cancer Center
- Allegheny General Hospital
- Medical University of South Carolina/Hollings Cancer Center
- Saint Francis Hospital Cancer Center
- Carolina Urologic Research Center
- Sarah Cannon Research Institute
- Tennessee Oncology / Sarah Cannon Research Institute
- Texas Oncology - Fort Worth Cancer Center
- University of Texas Health Science Center at San Antonio
- Texas Oncology - Tyler
- Utah Cancer Specialists
- University of Virginia
- Virginia Oncology Associates - Norfolk
- Medical Oncology Associates
- Medical College of Wisconsin (Milwaukee)
- Site CA11008
- Site CA11011
- Site CA11001
- Site CA11005
- Site CA11013
- Site CA11002
- Site FR33008
- Site FR33005
- Site FR33003
- Site FR33004
- Site FR33010
- Site FR33002
- Site FR33006
- Site FR33001
- Site IT39002
- Site PR78701
- Site ES34006
- Site ES34008
- Site ES34001
- Site ES34012
- Site ES34007
- Site ES34005
- Site ES34004
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Arm 12
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
EV + Pembrolizumab in cisplatin-ineligible 1L and in 2L
Cohort A: EV + Pembrolizumab in cisplatin-ineligible 1L
Optional Cohort B: Enfortumab Vedotin + Pembrolizumab in 2L
Cohort D: Enfortumab Vedotin + Cisplatin in 1L
Cohort E: Enfortumab Vedotin + Carboplatin in 1L
Optional Cohort F: Enfortumab Vedotin+Gemcitabine in 1L and 2L
Cohort G: Enfortumab Vedotin + Platinum + Pembrolizumab in 1L
Cohort H: Enfortumab vedotin in MIBC neoadjuvant setting
Optional Cohort J:EV+Pembrolizumab in MIBC neoadjuvant setting
Randomized Cohort K: Enfortumab Vedotin Monotherapy
Randomized Cohort K: Enfortumab Vedotin + Pembrolizumab
Cohort L: Enfortumab vedotin in MIBC in perioperative setting
Dose Escalation: Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days
Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days
Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 every 21 days
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 every 21 days
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Enfortumab vedotin on days 1 and 8 and every 21 days