Evaluation of TAR-200 and Cetrelimab Versus Bacillus Calmette-Guérin in BCG-naïve High-Risk Non-Muscle Invasive Bladder Cancer

The primary objective of this Phase 3, open-label, multi-center, randomized study is to compare **event-free survival (EFS)** in participants with BCG-naïve high-risk non-muscle invasive bladder cancer (HRNMIBC). The study evaluates the efficacy of TAR-200 in combination with **cetrelimab** (Group A) versus intravesical **Bacillus Calmette-Guérin (BCG)** (Group B), and TAR-200 alone (Group C) versus intravesical BCG (Group B). This comparison is clinically relevant as it aims to determine the most effective treatment strategy for improving EFS in this patient population, potentially offering alternative therapeutic options to the standard BCG treatment.

The clinical trial involves a total of **616 participants** diagnosed with **High-Risk Non-muscle-invasive Bladder Cancer** (HR-NMIBC). The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have a histologically confirmed initial diagnosis of HR-NMIBC, specifically high-grade papillary Ta, any T1, or carcinoma in situ (CIS), and must be BCG-naïve, meaning they have not received prior intravesical Bacillus Calmette-Guérin (BCG) therapy or have stopped BCG more than three years before randomization. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 0, 1, or 2, and normal or stable thyroid function tests. Participants must be willing to undergo all study procedures, including multiple cystoscopies and transurethral resection of bladder tumor (TURBT) or bladder biopsy for assessment of recurrence or progression. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is a **Phase 3**, open-label, multi-center, randomized study designed to evaluate the efficacy and safety of TAR-200 in combination with **cetrelimab** or TAR-200 alone versus intravesical Bacillus Calmette-Guérin (BCG) in participants with BCG-naïve high-risk non-muscle invasive bladder cancer (HRNMIBC). The trial aims to compare event-free survival (EFS) among different treatment groups, specifically TAR-200 combined with intravenous cetrelimab, TAR-200 alone, and intravesical BCG. The study is expected to conclude by May 31, 2028, with recruitment having commenced on March 31, 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, disease characteristics, and performance status. The inclusion criteria require participants to be at least 18 years old, have a histologically confirmed diagnosis of HRNMIBC, and be BCG-naïve. Exclusion criteria include the presence of certain histological features and unresolved adverse events from prior treatments. Following the screening, participants will be randomized into one of the treatment groups.

Study visits will include regular follow-up assessments to monitor disease progression, treatment response, and any adverse events. These visits will involve procedures such as cystoscopies and transurethral resection of bladder tumor (TURBT) or bladder biopsy as necessary. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent. The expected length of participant involvement is up to 146 weeks, depending on the treatment group and individual response to therapy.

Participants may be withdrawn from the study early if they experience disease progression, significant adverse events, or choose to withdraw consent. The primary endpoint of the study is EFS, defined as the time from randomization to the first recurrence of high-risk disease, progression, or death from any cause. Secondary endpoints will be evaluated as part of the overall study objectives. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The experimental medication **JNJ-17000139** contains the active substance **gemcitabine hydrochloride**. It is formulated as a **tablet** and is administered via **intravesical use**. The dosage is measured in milligrams, with a maximum daily dose of 1 mg and a total treatment period of up to 99 days. The medication is of chemical origin and is not a paediatric formulation.

The comparator treatment in the study is the **BCG vaccine**, which is of biotechnological origin. It is administered intravesically, similar to the experimental medication. The pharmaceutical form is denoted as **PHF1043MIG**, and the treatment period can extend up to 146 days. The BCG vaccine serves as a standard-of-care therapy in this trial, providing a benchmark against which the efficacy of the experimental treatments is measured.

Another experimental treatment in the trial is **JNJ-63723283**, which contains the active substance **cetrelimab**. This medication is available in two pharmaceutical forms: **solution for infusion** and **powder for solution for infusion**. Both forms are administered via **intravenous use**. The dosage is expressed in milligrams per millilitre, with a maximum daily dose of 1 mg/ml and a treatment period of up to 99 days. Cetrelimab is a monoclonal antibody, and like the other experimental treatments, it is not formulated for paediatric use.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy and safety of these treatments in participants with high-risk non-muscle invasive bladder cancer who are BCG-naïve. The study's primary objective is to compare event-free survival among the different treatment groups.

The efficacy of the clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)**. EFS is defined as the time from randomization to the first occurrence of high-risk disease recurrence, progression, or death from any cause. For participants with carcinoma in situ (CIS), persistent disease at 6 months (Week 24) will also be considered an EFS event. Progression is further characterized by an increase in stage from Ta to T1, from CIS to T1, or progression to muscle-invasive bladder cancer (MIBC) (T≥2), lymph node involvement (N+), or distant metastasis (M+), whichever occurs first.