Efficacy and Safety Evaluation of TAR-200 and Cetrelimab in High-Risk Non-Muscle Invasive Bladder Cancer Unresponsive to Bacillus Calmette-Guérin

The primary objective of this study is to evaluate the overall **Complete Response (CR)** rate in participants with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to intravesical Bacillus Calmette-Guérin (BCG) and are ineligible for or have elected not to undergo radical cystectomy. Participants will be treated with TAR-200 in combination with intravenous cetrelimab (Cohort 1), TAR-200 alone (Cohort 2), or intravenous cetrelimab alone (Cohort 3) in cases of carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 papillary disease. Additionally, the study aims to evaluate disease-free survival (DFS) in participants treated with TAR-200 alone with papillary disease only (Cohort 4). This objective is clinically relevant as it seeks to provide alternative therapeutic options for patients with limited treatment choices due to their ineligibility for radical cystectomy.

Secondary objectives include:

• Evaluating the duration of response (DoR) in participants achieving a CR.
• Determining the overall survival (OS) in all participants.
• Evaluating the pharmacokinetics (PK) of gemcitabine and its major metabolite in urine and plasma.
• Assessing the PK and immunogenicity of cetrelimab in serum.
• Evaluating health-related quality of life (HRQoL) in all participants.
• Assessing the safety and tolerability of the treatment regimens.

The clinical trial involves a total of **80 participants** diagnosed with **Non-Muscle-Invasive Urothelial Carcinoma (NMIBC) of the Bladder**. The study population includes both male and female subjects aged 18 years and older, with an emphasis on those who have adequate bone marrow, liver, and renal function. Participants were selected based on their diagnosis of persistent or recurrent high-risk NMIBC, with or without papillary disease, and their ineligibility or decision not to undergo radical cystectomy. The trial population is characterized by a diverse age range and includes individuals who are considered part of a vulnerable population. Participants are required to adhere to specific lifestyle restrictions, including contraceptive use consistent with local regulations, and must be willing to undergo multiple study procedures. The selection criteria ensure that all visible papillary disease is resected prior to randomization, and participants must have a resolved status of any adverse events associated with prior treatments to a CTCAE version 5.0 Grade less than 2. The trial aims to evaluate the complete response rate and disease-free survival in different cohorts, with participants having signed informed consent forms indicating their understanding and willingness to participate in the study.

The clinical trial is designed to evaluate the efficacy and safety of TAR-200 in combination with **cetrelimab**, TAR-200 alone, or cetrelimab alone in participants with high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette-Guérin (BCG) therapy. This is a Phase 2b, randomized, double-blind, controlled study. The trial is expected to run until November 30, 2027, with recruitment having commenced on March 26, 2021. Participants will be randomly assigned to one of four cohorts: Cohort 1 will receive TAR-200 in combination with intravenous cetrelimab, Cohort 2 will receive TAR-200 alone, Cohort 3 will receive intravenous cetrelimab alone, and Cohort 4 will receive TAR-200 alone with papillary disease only. The primary objective is to evaluate the overall complete response (CR) rate and disease-free survival (DFS) in the respective cohorts.

Study visits will follow a structured sequence, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, adequate organ function, and a histologically confirmed diagnosis of high-risk NMIBC. Participants must also be ineligible for or have elected not to undergo radical cystectomy. The screening visit will include assessments such as cystoscopy and urine cytology. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including cystoscopies, bladder biopsies, and imaging as necessary. The end-of-study visit will conclude the participant's involvement, assessing the final treatment outcomes and any long-term effects.

The expected length of participant involvement varies depending on the cohort assignment, with a maximum treatment period of 36 months for TAR-200 and 18 months for cetrelimab. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, withdrawal of consent, or any significant protocol deviations. Participants are required to adhere to lifestyle restrictions and contraceptive measures throughout the study and for a specified period after the last dose of study treatment. The trial will measure primary endpoints such as the overall CR rate and DFS, along with secondary endpoints including duration of response (DOR), overall survival (OS), and the incidence of adverse events. The study will also assess laboratory parameters and quality of life changes using validated questionnaires.

The clinical trial involves the administration of **gemcitabine hydrochloride** under the product name JNJ-17000139. This experimental medication is provided in the form of a **tablet** and is intended for **intravesical use**. The treatment is designed to be administered over a maximum period of 36 months. The specific dosage and frequency of administration are not detailed in the provided data. The product is a chemical entity and is part of a combination product that includes a device, specifically a urinary placement catheter, which serves as an accessory device to insert the drug-device combination product (TAR-200) into the bladder through the urethra. Participant compliance with the administration schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **cetrelimab**, marketed under the product name JNJ-63723283. This medication is available in two pharmaceutical forms: a **solution for infusion** and a **powder for solution for infusion**. Both forms are intended for **intravenous use**. The maximum treatment period for cetrelimab is 18 months. Cetrelimab is a monoclonal antibody of biological/biotechnological origin. The trial does not specify the exact dosage or frequency of administration for cetrelimab. Monitoring of participant compliance with the dosing schedule will be conducted as part of the trial protocol.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the overall **Complete Response (CR)** rate, which will be measured by determining the proportion of participants without the presence of high-grade disease using results from cystoscopy and centrally read urine cytology at any timepoint. For Cohort 4, Disease-Free Survival (DFS) will be measured as the time from the date of the first dose of study treatment to the first recurrence of high-risk disease, progression, or death due to any cause, whichever occurs first.

Secondary endpoints will include Duration of Response (DOR), defined as the time from the first CR achieved to the date of first evidence of recurrence, progression, or death, using cystoscopy, centrally read bladder biopsy, urine cytology, and imaging if available. Twelve-month DOR will also be determined. Overall Survival (OS) will be assessed as the time from the date of the first dose of study treatment to death, with participants censored at the date last known alive if they have not died at the time of analysis. Additional secondary endpoints include the measurement of gemcitabine and dFdU concentrations in urine and plasma, serum concentration, and incidence of anti-cetrelimab antibodies. Changes from baseline and time to symptom deterioration will be evaluated using the EORTC QLQ-C30 and EORTC QLQ-NMIBC24 scales.

Adverse events (AEs) will be monitored according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5, with frequency and grade being recorded. Laboratory abnormalities will be assessed by comparing CTCAE grades from baseline to the worst post-baseline value. Other safety data, such as vital signs, will be considered as appropriate. These efficacy and safety parameters will be collected and analyzed at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on participants with high-risk non-muscle invasive bladder cancer unresponsive to intravesical Bacillus Calmette-Guérin (BCG).