Clinical Trials

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 and J

• Histologically confirmed muscle invasive bladder cancer at clinical stage cT2-T4a.

• Medically fit (i.e. eligible for surgery) and scheduled for radical cystectomy.

• ECOG performance status 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.

Cohort H and J

• Ineligible for cisplatin-based chemotherapy and no prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-muscle invasive bladder cancer.

Cohort J

• Eligible for pembrolizumab.

Exclusion Criteria:

• Locally advanced or metastatic urothelial cancer (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 and J

• 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.

• Evidence of measurable nodal or metastatic disease.

• 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.

• History of another malignancy within 3 years before first dose of study drug.