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    Clinical Trial Results:
    A phase II single arm clinical trial of a Tailored ImmunoTherapy Approach with Nivolumab in subjects with metastatic or advanced Transitional Cell Carcinoma

    Summary
    EudraCT number
    		 2016-004857-33
    Trial protocol
    		 DE   AT  
    Global end of trial date
    17 Feb 2023

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    0416-ASG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03219775
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AIO-Studien-gGmbH
    Sponsor organisation address
    Kuno-Fischer-Str. 8, Berlin, Germany,
    Public contact
    Clinical trial desk of the sponsor, AIO-Studien-gGmbH, +49 30814534431, info@aio-studien-ggmbh.de
    Scientific contact
    Clinical trial desk of the sponsor, AIO-Studien-gGmbH, +49 30814534431, info@aio-studien-ggmbh.de
    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
    25 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to be measured by the primary endpoint of ORR (based on investigator assessments). The ORR was based on investigator assessment using RECIST 1.1 of the TITAN-TCC regimen in untreated (1st line) and platinum-based pretreated (2nd and 3rd line) subjects with metastatic or surgically unresectable TCC
    Protection of trial subjects
    This study was planned, analyzed and conducted according to the study protocol and in accordance with the International Conference on Harmonization (ICH) ‚Guideline for Good Clinical Practice E6(R1)‘, CPMP/ICH/135/95, based on the principles of the Declaration of Helsinki (1964) and its October 1996 amendment (Somerset West, South Africa). The study was duly conducted in compliance with the German Arzneimittelgesetz (AMG; German Drug Law), and the corresponding Directive 2001/20/EC. Subjects were fully informed regarding all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2017
    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
    Austria: 46
    Country: Number of subjects enrolled
    Germany: 123
    Worldwide total number of subjects
    169
    EEA total number of subjects
    169
    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)
    57
    From 65 to 84 years
    112
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The first patient was recruited on 14-Jul-2017; last patient last visit was on 17-Feb-2023. Recruitment of first-line patients was paused by the Sponsor on 25-Jan-2019 and definitively terminated on 06-Jan-2020.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1, 1st line
    Arm description
    		 Patients who received 1st-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 42 patients in this cohort, 14 continued nivo mono maintenance after induction, 17 received a first boost treatment, and 11 discontinued treatment. Of the 17 patients who received a first boost treatment, 6 could switch to nivo maintenance, 7 continued with a second boost treatment, and 4 discontinued treatment. Of the 7 patients who received a second boost treatment, 4 could switch to nivo maintenance, two discontinued treatment due to adverse events, and 1 was found immunotherapy resistant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab 240 mg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a fixed dose of 240 mg IV for four cycles of induction treatment (Q2W). Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, treatment was switched to a 'boost' treatment of combined nivolumab and ipilimumab. If patients developed progressive disease at any time point during maintenance therapy, treatment was also switched to a 'boost' using combined nivolumab and ipilimumab.

    Investigational medicinal product name
    Nivolumab 3 mg/kg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a dose of 3 mg/kg body weight during the first 'boost' treatment in cohort 1 for two cycles (Q2W) together with ipilimumab at 1 mg/kg. Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment with nivolumab at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, patients received a second 'boost' treatment.

    Investigational medicinal product name
    Ipilimumab 1 mg/kg
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered at a dose of 1 mg/kg body weight during the first 'boost' treatment in cohort 1 for two cycles (Q2W) together with nivolumab at 3 mg/kg. Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, patients received a second 'boost' treatment.

    Investigational medicinal product name
    Nivolumab 1 mg/kg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a dose of 1 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with ipilimumab at 3 mg/kg. 'Boost' treatment was to be administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Investigational medicinal product name
    Iplilimumab 3 mg/kg
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered at a dose of 3 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with nivolumab at 1 mg/kg. 'Boost' treatment was always administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Arm title
    		 Cohort 1, 2nd/3rd line
    Arm description
    		 Patients who received 2nd or 3rd-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 44 patients in this cohort, 10 continued nivo mono maintenance after induction, 23 received a first boost treatment, and 11 discontinued treatment. Of the 23 patients who received a first boost treatment, 1 could switch to nivo maintenance, 16 continued with a second boost treatment, and 6 discontinued treatment. Of the 16 patients who received a second boost treatment, 6 could switch to nivo maintenance, 6 discontinued treatment due to adverse events, death or other reasons, and 4 were found immunotherapy resistant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab 240 mg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a fixed dose of 240 mg IV for four cycles of induction treatment (Q2W). Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, treatment was switched to a 'boost' treatment of combined nivolumab and ipilimumab. If patients developed progressive disease at any time point during maintenance therapy, treatment was also switched to a 'boost' using combined nivolumab and ipilimumab.

    Investigational medicinal product name
    Nivolumab 3 mg/kg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a dose of 3 mg/kg body weight during the first 'boost' treatment in cohort 1 for two cycles (Q2W) together with ipilimumab at 1 mg/kg. Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, patients received a second 'boost' treatment.

    Investigational medicinal product name
    Ipilimumab 1 mg/kg
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered at a dose of 1 mg/kg body weight during the first 'boost' treatment in cohort 1 for two cycles (Q2W) together with nivolumab at 3 mg/kg. Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, patients received a second 'boost' treatment.

    Investigational medicinal product name
    Nivolumab 1 mg/kg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a dose of 1 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with ipilimumab at 3 mg/kg. 'Boost' treatment was to be administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Investigational medicinal product name
    Iplilimumab 3 mg/kg
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered at a dose of 3 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with nivolumab at 1 mg/kg. 'Boost' treatment was to be administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Arm title
    		 Cohort 2, 1st/2nd/3rd line
    Arm description
    		 Patients who received treatment under protocol version 4.0 or later versions. Under this version, all boost treatments were dosed at nivolumab 1 mg/kg and ipilimumab at 3 mg/kg. Of the 83 patients in this cohort, 3 received the study regimen as 1st-line treatment, 78 as 2nd line, and 3 as 3rd line. Of these 83 patients, 20 continued nivo mono maintenance after induction, 44 received a first boost treatment, and 19 discontinued treatment. Of the 44 patients who received a first boost treatment, 6 could switch to nivo maintenance, 14 continued with a second boost treatment, and 24 discontinued treatment. Of the 14 patients who received a second boost treatment, 4 could switch to nivo maintenance, 6 discontinued treatment, and 4 were found immunotherapy resistant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab 240 mg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a fixed dose of 240 mg IV for four cycles of induction treatment (Q2W). Subsequently, tumor assessment according to RECIST 1.1 was carried out. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, treatment was switched to a 'boost' treatment of combined nivolumab and ipilimumab. If patients developed progressive disease at any time point during maintenance therapy, treatment was also switched to a 'boost' using combined nivolumab and ipilimumab.

    Investigational medicinal product name
    Nivolumab 1 mg/kg
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administered at a dose of 1 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with ipilimumab at 3 mg/kg. 'Boost' treatment was to be administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Investigational medicinal product name
    Iplilimumab 3 mg/kg
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered at a dose of 3 mg/kg body weight during the second 'boost' treatment in cohort 1, and in both the first and the second 'boost' treatment in cohort 2 together with nivolumab at 1 mg/kg. 'Boost' treatment was to be administered for two cycles (Q2W). Subsequent tumor assessment according to RECIST 1.1 informed the next treatment. In case of complete or partial remission, treatment at 240 mg Q2W was continued as maintenance treatment. In case of stable or progressive disease, eligible patients received a second 'boost' treatment. Patients with stable disease and ineligible for further boosts treatment were also switched to nivolumab maintenance treatment at 240 mg fixed dose. Patients with progressive disease and ineligible for further 'boost' treatment were decleared as immunotherapy resistant, and discontiued treatment within the study.

    Number of subjects in period 1
    		Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Started
    42
    44
    83
    Completed
    42
    44
    83

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1, 1st line
    Reporting group description
    		 Patients who received 1st-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 42 patients in this cohort, 14 continued nivo mono maintenance after induction, 17 received a first boost treatment, and 11 discontinued treatment. Of the 17 patients who received a first boost treatment, 6 could switch to nivo maintenance, 7 continued with a second boost treatment, and 4 discontinued treatment. Of the 7 patients who received a second boost treatment, 4 could switch to nivo maintenance, two discontinued treatment due to adverse events, and 1 was found immunotherapy resistant.

    Reporting group title
    Cohort 1, 2nd/3rd line
    Reporting group description
    		 Patients who received 2nd or 3rd-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 44 patients in this cohort, 10 continued nivo mono maintenance after induction, 23 received a first boost treatment, and 11 discontinued treatment. Of the 23 patients who received a first boost treatment, 1 could switch to nivo maintenance, 16 continued with a second boost treatment, and 6 discontinued treatment. Of the 16 patients who received a second boost treatment, 6 could switch to nivo maintenance, 6 discontinued treatment due to adverse events, death or other reasons, and 4 were found immunotherapy resistant.

    Reporting group title
    Cohort 2, 1st/2nd/3rd line
    Reporting group description
    		 Patients who received treatment under protocol version 4.0 or later versions. Under this version, all boost treatments were dosed at nivolumab 1 mg/kg and ipilimumab at 3 mg/kg. Of the 83 patients in this cohort, 3 received the study regimen as 1st-line treatment, 78 as 2nd line, and 3 as 3rd line. Of these 83 patients, 20 continued nivo mono maintenance after induction, 44 received a first boost treatment, and 19 discontinued treatment. Of the 44 patients who received a first boost treatment, 6 could switch to nivo maintenance, 14 continued with a second boost treatment, and 24 discontinued treatment. Of the 14 patients who received a second boost treatment, 4 could switch to nivo maintenance, 6 discontinued treatment, and 4 were found immunotherapy resistant.

    Reporting group values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line Total
    Number of subjects
    		 42 44 83 169
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 12 18 27 57
        From 65-84 years
    		 30 26 56 112
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 13 12 26 51
        Male
    		 29 32 57 118
    Karnofsky performance status (screening)
    Units: Subjects
        70
    		 7 4 3 14
        80
    		 8 8 15 31
        90
    		 9 13 23 45
        100
    		 18 19 42 79
        not reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1, 1st line
    Reporting group description
    		 Patients who received 1st-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 42 patients in this cohort, 14 continued nivo mono maintenance after induction, 17 received a first boost treatment, and 11 discontinued treatment. Of the 17 patients who received a first boost treatment, 6 could switch to nivo maintenance, 7 continued with a second boost treatment, and 4 discontinued treatment. Of the 7 patients who received a second boost treatment, 4 could switch to nivo maintenance, two discontinued treatment due to adverse events, and 1 was found immunotherapy resistant.

    Reporting group title
    Cohort 1, 2nd/3rd line
    Reporting group description
    		 Patients who received 2nd or 3rd-line treatment under protocol version 3.0. Under this version, nivolumab was given at 3 mg/kg and ipilimumab at 1 mg/kg during the first boost treatment, and nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg during the second boost treatment. Of the 44 patients in this cohort, 10 continued nivo mono maintenance after induction, 23 received a first boost treatment, and 11 discontinued treatment. Of the 23 patients who received a first boost treatment, 1 could switch to nivo maintenance, 16 continued with a second boost treatment, and 6 discontinued treatment. Of the 16 patients who received a second boost treatment, 6 could switch to nivo maintenance, 6 discontinued treatment due to adverse events, death or other reasons, and 4 were found immunotherapy resistant.

    Reporting group title
    Cohort 2, 1st/2nd/3rd line
    Reporting group description
    		 Patients who received treatment under protocol version 4.0 or later versions. Under this version, all boost treatments were dosed at nivolumab 1 mg/kg and ipilimumab at 3 mg/kg. Of the 83 patients in this cohort, 3 received the study regimen as 1st-line treatment, 78 as 2nd line, and 3 as 3rd line. Of these 83 patients, 20 continued nivo mono maintenance after induction, 44 received a first boost treatment, and 19 discontinued treatment. Of the 44 patients who received a first boost treatment, 6 could switch to nivo maintenance, 14 continued with a second boost treatment, and 24 discontinued treatment. Of the 14 patients who received a second boost treatment, 4 could switch to nivo maintenance, 6 discontinued treatment, and 4 were found immunotherapy resistant.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the number of subjects with a best overall response of CR or PR divided by the number of all treated subjects, first-line subjects or second-line subjects. Best overall response was defined as the best response designation, as determined by investigator, recorded between the date of first dose and the date of objectively documented immunotherapy resistance per RECIST v1.1 or the date of subsequent therapy, whichever occurred first.
    End point type
    Primary
    End point timeframe
    Objective response observed between date of first dose and the date of objectively documented immunotherapy resistance per RECIST v1.1 or the date of subsequent therapy, whichever occurred first.
    End point values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Number of subjects analysed
    42
    44
    83
    Units: Subjects with objective response
        ORR
    20
    12
    27
        CR
    3
    3
    9
        PR
    17
    9
    18
        SD
    4
    8
    8
        PD
    10
    15
    35
        Death
    8
    8
    11
        NE
    0
    1
    2
    Statistical analysis title
    		 Clopper-Pearson anaylisis of ORR
    Statistical analysis description
    For cohort 1 - 1st line, ORR was significantly better than pre-specified: Clopper-Pearson (exact) 90%CI 0.34–0.61 (p<0.001, one-sided). For cohort 1 - 2nd/3rd line, ORR was 27% (n=12; Clopper-Pearson [exact] 90%CI 0.17–0.40 (p=0.15, one-sided). For cohort 2 - 1st/2nd/3rd line, ORR again was significantly better than pre-specified: Clopper-Pearson (exact) 90%CI 0.24–0.42 (p=0.005, one-sided).
    Comparison groups
    Cohort 1, 1st line v Cohort 2, 1st/2nd/3rd line v Cohort 1, 2nd/3rd line
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 Clopper-Pearson
    Confidence interval
    Notes
    [1] - Please refer to Analysis Description for results of individual statistical analysis of all treatment cohorts

    Secondary: Time to first response (TTR)

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    End point title
    		 Time to first response (TTR)
    End point description
    Medians that were not reached during the study's observation period, or confidence limits that were not estimable are represented as '10000000'.
    End point type
    Secondary
    End point timeframe
    TTR was defined as the time from first dosing date to the date of the first confirmed response thereafter.
    End point values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Number of subjects analysed
    42
    44
    83
    Units: Months
        median (confidence interval 95%)
    3.3 (2.5 to 10000000)
    10000000 (4.5 to 10000000)
    19.5 (4.8 to 10000000)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Confidence limits that were not estimable are represented as '10000000'.
    End point type
    Secondary
    End point timeframe
    DOR was defined as the time from first confirmed response (CR or PR) to the date of the documented progressive disease as determined using RECIST 1.1 criteria or death due to any cause, whichever occured first.
    End point values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Number of subjects analysed
    42
    44
    83
    Units: Months
        median (confidence interval 95%)
    9.1 (4.1 to 10000000)
    18.7 (4.2 to 40.0)
    18.0 (6.9 to 34.9)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    PFS was defined as the time from first dosing date to the date of the first documented tumor progression based on investigator assessments (per RECIST 1.1), or death due to any cause.
    End point values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Number of subjects analysed
    42
    44
    83
    Units: Months
        median (confidence interval 95%)
    3.0 (1.8 to 6.8)
    1.9 (1.7 to 5.8)
    1.9 (1.8 to 3.2)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    OS was defined as the time from first dosing date to the date of death. A subject who had not died was censored at last known date alive.
    End point values
    		 Cohort 1, 1st line Cohort 1, 2nd/3rd line Cohort 2, 1st/2nd/3rd line
    Number of subjects analysed
    42
    44
    83
    Units: Months
        median (confidence interval 95%)
    16.4 (7.3 to 28.5)
    8.3 (5.3 to 19.3)
    7.6 (5.0 to 14.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE were to be collected that occur from first IMP administration until 100 days of IMP discontinuation. Moreover, investigators were to report any SAE occuring after these time periods believed to be related to IMP or protocol-specified procedures.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    x
    Reporting groups
    Reporting group title
    CSP V3
    Reporting group description
    		 -

    Reporting group title
    CSP V4f
    Reporting group description
    		 -

    Serious adverse events
    		 CSP V3 CSP V4f
    Total subjects affected by serious adverse events
         subjects affected / exposed
    77 / 86 (89.53%)
    71 / 83 (85.54%)
         number of deaths (all causes)
    60
    53
         number of deaths resulting from adverse events
    38
    42
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumor pain
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumor associated fever
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    24 / 86 (27.91%)
    34 / 83 (40.96%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 36
         deaths causally related to treatment / all
    0 / 22
    0 / 31
    Metastases to spinal cord
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Elective surgery
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 86 (4.65%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 86 (4.65%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 86 (4.65%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated pneumonitis
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition decreased
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric anastomosis complication
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiovascular disorder
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Somnolence
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune neuropathy
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 86 (4.65%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    10 / 86 (11.63%)
    13 / 83 (15.66%)
         occurrences causally related to treatment / all
    10 / 11
    16 / 17
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric compression
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthalgia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Urethral abscess
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    14 / 86 (16.28%)
    8 / 83 (9.64%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 86 (2.33%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CSP V3 CSP V4f
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 86 (91.86%)
    80 / 83 (96.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 86 (6.98%)
    3 / 83 (3.61%)
         occurrences all number
    6
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 86 (32.56%)
    33 / 83 (39.76%)
         occurrences all number
    33
    36
    Oedema peripheral
         subjects affected / exposed
    9 / 86 (10.47%)
    5 / 83 (6.02%)
         occurrences all number
    9
    5
    Pain
         subjects affected / exposed
    3 / 86 (3.49%)
    8 / 83 (9.64%)
         occurrences all number
    3
    8
    Pyrexia
         subjects affected / exposed
    16 / 86 (18.60%)
    10 / 83 (12.05%)
         occurrences all number
    20
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 86 (17.44%)
    6 / 83 (7.23%)
         occurrences all number
    15
    6
    Dyspnoea
         subjects affected / exposed
    13 / 86 (15.12%)
    9 / 83 (10.84%)
         occurrences all number
    17
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 83 (2.41%)
         occurrences all number
    10
    2
    Sleep disorder
         subjects affected / exposed
    6 / 86 (6.98%)
    11 / 83 (13.25%)
         occurrences all number
    6
    11
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 86 (3.49%)
    6 / 83 (7.23%)
         occurrences all number
    5
    6
    Amylase increased
         subjects affected / exposed
    4 / 86 (4.65%)
    4 / 83 (4.82%)
         occurrences all number
    4
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 86 (3.49%)
    7 / 83 (8.43%)
         occurrences all number
    3
    8
    Blood creatinine increased
         subjects affected / exposed
    8 / 86 (9.30%)
    5 / 83 (6.02%)
         occurrences all number
    11
    6
    C-reactive protein increased
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 83 (6.02%)
         occurrences all number
    3
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
         occurrences all number
    0
    7
    Lipase increased
         subjects affected / exposed
    8 / 86 (9.30%)
    3 / 83 (3.61%)
         occurrences all number
    10
    6
    Weight decreased
         subjects affected / exposed
    2 / 86 (2.33%)
    7 / 83 (8.43%)
         occurrences all number
    2
    7
    Hepatic enzyme increased
         subjects affected / exposed
    6 / 86 (6.98%)
    4 / 83 (4.82%)
         occurrences all number
    10
    4
    Hyperkalaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    5 / 83 (6.02%)
         occurrences all number
    5
    5
    Hypokalaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    7 / 83 (8.43%)
         occurrences all number
    2
    9
    Decreased appetite
         subjects affected / exposed
    14 / 86 (16.28%)
    9 / 83 (10.84%)
         occurrences all number
    16
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 86 (4.65%)
    10 / 83 (12.05%)
         occurrences all number
    4
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 86 (13.95%)
    10 / 83 (12.05%)
         occurrences all number
    13
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 86 (6.98%)
    5 / 83 (6.02%)
         occurrences all number
    6
    5
    Abdominal pain upper
         subjects affected / exposed
    6 / 86 (6.98%)
    7 / 83 (8.43%)
         occurrences all number
    9
    8
    Constipation
         subjects affected / exposed
    10 / 86 (11.63%)
    13 / 83 (15.66%)
         occurrences all number
    12
    13
    Diarrhoea
         subjects affected / exposed
    20 / 86 (23.26%)
    20 / 83 (24.10%)
         occurrences all number
    38
    32
    Nausea
         subjects affected / exposed
    18 / 86 (20.93%)
    13 / 83 (15.66%)
         occurrences all number
    18
    15
    Vomiting
         subjects affected / exposed
    10 / 86 (11.63%)
    7 / 83 (8.43%)
         occurrences all number
    13
    13
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    6 / 86 (6.98%)
    3 / 83 (3.61%)
         occurrences all number
    6
    5
    Erythema
         subjects affected / exposed
    7 / 86 (8.14%)
    4 / 83 (4.82%)
         occurrences all number
    7
    4
    Hyperhidrosis
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 83 (1.20%)
         occurrences all number
    7
    1
    Pruritus
         subjects affected / exposed
    12 / 86 (13.95%)
    13 / 83 (15.66%)
         occurrences all number
    16
    18
    Rash
         subjects affected / exposed
    19 / 86 (22.09%)
    21 / 83 (25.30%)
         occurrences all number
    32
    25
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 83 (3.61%)
         occurrences all number
    6
    3
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    7 / 86 (8.14%)
    8 / 83 (9.64%)
         occurrences all number
    7
    8
    Hypothyroidism
         subjects affected / exposed
    11 / 86 (12.79%)
    11 / 83 (13.25%)
         occurrences all number
    11
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 86 (11.63%)
    5 / 83 (6.02%)
         occurrences all number
    14
    6
    Back pain
         subjects affected / exposed
    9 / 86 (10.47%)
    13 / 83 (15.66%)
         occurrences all number
    10
    14
    Bone pain
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 83 (6.02%)
         occurrences all number
    4
    5
    Flank pain
         subjects affected / exposed
    5 / 86 (5.81%)
    5 / 83 (6.02%)
         occurrences all number
    6
    5
    Muscular weakness
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 83 (3.61%)
         occurrences all number
    7
    3
    Musculoskeletal pain
         subjects affected / exposed
    7 / 86 (8.14%)
    5 / 83 (6.02%)
         occurrences all number
    7
    5
    Myalgia
         subjects affected / exposed
    4 / 86 (4.65%)
    5 / 83 (6.02%)
         occurrences all number
    5
    5
    Pain in extremity
         subjects affected / exposed
    6 / 86 (6.98%)
    9 / 83 (10.84%)
         occurrences all number
    7
    15
    Infections and infestations
    Infection
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Nasopharyngitis
         subjects affected / exposed
    14 / 86 (16.28%)
    7 / 83 (8.43%)
         occurrences all number
    19
    11
    Rhinitis
         subjects affected / exposed
    6 / 86 (6.98%)
    1 / 83 (1.20%)
         occurrences all number
    7
    1
    Urinary tract infection
         subjects affected / exposed
    17 / 86 (19.77%)
    13 / 83 (15.66%)
         occurrences all number
    38
    18
    Corona virus infection
         subjects affected / exposed
    1 / 86 (1.16%)
    6 / 83 (7.23%)
         occurrences all number
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2019
    In the initial version of the protocol, the two nivolumab/ipilimumab boost cycles used different dosing of the two IMPs: for the first boost (boost cycles 1 and 2), nivolumab was to be given at 3 mg/kg and ipilimumab at 1 mg/kg, while dosing was nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for the second boost (boost cycles 3 and 4). Following the publication of results of the Checkmate 032 study, the protocol was amended to change dosing for the first boost (cycles 1 and 2) to nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg, thus applying the same dosing in all boost cycles, since this dosing pattern had shown better efficacy and only slightly higher toxicity in the Checkmate 032 study. Furthermore, the recruitment target was reduced from initially 250 participants to 225, and the recruitment period was extended.
    07 Apr 2020
    Following a recruitment stop for 1st-line patients due to safety concerns, an interim analysis, and feedback from the competent authority, recruitment of 1st-line patients was terminated and the termination implemented with this amendment. Target enrollment was updated to 190 participants, and the planned statistical analysis was adapted accordingly, implementing a statistical power of 85%.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Jan 2019
    Recruitment of 1st-line participants was paused by the sponsor as a results of the scheduled activities of the study's data monitoring committee (DMC). Upon a routine analysis that was based on 39 study participants, the DMC observed an unexpected accumulation of SAEs with fatal outcomes in the 1st-line cohort that occured within 8 weeks of study inclusion. After the recruitment halt for 1st-line patients, an unplanned safety interim analysis was conducted that was based on 88 study participants. The DMC concluded that there were no unexpected safety risks and expressed no reservations about resuming the inclusion of first-line patients into the study. However, the sponsor'S request to reopen the study to 1st-line participants was denied by the competent authority, and recruitment of 1st-line patients therefore terminated and implemented by protocol amendment.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36868252
    http://www.ncbi.nlm.nih.gov/pubmed/38722641
    http://www.ncbi.nlm.nih.gov/pubmed/35275706
    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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