Evaluation of TAR-200 and Cetrelimab Versus Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder Without Radical Cystectomy

The primary objective of this study is to compare **bladder intact event-free survival (BI-EFS)** in participants with **Muscle-Invasive Urothelial Carcinoma (MIBC)** of the bladder who are receiving TAR-200 in combination with cetrelimab versus those receiving concurrent chemoradiotherapy. This objective is clinically relevant as it aims to evaluate the efficacy of a novel treatment regimen in maintaining bladder integrity and delaying disease progression, which is crucial for improving patient outcomes and quality of life.

Secondary objectives include:

• Comparing **metastasis-free survival (MFS)** in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy.
• Comparing **Overall Survival (OS)** in the same participant groups.
• Comparing the **Overall Response Rate (ORR)**, including Complete Response (CR) or Partial Response (PR), in both treatment arms at Week 18.
• Assessing the **safety and tolerability** of participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy.

The clinical trial involves a total of **379 participants** diagnosed with **Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder**. The study population includes both male and female subjects, aged 18 years and older, who are either ineligible for or have elected not to undergo radical cystectomy. Participants were selected based on their ability to adhere to specified lifestyle restrictions and their general health status, which includes adequate bone marrow, liver, and renal function. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 0, 1, or 2, and thyroid function tests within normal range or stable on hormone supplementation. Participants are required to follow local regulations regarding contraceptive use and are advised on reproductive conservation options due to potential fertility impairment from anti-cancer treatments. The selection process ensures that all adverse events from prior treatments have resolved to an acceptable level before randomization. The trial includes a vulnerable population, emphasizing the need for informed consent and understanding of the study's purpose and procedures.

The clinical trial is designed to evaluate the efficacy of **TAR-200** in combination with **cetrelimab** compared to concurrent chemoradiotherapy in participants with **muscle-invasive urothelial carcinoma** of the bladder who are not undergoing radical cystectomy. This is a Phase 3, multi-center, randomized, double-blind, controlled study. The trial aims to assess bladder intact event-free survival (BI-EFS) as the primary endpoint, with secondary endpoints including time to first radiologic evidence of metastatic disease or death, overall response rate, and frequency and grade of adverse events.

The trial is expected to last until February 2030, with recruitment having started in December 2020. Participants will be involved in the study for a maximum treatment period of 18 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess final outcomes. Participants will be randomly assigned to receive either the investigational treatment or the control treatment, with neither the participants nor the investigators aware of the group assignments, ensuring a double-blind design.

Inclusion criteria require participants to be at least 18 years old, with histologically confirmed cT2-T4a N0, M0 urothelial carcinoma of the bladder, and ineligible for or opting out of radical cystectomy. Participants must have adequate bone marrow, liver, and renal function, and agree to adhere to specified lifestyle restrictions. Exclusion criteria include the presence of small cell or neuroendocrine variants of the disease. Conditions for early termination from the study include significant adverse events or disease progression as per the study protocol.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Gemcitabine Accord** is utilized in multiple formulations, including a 100 mg/ml solution for infusion. This formulation is administered intravenously. The dosage is calculated based on body surface area, with a maximum total dose of 27 mg/m² over a treatment period of up to 6 cycles. The pharmaceutical form is a solution for infusion, and it is produced by Accord Healthcare. The active substance, **gemcitabine**, is of chemical origin and is classified under the ATC code L01BC05.

Another formulation of **Gemcitabine** used in the trial is a concentrate for solution for infusion, also administered intravenously. This formulation shares the same dosage and treatment period as the previous one, with a maximum total dose of 27 mg/m² over 6 cycles. It is also produced by Accord Healthcare and contains the same active substance, **gemcitabine**, of chemical origin.

**Cetrelimab**, marketed as JNJ-63723283, is a monoclonal antibody of biological origin used in the trial. It is provided as a powder for solution for infusion and administered intravenously. The treatment period for cetrelimab extends up to 18 cycles. This product is developed by Janssen-Cilag International N.V. and is not associated with a specific maximum total dose in the trial documentation.

**Cisplatin**, marketed as Cisplatinum Accord, is used as a comparator treatment in the trial. It is a 1 mg/ml concentrate for solution for infusion, administered intravenously. The maximum total dose is 35 mg/m² over a treatment period of up to 6 cycles. The active substance, **cisplatin**, is of chemical origin and is classified under the ATC code L01XA01. This product is manufactured by Accord Healthcare Polska Sp. z o.o.

Additionally, the trial includes the use of **Gemcitabine Hydrochloride**, marketed as JNJ-17000139, which is provided in tablet form for intravesical use. This product is a chemical entity and is part of a combination product that includes a device. The treatment period for this formulation can extend up to 36 cycles. The product is developed by Janssen-Cilag International N.V.

Participant compliance with the dosing schedule is monitored throughout the trial, ensuring adherence to the specified administration routes and treatment periods. The trial aims to evaluate the efficacy of these treatments in participants with muscle-invasive urothelial carcinoma of the bladder who are not receiving radical cystectomy.

The efficacy of the clinical trial will be assessed by evaluating the **bladder intact event-free survival (BI-EFS)** in participants. This primary endpoint measures the time from randomization to the first BI-EFS event, which includes the histologically proven presence of muscle-invasive bladder cancer (MIBC), clinical evidence of nodal or metastatic disease as assessed by RECIST 1.1 criteria, radical cystectomy, or death due to any cause. Secondary endpoints include the time from randomization to the first radiologic or evidence of metastatic disease or death, time from randomization to death, and the overall response rate (ORR), defined as the proportion of participants who achieve a complete response (CR) or partial response (PR).

Additionally, the frequency and grade of adverse events (AEs) will be monitored according to the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE). NCI PRO-CTCAE assessments will be conducted for all urinary and gastrointestinal items in the NCI PRO-CTCAE item library. Laboratory abnormalities will be evaluated by comparing CTCAE grades and NCI PRO-CTCAE grades from baseline to the worst post-baseline value. These assessments will provide comprehensive data on the efficacy and safety of the treatment regimen in participants with muscle-invasive urothelial carcinoma of the bladder who are not receiving radical cystectomy.