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    Clinical Trial Results:
    A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer

    Summary
    EudraCT number
    		 2017-000220-10
    Trial protocol
    		 NO   BE  
    Global end of trial date
    11 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2024
    First version publication date
    30 Oct 2024
    Other versions
    Summary report(s)
    		 Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    ICON-CA209-9FN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03409198
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oslo University Hospital, Department of Oncology
    Sponsor organisation address
    Ullernchausseen 70, Oslo, Norway, 0379
    Public contact
    Jon Amund Kyte , Oslo University Hospital, Department of Oncology, +47 97569619, jonky@ous-hf.no
    Scientific contact
    Jon Amund Kyte , Oslo University Hospital, Department of Oncology, +47 97569619, jonky@ous-hf.no
    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
    20 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Co-primary objectives: Assessment of toxicity of combined treatment with ipilimumab, nivolumab, pegylated liposomal doxorubicin and cyclophosphamide (ipi/nivo plus chemotherapy). Assessment of clinical response: Progression-free survival (PFS) in ipi/nivo-chemo group compared to the chemo-only group.
    Protection of trial subjects
    The trial was conducted according to the guidelines of Good Clinical Practice and the principles of the World Medical Association’s Declaration of Helsinki. All patients provided written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research, Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Norway: 66
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    65
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eighty-two subjects were recruited at 5 academic hospitals in Norway and Belgium; Oslo University Hospital (n= 48), CHU UCL Namur (n= 13), Stavanger University Hospital (n= 9), Kristiansand Hospital (n= 9) and Institut Jules Bordet (n= 3).

    Pre-assignment
    Screening details
    		 A total of 106 patients were assessed for eligibility in the trial. Eighty-two patients were randomized and started allocated therapy and was included in the full analysis set population.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Chemotherapy-only
    Arm description
    		 Pegylated liposomal doxorubicin plus cyclophosphamide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated liposomal doxorubicin 20/m2 i.v. every 2nd week. An upper limit of 44mg per dose was applied to patients with a body surface area >2.2 m2.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide tablets 50 mg per day, daily as continuous treatment for every 2nd cycle (i.e. first 2 weeks of each 4 week period)

    Arm title
    		 Ipi/nivo plus chemotherapy
    Arm description
    		 Ipilimumab plus nivolumab plus pegylated liposomal doxorubicin plus cyclophosphamide
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240 mg administered intravenously every 2nd week until disease progression or for a maximum of 24 months

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 1mg/kg administered intravenously every 6th week until disease progression or for a maximum of 24 months

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated liposomal doxorubicin 20/m2 i.v. every 2nd week. An upper limit of 44mg per dose was applied to patients with a body surface area >2.2 m2.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide tablets 50 mg per day, daily as continuous treatment for every 2nd cycle (i.e. first 2 weeks of each 4 week period)

    Arm title
    		 Ipi/nivo-only (cross-over)
    Arm description
    		 Ipilimumab plus nivolumab without chemotherapy (cross-over from chemo-only)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240 mg administered intravenously every 2nd week until disease progression or for a maximum of 24 months

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 1mg/kg administered intravenously every 6th week until disease progression or for a maximum of 24 months

    Number of subjects in period 1
    		Chemotherapy-only Ipi/nivo plus chemotherapy Ipi/nivo-only (cross-over)
    Started
    33
    49
    16
    Completed
    1
    1
    0
    Not completed
    32
    48
    16
         Adverse event, serious fatal
    -
    1
    -
         Patient withdrawal
    1
    -
    -
         Adverse event, non-fatal
    1
    6
    -
         Sponsors decision
    1
    1
    -
         Lack of efficacy
    29
    40
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy-only
    Reporting group description
    		 Pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Ipi/nivo plus chemotherapy
    Reporting group description
    		 Ipilimumab plus nivolumab plus pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Ipi/nivo-only (cross-over)
    Reporting group description
    		 Ipilimumab plus nivolumab without chemotherapy (cross-over from chemo-only)

    Reporting group values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy Ipi/nivo-only (cross-over) Total
    Number of subjects
    		 33 49 16 82
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 26 39 15 65
        From 65-84 years
    		 7 10 1 17
    Age continuous
    Units: years
        median (full range (min-max))
    		 55 (37 to 74) 53 (36 to 75) 56 (39 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 33 48 16 81
        Male
    		 0 1 0 1
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 18 19 11 37
        ECOG 1
    		 15 30 5 45
    De novo metastatic disease
    Units: Subjects
        Yes
    		 9 9 4 18
        No
    		 24 40 12 64
    Bone metastases
    Units: Subjects
        Yes
    		 28 45 14 73
        No
    		 5 4 2 9
    Liver metastases
    Units: Subjects
        Yes
    		 28 36 15 64
        No
    		 5 13 1 18
    Lung metastases
    Units: Subjects
        Yes
    		 6 18 3 24
        No
    		 27 31 13 58
    >3 sites of metastases
    Units: Subjects
        Yes
    		 9 14 4 23
        No
    		 24 35 12 59
    Previous CDK4/6 inhibitor
    Units: Subjects
        Yes
    		 30 44 15 74
        No
    		 3 5 1 8
    PD-L1 expression
    PD-L1 expression was assessed by immunohistochemistry on prestudy formalin-fixed paraffin-embedded (FFPE) sections by the VENTANA SP142 assay (Roche Diagnostics, Rotkreuz, Switzerland). Forty-five patients had more than one biopsy assessed and were categorized as PD-L1+ if any of the biopsies were positive.
    Units: Subjects
        Positive
    		 10 19 5 29
        Negative
    		 20 28 11 48
        Missing
    		 3 2 0 5
    PAM50 subtype
    Gene expression data were used to determine the intrinsic molecular subtype using the nCounter BC360 assay (NanoString Technologies, Seattle, USA). Analysis was performed on bulk RNA isolated from prestudy FFPE sections. In patients with more than one sample analyzed, the profile was based on the most recent sample.
    Units: Subjects
        Luminal A
    		 6 9 3 15
        Luminal B
    		 21 34 11 55
        HER2 enriched
    		 3 4 1 7
        Basal
    		 0 1 0 1
        Missing
    		 3 1 1 4
    Subject analysis sets

    Subject analysis set title
    Chemo-only per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaluated for response and received the equivalent of ≥2 treatment cycles

    Subject analysis set title
    Ipi/nivo plus chemotherapy per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaluated for tumor response and received the equivalent of ≥ 2 treatment cycles

    Subject analysis sets values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects
    31
    47
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    25
    37
        From 65-84 years
    6
    10
    Age continuous
    Units: years
        median (full range (min-max))
    55 (37 to 74)
    53 (36 to 75)
    Gender categorical
    Units: Subjects
        Female
    31
    46
        Male
    0
    1
    ECOG performance status
    Units: Subjects
        ECOG 0
    17
    18
        ECOG 1
    14
    29
    De novo metastatic disease
    Units: Subjects
        Yes
    9
    8
        No
    22
    39
    Bone metastases
    Units: Subjects
        Yes
    27
    43
        No
    4
    4
    Liver metastases
    Units: Subjects
        Yes
    27
    34
        No
    4
    13
    Lung metastases
    Units: Subjects
        Yes
    4
    17
        No
    27
    30
    >3 sites of metastases
    Units: Subjects
        Yes
    9
    13
        No
    22
    34
    Previous CDK4/6 inhibitor
    Units: Subjects
        Yes
    29
    42
        No
    2
    5
    PD-L1 expression
    PD-L1 expression was assessed by immunohistochemistry on prestudy formalin-fixed paraffin-embedded (FFPE) sections by the VENTANA SP142 assay (Roche Diagnostics, Rotkreuz, Switzerland). Forty-five patients had more than one biopsy assessed and were categorized as PD-L1+ if any of the biopsies were positive.
    Units: Subjects
        Positive
    10
    19
        Negative
    18
    26
        Missing
    3
    2
    PAM50 subtype
    Gene expression data were used to determine the intrinsic molecular subtype using the nCounter BC360 assay (NanoString Technologies, Seattle, USA). Analysis was performed on bulk RNA isolated from prestudy FFPE sections. In patients with more than one sample analyzed, the profile was based on the most recent sample.
    Units: Subjects
        Luminal A
    6
    9
        Luminal B
    19
    32
        HER2 enriched
    3
    4
        Basal
    0
    1
        Missing
    3
    1

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy-only
    Reporting group description
    		 Pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Ipi/nivo plus chemotherapy
    Reporting group description
    		 Ipilimumab plus nivolumab plus pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Ipi/nivo-only (cross-over)
    Reporting group description
    		 Ipilimumab plus nivolumab without chemotherapy (cross-over from chemo-only)

    Subject analysis set title
    Chemo-only per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaluated for response and received the equivalent of ≥2 treatment cycles

    Subject analysis set title
    Ipi/nivo plus chemotherapy per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaluated for tumor response and received the equivalent of ≥ 2 treatment cycles

    Primary: Progression-free survival, per-protocol population

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    End point title
    		 Progression-free survival, per-protocol population
    End point description
    PFS in the per-protocol population. PFS is, defined as the time from randomization to the occurrence of disease progression or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. Comparison between treatment arms will also be given by HR for disease progression or death using a Cox proportional hazards model.
    End point type
    Primary
    End point timeframe
    Until data cut-off 20 JAN 2023
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Months
        median (confidence interval 95%)
    3.6 (1.8 to 9.0)
    5.1 (3.4 to 6.5)
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Ipi/nivo plus chemotherapy per-protocol population v Chemo-only per-protocol population
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.51

    Secondary: Progression-free survival, full analysis set population

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    End point title
    		 Progression-free survival, full analysis set population [1]
    End point description
    PFS in the full analysis set population. PFS is, defined as the time from randomization to the occurrence of disease progression or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. Comparison between treatment arms will also be given by HR for disease progression or death using a Cox proportional hazards model.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Progression-free survival for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Months
        median (confidence interval 95%)
    3.6 (1.8 to 9.0)
    5.1 (3.4 to 6.5)
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Chemotherapy-only v Ipi/nivo plus chemotherapy
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.51

    Secondary: Overall survival, per-protocol population

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    End point title
    		 Overall survival, per-protocol population
    End point description
    Overall survival (OS) in the per-protocol population. OS will be calculated from time of randomization until death. Patients alive at the time of data analysis will be treated as censored. OS will be estimated by the Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Months
        median (confidence interval 95%)
    19.9 (13.8 to 28.7)
    19.7 (12.5 to 24.9)
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Chemo-only per-protocol population v Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.67

    Secondary: Overall survival, full analysis set population

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    End point title
    		 Overall survival, full analysis set population [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Overall survival for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Months
        median (confidence interval 95%)
    19.7 (13.8 to 28.7)
    19.5 (10.4 to 24.8)
    Statistical analysis title
    		 Cox proportional hazards model
    Statistical analysis description
    Overall survival (OS) in the full analysis set population. OS will be calculated from time of randomization until death. Patients alive at the time of data analysis will be treated as censored. OS will be estimated by the Kaplan Meier method.
    Comparison groups
    Chemotherapy-only v Ipi/nivo plus chemotherapy
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.71

    Secondary: Objective tumor response rate, per-protocol population

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    End point title
    		 Objective tumor response rate, per-protocol population
    End point description
    The number of patients with an objective response (CR or PR) in the per-protocol population of each treatment arm assessed by RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Subjects
        Complete or partial response
    9
    15
        Non-response
    22
    32
    No statistical analyses for this end point

    Secondary: Objective tumor response rate, full analysis set population

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    End point title
    		 Objective tumor response rate, full analysis set population [3]
    End point description
    The number of patients with an objective response (CR or PR) in the full analysis set population of each treatment arm assessed by RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Objective tumor response rate for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Subjects
        Complete or partial response
    9
    15
        Non-response
    24
    34
    No statistical analyses for this end point

    Secondary: Durable response rate, per-protocol population

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    End point title
    		 Durable response rate, per-protocol population
    End point description
    Durable response rate (DRR) in the per protocol population, defined as the proportion of patients with an objective tumor response lasting at least 6 months, according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Subjects
        Durable response
    6
    6
        Non-durable response
    25
    41
    No statistical analyses for this end point

    Secondary: Durable response rate, full analysis set population

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    End point title
    		 Durable response rate, full analysis set population [4]
    End point description
    Durable response rate (DRR) in the full analysis set population, defined as the proportion of patients with an objective tumor response lasting at least 6 months, according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Durable response rate for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Subjects
        Durable response
    6
    6
        Non-durable response
    27
    43
    No statistical analyses for this end point

    Secondary: Clinical benefit rate, per-protocol population

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    End point title
    		 Clinical benefit rate, per-protocol population
    End point description
    Clinical benefit (CB) is defined as the proportion of patients in the analyzed population with best overall response "PR" or "CR", or with stable disease (SD) lasting at least until the 6 month evaluation (performed at week 24 +/- 10 days). This means that patients where PD was first recorded at the 6 month evaluation will be considered to have clinical benefit.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Subjects
        CB
    15
    26
        Non-CB
    16
    21
    No statistical analyses for this end point

    Secondary: Clinical benefit rate, full analysis set population

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    End point title
    		 Clinical benefit rate, full analysis set population [5]
    End point description
    Clinical benefit (CB) is defined as the proportion of patients in the analyzed population with best overall response "PR" or "CR", or with stable disease (SD) lasting at least until the 6 month evaluation (performed at week 24 +/- 10 days). This means that patients where PD was first recorded at the 6 month evaluation will be considered to have clinical benefit.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Clinical benefit rate for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Subjects
        CB
    15
    26
        Non-CB
    18
    23
    No statistical analyses for this end point

    Secondary: Duration of response, per-protocol population

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    End point title
    		 Duration of response, per-protocol population
    End point description
    Duration of response is defined as the interval from response was first documented (CR or PR) to either progression of disease or death from any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    End point values
    		 Chemo-only per-protocol population Ipi/nivo plus chemotherapy per-protocol population
    Number of subjects analysed
    31
    47
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.4 (3.7 to 11.3)
    5.5 (2.8 to 10.3)
    No statistical analyses for this end point

    Secondary: Duration of response, full analysis set population

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    End point title
    		 Duration of response, full analysis set population [6]
    End point description
    Duration of response is defined as the interval from response was first documented (CR or PR) to either progression of disease or death from any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Duration of response for the ipi/nivo-only cross-over arm is reported separately.
    End point values
    		 Chemotherapy-only Ipi/nivo plus chemotherapy
    Number of subjects analysed
    33
    49
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.4 (3.7 to 11.3)
    5.5 (2.8 to 10.3)
    No statistical analyses for this end point

    Secondary: Progression-free survival, ipi/nivo-only (cross-over)

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    End point title
    		 Progression-free survival, ipi/nivo-only (cross-over) [7]
    End point description
    PFS in the cross-over arm is, defined as the time from "Day 1/Cycle 1" to the occurrence of disease progression or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after start of therapy, data will be censored at the "Day 1/Cycle 1" date +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Progression-free survival for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Months
        median (inter-quartile range (Q1-Q3))
    1.9 (1.6 to 5.5)
    No statistical analyses for this end point

    Secondary: Overall survival, ipi/nivo-only (cross-over)

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    End point title
    		 Overall survival, ipi/nivo-only (cross-over) [8]
    End point description
    Overall survival (OS) will be calculated from time of "Day 1/Cycle 1"until death. Patients alive at the time of data analysis will be treated as censored.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Overall survival for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Months
        median (inter-quartile range (Q1-Q3))
    22.9 (16.5 to 28.9)
    No statistical analyses for this end point

    Secondary: Objective tumor response rate, ipi/nivo-only (cross-over)

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    End point title
    		 Objective tumor response rate, ipi/nivo-only (cross-over) [9]
    End point description
    The number of patients with an objective response (CR or PR) assessed by RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Objective tumor response rate for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Subjects
        Complete or partial response
    3
        Non-response
    13
    No statistical analyses for this end point

    Secondary: Durable response rate, ipi/nivo-only (cross-over)

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    End point title
    		 Durable response rate, ipi/nivo-only (cross-over) [10]
    End point description
    Durable response rate, defined as the proportion of patients with an objective tumor response lasting at least 6 months, according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Durable response rate for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Subjects
        Durable response
    2
        No durable response
    14
    No statistical analyses for this end point

    Secondary: Clinical benefit rate, ipi/nivo-only (cross-over)

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    End point title
    		 Clinical benefit rate, ipi/nivo-only (cross-over) [11]
    End point description
    Clinical benefit (CB) is defined as the proportion of patients in the analyzed population with best overall response "PR" or "CR", or with stable disease (SD) lasting at least until the 6 month evaluation (performed at week 24 +/- 10 days). This means that patients where PD was first recorded at the 6 month evaluation will be considered to have clinical benefit.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Clinical benefit rate for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Subjects
        Clinical benefit
    4
        No clinical benefit
    12
    No statistical analyses for this end point

    Secondary: Duration of response, ipi/nivo-only (cross-over)

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    End point title
    		 Duration of response, ipi/nivo-only (cross-over) [12]
    End point description
    Duration of response is defined as the interval from response was first documented (CR or PR) to either progression of disease or death from any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 20 JAN 2023.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The arms are not mutually exclusive because of cross-over for a subset of patients (16/33) from the chemo-only arm to the separate ipi/nivo-only arm. Duration of response for the ipi/nivo-chemo and chemo-only arms in the main trial is reported separately.
    End point values
    		 Ipi/nivo-only (cross-over)
    Number of subjects analysed
    16
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.0 (3.7 to 10.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 21 FEB 2018 until data cut-off 20 JAN 2023.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Chemotherapy-only
    Reporting group description
    		 -

    Reporting group title
    Ipi/nivo plus chemotherapy
    Reporting group description
    		 -

    Reporting group title
    Ipi/nivo-only (cross-over)
    Reporting group description
    		 -

    Serious adverse events
    		 Chemotherapy-only Ipi/nivo plus chemotherapy Ipi/nivo-only (cross-over)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 33 (39.39%)
    31 / 49 (63.27%)
    5 / 16 (31.25%)
         number of deaths (all causes)
    28
    39
    12
         number of deaths resulting from adverse events
    0
    2
    0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 49 (12.24%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Pleural effusion
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Cardiac disorders
    Conduction disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 16 (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
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Spinal cord compression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Ascites
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Colitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Pancreatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Hypophysitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Pain in extremity
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Lung infection
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 49 (12.24%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 16 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Chemotherapy-only Ipi/nivo plus chemotherapy Ipi/nivo-only (cross-over)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    49 / 49 (100.00%)
    15 / 16 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 33 (48.48%)
    27 / 49 (55.10%)
    6 / 16 (37.50%)
         occurrences all number
    21
    28
    6
    Influenza like illness
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    1
    Oedema
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 49 (8.16%)
    0 / 16 (0.00%)
         occurrences all number
    2
    4
    0
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    3 / 16 (18.75%)
         occurrences all number
    0
    2
    3
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Mycotic allergy
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Vulvovaginal discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 49 (8.16%)
    1 / 16 (6.25%)
         occurrences all number
    3
    4
    1
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    5
    0
    Pneumonitis
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    1 / 16 (6.25%)
         occurrences all number
    0
    3
    1
    Rhinitis
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    7 / 49 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    1
    7
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Ejection fraction decreased
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    2
    4
    0
    Haemoglobin decreased
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 49 (8.16%)
    0 / 16 (0.00%)
         occurrences all number
    9
    5
    0
    Lipase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    15 / 33 (45.45%)
    32 / 49 (65.31%)
    0 / 16 (0.00%)
         occurrences all number
    23
    35
    0
    Neutrophil count decreased
         subjects affected / exposed
    10 / 33 (30.30%)
    11 / 49 (22.45%)
    1 / 16 (6.25%)
         occurrences all number
    29
    20
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 49 (8.16%)
    0 / 16 (0.00%)
         occurrences all number
    0
    4
    0
    Weight decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    3
    4
    0
    Procedural pain
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 49 (2.04%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    Headache
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    4
    3
    0
    Neuropathy peripheral
         subjects affected / exposed
    6 / 33 (18.18%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    6
    3
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    Tinnitus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    1
    Vertigo
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 49 (16.33%)
    1 / 16 (6.25%)
         occurrences all number
    2
    9
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 49 (4.08%)
    1 / 16 (6.25%)
         occurrences all number
    2
    2
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Visual impairment
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 33 (21.21%)
    8 / 49 (16.33%)
    1 / 16 (6.25%)
         occurrences all number
    10
    10
    1
    Colitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    18 / 33 (54.55%)
    16 / 49 (32.65%)
    0 / 16 (0.00%)
         occurrences all number
    20
    21
    0
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    13 / 49 (26.53%)
    3 / 16 (18.75%)
         occurrences all number
    1
    14
    6
    Dysphagia
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences all number
    3
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 49 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    3
    10
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Nausea
         subjects affected / exposed
    16 / 33 (48.48%)
    25 / 49 (51.02%)
    2 / 16 (12.50%)
         occurrences all number
    20
    29
    2
    Stomatitis
         subjects affected / exposed
    12 / 33 (36.36%)
    20 / 49 (40.82%)
    2 / 16 (12.50%)
         occurrences all number
    18
    35
    3
    Toothache
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    2
    3
    0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hepatocellular injury
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 33 (12.12%)
    8 / 49 (16.33%)
    0 / 16 (0.00%)
         occurrences all number
    4
    8
    0
    Nail disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    10 / 33 (30.30%)
    16 / 49 (32.65%)
    0 / 16 (0.00%)
         occurrences all number
    11
    16
    0
    Pruritus
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 49 (6.12%)
    5 / 16 (31.25%)
         occurrences all number
    2
    3
    5
    Rash
         subjects affected / exposed
    13 / 33 (39.39%)
    28 / 49 (57.14%)
    6 / 16 (37.50%)
         occurrences all number
    17
    33
    7
    Skin fissures
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences all number
    4
    2
    0
    Xeroderma
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 49 (2.04%)
    2 / 16 (12.50%)
         occurrences all number
    2
    1
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 49 (8.16%)
    0 / 16 (0.00%)
         occurrences all number
    0
    5
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 33 (0.00%)
    10 / 49 (20.41%)
    1 / 16 (6.25%)
         occurrences all number
    0
    10
    1
    Hypophysitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 33 (3.03%)
    23 / 49 (46.94%)
    2 / 16 (12.50%)
         occurrences all number
    1
    23
    2
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    Back pain
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 49 (2.04%)
    0 / 16 (0.00%)
         occurrences all number
    3
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    11 / 49 (22.45%)
    5 / 16 (31.25%)
         occurrences all number
    5
    14
    6
    Neck pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 49 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    1
    0
    2
    Infections and infestations
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    0
    5
    0
    Skin infection
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 49 (10.20%)
    0 / 16 (0.00%)
         occurrences all number
    3
    8
    0
    Tooth infection
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 49 (6.12%)
    0 / 16 (0.00%)
         occurrences all number
    2
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    7 / 49 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    8
    8
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    10 / 49 (20.41%)
    0 / 16 (0.00%)
         occurrences all number
    3
    16
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 49 (8.16%)
    1 / 16 (6.25%)
         occurrences all number
    3
    4
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 49 (4.08%)
    0 / 16 (0.00%)
         occurrences all number
    3
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 49 (8.16%)
    0 / 16 (0.00%)
         occurrences all number
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2019
    Adjustment of inclusion and excusion criteria. Adjustment of the per-protocol population criteria including specification of the full analysis set population. Specification of planned statistical analyses.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38242720
    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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