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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2018-002676-40
    Trial protocol
    		 DE   NL   AT   GR   ES   CZ   PL   FR   BE   GB   IT  
    Global end of trial date
    09 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2024
    First version publication date
    14 Jun 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA045-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the pCR rate of neoadjuvant bempeg+nivo to SOC (no neoadjuvant therapy) in all randomized subjects.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Argentina: 22
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Mexico: 4
    Worldwide total number of subjects
    114
    EEA total number of subjects
    56
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    88
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue to receive nivolumab monotherapy.

    Period 1
    Period 1 title
    Pre-Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab + Bempegaldesleukin
    Arm description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection, Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bempegaldesleukin 0.006 mg/kg once every 3 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 360 mg once every 3 weeks

    Arm title
    		 Arm B: Nivolumab
    Arm description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 360 mg once every 3 weeks

    Arm title
    		 Arm C: Standard of Care
    Arm description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Started
    37
    37
    40
    Completed
    37
    37
    32
    Not completed
    0
    0
    8
         Adverse event, serious fatal
    -
    -
    1
         Participant withdrew consent
    -
    -
    1
         Completed without radical cystectomy
    -
    -
    5
         Other reasons
    -
    -
    1
    Period 2
    Period 2 title
    Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab + Bempegaldesleukin
    Arm description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection, Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bempegaldesleukin 0.006 mg/kg once every 3 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 360 mg once every 3 weeks

    Arm title
    		 Arm B: Nivolumab
    Arm description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 360 mg once every 3 weeks

    Arm title
    		 Arm C: Standard of Care
    Arm description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Started
    37
    37
    32
    Completed
    15
    13
    32
    Not completed
    22
    24
    0
         Adverse event, serious fatal
    4
    1
    -
         Disease progression
    6
    9
    -
         Participant withdrew consent
    1
    -
    -
         Study drug toxicity
    4
    6
    -
         Adverse event unrelated to study drug
    1
    5
    -
         Other reasons
    5
    3
    -
         Lost to follow-up
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivolumab + Bempegaldesleukin
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm C: Standard of Care
    Reporting group description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.

    Reporting group values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care Total
    Number of subjects
    		 37 37 40 114
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 10 8 25
        From 65-84 years
    		 29 27 32 88
        85 years and over
    		 1 0 0 1
    Age Continuous
    Units: Years
        median (standard deviation)
    		 73.0 ( 8.8 ) 72.0 ( 7.5 ) 74.5 ( 8.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 6 7 9 22
        Male
    		 31 30 31 92
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 36 35 36 107
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 1 2 3 6

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivolumab + Bempegaldesleukin
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm C: Standard of Care
    Reporting group description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.
    Reporting group title
    Arm A: Nivolumab + Bempegaldesleukin
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm C: Standard of Care
    Reporting group description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.

    Primary: Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care

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    End point title
    		 Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care [1] [2]
    End point description
    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). "99999"=N/A
    End point type
    Primary
    End point timeframe
    From randomization up to first EFS event (up to approximately 30 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary data only was planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the missing arm is included as a secondary endpoint.
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm C: Standard of Care
    Number of subjects analysed
    37
    40
    Units: Months
        median (confidence interval 95%)
    22.11 (8.21 to 99999)
    15.18 (11.63 to 99999)
    No statistical analyses for this end point

    Primary: Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care

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    End point title
    		 Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care [3] [4]
    End point description
    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.
    End point type
    Primary
    End point timeframe
    From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary data only was planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the missing arm is included as a secondary endpoint.
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm C: Standard of Care
    Number of subjects analysed
    37
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    10.8 (3.0 to 25.4)
    2.5 (0.1 to 13.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    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. "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From randomization to study completion, up to approximately 40 months
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    40
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    23.23 (14.36 to 99999)
    No statistical analyses for this end point

    Secondary: Event Free Survival (EFS) - Nivolumab Compared to Standard of Care

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    End point title
    		 Event Free Survival (EFS) - Nivolumab Compared to Standard of Care [5]
    End point description
    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). "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From randomization up to first EFS event (up to approximately 30 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the missing arm is included as a primary endpoint.
    End point values
    		 Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    40
    Units: Months
        median (confidence interval 95%)
    99999 (10.84 to 99999)
    15.18 (11.63 to 99999)
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Immune-Mediated Adverse Events (IMAEs)

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    End point title
    		 The Number of Participants Experiencing Immune-Mediated Adverse Events (IMAEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    from first dose to 100 days following last dose (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    32
    Units: Participants
    10
    10
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation

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    End point title
    		 The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    from first dose to 100 days following last dose (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    32
    Units: Participants
    8
    8
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Adverse Events (AEs)

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    End point title
    		 The Number of Participants Experiencing Adverse Events (AEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    from first dose to 100 days following last dose (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    32
    Units: Participants
    34
    36
    19
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Serious Adverse Events (SAEs)

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    End point title
    		 The Number of Participants Experiencing Serious Adverse Events (SAEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    from first dose to 100 days following last dose (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    32
    Units: Participants
    15
    18
    14
    No statistical analyses for this end point

    Secondary: Worst Grade Clinical Laboratory Values

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    End point title
    		 Worst Grade Clinical Laboratory Values
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days following last dose (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    32
    Units: Participants
        Hemoglobin|Grade 0
    5
    5
    0
        Platelet Count|Grade 0
    35
    34
    5
        Leukocytes, Local Lab|Grade 0
    33
    35
    6
        Lymphocytes (Absolute), Local Lab|Grade 0
    23
    12
    0
        Absolute Neutrophil Count|Grade 0
    31
    36
    0
        Alkaline Phosphate, Local Lab|Grade 0
    24
    30
    2
        Aspartate Aminotransferase, Local Lab|Grade 0
    31
    30
    2
        Alanine Aminotransferase, Local Lab|Grade 0
    26
    30
    2
        Total Bilirubin, Local Lab|Grade 0
    33
    35
    2
        Creatinine, Local Lab|Grade 0
    11
    13
    5
        Hypernatremia|Grade 0
    34
    36
    6
        Hyponatremia|Grade 0
    24
    29
    5
        Hyperkalemia|Grade 0
    24
    25
    6
        Hypokalemia|Grade 0
    24
    25
    6
        Hypercalcemia|Grade 0
    33
    34
    4
        Hypocalcemia|Grade 0
    29
    28
    0
        Hemoglobin|Grade 1
    23
    23
    2
        Platelet Count|Grade 1
    1
    3
    1
        Leukocytes, Local Lab|Grade 1
    2
    2
    0
        Lymphocytes (Absolute), Local Lab|Grade 1
    4
    6
    0
        Absolute Neutrophil Count|Grade 1
    4
    1
    0
        Alkaline Phosphate, Local Lab|Grade 1
    10
    7
    0
        Aspartate Aminotransferase, Local Lab|Grade 1
    5
    6
    0
        Alanine Aminotransferase, Local Lab|Grade 1
    10
    7
    0
        Total Bilirubin, Local Lab|Grade 1
    2
    2
    0
        Creatinine, Local Lab|Grade 1
    10
    14
    1
        Hypernatremia|Grade 1
    2
    1
    0
        Hyponatremia|Grade 1
    12
    7
    1
        Hyperkalemia|Grade 1
    7
    9
    0
        Hypokalemia|Grade 1
    7
    9
    0
        Hypercalcemia|Grade 1
    3
    3
    0
        Hypocalcemia|Grade 1
    6
    7
    3
        Hemoglobin|Grade 2
    7
    8
    3
        Platelet Count|Grade 2
    0
    0
    0
        Leukocytes, Local Lab|Grade 2
    0
    0
    0
        Lymphocytes (Absolute), Local Lab|Grade 2
    0
    6
    0
        Absolute Neutrophil Count|Grade 2
    0
    0
    0
        Alkaline Phosphate, Local Lab|Grade 2
    2
    0
    0
        Aspartate Aminotransferase, Local Lab|Grade 2
    0
    1
    0
        Alanine Aminotransferase, Local Lab|Grade 2
    0
    0
    0
        Total Bilirubin, Local Lab|Grade 2
    1
    0
    0
        Creatinine, Local Lab|Grade 2
    12
    9
    0
        Hypernatremia|Grade 2
    0
    0
    0
        Hyponatremia|Grade 2
    0
    0
    0
        Hyperkalemia|Grade 2
    4
    3
    0
        Hypokalemia|Grade 2
    4
    3
    0
        Hypercalcemia|Grade 2
    0
    0
    0
        Hypocalcemia|Grade 2
    1
    1
    1
        Hemoglobin|Grade 3
    1
    1
    1
        Platelet Count|Grade 3
    0
    0
    0
        Leukocytes, Local Lab|Grade 3
    1
    0
    0
        Lymphocytes (Absolute), Local Lab|Grade 3
    3
    2
    0
        Absolute Neutrophil Count|Grade 3
    0
    0
    0
        Alkaline Phosphate, Local Lab|Grade 3
    0
    0
    0
        Aspartate Aminotransferase, Local Lab|Grade 3
    0
    0
    0
        Alanine Aminotransferase, Local Lab|Grade 3
    0
    0
    0
        Total Bilirubin, Local Lab|Grade 3
    0
    0
    0
        Creatinine, Local Lab|Grade 3
    3
    1
    0
        Hypernatremia|Grade 3
    0
    0
    0
        Hyponatremia|Grade 3
    0
    1
    0
        Hyperkalemia|Grade 3
    1
    0
    0
        Hypokalemia|Grade 3
    1
    0
    0
        Hypercalcemia|Grade 3
    0
    0
    0
        Hypocalcemia|Grade 3
    0
    1
    0
        Hemoglobin|Grade 4
    0
    0
    0
        Platelet Count|Grade 4
    0
    0
    0
        Leukocytes, Local Lab|Grade 4
    0
    0
    0
        Lymphocytes (Absolute), Local Lab|Grade 4
    0
    0
    0
        Absolute Neutrophil Count|Grade 4
    1
    0
    0
        Alkaline Phosphate, Local Lab|Grade 4
    0
    0
    0
        Aspartate Aminotransferase, Local Lab|Grade 4
    0
    0
    0
        Alanine Aminotransferase, Local Lab|Grade 4
    0
    0
    0
        Total Bilirubin, Local Lab|Grade 4
    0
    0
    0
        Creatinine, Local Lab|Grade 4
    0
    0
    0
        Hypernatremia|Grade 4
    0
    0
    0
        Hyponatremia|Grade 4
    0
    0
    0
        Hyperkalemia|Grade 4
    0
    0
    0
        Hypokalemia|Grade 4
    0
    0
    0
        Hypercalcemia|Grade 4
    0
    0
    0
        Hypocalcemia|Grade 4
    0
    0
    0
        Hemoglobin|Not Reported
    1
    0
    26
        Platelet Count|Not Reported
    1
    0
    26
        Leukocytes, Local Lab|Not Reported
    1
    0
    26
        Lymphocytes (Absolute), Local Lab|Not Reported
    7
    11
    32
        Absolute Neutrophil Count|Not Reported
    1
    0
    32
        Alkaline Phosphate, Local Lab|Not Reported
    1
    0
    30
        Aspartate Aminotransferase, Local Lab|Not Reported
    1
    0
    30
        Alanine Aminotransferase, Local Lab|Not Reported
    1
    0
    30
        Total Bilirubin, Local Lab|Not Reported
    1
    0
    30
        Creatinine, Local Lab|Not Reported
    1
    0
    26
        Hypernatremia|Not Reported
    1
    0
    26
        Hyponatremia|Not Reported
    1
    0
    26
        Hyperkalemia|Not Reported
    1
    0
    26
        Hypokalemia|Not Reported
    1
    0
    26
        Hypercalcemia|Not Reported
    1
    0
    28
        Hypocalcemia|Not Reported
    1
    0
    28
    No statistical analyses for this end point

    Secondary: Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care

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    End point title
    		 Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care [6]
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the missing arm is included as a primary endpoint.
    End point values
    		 Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    10.8 (3.0 to 25.4)
    2.5 (0.1 to 13.2)
    No statistical analyses for this end point

    Post-hoc: Time to Death

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    End point title
    		 Time to Death
    End point description
    The amount of time in months from when participants were randomized until death. Survival was reported as time to death instead of overall survival by Kaplan-Meier analysis due to the small number of events at the time of early study completion.
    End point type
    Post-hoc
    End point timeframe
    From randomization to study completion, up to approximately 40 months
    End point values
    		 Arm A: Nivolumab + Bempegaldesleukin Arm B: Nivolumab Arm C: Standard of Care
    Number of subjects analysed
    37
    37
    40
    Units: Months
        median (full range (min-max))
    6.77 (3.2 to 18.4)
    9.43 (1.8 to 20.1)
    8.49 (1.6 to 23.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants were assessed for all-cause mortality from randomization to study completion, up to approx. 40 months. Serious adverse events (SAEs) and AEs were assessed from first dose to 100 days following last dose, up to approx. 20 months.
    Adverse event reporting additional description
    The number at risk for All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Arm A: Nivolumab + Bempegaldesleukin
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Reporting group title
    Arm C: Standard of Care
    Reporting group description
    		 Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.

    Serious adverse events
    		 Arm A: Nivolumab + Bempegaldesleukin Arm C: Standard of Care Arm B: Nivolumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 37 (43.24%)
    15 / 32 (46.88%)
    22 / 37 (59.46%)
         number of deaths (all causes)
    8
    11
    6
         number of deaths resulting from adverse events
    5
    3
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 32 (6.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lung disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site impaired healing
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Vallecular cyst
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Endocarditis noninfective
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypereosinophilic syndrome
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal barrier dysfunction
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Rectal perforation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 32 (12.50%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 32 (3.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 32 (9.38%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 32 (3.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Nivolumab + Bempegaldesleukin Arm C: Standard of Care Arm B: Nivolumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 37 (86.49%)
    18 / 32 (56.25%)
    29 / 37 (78.38%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 32 (3.13%)
    2 / 37 (5.41%)
         occurrences all number
    1
    1
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 32 (6.25%)
    4 / 37 (10.81%)
         occurrences all number
    3
    2
    4
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    6 / 37 (16.22%)
         occurrences all number
    1
    0
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 37 (24.32%)
    1 / 32 (3.13%)
    5 / 37 (13.51%)
         occurrences all number
    9
    1
    5
    Chills
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    Fatigue
         subjects affected / exposed
    8 / 37 (21.62%)
    3 / 32 (9.38%)
    6 / 37 (16.22%)
         occurrences all number
    8
    3
    6
    Influenza like illness
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 32 (3.13%)
    4 / 37 (10.81%)
         occurrences all number
    2
    1
    4
    Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    10 / 37 (27.03%)
    4 / 32 (12.50%)
    3 / 37 (8.11%)
         occurrences all number
    10
    4
    3
    Xerosis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 32 (3.13%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    1
    0
    4
    Cough
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 32 (6.25%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    1
    Anxiety
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    1
    0
    2
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Investigations
    Amylase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    2
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    3
    0
    2
    Weight increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    1
    0
    2
    Weight decreased
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 32 (6.25%)
    7 / 37 (18.92%)
         occurrences all number
    4
    2
    7
    Lipase increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    1
    0
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    3
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 32 (6.25%)
    4 / 37 (10.81%)
         occurrences all number
    5
    2
    4
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 32 (6.25%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    1
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    3
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 32 (6.25%)
    7 / 37 (18.92%)
         occurrences all number
    4
    2
    7
    Eosinophilia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Hyperleukocytosis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 32 (9.38%)
    1 / 37 (2.70%)
         occurrences all number
    0
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    Constipation
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 32 (12.50%)
    7 / 37 (18.92%)
         occurrences all number
    4
    4
    7
    Diarrhoea
         subjects affected / exposed
    8 / 37 (21.62%)
    0 / 32 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    8
    0
    3
    Nausea
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 32 (9.38%)
    2 / 37 (5.41%)
         occurrences all number
    4
    3
    2
    Oesophagitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    1
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 32 (6.25%)
    0 / 37 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 32 (12.50%)
    4 / 37 (10.81%)
         occurrences all number
    1
    4
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 32 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    4
    0
    4
    Pruritus
         subjects affected / exposed
    13 / 37 (35.14%)
    0 / 32 (0.00%)
    6 / 37 (16.22%)
         occurrences all number
    13
    0
    6
    Dry skin
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    3
    0
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 32 (3.13%)
    4 / 37 (10.81%)
         occurrences all number
    2
    1
    4
    Dysuria
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Hypothyroidism
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    5 / 37 (13.51%)
         occurrences all number
    3
    0
    5
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Back pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 32 (3.13%)
    2 / 37 (5.41%)
         occurrences all number
    1
    1
    2
    Arthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Arthralgia
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 32 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    3
    0
    4
    Groin pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    2
    0
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 32 (6.25%)
    7 / 37 (18.92%)
         occurrences all number
    5
    2
    7
    Cystitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 32 (3.13%)
    2 / 37 (5.41%)
         occurrences all number
    1
    1
    2
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 32 (9.38%)
    1 / 37 (2.70%)
         occurrences all number
    1
    3
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 32 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 32 (6.25%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 32 (6.25%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    2
    Decreased appetite
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 32 (6.25%)
    2 / 37 (5.41%)
         occurrences all number
    4
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2019
    - Modifications made to align with BMS policy updates - Added nivolumab and NKTR-214 program updates - Correction to Section 5.1.4: added missing paragraph regarding adjudicated events - Appendix 3 updated (Adverse Events) - Appendix 4 updated (WOCBP) - Appendix 9 added (Country Specific Requirements)
    05 Mar 2020
    - Revised to align with most recent language for BMS program updates - Modifications made to align with NKTR-214 program and IB updates - Appendix 2 updated (Study Governance Considerations) - Appendix 6 updated (Management Algorithms) - Appendix 7 added (CVA Management Algorithm)
    26 Aug 2021
    - Revised to include participants with high-risk urothelial carcinoma (UC) of the bladder with N1 disease and muscleinvasive bladder cancer (MIBC), addition of nivolumab + bempegaldesleukin vs nivolumab secondary endpoint comparisons, and the updated alpha allocation for the pathologic complete response (pCR) and event free survival (EFS) primary endpoints. - Modifications made to align with Bempegaldesleukin and Nivolumab program standards. - Align with changes to safety assessments including safety management algorithms, guidance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status, and coronavirus disease 2019 (COVID-19) vaccine.
    10 Jun 2022
    - Participants who are currently receiving bempegaldesleukin plus nivolumab are required to discontinue bempegaldesleukin and may continue nivolumab monotherapy on protocol for the remainder of their treatment duration. New enrollment in this study has been stopped. - Imaging will be performed per local standard of care; blinded independent central review is discontinued. All study treatment decisions including progression and recurrence will be based on the investigator’s assessment of tumor images. - The efficacy endpoints of pathologic complete response, event-free survival, and overall survival, as well as safety and tolerability for each treatment arm, will be summarized descriptively in all randomized participants. Secondary and exploratory objectives except for safety and biomarker parameters will not be required. No further efficacy data will be collected/analyzed. - For each randomized participant, the maximum duration of the study is 62 weeks plus 100 days of safety follow-up. - Participants currently in survival follow-up will discontinue from the study following one recurrence update and survival status update.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    BMS and Nektar jointly terminated this clinical development program. Discontinued survival follow-up and stopping submission of local labs to vendors, imaging to the BICR vendor, and PROs have resulted in confounded and incomplete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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