A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer
This study will test an experimental drug (enfortumab vedotin) alone and with different
 combinations of anticancer therapies. Pembrolizumab is an immune checkpoint inhibitor (CPI)
 that is used to treat patients with cancer of the urinary system (urothelial cancer). This
 type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra. Some parts of
 the study will look at locally-advanced and metastatic urothelial cancer, which means the
 cancer has spread to nearby tissues or to other areas of the body. Other parts of the study
 will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that
 has spread into the muscle wall of the bladder. This study will look at the side effects of
 enfortumab vedotin alone and with other anticancer therapies. A side effect is a response to
 a drug that is not part of the treatment effect. This study will also test if the cancer
 shrinks with the different treatment combinations.
This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given
 intravenously as monotherapy and in combination with other anticancer therapies as first line
 (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of
 the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone
 and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in
 multiple parts:

 Locally advanced or metastatic urothelial cancer:

 -  Dose escalation

 -  Expansion

 -  Part 1: Cohorts A and Optional B

 -  Part 2: Cohorts D, E, and Optional F

 -  Part 3: Cohort G.

 -  Randomized Cohort K

 -  EV Monotherapy Arm

 -  EV Combination Arm

 Muscle invasive bladder cancer:

 -  Cohort H

 -  Optional Cohort J

 -  Cohort L
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.

 -  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 radical cystectomy and pelvic lymph node
 dissection.

 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.

 -  Evidence of nodal or metastatic disease on imaging per local assessment.
 Participants in Cohort L with pT1 disease may not have ≥N2 nodal disease on
 imaging.

 -  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.