A Study of Nivolumab Plus Bempegaldesleukin (Bempeg/NKTR-214) vs Nivolumab Alone vs Standard of Care in Participants With Bladder Cancer That May Have Invaded The Muscle Wall of the Bladder and Who Cannot Get Cisplatin, A Type of Medicine Given To Treat Bladder Cancer

Study Overview
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Brief Summary
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The purpose of the study is to see if treatment with nivolumab plus bempegaldesleukin or nivolumab alone, before and after surgery to remove the bladder, is more effective than surgery alone in participants with high-risk urothelial cancer, including muscle-invasive bladder cancer who are not able to receive cisplatin chemotherapy.

Official Title
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A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus Bempegaldesleukin (NKTR-214), Versus Nivolumab Alone Versus Standard of Care in Participants With Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible

Conditions
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Bladder Cancer, Bladder Tumor, Muscle-Invasive Bladder Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Procedure: Radical cystectomy (RC)
* Biological: Bempegaldesleukin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Urothelial carcinoma (UC) of the bladder, clinical stage T2-T4aN0, M0 or T1-T4aN1, M0, diagnosed at transurethral resection of bladder tumor (TURBT) Must be deemed eligible for Radical Cystectomy (RC) by urologist, and must agree to undergo RC. For arms A and B, participants must agree to undergo RC after completion of neoadjuvant therapy. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Cisplatin-ineligible participants will be defined by any one of the following criteria: i) Impaired renal function (glomerular filtration rate [GFR] ≥ 30 but < 60 mL/min) ii) GFR should be assessed by direct measurement (ie, creatinine clearance) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula) iii) Common Terminology Criteria for Adverse Events (CTCAE) version 5, ≥ Grade 2 hearing loss (assessed per local SOC). iv) CTCAE version 5, ≥ Grade 2 peripheral neuropathy. Documented Left Ventricular Ejection Fraction (LVEF) more than 45% Exclusion Criteria: Clinical evidence of ≥ N2 or metastatic bladder cancer Prior systemic therapy, radiation therapy, or surgery for bladder cancer other than TURBT or biopsies is not permitted. Prior Bacillus Calmette-Guerin (BCG) or other intravesicular treatment of non-muscle invasive bladder cancer (NMIBC) is permitted if completed at least 6 weeks prior to initiating study treatment. Evidence of urothelial carcinoma (UC) in upper urinary tracts (ureters or renal pelvis) or history of previous MIBC History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically significant venous or non-CVA(cerebrovascular accident)/TIA (Transient ischemic attack) arterial thromboembolic event Known cardiovascular history, including unstable or deteriorating cardiac disease within the previous 12 months (including unstable angina or myocardial infarction, congestive heart failure or uncontrolled clinically significant arrhythmias) Other protocol-defined inclusion/exclusion criteria apply

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: Arm A: Combination Therapy<br>Neoadjuvant (pre-surgical treatment) nivolumab + bempeg, followed by radical cystectomy (RC), followed by adjuvant (post-surgical treatment) nivolumab + bempeg | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Procedure: Radical cystectomy (RC)<br>* Surgical removal of the bladder<br>Biological: Bempegaldesleukin<br>* Specified dose on specified days<br>* Other names: Bempeg;|
| Experimental: Arm B: Monotherapy<br>Neoadjuvant nivolumab, followed by RC, followed by adjuvant nivolumab | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Procedure: Radical cystectomy (RC)<br>* Surgical removal of the bladder<br>|
| Other: Arm C: Standard-of-care<br>RC alone, without neoadjuvant or adjuvant therapy | Procedure: Radical cystectomy (RC)<br>* Surgical removal of the bladder<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) rate of Arm A to Arm C |  | Approximately 43 months | 
| Event-Free Survival (EFS) of Arm A vs Arm C |  | Approximately 43 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rate of Arm B to Arm C |  | Approximately 43 months | 
| EFS of Arm B vs Arm C |  | Approximately 43 months | 
| Overall Survival (OS) |  | Approximately 43 months | 
| Incidence of Adverse Events (AEs) |  | Up to 76.5 weeks | 
| Incidence of Serious Adverse Events (SAEs) |  | Up to 76.5 weeks | 
| Incidence of AEs leading to discontinuation |  | Up to 76.5 weeks | 
| Incidence of immune-mediated AEs (imAEs) |  | Up to 76.5 weeks | 
| Incidence of participants with clinical laboratory abnormalities |  | Up to 76.5 weeks | 
| pCR rate of Arm A to Arm B |  | Approximately 43 months | 
| EFS of Arm A vs Arm B |  | Approximately 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, NKTR-214, nivolumab, bempeg