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    Clinical Trial Results:
    Phase II trial of durvalumab (Medi4736) plus tremelimumab with concurrent radiotherapy in patients with localized muscle invasive bladder cancer treated with a selective bladder preservation approach

    Summary
    EudraCT number
    		 2017-003159-44
    Trial protocol
    		 ES  
    Global end of trial date
    16 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2023
    First version publication date
    26 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SOGUG-2017-A-IEC(VEJ)-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03702179
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Spanish Oncology Genitourinary Group (SOGUG)
    Sponsor organisation address
    C/ Velazquez 7 3ª planta, Madrid, Spain, 28001
    Public contact
    Federico Nepote, MFAR Clinical Research, investigacion@mfar.net
    Scientific contact
    Federico Nepote, MFAR Clinical Research, investigacion@mfar.net
    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
    16 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of durvalumab plus tremelimumab with concurrent radiotherapy in terms of pathological response rate in patients with localized muscle invasive bladder cancer treated with bladder preservation intent.
    Protection of trial subjects
    The protocol already includes all measures required to protect the patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    5
    From 65 to 84 years
    25
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients diagnosed with urothelial carcinoma of the bladder, in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice.

    Pre-assignment
    Screening details
    		 Screening procedures will be performed up to 28 days before Day 1 of Week 1, unless otherwise specified. All patients must first read, understand, and sign the IEC-approved ICF before any study-specific screening procedures are performed.

    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    single-arm study

    Arms
    Arm title
    		 Experimental arm
    Arm description
    		 Durvalumab ) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Radiotherapy 46 Gy to the minor pelvis and 64-66 Gy to the bladder.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500mg every 4 weeks for up to 3 cycles, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg every 4 weeks for up to 3 cycles, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met

    Number of subjects in period 1
    		Experimental arm
    Started
    32
    Completed
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study period
    Reporting group description
    		 -

    Reporting group values
    		 Study period Total
    Number of subjects
    		 32 32
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 71 (49 to 91) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 25 25
    Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
    Measure Description: Describes a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working...). The scale ranges from 0 (Fully active, able to carry on all pre-disease performance without restriction) to 5 (Dead).
    Units: Subjects
        ECOG 0
    		 25 25
        ECOG 1
    		 7 7
    Histology
    Measure Description: Describes the histology subtype of tumor, the type of cells from which the tumor has arisen
    Units: Subjects
        Urothelial carcinoma
    		 31 31
        Mixed urothelial carcinoma
    		 1 1
    Clinical T stage
    ] Measure Description: T stage according to AJCC criteria. Describes the extent of tumor spread and size. T ranges from T1 (The tumor has spread to the connective tissue but it does not involve the bladder wall muscle) to T4 (The tumor has spread to any of the following: the abdominal wall, the pelvic wall, the prostate or seminal vesicle, or the uterus or vagina).
    Units: Subjects
        T2
    		 28 28
        T3
    		 3 3
        T4
    		 1 1
    Previous bladder cancer non muscle invasive
    Measure Description: Describes the history of bladder cancer for patients, the presence or not of previous local bladder cancer that may have occured earlier before inclusion and that may be treated with resection of local treatments
    Units: Subjects
        Yes
    		 14 14
        No
    		 18 18
    Previous treatment
    Measure Description: Type of previous treatments for bladder cancer before patient inclusion
    Units: Subjects
        Bacillus CalmetteGuérin (BCG)
    		 9 9
        Mitomycin
    		 1 1
        Transurethral Resection of Bladder Tumor (TURBT)
    		 1 1
        No treatment
    		 21 21
    PD-L1 expression
    Measure Description: Programmed death-1 ligand 1 (PD-L1) expression levels in tumor tissue samples has been described as correlated with response to immunotherapy such as the experimental treatment studied in this trial. PD-L1 expression is measured by immunohistochemistry in tumor sample and could be positive (high expression) or negative (low expression).
    Units: Subjects
        Positive
    		 15 15
        Negative
    		 12 12
        Unknown
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 Durvalumab ) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Radiotherapy 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

    Primary: Proportion of Patients With Pathological Response

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    End point title
    		 Proportion of Patients With Pathological Response [1]
    End point description
    Pathological response is defined as the absence of muscle- invasive bladder cancer at post-treatment biopsy (≤cT1). Cystoscopy and bladder biopsy six weeks since the end of radiotherapy
    End point type
    Primary
    End point timeframe
    12 weeks
    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: This is a single arm trial. No comparisons were scheduled as only one group of patients is evaluated. the trial results are discussed and compared to previous data in scientific publications.
    End point values
    		 Experimental arm
    Number of subjects analysed
    28 [2]
    Units: Patients
        Complete Response (≤T1)
    26
        Non-response (MIBC)
    2
    Notes
    [2] - 4 patients not evaluated: 2 died, 1 withdrawn and 1 clinical deterioration before evaluation
    No statistical analyses for this end point

    Secondary: Rate of Patients With Bladder Preserved

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    End point title
    		 Rate of Patients With Bladder Preserved
    End point description
    Number of patients whom bladder has been preserved after cytoscopic evaluation.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    28 [3]
    Units: Patients
        Preserved bladder
    28
        Not preserved bladder
    0
    Notes
    [3] - 4 patients not evaluated: 2 died, 1 withdrawn and 1 clinical deterioration before evaluation
    No statistical analyses for this end point

    Secondary: Rate of Immediate Salvage Cystectomies

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    End point title
    		 Rate of Immediate Salvage Cystectomies
    End point description
    Number of patients with indication of salvage cystectomies after first trial-related cystoscopic evaluation.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: Patients
        Radical cystectomy performed
    1
        Radical cystectomy not required
    31
    No statistical analyses for this end point

    Secondary: Rate of Late Salvage Cystectomies

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    End point title
    		 Rate of Late Salvage Cystectomies
    End point description
    Number of patients with indication of salvage cystectomies based on follow-up cystoscopic evaluation.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: Patients
        Required late cystectomy
    2
        Not required late cystectomy
    30
    No statistical analyses for this end point

    Secondary: Survival With Bladder Preserved Free of Tumor

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    End point title
    		 Survival With Bladder Preserved Free of Tumor
    End point description
    Time from the start of immunotherapy to either the date of cystectomy or the date of recurrence of muscle- invasive bladder carcinoma or metastasis. Here we report the estimated rate of patients free of event at 24 months after the start of immunotherapy. Estimation by kaplan meier method.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: percentage of patients (%) free of event
        arithmetic mean (confidence interval 95%)
    65 (50.3 to 84.1)
    No statistical analyses for this end point

    Secondary: Disease-free Survival

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    End point title
    		 Disease-free Survival
    End point description
    Time from treatment start to tumour relapse or distant progression (without Salvage cystectomy). Bladder relapse with salvage cystectomy is not considered as an event. Deaths are also considered as events. Here we report the estimated rate of patients free of events at 24 months after the start of the immunotherapy. Estimation by kaplan meier method
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: percentage of patients (%) free of event
        arithmetic mean (confidence interval 95%)
    71.4 (57.2 to 89.1)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Time from the start of immunotherapy to the date of death due to any cause. The reported outcome is the estimated ratio of patients alive at 24 months after start of immunotherapy using kaplan meier method.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: percentage of patients (%) alive
        arithmetic mean (confidence interval 95%)
    84.3 (72.5 to 97.9)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0

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    End point title
    		 Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
    End point description
    Frequency, nature and number of patients developing adverse events throughout follow up
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: Patients
        Had treatment-related adverse events
    31
        Had not treatment-related adverse events
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-related Adverse Event Grade ≥3

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    End point title
    		 Number of Participants With Treatment-related Adverse Event Grade ≥3
    End point description
    Frequency, nature and number of patients developing high grade adverse events throughout follow up
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    32
    Units: Patients
        Had treatment-related adverse events
    10
        Had not treatment-related adverse events
    22
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period, approximately a median o 24 months follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCICTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Full dataset
    Reporting group description
    		 All patients who received at least one dose of studry treatment.

    Serious adverse events
    		 Full dataset
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 32 (34.38%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Platelet count decreased
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Other, specify
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Fecaloid peritonitis
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Immunomediated colitis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    other specify
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute pyelonephritis
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Other specify
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Full dataset
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Hematuria
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    7 / 32 (21.88%)
         occurrences all number
    7
    Other specify
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Diarrhea
         subjects affected / exposed
    9 / 32 (28.13%)
         occurrences all number
    9
    Other specify
         subjects affected / exposed
    7 / 32 (21.88%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    7 / 32 (21.88%)
         occurrences all number
    7
    Rash maculo-papular
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Other specify
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    5
    Renal and urinary disorders
    Other specify
         subjects affected / exposed
    15 / 32 (46.88%)
         occurrences all number
    15
    Urinary frequency
         subjects affected / exposed
    11 / 32 (34.38%)
         occurrences all number
    11
    Urinary tract infection
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    5
    Urinary tract pain
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Other specify
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Hyperthyroidism
         subjects affected / exposed
    8 / 32 (25.00%)
         occurrences all number
    8
    Hypothyroidism
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Other specify
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2019
    Substantial amendment No. 1 is requested as a result of: - Substantial amendment of part II of the trial with EudraCT 2017-003159-44 due to expansion of centers (IVO) and change of principal investigator at the Hospital Universitari i Politècnic La Fe. - The possibility of collecting urine samples from patients included in the Catalan Institute of Oncology L'Hospitalet is also included, for which changes are applied both in the protocol and by generating a specific patient information sheet for this purpose. - References to personal data protection are updated to current legislation.
    20 Nov 2019
    Substantial amendment No. 2 is requested as a result of: Due to problems with the stock of tremelimumab vials by the laboratory supplying the AstraZeneca molecule, the doses of the vials are modified, changing to 25 mg/mL of liquid solution at a concentration of 20 mg/mL with an expiration date. longer
    16 Oct 2020
    Substantial amendment No. 3 is requested as a result of: - Safety changes due to the update of the investigator brochure from version 14 of Durvalumab to version 15 and from version 9 of Tremelimumab to version 10. These changes must be recorded in the Trial Protocol as well as in the Information Sheet. Patient Information. - Change of Principal Investigator at the ICO Hospital Germans Trias i Pujol Hospital, Badalona, Dr Olatz Etxaniz will replace Dr Alberto Font Pous.
    21 Jun 2021
    Substantial amendment No. 4 is requested as a result of: - Update of the safety aspects of Imfinzi (Durvalumab) due to the new update of the Investigator's Brochure.

    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.
    None reported
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    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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