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

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.
• •* 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.