A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Study of Investigational Agents in Combination With Enfortumab Vedotin Plus Pembrolizumab as First-Line Treatment in Participants With Locally Advanced or Metastatic Urothelial Carcinoma: KEYMAKER-U04–Substudy 04D

The primary objectives of this study are to evaluate the safety and tolerability of an investigational agent in combination with enfortumab vedotin plus pembrolizumab, and to assess the objective response rate per RECIST 1.1 by investigator assessment of this triple combination regimen. These objectives are clinically relevant for establishing the feasibility and preliminary efficacy of novel therapeutic combinations in patients with locally advanced or metastatic urothelial carcinoma receiving first-line treatment.

The secondary objectives include:

• Evaluation of duration of response per RECIST 1.1 by investigator assessment with the investigational agent in combination with enfortumab vedotin plus pembrolizumab.

• Characterization of the pharmacokinetic profile of the investigational agent and enfortumab vedotin when administered in combination.

The clinical trial enrolled a total of **38 participants** diagnosed with **urothelial carcinoma** that was locally advanced and unresectable or **metastatic**. Both male and female subjects were included in the study population. The trial recruited adults and elderly individuals, as indicated by the age range categories. Participants were selected based on histologically documented disease and were required to be treatment-naïve for their locally advanced or metastatic condition, meaning they had not received prior systemic therapy for this stage of disease. All participants were required to provide either newly obtained or archival tumor tissue samples through core or excisional biopsy. Specific inclusion criteria addressed participants with certain viral infections: those with **HIV** infection were eligible if they had well-controlled disease on antiretroviral therapy, individuals positive for **hepatitis B surface antigen** were required to have received HBV antiviral therapy for at least 4 weeks with undetectable viral load, and participants with a history of **hepatitis C virus** infection needed to demonstrate undetectable HCV viral load prior to enrollment. The study population did not include vulnerable populations.

This is a Phase 1/2, open-label, rolling-arm umbrella platform study evaluating investigational agents in combination with **enfortumab vedotin** and **pembrolizumab** as first-line treatment in participants with locally advanced or **metastatic urothelial carcinoma**. The trial employs a non-randomized design without blinding procedures. The study will utilize **MK-3120** (SKB410) administered as a solution for injection/infusion via **intravenous** route, enfortumab vedotin administered via intravenous infusion, and **KEYTRUDA** (pembrolizumab) 25 mg/mL concentrate for solution for infusion administered via intravenous infusion. All investigational products are classified as biological medicinal products with protein-based active substances.

The primary objectives are to evaluate the safety and tolerability of the investigational agent in combination with enfortumab vedotin plus pembrolizumab, and to assess the **objective response rate** per RECIST 1.1 by investigator assessment. The primary endpoints include the number of participants who experienced at least one **adverse event**, the number of participants with **dose-limiting toxicities**, the number of participants who discontinued study treatment due to an adverse event, and the objective response rate as assessed by the investigator. Secondary endpoints encompass **duration of response** as assessed by the investigator, and comprehensive **pharmacokinetic** parameters including serum maximum concentration and trough concentration of MK-3120 antibody-drug conjugate and total antibodies, plasma maximum concentration and trough concentration of MK-3120 free payload, as well as corresponding pharmacokinetic parameters for enfortumab vedotin antibody-drug conjugate, total antibodies, and free payload.

Eligible participants must have histologically documented urothelial carcinoma that is locally advanced and unresectable or metastatic. Participants must provide a newly obtained or archival tumor tissue sample (core or excisional biopsy) and must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma. Participants infected with **Human Immunodeficiency Virus** must have well-controlled HIV on antiretroviral therapy. Those positive for **hepatitis B** surface antigen must have received hepatitis B virus antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization. Participants with a history of **hepatitis C virus** must have undetectable HCV viral load before randomization.

The estimated recruitment start date is December 15, 2025, with an estimated study completion date of October 18, 2030. The total duration of the trial is approximately 5 years from the initiation of participant recruitment to the final study completion. Participant involvement duration will vary based on individual response to treatment and tolerability. Participants may be withdrawn from the study due to adverse events requiring discontinuation of study treatment, disease progression, withdrawal of consent, or other safety concerns as determined by the investigator. Early termination from the study may occur if participants experience unacceptable toxicity, develop dose-limiting toxicities, or meet other protocol-specified discontinuation criteria.

The experimental treatment regimen consists of three biological medicinal products administered in combination. MK-3120, containing the active substance SKB410, is provided as a solution for injection/infusion and is administered via intravenous use. This investigational agent is manufactured by MERCK & CO. INC. and represents a protein-based biological product currently under investigation.

Enfortumab vedotin is administered as part of the combination therapy via intravenous infusion. This biological medicinal product is classified under ATC code L01FX13 and serves as one of the experimental components in the treatment protocol. The product is formulated for intravenous administration and is utilized in conjunction with the other investigational agents in this clinical trial.

Pembrolizumab is administered as KEYTRUDA 25 mg/mL concentrate for solution for infusion. This biological medicinal product, manufactured by MERCK SHARP & DOHME B.V., is provided as a solution for infusion administered via intravenous infusion. The product holds marketing authorization number EU/1/15/1024/003 and is classified under ATC code L01FF02. Pembrolizumab is also known by alternative designations including Lambrolizumab, MK-3475, and SCH-900475. This agent represents a protein-based biological product with established regulatory approval in the European Union.

The study is designed as a Phase 1/2 open-label investigation evaluating the safety, tolerability, and objective response rate per RECIST 1.1 criteria by investigator assessment of the investigational agent in combination with enfortumab vedotin plus pembrolizumab as first-line treatment in participants with locally advanced or metastatic urothelial carcinoma.

Efficacy will be assessed through multiple endpoints in this clinical trial. The primary efficacy endpoint is the **objective response rate** as assessed by investigator per RECIST 1.1 criteria. Safety and tolerability of the investigational agent in combination with enfortumab vedotin plus pembrolizumab will also be evaluated as primary objectives through the number of participants who experienced at least one adverse event, the number of participants with dose-limiting toxicities, and the number of participants who discontinued study treatment due to an adverse event. Secondary efficacy assessments include **duration of response** as assessed by investigator. Additionally, pharmacokinetic parameters will be measured including serum maximum concentration and trough concentration of MK-3120 antibody-drug conjugate, MK-3120 total antibodies, enfortumab vedotin antibody-drug conjugate, and enfortumab vedotin total antibodies, as well as plasma maximum concentration and trough concentration of MK-3120 free payload and enfortumab vedotin free payload.