A Study of TAR-200 in Combination With Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants With Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Intravesical Bacillus Calmette-Guérin Who Are Ineligible for or Elected Not to Undergo Radical Cystectomy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the overall complete response (CR) rate in participants treated with TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3) with Carcinoma in Situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease; and disease-free survival (DFS) in participants treated with TAR-200 alone with papillary disease only (Cohort 4).

Official Title
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Phase 2b Clinical Study Evaluating 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) Who Are Ineligible for or Elected Not to Undergo Radical Cystectomy

Conditions
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Urinary Bladder Neoplasms

Intervention / Treatment
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* Drug: TAR-200
* Biological: Cetrelimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of persistent or recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC), (carcinoma in situ [CIS] or tumor in situ [Tis]), with or without papillary disease (T1, high-grade Ta) or papillary disease only (high-grade Ta or any T1 and absence of CIS), within 12 months of completion of the last dose of Bacillus Calmette-Guerin (BCG) therapy, in participants who have received adequate BCG. Mixed histology tumors are allowed if urothelial differentiation (transitional cell histology) is predominant. However, the presence of neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features will make a participant ineligible. For participants with lamina propria invasion (T1) on the screening biopsy/ transurethral resection of bladder tumor (TURBT), muscularis propria must be present in order to rule out Muscle Invasive Bladder Cancer (MIBC) All visible papillary disease must be fully resected (absent) prior to randomization (residual CIS is acceptable for participants eligible for Cohorts 1, 2, and 3 only) and documented in the electronic case report form (eCRF) at screening cystoscopy. For participants with papillary disease only (Cohort 4), local urine cytology at screening must be negative or atypical (for High-Grade Urothelial Carcinoma [HGUC]) Participants must be ineligible for or have elected not to undergo radical cystectomy BCG-unresponsive high-risk NMIBC after treatment with adequate BCG therapy defined as a minimum of 5 of 6 full doses of an induction course (adequate induction) plus 2 of 3 doses of a maintenance course, or at least 2 of 6 doses of a second induction course Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2 Exclusion Criteria: Presence or history of histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (that is, T2, T3, T4, and/or Stage IV) Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/T1/CIS of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to randomization Received a live virus vaccine within 30 days prior to the initiation of study treatment. Inactivated (non-live or non-replicating) vaccines approved or authorized for emergency use (for example, COVID-19) by local health authorities are allowed Active hepatitis B or C infection (for example, participants with history of hepatitis C infection but undetectable hepatitis C virus polymerase chain reaction (PCR) test and participants with history of hepatitis B infection with positive hepatitis B surface antigen (HBsAg) antibody and undetectable PCR are allowed) Prior therapy with an anti-programmed-cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: TAR-200 and Cetrelimab<br>TAR-200 is placed into the bladder through a urinary placement catheter in participants with carcinoma in situ (CIS), with or without papillary disease, on Day 0 and will be dosed every 3 weeks (Q3W) for up to the first 24 weeks (6 months), then every 12 weeks through Week 99 (Year 2). In addition, Cetrelimab will be dosed Q3W through Week 78 (18 months). | Drug: TAR-200<br>* TAR-200 will be administered transuretherally.<br>* Other names: Gemcitabine-Releasing Intravesical System;Biological: Cetrelimab<br>* Cetrelimab will be administered.<br>* Other names: JNJ-63723283;|
| Experimental: Cohort 2: TAR-200<br>TAR-200 is placed into the bladder through a urinary placement catheter in participants with CIS, with or without papillary disease, on Day 0 and will be dosed Q3W for up to the first 24 weeks (6 months), then every 12 weeks through Week 99 (Year 2). | Drug: TAR-200<br>* TAR-200 will be administered transuretherally.<br>* Other names: Gemcitabine-Releasing Intravesical System;|
| Experimental: Cohort 3: Cetrelimab<br>Participants with CIS, with or without papillary disease, will receive Cetrelimab which will be dosed Q3W through Week 78 (18 months). | Biological: Cetrelimab<br>* Cetrelimab will be administered.<br>* Other names: JNJ-63723283;|
| Experimental: Cohort 4: TAR-200 (Participants with Papillary Disease only)<br>TAR-200 is placed into the bladder through a urinary placement catheter in participants with papillary disease only, on Day 0 and will be dosed Q3W for up to the first 24 weeks (6 months), then every 12 weeks through Week 99 (Year 2). | Drug: TAR-200<br>* TAR-200 will be administered transuretherally.<br>* Other names: Gemcitabine-Releasing Intravesical System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1, 2, and 3: Overall Complete Response (CR) Rate | Overall CR rate is defined as the percentage of participants achieving a CR at any time post-treatment. It will be measured by determining the percentage of participants without presence of high-grade disease using results from cystoscopy and centrally read urine cytology at any time point. | Up to 5 years | 
| Cohort 4: Disease-free Survival (DFS) | DFS will be measured as the time from the date of first dose of study treatment to either the time of the first recurrence of high-risk disease, progression, or death due to any cause, whichever occurs first. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1, 2, and 3: Duration of Response (DOR) | DOR is defined from the date of first CR achieved to the date of first evidence of recurrence or progression or death (whichever is earlier) for participants who achieve a CR. | Up to 5 years | 
| Overall Survival (OS) | OS, defined as the time from the date of first dose of study treatment to death; if a participant has not died at the time of analysis, the participant will be censored at the date last known alive. | Up to 5 years | 
| Cohort 1, 2, and 4: Concentrations of Gemcitabine and 2',2' difluorodeoxyuridine (dFdU) in Urine and Plasma | Concentrations of gemcitabine and its metabolite dFdU in urine and plasma will be assessed. | Up to Week 21 | 
| Cohort 1 and 3: Serum Concentration of Anti-cetrelimab Antibodies | Serum concentration of anti-cetrelimab antibodies will be assessed using a validated immunoassay for anti-drug antibody (ADA) analysis. | Predose, up to 3 years | 
| Number of Participants with Anti-cetrelimab Antibodies | Number of participants with anti-cetrelimab antibodies will be reported. | Predose, up to 3 years | 
| Change from Baseline in European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire (EORTC QLQ) -C30 Scores | EORTC QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies. It incorporates 5 functional scales (physical, role, cognitive, emotional, and social functioning), 3 symptom scales (fatigue, pain, and nausea or vomiting), and a global health status or HRQoL scale. Ratings for each item range from 1 (not at all) to 4 (very much). | Baseline, up to 3 years and 4 months | 
| Change from Baseline in EORTC QLQ- Non-Muscle-Invasive Bladder Cancer (NMIBC) 24 Scores | EORTC QLQ-NMIBC24 is a 24-item questionnaire for evaluating the HRQoL of participants with superficial (non-muscle-invasive) bladder cancer. The questionnaire is designed to supplement the QLQ-C30 and incorporates 6 multi-item scales and 5 single items. Ratings for each item range from 1 (not at all) to 4 (very much). | Baseline, up to 3 years and 4 months | 
| Number of Participants with Adverse Events (AEs) by Severity Grades | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Severity grades ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event. | Up to 5 years |