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

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

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.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer; Bladder Tumor; Muscle-Invasive Bladder Cancer
• Intervention / Treatment: Biological: Nivolumab; Procedure: Radical cystectomy (RC); Biological: Bempegaldesleukin

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5000
    • Local Institution - 0097
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, 1419
      • Local Institution - 0096
    • Ciudad Autónoma De Buenos Aires, Buenos Aires, Argentina, 1426
      • Local Institution - 0028
    • La Plata, Buenos Aires, Argentina, 1900
      • Local Institution - 0124
  • Distrito Federal
    • Capital Federal, Distrito Federal, Argentina, C1280AEB
      • Local Institution - 0027
  • Santa FE
    • Rosario, Santa FE, Argentina, S2000DTC
      • Local Institution - 0174
• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Local Institution - 0137
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • Local Institution - 0158
    • Fitzroy, Victoria, Australia, 3065
      • Local Institution - 0157
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution - 0011
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Local Institution - 0013
• Austria
  • Graz, Austria, 8036
    • Local Institution - 0148
  • Vienna, Austria, 1160
    • Local Institution - 0150
  • Wien, Austria, 1090
    • Local Institution - 0123
• Belgium
  • Edegem, Belgium, 2650
    • Local Institution - 0098
  • Gent, Belgium, 9000
    • Local Institution - 0068
  • Liège, Belgium, 4000
    • Local Institution - 0100
  • Antwerpen
    • Wilrijk, Antwerpen, Belgium, 2610
      • Local Institution - 0083
  • Brussels
    • Brussel, Brussels, Belgium, 1090
      • Local Institution - 0101
• Brazil
  • Rio de Janeiro, Brazil, 20231-050
    • Local Institution - 0041
  • Sao Paulo, Brazil, 01246-000
    • Local Institution - 0040
  • RIO Grande DO SUL
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90560-030
      • Local Institution - 0177
    • Porto Alegre, RIO Grande DO SUL, Brazil, 91350-200
      • Local Institution - 0039
  • SAO Paulo
    • Barretos, SAO Paulo, Brazil, 14784400
      • Local Institution - 0176
  • Sao Paulo
    • Jau, Sao Paulo, Brazil, 17210-120
      • Local Institution - 0037
  • São Paulo
    • Sao Paulo, São Paulo, Brazil, 01509-010
      • Local Institution - 0038
• Canada
  • Quebec, Canada, G1R3S1
    • Local Institution - 0018
  • Ontario
    • Oshawa, Ontario, Canada, L1G 2B9
      • Local Institution - 0082
  • Quebec
    • Sherbrooke, Quebec, Canada, JiH 5N4
      • Local Institution - 0036
• China
  • Chongqing
    • Chongqing, Chongqing, China, 400016
      • Local Institution - 0204
  • Fujian
    • Xiamen, Fujian, China, 361003
      • Local Institution
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Local Institution
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Local Institution
  • Hunan
    • Changsha, Hunan, China, 410031
      • Local Institution
  • Shan1xi
    • Taiyuan, Shan1xi, China
      • Local Institution
  • Shandong
    • Jinan, Shandong, China, 250117
      • Local Institution
• Czechia
  • Olomouc, Czechia, 77900
    • Local Institution - 0022
  • Praha, Czechia, 14059
    • Local Institution - 0021
  • Praha 5, Czechia, 150 06
    • Local Institution - 0020
• France
  • Avignon Cedex 9, France, 84918
    • Local Institution - 0077
  • Bordeaux, France, 33075
    • Local Institution - 0091
  • Clermont-Ferrand, France, 63011
    • Local Institution - 0151
  • La Roche-sur-Yon, France, 85000
    • Local Institution - 0059
  • Lyon, France, 69008
    • Local Institution - 0071
  • Marseille Cedex 9, France, 13273
    • Local Institution - 0057
  • Montpellier, France, 34298
    • Local Institution - 0075
  • Nice, France, 06189
    • Local Institution - 0070
  • Paris, France, 75014
    • Local Institution - 0062
  • Paris, France, 75908
    • Local Institution - 0060
  • Quimper, France, 29000
    • Local Institution - 0064
  • Reims, France, 51726
    • Local Institution - 0161
  • Strasbourg, France, 67200
    • Local Institution - 0058
  • Suresnes, France, 92151
    • Local Institution - 0056
  • Tours, France, 37000
    • Local Institution - 0074
• Germany
  • Dresden, Germany, 01307
    • Universitatsklinikum Carl Gustav Carus
  • Duesseldorf, Germany, 40225
    • Local Institution - 0117
  • Erlangen, Germany, 91054
    • Local Institution - 0119
  • Essen, Germany, 45147
    • Local Institution - 0050
  • Hamburg, Germany, 20246
    • Local Institution - 0052
  • Hamburg, Germany, 22763
    • Local Institution - 0051
  • Herne, Germany, 44625
    • Local Institution - 0049
  • Jena, Germany, 07747
    • Local Institution - 0045
  • Luebeck, Germany, 23538
    • Local Institution - 0053
  • Muenster, Germany, 48149
    • Local Institution - 0113
  • Nuernberg, Germany, 90419
    • Local Institution - 0048
  • Tuebingen, Germany, 72076
    • Local Institution - 0046
• Greece
  • Athens, Greece, 11528
    • Local Institution - 0178
  • Athens, Greece, 15125
    • Local Institution - 0088
  • Chaidari, Greece, 12462
    • Local Institution - 0033
  • Thessaloniki, Greece, 56429
    • Local Institution - 0035
• Israel
  • Haifa, Israel, 31096
    • Local Institution - 0129
  • Tel Aviv, Israel, 6423906
    • Local Institution - 0131
  • Tel Hashomer, Israel, 52621
    • Local Institution - 0130
• Italy
  • Firenze, Italy, 50134
    • Local Institution - 0149
  • Milano, Italy, 20132
    • Local Institution - 0162
  • Milano, Italy, 20133
    • Local Institution - 0025
  • Pavia, Italy, 27100
    • Local Institution
  • Pisa, Italy, 56126
    • Local Institution - 0026
  • Roma, Italy, 00168
    • Local Institution - 0065
  • Rozzano, Italy, 20089
    • Local Institution - 0044
• Mexico
  • BAJA Californa SUR
    • La Paz, BAJA Californa SUR, Mexico, 23040
      • Local Institution - 0154
  • Distrito Federal
    • Ciudad de Mexico, Distrito Federal, Mexico, 06100
      • Local Institution - 0132
    • Mexico, Distrito Federal, Mexico, 06700
      • Local Institution - 0160
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64460
      • Local Institution - 0133
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Local Institution - 0069
• Poland
  • Biala Podlaska, Poland, 21-505
    • Local Institution - 0167
  • Warszawa, Poland, 02-781
    • Local Institution - 0054
• Russian Federation
  • Omsk, Russian Federation, 644013
    • Local Institution
  • Saint-Petersburg, Russian Federation, 197758
    • Local Institution
• Spain
  • A Coruña, Spain, 15006
    • Local Institution - 0104
  • Badalona, Spain, 08916
    • Local Institution - 0106
  • Barcelona, Spain, 08035
    • Local Institution - 0110
  • Cordoba, Spain, 14004
    • Local Institution - 0109
  • Madrid, Spain, 28007
    • Local Institution - 0105
  • Madrid, Spain, 28034
    • Local Institution - 0108
  • Madrid, Spain, 28041
    • Local Institution - 0103
  • Santander, Spain, 39008
    • Local Institution - 0107
  • Sevilla, Spain, 41013
    • Local Institution - 0111
• United Kingdom
  • Leicester, United Kingdom, LE1 5WW
    • Local Institution - 0085
  • London, United Kingdom, W6 8RF
    • Local Institution - 0042
  • Hertfordshire
    • Stevenage, Hertfordshire, United Kingdom, SG1 4AB
      • Local Institution
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Local Institution - 0080
    • Tucson, Arizona, United States, 85724
      • Local Institution - 0136
  • California
    • La Jolla, California, United States, 92092-0698
      • Local Institution - 0029
    • Orange, California, United States, 92868
      • Local Institution - 0015
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Local Institution - 0002
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Local Institution
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Local Institution - 0006
  • New York
    • Bronx, New York, United States, 10461
      • Local Institution - 0009
    • Buffalo, New York, United States, 14263
      • Local Institution - 0004
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Local Institution - 0005
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Local Institution - 0007
  • Texas
    • Houston, Texas, United States, 77030
      • Local Institution - 0139
    • Temple, Texas, United States, 76508
      • Local Institution - 0023
  • Washington
    • Gig Harbor, Washington, United States, 98332
      • Local Institution - 0122
    • Seattle, Washington, United States, 98109
      • Local Institution - 0102

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Combination Therapy; Neoadjuvant (pre-surgical treatment) nivolumab + bempeg, followed by radical cystectomy (RC), followed by adjuvant (post-surgical treatment) nivolumab + bempeg	Biological: Nivolumab; Specified dose on specified days; Other Names: BMS-936558; Opdivo; Procedure: Radical cystectomy (RC); Surgical removal of the bladder; Biological: Bempegaldesleukin; Specified dose on specified days; Other Names: NKTR-214; BMS-986321; Bempeg
Experimental: Arm B: Monotherapy; Neoadjuvant nivolumab, followed by RC, followed by adjuvant nivolumab	Biological: Nivolumab; Specified dose on specified days; Other Names: BMS-936558; Opdivo; Procedure: Radical cystectomy (RC); Surgical removal of the bladder
Other: Arm C: Standard-of-care; RC alone, without neoadjuvant or adjuvant therapy	Procedure: Radical cystectomy (RC); Surgical removal of the bladder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care	Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.	From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)
Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care	Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).	From randomization up to first EFS event (up to approximately 30 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care	Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.	From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)
Event Free Survival (EFS) - Nivolumab Compared to Standard of Care	Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).	From randomization up to first EFS event (up to approximately 30 months)
Overall Survival (OS)	Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. OS was not calculated for Arm A and Arm B because the number of events did not meet the threshold due to early study termination. In lieu of OS, time to death is reported as a Post-Hoc endpoint.	From randomization to study completion, up to approximately 40 months
The Number of Participants Experiencing Adverse Events (AEs)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.	from first dose to 100 days following last dose (up to approximately 20 months)
The Number of Participants Experiencing Serious Adverse Events (SAEs)	A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization.	from first dose to 100 days following last dose (up to approximately 20 months)
The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.	from first dose to 100 days following last dose (up to approximately 20 months)
The Number of Participants Experiencing Immune-Mediated Adverse Events (IMAEs)	IMAEs are specific AEs that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis), and other specific events, considered as potential immune-mediated events by investigator that meet the definition summarized below: those occurring within 100 days of the last dose,; regardless of causality,; treated with immune-modulating medication (of note, endocrine AEs such as adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating medication use, since endocrine drug reactions are often managed without immune-modulating medication).; with no clear alternate etiology based on investigator assessment, or with an immune-mediated component.	from first dose to 100 days following last dose (up to approximately 20 months)
Worst Grade Clinical Laboratory Values	Clinical laboratory values by worst CTC grade are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.	From first dose to 100 days following last dose (up to approximately 20 months)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Nektar Therapeutics
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2020
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): June 7, 2023

Study Registration Dates

• First Submitted: December 20, 2019
• First Submitted That Met QC Criteria: December 20, 2019
• First Posted (Actual): December 23, 2019

Study Record Updates

• Last Update Posted (Actual): June 27, 2024
• Last Update Submitted That Met QC Criteria: June 5, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; nivolumab; NKTR-214; bempeg
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CA045-009; 2018-002676-40 (EudraCT Number); 18-214-13 (Other Identifier: Nektar Therapeutics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual patient level data from this study may be shared with qualified researchers, upon request, following the timelines and process detailed on https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No