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    Clinical Trial Results:
    Open-label, uncontrolled Phase II trial of intravenous PI3K inhibitor BAY 80-6946 in patients with relapsed, indolent or aggressive Non-Hodgkin’s lymphomas

    Summary
    EudraCT number
    2012-002602-52
    Trial protocol
    GB   FI   DE   BE   ES   IT   SE   PL   AT   PT   HU   DK   IE   GR   LU  
    Global end of trial date
    18 May 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2024
    First version publication date
    29 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY80-6946/16349
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01660451
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, 49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, 49 30 300139003, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of study part A was to evaluate the efficacy and safety of copanlisib in patients with indolent or aggressive NHL who have progressed after standard therapy. The objective of study part B was to evaluate the efficacy and safety of copanlisib in patients with indolent B-cellNHL relapsed after, or refractory to widely used approved therapies in standard practice.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Oct 2012
    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
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Finland: 15
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Türkiye: 10
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    338
    EEA total number of subjects
    200
    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)
    162
    From 65 to 84 years
    170
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    Part A-Study enrolled subjects from 41 study centers in 10 countries, between 19 NOV 2012 (first subject first visit [FPFV]) and 13 AUG 2018 (last subject last visit [LPLV]). Part B-Study enrolled subjects from 81 study centers in 24 countries, between 04 NOV 2013 (FPFV) and 18 MAY 2023 (LPLV),

    Pre-assignment
    Screening details
    Part A: 125 subjects were screened, 41 were screened but never assigned to treatment. Total 84 were assigned to treatment. Part B: 213 subjects were screened, 70 were screened but never assigned to treatment. Total 143 were assigned to treatment, of them 1 was suspected as fraudulent and excluded from analysis sets. Therefore 142 were evaluable.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A: Indolent NHL/CLL
    Arm description
    Subjects with indolent Non-Hodgkin’s lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.
    Arm type
    Experimental

    Investigational medicinal product name
    Copanlisib (Aliqopa)
    Investigational medicinal product code
    BAY80-6946
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosing was weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

    Arm title
    Part A: Aggressive NHL
    Arm description
    Subjects with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.
    Arm type
    Experimental

    Investigational medicinal product name
    Copanlisib (Aliqopa)
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosing was weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

    Arm title
    Part B: Indolent NHL
    Arm description
    Subjects with indolent B-cell NHL received copanlisib fixed 60 mg or 0.8 mg/kg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.
    Arm type
    Experimental

    Investigational medicinal product name
    Copanlisib (Aliqopa)
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosing was weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

    Number of subjects in period 1 [1]
    Part A: Indolent NHL/CLL Part A: Aggressive NHL Part B: Indolent NHL
    Started
    33
    51
    142
    Completed
    0
    0
    0
    Not completed
    33
    51
    142
         Progressive disease – radiological progression
    12
    23
    50
         Physician decision
    1
    2
    5
         Trial closure
    -
    -
    1
         Protocol Deviation
    -
    -
    1
         AE not related to clinical disease progression
    13
    10
    40
         Progressive disease – clinical progression
    4
    10
    9
         Consent withdrawn by subject
    1
    1
    20
         Death
    1
    -
    1
         Other
    -
    -
    1
         AE related to clinical disease progression
    1
    3
    11
         Switching to other therapy
    -
    1
    1
         Sponsor Decision
    -
    -
    1
         Protocol deviation
    -
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In study part A, 125 subjects were screened, 41 were screened but never assigned to treatment, total 84 were assigned to treatment. In study part B, 213 subjects were screened, 70 were screened but never assigned to treatment, total 143 were assigned to treatment, of them 1 was suspected as fraudulent and excluded from analysis sets. Therefore 142 were evaluable.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Indolent NHL/CLL
    Reporting group description
    Subjects with indolent Non-Hodgkin’s lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part A: Aggressive NHL
    Reporting group description
    Subjects with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part B: Indolent NHL
    Reporting group description
    Subjects with indolent B-cell NHL received copanlisib fixed 60 mg or 0.8 mg/kg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL Part B: Indolent NHL Total
    Number of subjects
    33 51 142 226
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    11 27 78 116
        From 65-84 years
    21 22 64 107
        85 years and over
    1 2 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.7 ( 9.8 ) 62.2 ( 15.5 ) 61.4 ( 12.1 ) -
    Gender categorical
    Units: Subjects
        Female
    18 22 71 111
        Male
    15 29 71 115
    Race
    Units: Subjects
        Asian
    0 0 15 15
        White
    25 40 120 185
        Unknown or Not Reported
    8 11 7 26
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 2 6 10
        Not Hispanic or Latino
    21 36 124 181
        Unknown or Not Reported
    10 13 12 35

    End points

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    End points reporting groups
    Reporting group title
    Part A: Indolent NHL/CLL
    Reporting group description
    Subjects with indolent Non-Hodgkin’s lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part A: Aggressive NHL
    Reporting group description
    Subjects with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part B: Indolent NHL
    Reporting group description
    Subjects with indolent B-cell NHL received copanlisib fixed 60 mg or 0.8 mg/kg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Subject analysis set title
    Full analysis set (FAS) - Part A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects assigned to study treatment.

    Subject analysis set title
    Full analysis set (FAS) - Part B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects assigned to study treatment.

    Subject analysis set title
    Safety analysis set (SAF)-Part A
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All FAS subjects with at least one study drug administration.

    Subject analysis set title
    Safety analysis set (SAF)-Part B
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All FAS subjects with at least one study drug administration.

    Subject analysis set title
    Per protocol set (PPS)- Part A
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects with drug administration that were evaluable for objective tumor response (OR) and that had no major protocol deviation effecting the primary efficacy evaluation. At least one post baseline tumor assessment was available in order to consider the patient evaluable. Subjects who were not evaluable for tumor response and who discontinued due to a drug-related toxicity, death or progression by clinical judgment before disease was re-evaluated were also to be considered evaluable. The detailed definitions and the assignment of subjects to this analysis set were based on the Validity Review Meeting.

    Primary: Objective Response Rate (ORR) Based on Independent Review-Part A

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    End point title
    Objective Response Rate (ORR) Based on Independent Review-Part A [1] [2]
    End point description
    Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.
    End point type
    Primary
    End point timeframe
    Baseline up to the last patient has completed the 16 weeks of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    32 [3]
    48 [4]
    Units: Percentage
        number (confidence interval 90%)
    43.75 (28.73 to 59.68)
    27.08 (16.83 to 39.57)
    Notes
    [3] - PPS
    [4] - PPS
    No statistical analyses for this end point

    Primary: ORR Based on Independent Review-Part B

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    End point title
    ORR Based on Independent Review-Part B [5] [6]
    End point description
    Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
    End point type
    Primary
    End point timeframe
    Baseline up to the last patient has completed the 16 weeks of treatment
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    142 [7]
    Units: Percentage
        number (confidence interval 95%)
    59.15 (50.60 to 67.32)
    Notes
    [7] - FAS
    No statistical analyses for this end point

    Primary: ORR Based on Investigator Assessment-Part A

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    End point title
    ORR Based on Investigator Assessment-Part A [8] [9]
    End point description
    Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.
    End point type
    Primary
    End point timeframe
    Baseline up to the last patient has completed the 16 weeks of treatment
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    32 [10]
    48 [11]
    Units: Percentage
        number (confidence interval 90%)
    46.88 (31.54 to 62.66)
    31.25 (20.35 to 43.97)
    Notes
    [10] - PPS
    [11] - PPS
    No statistical analyses for this end point

    Primary: ORR Based on Investigator Assessment-Part B

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    End point title
    ORR Based on Investigator Assessment-Part B [12] [13]
    End point description
    Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
    End point type
    Primary
    End point timeframe
    Baseline up to the last patient has completed the 16 weeks of treatment
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [13] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    142 [14]
    Units: Percentage
        number (confidence interval 95%)
    51.41 (42.88 to 59.87)
    Notes
    [14] - FAS
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Based on Independent Review-Part A

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    End point title
    Duration of Response (DOR) Based on Independent Review-Part A [15]
    End point description
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as ‘caused by disease progression’ except deaths with the reason “other” or “AE not related to disease progression. "99999" denotes value can't be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    Notes
    [15] - 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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    14 [16]
    14 [17]
    Units: Days
        median (confidence interval 95%)
    322 (61 to 99999)
    99999 (61 to 99999)
    Notes
    [16] - PPS
    [17] - PPS
    No statistical analyses for this end point

    Secondary: DOR Based on Independent Review-Part B

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    End point title
    DOR Based on Independent Review-Part B [18]
    End point description
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as ‘caused by disease progression’ except deaths with the reason “other” or “AE not related to disease progression.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 10 years
    Notes
    [18] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    85 [19]
    Units: Months
        median (confidence interval 95%)
    14.9 (9.2 to 22.6)
    Notes
    [19] - FAS
    No statistical analyses for this end point

    Secondary: DOR Based on Investigator Assessment-Part A

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    End point title
    DOR Based on Investigator Assessment-Part A [20]
    End point description
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as ‘caused by disease progression’ except deaths with the reason “other” or “AE not related to disease progression. "99999" denotes value can't be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    Notes
    [20] - 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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    15 [21]
    15 [22]
    Units: Days
        median (confidence interval 95%)
    189 (56 to 574)
    190 (112 to 99999)
    Notes
    [21] - PPS
    [22] - PPS
    No statistical analyses for this end point

    Secondary: DOR Based on Investigator Assessment-Part B

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    End point title
    DOR Based on Investigator Assessment-Part B [23]
    End point description
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as ‘caused by disease progression’ except deaths with the reason “other” or “AE not related to disease progression.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 10 years
    Notes
    [23] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    78 [24]
    Units: Months
        median (confidence interval 95%)
    11.5 (9.2 to 16.1)
    Notes
    [24] - PPS
    No statistical analyses for this end point

    Secondary: PFS Based on Investigator Assessment-Part A

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    End point title
    PFS Based on Investigator Assessment-Part A [25]
    End point description
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    Notes
    [25] - 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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    33 [26]
    51 [27]
    Units: Days
        median (confidence interval 95%)
    224 (172 to 419)
    70 (47 to 115)
    Notes
    [26] - FAS
    [27] - FAS
    No statistical analyses for this end point

    Secondary: PFS Based on Independent Review-Part B

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    End point title
    PFS Based on Independent Review-Part B [28]
    End point description
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 10 years
    Notes
    [28] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    142
    Units: Months
        median (confidence interval 95%)
    11.3 (8.1 to 17.6)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Based on Independent Review-Part A

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    End point title
    Progression Free Survival (PFS) Based on Independent Review-Part A [29]
    End point description
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    Notes
    [29] - 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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    33 [30]
    51 [31]
    Units: Days
        median (confidence interval 95%)
    223 (147 to 546)
    70 (47 to 115)
    Notes
    [30] - FAS
    [31] - FAS
    No statistical analyses for this end point

    Secondary: PFS Based on Investigator Assessment-Part B

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    End point title
    PFS Based on Investigator Assessment-Part B [32]
    End point description
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 10 years
    Notes
    [32] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    142 [33]
    Units: Months
        median (confidence interval 95%)
    10.8 (7.2 to 12.8)
    Notes
    [33] - FAS
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy – Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B

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    End point title
    Functional Assessment of Cancer Therapy – Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B [34]
    End point description
    HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table “n” signifies evaluable participants for the respective category.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    Notes
    [34] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    141 [35]
    Units: units on a scale
    median (inter-quartile range (Q1-Q3))
        Baseline
    46.50 (40.50 to 52.00)
        Value at Week 16
    49.00 (42.00 to 54.00)
    Notes
    [35] - FAS; Baseline N=132; Week 16 N=141
    No statistical analyses for this end point

    Secondary: OS-Part B

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    End point title
    OS-Part B [36]
    End point description
    OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. "99999" denotes value can't be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 10 years
    Notes
    [36] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    142 [37]
    Units: Months
        median (confidence interval 95%)
    59.1 (36.5 to 99999)
    Notes
    [37] - FAS
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)-Part A

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    End point title
    Overall Survival (OS)-Part A [38]
    End point description
    OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. "99999" denotes value can't be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    Notes
    [38] - 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: This endpoint analysis is only for part A arms.
    End point values
    Part A: Indolent NHL/CLL Part A: Aggressive NHL
    Number of subjects analysed
    33 [39]
    51 [40]
    Units: Days
        median (confidence interval 95%)
    657 (391 to 99999)
    211 (140 to 399)
    Notes
    [39] - FAS
    [40] - FAS
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) total score at Week 16 - Part B

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    End point title
    Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) total score at Week 16 - Part B [41]
    End point description
    HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table “n” signifies evaluable participants for the respective category.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    Notes
    [41] - 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: This endpoint analysis is only for part B arms.
    End point values
    Part B: Indolent NHL
    Number of subjects analysed
    141 [42]
    Units: units on a scale
    median (inter-quartile range (Q1-Q3))
        Baseline
    127.50 (113.75 to 145.75)
        Value at Week 16
    130.83 (113.33 to 146.50)
    Notes
    [42] - FAS; Baseline N=132; Week 16 N=141
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first study intervention up to 35 days after the end of study intervention, Part A: approximately 6 years. Part B: approximately 10 years.
    Adverse event reporting additional description
    Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact, Part A: approximately 6 years. Part B: approximately 10 years.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Part A: Indolent NHL/CLL
    Reporting group description
    Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part B: Indolent NHL
    Reporting group description
    Subjects with indolent B-cell NHL received copanlisib fixed 60 mg or 0.8 mg/kg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Reporting group title
    Part A: Aggressive NHL
    Reporting group description
    Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.

    Serious adverse events
    Part A: Indolent NHL/CLL Part B: Indolent NHL Part A: Aggressive NHL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 33 (48.48%)
    81 / 142 (57.04%)
    31 / 51 (60.78%)
         number of deaths (all causes)
    21
    75
    39
         number of deaths resulting from adverse events
    3
    6
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour compression
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Porocarcinoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Tumour flare
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Basal cell carcinoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Superficial vein thrombosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Surgical and medical procedures
    Preoperative care
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 142 (1.41%)
    4 / 51 (7.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 33 (3.03%)
    9 / 142 (6.34%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Fatigue
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Reproductive system and breast disorders
    Scrotal swelling
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 142 (4.23%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Lung disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Organising pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Respiratory failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Neutrophil count decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 142 (1.41%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Biliary-vascular fistula
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Afferent loop syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Femur fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Limb injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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%)
    3 / 142 (2.11%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 142 (2.82%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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%)
    1 / 142 (0.70%)
    0 / 51 (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
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 142 (2.82%)
    3 / 51 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Melaena
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Stomatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Cholangitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Groin pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Back pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Bronchitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Cellulitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pneumonia viral
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pneumonia
         subjects affected / exposed
    4 / 33 (12.12%)
    20 / 142 (14.08%)
    4 / 51 (7.84%)
         occurrences causally related to treatment / all
    2 / 4
    20 / 25
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    3 / 51 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Influenza
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (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
    Herpes zoster
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Cryptococcosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Rectal abscess
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis aspergillus
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Enterocolitis infectious
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pneumonia fungal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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 tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Systemic infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Varicella zoster pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 142 (0.70%)
    0 / 51 (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
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 142 (1.41%)
    0 / 51 (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
    Diabetes mellitus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    7 / 142 (4.93%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: Indolent NHL/CLL Part B: Indolent NHL Part A: Aggressive NHL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    138 / 142 (97.18%)
    50 / 51 (98.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 33 (69.70%)
    42 / 142 (29.58%)
    24 / 51 (47.06%)
         occurrences all number
    94
    330
    82
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 33 (48.48%)
    36 / 142 (25.35%)
    14 / 51 (27.45%)
         occurrences all number
    20
    41
    15
    Chills
         subjects affected / exposed
    2 / 33 (6.06%)
    12 / 142 (8.45%)
    1 / 51 (1.96%)
         occurrences all number
    2
    13
    1
    Chest pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 142 (1.41%)
    3 / 51 (5.88%)
         occurrences all number
    1
    2
    4
    Influenza like illness
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 142 (4.23%)
    2 / 51 (3.92%)
         occurrences all number
    2
    6
    2
    Asthenia
         subjects affected / exposed
    8 / 33 (24.24%)
    11 / 142 (7.75%)
    6 / 51 (11.76%)
         occurrences all number
    13
    14
    6
    Mucosal inflammation
         subjects affected / exposed
    4 / 33 (12.12%)
    10 / 142 (7.04%)
    6 / 51 (11.76%)
         occurrences all number
    5
    17
    8
    Oedema peripheral
         subjects affected / exposed
    3 / 33 (9.09%)
    12 / 142 (8.45%)
    2 / 51 (3.92%)
         occurrences all number
    7
    14
    2
    Pyrexia
         subjects affected / exposed
    10 / 33 (30.30%)
    35 / 142 (24.65%)
    8 / 51 (15.69%)
         occurrences all number
    14
    54
    22
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 142 (2.82%)
    2 / 51 (3.92%)
         occurrences all number
    2
    5
    3
    Productive cough
         subjects affected / exposed
    3 / 33 (9.09%)
    10 / 142 (7.04%)
    3 / 51 (5.88%)
         occurrences all number
    3
    12
    3
    Nasal congestion
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 142 (2.82%)
    0 / 51 (0.00%)
         occurrences all number
    3
    5
    0
    Epistaxis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 142 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    0
    3
    Dyspnoea exertional
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 142 (2.82%)
    1 / 51 (1.96%)
         occurrences all number
    3
    4
    1
    Dyspnoea
         subjects affected / exposed
    4 / 33 (12.12%)
    11 / 142 (7.75%)
    4 / 51 (7.84%)
         occurrences all number
    4
    11
    4
    Cough
         subjects affected / exposed
    7 / 33 (21.21%)
    27 / 142 (19.01%)
    6 / 51 (11.76%)
         occurrences all number
    13
    45
    6
    Oropharyngeal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    15 / 142 (10.56%)
    2 / 51 (3.92%)
         occurrences all number
    1
    20
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 142 (5.63%)
    3 / 51 (5.88%)
         occurrences all number
    0
    8
    3
    Anxiety
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 142 (2.82%)
    3 / 51 (5.88%)
         occurrences all number
    0
    5
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 33 (3.03%)
    6 / 142 (4.23%)
    4 / 51 (7.84%)
         occurrences all number
    1
    6
    5
    Blood glucose increased
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences all number
    5
    42
    0
    Eosinophil count increased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    Lipase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 142 (5.63%)
    2 / 51 (3.92%)
         occurrences all number
    4
    9
    2
    Neutrophil count decreased
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 142 (4.93%)
    1 / 51 (1.96%)
         occurrences all number
    15
    19
    2
    Platelet count decreased
         subjects affected / exposed
    5 / 33 (15.15%)
    13 / 142 (9.15%)
    4 / 51 (7.84%)
         occurrences all number
    5
    16
    4
    Weight decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    9 / 142 (6.34%)
    2 / 51 (3.92%)
         occurrences all number
    0
    9
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    8 / 142 (5.63%)
    0 / 51 (0.00%)
         occurrences all number
    1
    8
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences all number
    2
    2
    0
    Nervous system disorders
    Taste disorder
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    1
    Somnolence
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 142 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Paraesthesia
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 142 (2.82%)
    1 / 51 (1.96%)
         occurrences all number
    3
    5
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 33 (3.03%)
    6 / 142 (4.23%)
    3 / 51 (5.88%)
         occurrences all number
    1
    6
    3
    Headache
         subjects affected / exposed
    7 / 33 (21.21%)
    14 / 142 (9.86%)
    9 / 51 (17.65%)
         occurrences all number
    9
    22
    12
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 142 (2.82%)
    3 / 51 (5.88%)
         occurrences all number
    4
    5
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 33 (33.33%)
    27 / 142 (19.01%)
    12 / 51 (23.53%)
         occurrences all number
    21
    43
    13
    Lymphopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 142 (5.63%)
    0 / 51 (0.00%)
         occurrences all number
    0
    16
    0
    Thrombocytopenia
         subjects affected / exposed
    3 / 33 (9.09%)
    21 / 142 (14.79%)
    3 / 51 (5.88%)
         occurrences all number
    3
    30
    3
    Neutropenia
         subjects affected / exposed
    9 / 33 (27.27%)
    40 / 142 (28.17%)
    15 / 51 (29.41%)
         occurrences all number
    12
    117
    25
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 142 (0.70%)
    3 / 51 (5.88%)
         occurrences all number
    3
    1
    3
    Diarrhoea
         subjects affected / exposed
    13 / 33 (39.39%)
    51 / 142 (35.92%)
    21 / 51 (41.18%)
         occurrences all number
    65
    98
    39
    Constipation
         subjects affected / exposed
    5 / 33 (15.15%)
    18 / 142 (12.68%)
    8 / 51 (15.69%)
         occurrences all number
    7
    21
    11
    Abdominal pain upper
         subjects affected / exposed
    3 / 33 (9.09%)
    11 / 142 (7.75%)
    3 / 51 (5.88%)
         occurrences all number
    4
    16
    3
    Abdominal pain
         subjects affected / exposed
    4 / 33 (12.12%)
    10 / 142 (7.04%)
    1 / 51 (1.96%)
         occurrences all number
    6
    10
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 142 (3.52%)
    2 / 51 (3.92%)
         occurrences all number
    2
    5
    2
    Vomiting
         subjects affected / exposed
    5 / 33 (15.15%)
    20 / 142 (14.08%)
    5 / 51 (9.80%)
         occurrences all number
    10
    25
    7
    Stomatitis
         subjects affected / exposed
    4 / 33 (12.12%)
    14 / 142 (9.86%)
    4 / 51 (7.84%)
         occurrences all number
    6
    24
    4
    Oral pain
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 142 (2.11%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    3
    Nausea
         subjects affected / exposed
    10 / 33 (30.30%)
    33 / 142 (23.24%)
    18 / 51 (35.29%)
         occurrences all number
    17
    45
    22
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 33 (3.03%)
    7 / 142 (4.93%)
    3 / 51 (5.88%)
         occurrences all number
    1
    10
    3
    Rash
         subjects affected / exposed
    5 / 33 (15.15%)
    14 / 142 (9.86%)
    6 / 51 (11.76%)
         occurrences all number
    6
    31
    8
    Pruritus
         subjects affected / exposed
    3 / 33 (9.09%)
    14 / 142 (9.86%)
    3 / 51 (5.88%)
         occurrences all number
    3
    37
    5
    Hyperhidrosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 142 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    Erythema
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 142 (1.41%)
    3 / 51 (5.88%)
         occurrences all number
    3
    3
    3
    Eczema
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 142 (2.82%)
    2 / 51 (3.92%)
         occurrences all number
    4
    10
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 142 (1.41%)
    0 / 51 (0.00%)
         occurrences all number
    2
    2
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    7 / 33 (21.21%)
    12 / 142 (8.45%)
    3 / 51 (5.88%)
         occurrences all number
    10
    17
    5
    Back pain
         subjects affected / exposed
    2 / 33 (6.06%)
    14 / 142 (9.86%)
    4 / 51 (7.84%)
         occurrences all number
    4
    22
    4
    Arthralgia
         subjects affected / exposed
    5 / 33 (15.15%)
    14 / 142 (9.86%)
    5 / 51 (9.80%)
         occurrences all number
    6
    15
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 33 (12.12%)
    16 / 142 (11.27%)
    5 / 51 (9.80%)
         occurrences all number
    10
    22
    8
    Conjunctivitis
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 142 (4.23%)
    1 / 51 (1.96%)
         occurrences all number
    4
    9
    2
    Cystitis
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 142 (0.70%)
    1 / 51 (1.96%)
         occurrences all number
    5
    1
    1
    Herpes zoster
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 142 (2.11%)
    1 / 51 (1.96%)
         occurrences all number
    2
    4
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 142 (2.82%)
    3 / 51 (5.88%)
         occurrences all number
    1
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    1 / 33 (3.03%)
    9 / 142 (6.34%)
    2 / 51 (3.92%)
         occurrences all number
    2
    16
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 142 (4.23%)
    3 / 51 (5.88%)
         occurrences all number
    0
    7
    3
    Pneumonia
         subjects affected / exposed
    3 / 33 (9.09%)
    12 / 142 (8.45%)
    2 / 51 (3.92%)
         occurrences all number
    3
    14
    2
    Rhinitis
         subjects affected / exposed
    1 / 33 (3.03%)
    9 / 142 (6.34%)
    1 / 51 (1.96%)
         occurrences all number
    1
    13
    1
    Sinusitis
         subjects affected / exposed
    1 / 33 (3.03%)
    10 / 142 (7.04%)
    2 / 51 (3.92%)
         occurrences all number
    1
    13
    4
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    22 / 142 (15.49%)
    2 / 51 (3.92%)
         occurrences all number
    2
    45
    2
    Urinary tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    7 / 142 (4.93%)
    7 / 51 (13.73%)
         occurrences all number
    6
    10
    7
    Oral herpes
         subjects affected / exposed
    1 / 33 (3.03%)
    9 / 142 (6.34%)
    2 / 51 (3.92%)
         occurrences all number
    2
    13
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 33 (15.15%)
    15 / 142 (10.56%)
    7 / 51 (13.73%)
         occurrences all number
    6
    15
    8
    Hypophosphataemia
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 142 (2.82%)
    4 / 51 (7.84%)
         occurrences all number
    2
    10
    4
    Hyperglycaemia
         subjects affected / exposed
    21 / 33 (63.64%)
    71 / 142 (50.00%)
    27 / 51 (52.94%)
         occurrences all number
    88
    515
    55
    Hypokalaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    11 / 142 (7.75%)
    5 / 51 (9.80%)
         occurrences all number
    3
    11
    5
    Hypomagnesaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    10 / 142 (7.04%)
    2 / 51 (3.92%)
         occurrences all number
    1
    11
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2013
    Amendment 2: Inclusion criteria: the wording of the inclusion criterion applicable for patients with aggressive NHL was slightly changed to clarify that patients who failed first line chemo /immunotherapy but who were not eligible for a high dose regimen followed by transplant were considered suitable for the study even if they had undergone only one previous treatment. Introduction of mandatory collection of archival tumor tissue for biomarker analysis. Introduction of the ECG sub-study at the request of Food and Drug Administration (FDA). Exclusion criteria: Patients affected by central nervous system lymphoma involvement were excluded from the study. Clarification of the requirement to perform CT/MRI to all suspected sites of disease. Clarification of the tumor response evaluation criteria: CT/MRI was to be required at EOT if a patient discontinued due to progressive disease in order to radiologically assess such progression. Imaging was not required if progressive disease was radiologically evaluated within previous 4 weeks. Inclusion of interstitial lung disease and pneumonitis as AEs of special safety interest based on recently available data from Phase I studies.
    28 Mar 2013
    Amendment 3: Introduction of study Part B: New cohort (extension cohort) of patients with FL was added (further changes related only to study Part B are not listed below). Introduction of mandatory collection of fresh biopsies from patients with aggressive lymphoma. Introduction of the possibility to re-screen patients. Replacement criteria: Patients whose participation was terminated due to disease progression before the first evaluable post-baseline tumor evaluation could be replaced. Specification of validity of signed informed consent: It was clarified that the maximum allowed interval between signing of informed consent and start of treatment was 28 days. Inclusion and exclusion criteria: patients with transformed indolent lymphoma must have received at least 2 prior chemotherapy- and/or immunotherapy-based regimens. The measurable lesion must not have been previously irradiated. Inclusion criterion related to alkaline phosphatase was removed. Exclusion criterion related to dehydration was removed. Open biopsy was excluded within the previous 7 days before start of study medication. Wording of the exclusion criterion referring to phaeochromocytoma was clarified. Changes in the laboratory analyses: Bands were removed as a parameter for differential white blood cell count and turbidity was added to the urinalysis parameters. Urea could now be measured alternatively to BUN (blood urea nitrogen) if BUN was not routinely measured at the site. Additional PK sampling was added for patients participating in the ECG sub-study.
    17 Feb 2014
    Amendment 4: following modifications applicable to study Part A: It was specified that the end of the safety follow-up would take place 35 days after the last study drug administration. Inclusion criteria: An additional T-cell histotype was added to the inclusion criteria for patients with aggressive NHL and a previously existing histotype was further specified according to the World Health Organization (WHO) classification. Exclusion criteria: The requirement for laboratory screening for hepatitis B and C to be carried out up to 28 days before starting the study drug administration was added. Text was included which only allowed the use of short acting insulin for the treatment of transient hyperglycemia and not permitting prophylactic administration of short acting insulin prior to copanlisib infusion. Dose modification guidance was clarified in case of skin toxicity (since some rash events were reported in Part A of the study) and non-infectious pneumonitis. Additional assessments were included for hepatitis to be performed 28 days prior to the first administration of study drug to be consistent with the protocol’s exclusion criteria regarding known history of chronic hepatitis B or C. Statistical analysis text regarding additional aggressive NHL patients was amended. Data for these patients was to be analyzed separately from the patients in the primary analysis, i.e., 16 weeks after the last of these patients started treatment. In addition, these patients were to be analyzed in separate FAS (full analysis set), SAF (safety analysis set) and PPS (per protocol set) analysis sets. Definition of duration of response (DOR) was amended to state that duration of response is defined as the time from the date of first observed tumor response (CR or PR) until first subsequent disease progression or until death “due to any cause”. In addition, unconfirmed responses were also to be included in the analysis.
    04 Jul 2014
    Amendment 5: following modifications applicable to study Part A: Collection of tumor tissue was clarified: For patients with aggressive NHL, fresh tissue was mandatory. For all patients: If the patient has undergone a fresh biopsy for any reason and archival tumor tissue is not available, fresh biopsy is sufficient for central pathology review and biomarker analysis. The text describing conditions for withdrawal from study treatment was clarified to reduce occurrence of screening failures. In addition, withdrawal criterion for drug-induced pancreatitis was added. It was clarified that phenytoin, carbamazepine and phenobarbital were prohibited medications. Text regarding AEs of special safety interest was clarified. Unspecific interstitial lung disease (ILD) was removed as it had not been observed within the copanlisib program. All observed cases of ILD were likely attributable to non-infectious pneumonitis, which remained as an AE of special safety interest.
    25 Aug 2015
    Amendment 7: It introduced changes to the Part B integrated protocol, Part A integrated protocol remained unchanged, except for two administrative changes.
    20 Oct 2015
    Amendment 8: The amendment introduced changes to the Part B integrated protocol. The Part A integrated protocol remained unchanged.
    18 Jul 2016
    Amendment 9: following modifications applicable to study Part A: Enhanced monitoring of respiratory symptoms. Added monitoring guidelines for opportunistic infection prophylaxis.
    11 Apr 2017
    Amendment 10: following modifications applicable to study Part A: Extended the possibility to collect tumor assessment data for beyond 3 years. Identified a new Sponsor’s Medical Expert.
    21 Nov 2017
    Amendment 11: Replacement of 80 mg vials with 60 mg vials.
    31 Jan 2019
    Amendment 13: Extend the study from 3 to 4 years after the last patient started study treatment.
    02 Mar 2022
    Amendment 14: Extend the study up to 4 years after the last patient has completed study treatment.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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