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    Clinical Trial Results:
    The DUTRENEO Trial: A Prospective Study to Individualize the Approach with DUrvalumab (MEDI4736) and TREmelimumab in NEOadjuvant Bladder Cancer patients.

    Summary
    EudraCT number
    		 2017-002246-68
    Trial protocol
    		 ES  
    Global end of trial date
    12 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Feb 2025
    First version publication date
    12 Feb 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DUTRENEO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03472274
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación CRIS de investigación para vencer el cáncer
    Sponsor organisation address
    Avda. Manoteras, 22, 3º - Office 109, Madrid, Spain, 28050
    Public contact
    Fundación CRIS contra el Cáncer, Fundación CRIS contra el Cáncer, alopez@criscancer.org
    Scientific contact
    Enrique Grande, MD Anderson cancer Center Madrid, 0034 917878600, info@mdanderson.es
    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
    02 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the antitumor activity measured as pT0 rate of durvalumab plus tremelimumab in comparison with the activity shown by standard chemo-based approach in selected patients with locally advanced urothelial bladder tumors with a pro-inflammatory composite biomarker selection.
    Protection of trial subjects
    The patient signed the informed consent before carrying out any procedure related to the study. Physical examination, hematology, biochemistry, ECG, vital signs, pregnancy test, evaluation of adverse events and evaluation of the tumor were made before the inclusion of the patient in the study and during the study. All adverse events that occur during the period comprehended from the time of enrollment of the patient in the study to 100 days after discontinuation of the investigational products were recorded.
    Background therapy
    		 -
    Evidence for comparator
    		 The comparator selected for this study is standard cisplatin-based neoadjuvant chemotherapy, which is the recommended treatment for patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin. Key studies and meta-analyses, have shown an improvement in survival rates with cisplatin-based chemotherapy compared to surgery alone. The regimens included in this trial (Gemcitabine/Cisplatin, ddMVAC, and others) represent current standards of care as recommended by major clinical guidelines. Moreover, cisplatin-based chemotherapy serves as a robust benchmark for evaluating the efficacy of novel therapeutic approaches, such as the immunotherapy combination (durvalumab + tremelimumab) being tested in this trial. Its inclusion ensures the validity and comparability of study outcomes within the established standard of care.
    Actual start date of recruitment
    16 Aug 2018
    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: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    29
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Of the 101 patients that signed the informed consent, 28 were screening failures. 21 patients were assigned to the COLD: STANDARD arm, and 52 patients were randomized, 22 to the HOT: STANDARD arm and 30 to the HOT: DUTRENEO arm. All patients included in the analysis received study treatment.

    Pre-assignment
    Screening details
    		 All patients with a negative pro-inflammatory signature who met the selection criteria and signed the informed consent were assigned to the control group. All patients with a positive pro-inflammatory signature who met the selection criteria and signed the informed consent were randomly assigned to either the control or experimental group.

    Period 1
    Period 1 title
    Global (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Patients were randomised centrally through an Interactive Voice/Web Response System (IXRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 COLD: STANDARD
    Arm description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1,000-1,200 mg/m² was administered intravenously on days 1 and 8 of each 21-day cycle as part of Regimen 1 in combination with Cisplatin.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m² was administered intravenously on day 1 of each 21-day treatment cycle for 3 cycles as part of as part of Regimen 1 in combination with Gemcitabine.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate 30 mg/m² was administered intravenously on day 1 as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinblastine 3 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Doxorubicin and Cisplatin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 30 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Vinblastine and Cisplatin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Vinblastine and Doxorubicin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Arm title
    		 HOT: STANDARD
    Arm description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1,000-1,200 mg/m² was administered intravenously on days 1 and 8 of each 21-day cycle as part of Regimen 1 in combination with Cisplatin.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m² was administered intravenously on day 1 of each 21-day treatment cycle for 3 cycles as part of as part of Regimen 1 in combination with Gemcitabine.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate 30 mg/m² was administered intravenously on day 1 as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinblastine 3 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Doxorubicin and Cisplatin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 30 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Vinblastine and Cisplatin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m² was administered intravenously on day 2 of each 14-day cycle, in combination with Vinblastine and Doxorubicin, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for 7 consecutive days (days 4 through 10) as part of the combined treatment in Regimen 2.

    Arm title
    		 HOT: DUTRENEO
    Arm description
    		 Patients in this arm received the combination of Durvalumab + Tremelimumab. Initially, a safety run-in was conducted with a small group of patients to assess the safety and tolerability of the combination therapy. This early phase was crucial to ensure that the treatment regimen was well-tolerated before proceeding with full recruitment. If no significant safety concerns were observed, recruitment would continue as planned.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1500 mg was administered intravenously every 4 weeks for 3 months as part of the combined treatment.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab 75 mg was administered intravenously every 4 weeks for 3 months as part of the combined treatment.

    Number of subjects in period 1
    		COLD: STANDARD HOT: STANDARD HOT: DUTRENEO
    Started
    21
    22
    30
    Completed
    16
    19
    23
    Not completed
    5
    3
    7
         Consent withdrawn by subject
    1
    1
    -
         Death
    3
    2
    6
         Lost to follow-up
    -
    -
    1
         Incorrectly enrolled
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    COLD: STANDARD
    Reporting group description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)

    Reporting group title
    HOT: STANDARD
    Reporting group description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)

    Reporting group title
    HOT: DUTRENEO
    Reporting group description
    		 Patients in this arm received the combination of Durvalumab + Tremelimumab. Initially, a safety run-in was conducted with a small group of patients to assess the safety and tolerability of the combination therapy. This early phase was crucial to ensure that the treatment regimen was well-tolerated before proceeding with full recruitment. If no significant safety concerns were observed, recruitment would continue as planned.

    Reporting group values
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO Total
    Number of subjects
    		 21 22 30 73
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 10 12 29
        From 65-84 years
    		 14 12 18 44
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 66.3 (62.0 to 72.0) 66.4 (61.0 to 73.0) 64.9 (60.0 to 72.0) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 3 7
        Male
    		 18 21 27 66
    Race
    Units: Subjects
        Caucasian
    		 21 21 30 72
        Asian
    		 0 1 0 1
    ECOG-PS
    Units: Subjects
        ECOG-PS 0
    		 12 18 19 49
        ECOG-PS 1
    		 9 4 11 24
    Number of patients in each location
    Units: Subjects
        Bladder
    		 16 17 24 57
        Lymph nodes
    		 1 1 6 8
        No location
    		 4 4 0 8
    Treatment type by group
    Units: Subjects
        DUTRENEO
    		 0 0 30 30
        Regimen 1
    		 10 14 0 24
        Regimen 2
    		 11 8 0 19
    Previous surgery
    Units: Subjects
        Yes
    		 21 22 30 73
        No
    		 0 0 0 0
    Previous radiotherapy
    Units: Subjects
        Yes
    		 0 0 1 1
        No
    		 21 22 29 72
    Previous chemotherapy
    Units: Subjects
        Yes
    		 0 1 1 2
        No
    		 21 21 29 71
    Other previous anticancer therapies
    Units: Subjects
        BCG
    		 1 4 3 8
        Homeopathic treatment (oral)
    		 0 0 1 1
        No previous anticancer therapiess
    		 20 18 26 64
    Cystectomy performed
    Units: Subjects
        No
    		 0 1 3 4
        Yes
    		 20 20 26 66
        Not available
    		 1 1 1 3
    Number of cycles by Group
    Units: Number of cycles
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 2.4 (2.0 to 3.0) 2.4 (2.0 to 3.0) 2.7 (2.0 to 3.0) -
    Subject analysis sets

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Received study medication

    Subject analysis sets values
    		 Overall
    Number of subjects
    73
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    29
        From 65-84 years
    44
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    65.7 (61.0 to 72.0)
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    66
    Race
    Units: Subjects
        Caucasian
    72
        Asian
    1
    ECOG-PS
    Units: Subjects
        ECOG-PS 0
    49
        ECOG-PS 1
    24
    Number of patients in each location
    Units: Subjects
        Bladder
    57
        Lymph nodes
    8
        No location
    8
    Treatment type by group
    Units: Subjects
        DUTRENEO
    30
        Regimen 1
    24
        Regimen 2
    19
    Previous surgery
    Units: Subjects
        Yes
    73
        No
    0
    Previous radiotherapy
    Units: Subjects
        Yes
    1
        No
    72
    Previous chemotherapy
    Units: Subjects
        Yes
    2
        No
    71
    Other previous anticancer therapies
    Units: Subjects
        BCG
    8
        Homeopathic treatment (oral)
    1
        No previous anticancer therapiess
    64
    Cystectomy performed
    Units: Subjects
        No
    4
        Yes
    66
        Not available
    3
    Number of cycles by Group
    Units: Number of cycles
        arithmetic mean (inter-quartile range (Q1-Q3))
    2.5 (2.0 to 3.0)

    End points

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    End points reporting groups
    Reporting group title
    COLD: STANDARD
    Reporting group description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)

    Reporting group title
    HOT: STANDARD
    Reporting group description
    		 Patients in this arm received standard neoadjuvant chemotherapy based on their clinical evaluation and eligibility: -Regimen 1: Combination of Gemcitabine + Cisplatin -Regimen 2: Combination of ddMVAC (Methotrexate + Vinblastine + Doxorubicin + Cisplatin)

    Reporting group title
    HOT: DUTRENEO
    Reporting group description
    		 Patients in this arm received the combination of Durvalumab + Tremelimumab. Initially, a safety run-in was conducted with a small group of patients to assess the safety and tolerability of the combination therapy. This early phase was crucial to ensure that the treatment regimen was well-tolerated before proceeding with full recruitment. If no significant safety concerns were observed, recruitment would continue as planned.

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Received study medication

    Primary: Pathological complete response (pT0)

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    End point title
    		 Pathological complete response (pT0) [1]
    End point description
    The antitumor activity is measured as pT0 rate (defined as no evidence of residual disease based on pathological review of the surgical specimen) of durvalumab plus tremelimumab in comparison with the activity shown by standard chemo-based approach in selected patients with locally advanced urothelial bladder cancer with a pro-inflammatory composite biomarker selection.
    End point type
    Primary
    End point timeframe
    20 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: Statistical analysis is not included for this primary endpoint according to the study design.
    End point values
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO Overall
    Number of subjects analysed
    21
    22
    30
    73
    Units: Patients
    11
    6
    10
    27
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group. The BOR is defined as the best response designation, as determined investigator assessment, recorded between the date of randomization and the date of cystectomy, as assessed by investigator per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    20 weeks
    End point values
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO Overall
    Number of subjects analysed
    21
    22
    30
    73
    Units: percent
        number (confidence interval 95%)
    42.9 (21.7 to 64.0)
    18.8 (2.1 to 34.3)
    13.3 (1.2 to 25.5)
    23.3 (13.6 to 33.0)
    No statistical analyses for this end point

    Secondary: Disease Free Survival (DFS)

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    End point title
    		 Disease Free Survival (DFS)
    End point description
    Disease Free Survival (DFS) is defined as the time (in months) elapsed between the start of treatment with durvalumab and tremelimumab or cisplatin-based chemotherapy until the documentation of disease recurrence according to RECIST v1.1 or death due to any cause, whichever occurs first. For subjects who are alive and disease-free at the time of data cut-off for analysis, DFS has been censored at the last tumor assessment date.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO Overall
    Number of subjects analysed
    21
    22
    30
    73
    Units: month
        median (confidence interval 95%)
    14.671 (0.000 to 32.230)
    27.632 (27.632 to 27.632)
    26.480 (1.992 to 50.968)
    14.737 (6.932 to 22.541)
    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 (in months) from the start of treatment with the combination of durvalumab and tremelimumab or cisplatin-based chemotherapy until death due to any cause. For subjects who are alive at the time of data cut-off, OS has been censored on the last date when subjects are known to be alive.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Overall
    Number of subjects analysed
    73
    Units: month
        median (confidence interval 95%)
    41.809 (26.674 to 56.945)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were documented during study treatment at each study visit and for minimum of 100 days after the last dose of study medications.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    COLD: STANDARD
    Reporting group description
    		 -

    Reporting group title
    HOT: STANDARD
    Reporting group description
    		 -

    Reporting group title
    HOT: DUTRENEO
    Reporting group description
    		 -

    Serious adverse events
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    4 / 22 (18.18%)
    15 / 30 (50.00%)
         number of deaths (all causes)
    3
    3
    6
         number of deaths resulting from adverse events
    1
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Follicular lymphoma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Tumour pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         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
    Myocardial infarction
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Myocarditis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic fluid collection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 30 (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
    COVID-19
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Peritonitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 30 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 22 (13.64%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         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
    		 COLD: STANDARD HOT: STANDARD HOT: DUTRENEO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    22 / 22 (100.00%)
    26 / 30 (86.67%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 21 (66.67%)
    18 / 22 (81.82%)
    14 / 30 (46.67%)
         occurrences all number
    25
    32
    24
    Mucosal inflammation
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    1 / 30 (3.33%)
         occurrences all number
    5
    3
    1
    Pyrexia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    3
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    3 / 30 (10.00%)
         occurrences all number
    1
    1
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    1 / 30 (3.33%)
         occurrences all number
    1
    4
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    0
    3
    Lipase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    0 / 30 (0.00%)
         occurrences all number
    8
    4
    0
    Platelet count decreased
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    0 / 30 (0.00%)
         occurrences all number
    8
    6
    0
    Weight decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    8 / 21 (38.10%)
    2 / 22 (9.09%)
    0 / 30 (0.00%)
         occurrences all number
    13
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 21 (52.38%)
    7 / 22 (31.82%)
    5 / 30 (16.67%)
         occurrences all number
    13
    14
    7
    Neutropenia
         subjects affected / exposed
    9 / 21 (42.86%)
    8 / 22 (36.36%)
    0 / 30 (0.00%)
         occurrences all number
    12
    12
    0
    Thrombocytopenia
         subjects affected / exposed
    7 / 21 (33.33%)
    12 / 22 (54.55%)
    0 / 30 (0.00%)
         occurrences all number
    8
    18
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    4
    Constipation
         subjects affected / exposed
    7 / 21 (33.33%)
    6 / 22 (27.27%)
    3 / 30 (10.00%)
         occurrences all number
    12
    8
    3
    Diarrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 22 (13.64%)
    4 / 30 (13.33%)
         occurrences all number
    5
    4
    9
    Dyspepsia
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 22 (4.55%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Nausea
         subjects affected / exposed
    10 / 21 (47.62%)
    15 / 22 (68.18%)
    2 / 30 (6.67%)
         occurrences all number
    17
    26
    2
    Vomiting
         subjects affected / exposed
    5 / 21 (23.81%)
    4 / 22 (18.18%)
    1 / 30 (3.33%)
         occurrences all number
    5
    5
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 21 (28.57%)
    5 / 22 (22.73%)
    1 / 30 (3.33%)
         occurrences all number
    6
    5
    1
    Pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    7 / 30 (23.33%)
         occurrences all number
    1
    1
    10
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    6 / 30 (20.00%)
         occurrences all number
    0
    3
    6
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    3
    Haematuria
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    5 / 30 (16.67%)
         occurrences all number
    2
    1
    5
    Nocturia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    3
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    5
    Hypothyroidism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 21 (23.81%)
    4 / 22 (18.18%)
    8 / 30 (26.67%)
         occurrences all number
    8
    6
    9
    Urosepsis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 21 (42.86%)
    8 / 22 (36.36%)
    2 / 30 (6.67%)
         occurrences all number
    15
    10
    2
    Hypomagnesaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2018
    Durvalumab Investigator Brochure has been updated from 12th version to 13th version. New AESIs have been described. Protocol and Patient Information Sheet have been updated according to new IB safety information.
    14 Oct 2019
    AstraZeneca will provide for this study 25 mg vials in addition to the initially foreseen 400 mg vials in order to avoid stock issues.
    22 Dec 2020
    This relevant amendment modifies the protocol due to the latest update of the durvalumab investigator's brochure. The changes apply mainly to adverse events of special interest and durvalumab-associated toxicity management guidelines. The FUNDACION CRIS address has been updated in the protocol. This change has not been detailed in the amendment document.

    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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