Phase 1/2 Evaluation of V940 and Pembrolizumab, With or Without Enfortumab Vedotin, in Muscle-Invasive Urothelial Carcinoma Patients

The primary objective of this study is to assess the efficacy of **V940** in combination with **pembrolizumab** compared to placebo plus pembrolizumab in terms of disease-free survival (DFS) in patients with **muscle-invasive urothelial carcinoma**. This evaluation is clinically significant as it aims to determine the potential of V940 to improve DFS, which is a critical endpoint in cancer treatment, indicating the period during which a patient remains free from any signs and symptoms of the disease after treatment.

Secondary objectives include:

• Adjuvant Cohort: To evaluate overall survival (OS) in participants treated with V940 plus pembrolizumab and placebo plus pembrolizumab.
• Adjuvant Cohort: To assess distant metastasis-free survival (DMFS) as evaluated by the investigator in participants treated with V940 plus pembrolizumab and placebo plus pembrolizumab.
• Adjuvant Cohort: To evaluate the safety and tolerability of V940 plus pembrolizumab.
• Perioperative Cohort: To evaluate pathological complete response (pCR) as assessed by the local pathologist in participants treated with V940 plus pembrolizumab plus enfortumab vedotin (EV).
• Perioperative Cohort: To evaluate pathological downstaging (pDS) as assessed by the investigator in participants treated with V940 plus pembrolizumab plus EV.

The clinical trial involves a total of **142 participants** diagnosed with **Muscle-invasive Urothelial Carcinoma**. The study population includes both male and female subjects, with an age range that spans from young adults to older adults, as indicated by the age range categories 3 and 4. Participants were selected based on specific inclusion criteria, such as the requirement to provide blood samples for V940 production and circulating tumor DNA testing, and the necessity to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The trial includes individuals eligible for radical cystectomy and pelvic lymph node dissection, as well as those with high-risk pathologic disease post-radical resection. Both adjuvant and perioperative cohorts are considered, with the latter including participants ineligible for cisplatin treatment. The trial population is characterized by a diverse health status, with a focus on those with a histological diagnosis of urothelial carcinoma. Lifestyle considerations such as diet and physical activity are not specified, and the trial includes a vulnerable population. The selection process ensures a comprehensive representation of the target demographic, adhering to the protocol's predefined criteria.

The clinical trial is designed to evaluate the efficacy and safety of **V940** plus **pembrolizumab** with or without **enfortumab vedotin** in patients with **muscle-invasive urothelial carcinoma**. This study is structured as a randomized, double-blind, controlled trial, with an estimated duration extending until May 2032. The trial will commence recruitment in April 2024. Participants will be randomly assigned to receive either the investigational treatment or a placebo, ensuring the study's integrity through blinding and control measures.

The trial involves a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on predefined criteria, such as the provision of blood samples for V940 production and circulating tumor DNA testing. Participants must also provide a formalin-fixed paraffin-embedded tumor tissue sample for next-generation sequencing. Following the screening, participants will undergo regular follow-up visits to monitor safety, tolerability, and treatment efficacy. These visits will include assessments of disease-free survival, adverse events, and overall survival, among other endpoints. The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any adverse events experienced.

Participant involvement is expected to last up to 54 weeks, depending on the treatment cohort. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's decision to withdraw consent. The trial's primary endpoints focus on disease-free survival and the number of participants experiencing adverse events, while secondary endpoints include overall survival and distant metastasis-free survival. The study aims to provide valuable insights into the treatment of muscle-invasive urothelial carcinoma, contributing to the development of effective therapeutic strategies.

**Enfortumab Vedotin** is an experimental medication used in this clinical trial. It is administered as a **biological** agent in the form of a **PHF00230MIG** pharmaceutical formulation. The medication is delivered via **intravenous infusion**. The maximum daily dose is 125 mg, with a total maximum dose of 2250 mg over a treatment period of 27 weeks. Enfortumab Vedotin is a protein-based substance, specifically categorized under the ATC code **L01FX13**. Participant compliance with the dosing schedule is monitored throughout the trial.

The trial also includes a **placebo** treatment, referred to as "Placebo to V940." This placebo is used as a comparator in the study to evaluate the efficacy of the experimental treatments. The pharmaceutical form and route of administration for the placebo are not specified in the trial data.

**mRNA-4157** is another experimental treatment in the trial, classified as an **ATMP** (Advanced Therapy Medicinal Product). It is provided as a **dispersion for injection** and administered via **intramuscular injection**. The maximum daily dose is 1 mg, with a total maximum dose of 9 mg over a 27-week treatment period. mRNA-4157 is a nucleic acid-based substance, encapsulated in a synthetic lipid nanoparticle, designed to deliver a patient-specific mRNA sequence. The dosing schedule and participant adherence are closely monitored.

**Pembrolizumab**, marketed as **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, is used as a standard-of-care therapy in this trial. It is a **biological** agent administered through **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 3600 mg over a 54-week treatment period. Pembrolizumab is a protein-based substance, and its administration is carefully monitored to ensure participant compliance with the treatment regimen.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. For the **Adjuvant Cohort**, the primary endpoint is Disease-Free Survival (DFS), while secondary endpoints include Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), the number of participants experiencing an adverse event (AE), and the number of participants discontinuing study treatment due to an AE. In the **Perioperative Cohort**, the primary endpoints are the number of participants who experience an AE and the number of participants who discontinue study treatment due to an AE. Secondary endpoints for this cohort include Pathologic Complete Response (pCR) Rate and Pathologic Downstaging (pDS) Rate.

The trial will involve the administration of V940 plus pembrolizumab, with or without **Enfortumab Vedotin**, in participants with muscle-invasive urothelial carcinoma (MIUC). The efficacy parameters will be measured and collected at various timepoints throughout the study, although specific timepoints are not detailed in the provided data. The analysis of these endpoints will help determine the efficacy of the treatment regimens in both the adjuvant and perioperative settings. The trial is designed to evaluate the safety, tolerability, and efficacy of the treatment combinations, with the estimated end date set for May 17, 2032.