Brief Title: Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Part 1: Objective Response Rate (ORR)

Primary Outcome 1 - Timeframe: Up to ~4 years

Primary Outcome 2 - Measure: Part 1: Percentage of Participants experiencing an Adverse Event (AE)

Primary Outcome 2 - Timeframe: Up to ~4 years

Primary Outcome 3 - Measure: Part 1: Percentage of Participants who Discontinue study interventions due to an AE

Primary Outcome 3 - Timeframe: Up to ~4 years

Primary Outcome 4 - Measure: Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)

Primary Outcome 4 - Timeframe: Up to 21 days

Primary Outcome 5 - Measure: Part 2: Progression Free Survival (PFS)

Primary Outcome 5 - Timeframe: Up to ~4 years

CONDITION

• Metastatic Urothelial Carcinoma
• Urothelial Neoplasms

ELIGIBILITY

Inclusion Criteria:
* Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
* Participants with mixed histology are eligible provided the urothelial component is ≥50% (and <10% plasmacytoid component) - * Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally) - * Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:
* Participants that received neoadjuvant or adjuvant chemotherapy are permitted.

- * Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence >12 months from completion of therapy are permitted.

- * Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.

- * Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with Exclusion Criteria:
* Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.

- * Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.

- * Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.

- * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

- * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.

- * Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.

- * Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.

- * Has a history of uncontrolled diabetes.

- * Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis

- * Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.

- * Has a known history of human immunodeficiency virus (HIV) infection.

- * Has hepatitis B or hepatitis C virus infection.

- * Has had major surgery within 4 weeks prior to first dose of study intervention.

- * Has had an allogenic tissue/solid organ transplant

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Medical Director

Role: Study Director

Affiliation: Merck Sharp & Dohme LLC

Overall Contact

Name: Medical Director

Phone: 1-888-577-8839

Email: Trialsites@merck.com

LOCATION