A Study of Enfortumab Vedotin Plus Pembrolizumab and/or Chemotherapy for Patients With Urothelial Bladder Cancer (EV-103)

This study will examine the safety and anticancer activity of enfortumab vedotin given
intravenously in combination with pembrolizumab and/or chemotherapy to patients with locally
advanced or metastatic urothelial cancer. The primary goal of the study is to determine the
safety and tolerability of enfortumab vedotin in combination with pembrolizumab and/or
chemotherapy. The study will be conducted in multiple parts: dose escalation (enfortumab
vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin + pembrolizumab
and/or chemotherapy).

Inclusion Criteria:

- Histologically documented locally advanced or metastatic urothelial carcinoma
(la/mUC), including squamous differentiation or mixed cell types.

- An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.

- Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, and G)

- 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.

Exclusion Criteria:

- 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