A Study 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

Study Overview
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Brief Summary
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The purpose of this study is to compare event-free survival (EFS) in participants with Bacillus Calmette-Guerin (BCG)-naive high-risk non-muscle invasive bladder cancer (HR-NMIBC), including high-grade papillary Ta, any T1, or carcinoma in situ (CIS), between TAR-200 plus cetrelimab (Group A) and TAR-200 alone (Group C) versus intravesical BCG (Group B).

Detailed Description
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Bladder cancer is the tenth most common malignancy worldwide. About 75 percent (%) of bladder cancers are non-muscle invasive at diagnosis with approximately 25% of NMIBC patients have HR, NMIBC. The TAR-200/gemcitabine (JNJ-17000139) product is an intravesical drug delivery system regulated as an investigational drug. The drug constituent consists of gemcitabine and osmotic minitablets. Cetrelimab (JNJ-63723283) is a fully human immunoglobulin G4 (IgG4) kappa monoclonal antibody (mAb) that binds programmed-cell death protein (PD)-1. The mainstay of treatment for HR-NMIBC is transurethral resection of bladder tumor, followed by intravesical treatment with BCG. In this study metronomic dosing of intravesical gemcitabine, delivered via TAR-200, alone or in combination with cetrelimab will be evaluated and compared against intravesical BCG. The study consists of a Screening phase, Treatment phase, and Follow-up phase. The total duration of the study will be up to 5 years and 2 months. Efficacy, Safety, pharmacokinetics (PK), and biomarkers will be assessed at specific time points during the study.

Official Title
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A Phase 3, Open-Label, Multi-Center, Randomized Study Evaluating 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

Conditions
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Bladder Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed initial diagnosis by local pathology (within 90 days of the most recent signed informed consent) of high grade non-muscle invasive bladder cancer (HR-NMIBC) (high-grade Ta, any T1 or carcinoma in-situ [CIS]), in participants who are Bacillus Calmette Guérin (BCG)-naïve BCG-naïve (participants who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before date of randomization are eligible) All visible papillary disease must be fully resected (absent) prior to date of randomization and documented at baseline cystoscopy. Local urine cytology at screening must be negative or atypical (for high-grade urothelial carcinoma [HGUC]) for patients with papillary only disease (without CIS) Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2 All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to common terminology criteria for adverse events (CTCAE) version 5.0 Grade less than (<) 2 prior to date of randomization Participants must be willing to undergo all study procedures Exclusion Criteria: Presence or history of histologically confirmed, muscle invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (that is, greater than and equal to [>=] T2) Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder (that is, urethra, ureter, or renal pelvis). Ta/any 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 Presence of any bladder or urethral anatomic feature (example, urethral stricture) that, in the opinion of the investigator, may prevent the safe insertion, indwelling use, removal of TAR-200 or administration of intravesical BCG. Participants with tumors involving the prostatic urethra in men will be excluded A history of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 milliliters (mL) Indwelling catheters are not permitted; however, intermittent catheterization is acceptable

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: Treatment Group A: TAR-200 + Cetrelimab<br>Participants will receive intravesical TAR-200 once every 3 weeks (Q3W) and cetrelimab. | Drug: TAR-200<br>* TAR-200 will be administered intravesically.<br>* Other names: JNJ-17000139;Biological: Cetrelimab<br>* Cetrelimab will be administered.<br>* Other names: JNJ-63723283;|
| Active Comparator: Treatment Group B: Bacillus Calmette-Guerin (BCG) Vesiculture<br>Participants will receive intravesical BCG once every week for 6 weeks (induction) and then followed by once every week for 3 weeks starting at Weeks 12, 24, 48, 72, and 96 (maintenance). | Biological: BCG Vesiculture<br>* BCG will be administered intravesically.<br>|
| Experimental: Treatment Group C: TAR-200 Alone<br>Participants will receive intravesical TAR-200 alone once Q3W. | Drug: TAR-200<br>* TAR-200 will be administered intravesically.<br>* Other names: JNJ-17000139;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS is defined as the time from randomization to either the time of the first recurrence of high-risk disease, progression, or death due to any cause, whichever occurs first. For participants with carcinoma In-situ (CIS), persistent disease at 6 months (Week 24) is also considered an EFS event. Progression is defined as: an increase of stage from Ta to T1 or from CIS to T1 or progression to muscle invasive bladder cancer (MIBC) (T greater than or equal to [>=] 2) or to lymph node (N+) or to distant disease (M+), whichever occurs first. | Up to 5 years 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Complete Response (CR) Rate | Overall CR will be measured by determining the percentage of participants with CIS who have no presence of high-risk disease at 6 months. | Up to 5 years 2 months | 
| Duration of CR | Duration of CR is defined from the time of first CR achieved to first evidence of recurrence, progression or death due to any cause (whichever occurs first) for participants who achieve a CR. | Up to 5 years 2 months | 
| Recurrence-Free Survival (RFS) | RFS is defined as the time from randomization to the time of the first recurrence of high-risk disease, or death due to any cause, whichever occurs first. | Up to 5 years 2 months | 
| Time to Progression (TTP) | TTP is defined as the time from randomization to the date of first documented evidence of disease progression or death due to disease progression, whichever occurs first. | Up to 5 years 2 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death, due to any cause. | Up to 5 years 2 months | 
| Cancer Specific Survival (CSS) | CSS is defined as the time from randomization to the date of death due to bladder cancer. | Up to 5 years 2 months | 
| Number of Participants with Adverse Events (AEs) by Grades According to Common Terminology Criteria for Adverse Events (CTCAE) | Number of participants with AEs by severity grade as assessed by CTCAE version 5 will be reported. Grade refers to the severity of AE as follows: Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe; Grade 4- Life-threatening; Grade 5- Death related to adverse event. | Up to 5 years 2 months | 
| Number of Participants with Adverse Events (AEs) | Number of participants with AEs will be reported. An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. | Up to 5 years 2 months | 
| Number of Participants with Change from Baseline in Laboratory Abnormalities | Number of participants with change from baseline in laboratory abnormalities will be reported. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale 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 2 months | 
| Number of Participants with Change from Baseline in Vital Signs Abnormalities | Number of participants with change from baseline in vital signs (blood pressure [systolic and diastolic], heart rate, temperature, and weight) abnormalities will be reported. | Up to 5 years 2 months | 
| Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of life Questionnaire - Non-muscle Invasive Bladder Cancer EORTC QLQ- NMIBC 24 | EORTC QLQ-NMIBC 24 is a 24-item questionnaire for evaluating the Health-related quality of life (HRQoL) of participants with superficial (non-muscle-invasive) bladder cancer. The questionnaire is designed to supplement the quality of life questionnaire (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). | Up to 5 years 2 months | 
| Time to Symptom Deterioration as Assessed by EORTC-QLQ-NMIBC 24 Scores | EORTC QLQ-NMIBC 24 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). | Up to 5 years 2 months |