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. 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.
