Clinical Trial Summary

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Phase

Phase 1/Phase 2

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Funding Agency/Sponsor

Industrial

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Disease

Prostate, Bladder, and Kidney Cancers

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Enrollment Eligibility

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.

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