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.

      - 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.