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    Clinical Trial Results:
    A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin’s lymphoma (iNHL) – CHRONOS-3

    Summary
    EudraCT number
    		 2013-003893-29
    Trial protocol
    		 IE   PT   DE   ES   BE   LT   HU   AT   DK   FR   BG   LU   GR   SK   IT   RO  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    12 Sep 2021
    First version publication date
    12 Sep 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY806946/17067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02367040
    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, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, 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
    Interim
    Date of interim/final analysis
    31 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression-free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all 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
    03 Aug 2015
    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
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Brazil: 28
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    China: 81
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Turkey: 26
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Vietnam: 4
    Worldwide total number of subjects
    458
    EEA total number of subjects
    130
    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)
    255
    From 65 to 84 years
    197
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at multiple centers in North America, South America, South Africa, Europe, Asia, and Australia between 03 August 2015 (first subject first visit) and 31 August 2020 (primary completion date).

    Pre-assignment
    Screening details
    		 Overall, 652 were screened and total of 458 participants were randomized in a 2:1 ratio to study treatment: 307 participants to copanlisib /rituximab and 151 participants to placebo/rituximab.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Copanlisib + Rituximab
    Arm description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib is supplied as lyophilized preparation in a 6 ml injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.

    Arm title
    		 Placebo + Rituximab
    Arm description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo is supplied as lyophilized preparation in a 6 ml injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.

    Number of subjects in period 1
    		Copanlisib + Rituximab Placebo + Rituximab
    Started
    307
    151
    Received treatment
    304
    149
    Completed
    70
    29
    Not completed
    237
    122
         Progressive disease – radiological progression
    39
    67
         AE associated with clinical disease progression
    1
    3
         Physician decision
    2
    8
         Drug not administered
    3
    2
         Randomized by mistake with study treatment
    1
    -
         AE not associated clinical disease progression
    104
    9
         Failure to meet continuation criteria
    1
    -
         Progressive disease – clinical progression
    2
    6
         Consent withdrawn by subject
    41
    14
         Patient decision
    35
    11
         Non-compliance with study drug
    1
    -
         Switching to other therapy
    2
    -
         Lost to follow-up
    1
    1
         Patient decision: COVID-19 pandemic related
    1
    -
         Required procedure failed
    1
    -
         Lack of efficacy
    1
    -
         Protocol deviation
    1
    -
         Additional primary malignancy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Reporting group values
    		 Copanlisib + Rituximab Placebo + Rituximab Total
    Number of subjects
    		 307 151 458
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 167 88 255
        From 65-84 years
    		 140 63 203
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.0 ( 12.1 ) 61.5 ( 11.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 154 66 220
        Male
    		 153 85 238
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 4 7
        Asian
    		 125 50 175
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 1 5
        White
    		 164 89 253
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 11 7 18
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 29 26 55
        Not Hispanic or Latino
    		 262 118 380
        Unknown or Not Reported
    		 16 7 23
    Eastern cooperative oncology group (ECOG) Performance Status (PS)
    ECOG PS was measured in a scale from 0 (best) to grade 2 , where 0= Fully active, able to carry on all pre-diseases performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours (h).
    Units: Subjects
        0 – Fully active
    		 182 95 277
        1 – Restricted active
    		 113 55 168
        2 – Ambulatory and capable of all self-care
    		 12 1 13

    End points

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    End points reporting groups
    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Primary: Progression free survival (PFS) based on independent central review.

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    End point title
    		 Progression free survival (PFS) based on independent central review.
    End point description
    Progression-free survival (PFS), was defined as the time (in days) from randomization to progressive disease (PD) or death from any cause (if no progression was documented), whichever occurred earlier. PFS for patients without progression or death at the time of analysis was censored at the last actual date of tumor assessment or last biochemical assessment for patients with Waldenstrom macroglobulinemia (WM) without lesions evaluable by imaging.
    End point type
    Primary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
        median (confidence interval 95%)
    21.5 (17.8 to 33.0)
    13.8 (10.2 to 17.5)
    Statistical analysis title
    		 Progression free survival (PFS)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.000002 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.393
         upper limit
    		 0.688
    Notes
    [1] - PFS was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [2] - 1-sided p-value

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate (ORR) was defined as the percentage of patients who had a best response rating over the whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Cheson 2014 criteria and for patients with Waldenström macroglobulinemia (WM) a response rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen criteria.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of participants
        number (not applicable)
    80.8
    47.7
    Statistical analysis title
    		 Objective response rate (ORR)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.000001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR
    Point estimate
    32.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23.95
         upper limit
    		 42.03
    Notes
    [3] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [4] - 1-sided p-value

    Secondary: Complete response rate (CRR)

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    End point title
    		 Complete response rate (CRR)
    End point description
    Complete response rate (CRR) was assessed in all patients up to the time of analysis of PFS. CRR was defined as the proportion of patients who had a best response rating over the whole duration of the study (i.e., until the time of analysis of PFS) of CR according to the Cheson 2014 criteria and for patients with Waldenstrom macroglobulinemia (WM) a response rating of CR according to the Owen criteria.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of participants
        number (not applicable)
    33.9
    14.6
    Statistical analysis title
    		 Complete response rate (CRR)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.000001 [6]
    Method
    		 Logrank
    Parameter type
    		 Difference in CRR
    Point estimate
    19.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.57
         upper limit
    		 26.96
    Notes
    [5] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified.
    [6] - 1-sided p-value

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    Duration of response (DOR) was defined as the time (in days) from first observed tumor response (Complete Response (CR), Very good partial response (VGPR), Partial Response (PR) or Minor Response(MR) until progression or death from any cause, whichever occurred earlier. DOR was only defined for patients with at least one CR, VGPR, PR, or MR.
    End point type
    Secondary
    End point timeframe
    From randomization to to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
        median (confidence interval 95%)
    20.4 (17.0 to 30.8)
    17.3 (11.8 to 25.3)
    Statistical analysis title
    		 Duration of response (DOR)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.058262 [8]
    Method
    		 Logrank
    Parameter type
    		 Difference in DOR
    Point estimate
    0.741
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.508
         upper limit
    		 1.079
    Notes
    [7] - DOR was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [8] - 1-sided p-value

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    Disease control rate (DCR) was defined as the proportion of patients who had a best response rating of complete response (CR), very good partial response (VGPR), partial response (PR) according or minor response (MR) or stable disease (SD) (excluding unconfirmed early SD [uSD]) that was achieved during treatment or within 35 days after termination of study treatment. The uSD was defined as SD on or before Study Day 48.
    End point type
    Secondary
    End point timeframe
    From randomization to to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of participants
        number (not applicable)
    89.3
    84.8
    Statistical analysis title
    		 Disease control rate (DCR)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.097339 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 11.12
    Notes
    [9] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [10] - 1-sided p-value

    Secondary: Time to progression (TTP)

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    End point title
    		 Time to progression (TTP)
    End point description
    Time to progression (TTP) was defined as the time (in days) from randomization to progression or death related to progression, whichever occurred earlier.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
        median (confidence interval 95%)
    22.3 (19.4 to 33.2)
    13.8 (10.8 to 18.7)
    Statistical analysis title
    		 Time to progression (TTP)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.000001 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.357
         upper limit
    		 0.635
    Notes
    [11] - TTP was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [12] - 1-sided p-value

    Secondary: Overall survival (OS) till Primary Completion date.

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    End point title
    		 Overall survival (OS) till Primary Completion date.
    End point description
    Overall survival (OS) was defined as the time (in days) from randomization until death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020.
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307 [13]
    151 [14]
    Units: Months
        median (confidence interval 95%)
    57.4 (-99999 to 99999)
    99999 (-99999 to 99999)
    Notes
    [13] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    [14] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    Statistical analysis title
    		 Overall survival (OS)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.597747 [16]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.628
         upper limit
    		 1.821
    Notes
    [15] - OS was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [16] - 1-sided p-value

    Secondary: Time to deterioration in DRS-P (Disease-Related Symptoms –Physical) of at least three points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.

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    End point title
    		 Time to deterioration in DRS-P (Disease-Related Symptoms –Physical) of at least three points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.
    End point description
    Time to deterioration in DRS-P (Disease-Related Symptoms –Physical) of at least three points was defined as the time (in days) from randomization to DRS-P decline, progression, or death due to any reason, whichever occurred earlier.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
        median (confidence interval 95%)
    5.5 (4.2 to 5.9)
    5.5 (4.0 to 7.4)
    Statistical analysis title
    		 Time to deterioration in DRS-P
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.69261 [18]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.843
         upper limit
    		 1.331
    Notes
    [17] - Time to deterioration in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [18] - 1-sided p-value

    Secondary: Time to improvement in DRS-P (Disease-Related Symptoms –Physical) of at least 3 points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.

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    End point title
    		 Time to improvement in DRS-P (Disease-Related Symptoms –Physical) of at least 3 points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.
    End point description
    Time to improvement in DRS-P (Disease-Related Symptoms –Physical) was defined as the time (in days) from randomization to DRS-P improvement of at least three points.
    End point type
    Secondary
    End point timeframe
    From randomization to 31-Aug-2020
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307 [19]
    151 [20]
    Units: Months
        median (confidence interval 95%)
    99999 (8.3 to 99999)
    99999 (6.0 to 99999)
    Notes
    [19] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    [20] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    Statistical analysis title
    		 Time to improvement in DRS-P
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.510038 [22]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.996
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.732
         upper limit
    		 1.355
    Notes
    [21] - Time to improvement in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [22] - 1-sided p-value

    Secondary: Number of participants with treatment-emergent adverse events (TEAEs).

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    End point title
    		 Number of participants with treatment-emergent adverse events (TEAEs).
    End point description
    Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after end of treatment with study drug
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    146
    Units: Participants
        Any TEAEs
    307
    134
        Any copanlisib- or placebo-related TEAE
    293
    95
        Any rituximab-related TEAE
    218
    92
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study drug until 30 days after the last study drug intake.
    Adverse event reporting additional description
    Three patients were randomized to the placebo/rituximab arm but received at least one dose of copanlisib by mistake. These patients were included in the copanlisib/rituximab arm in the analysis of safety variables.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Serious adverse events
    		 Placebo + Rituximab Copanlisib + Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 146 (18.49%)
    145 / 307 (47.23%)
         number of deaths (all causes)
    20
    43
         number of deaths resulting from adverse events
    1
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthrodesis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral stent removal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 146 (0.00%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Administration site extravasation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis chronic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 146 (0.00%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 146 (2.74%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 146 (0.00%)
    15 / 307 (4.89%)
         occurrences causally related to treatment / all
    0 / 0
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Idiopathic interstitial pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 146 (0.00%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Dislocation of vertebra
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eustachian valve hypertrophy
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 146 (2.05%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enteritis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 146 (0.68%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parvovirus B19 infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 146 (3.42%)
    17 / 307 (5.54%)
         occurrences causally related to treatment / all
    4 / 5
    10 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 146 (1.37%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 146 (0.68%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Penile infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 146 (0.00%)
    21 / 307 (6.84%)
         occurrences causally related to treatment / all
    0 / 0
    27 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Rituximab Copanlisib + Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    122 / 146 (83.56%)
    296 / 307 (96.42%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 146 (6.85%)
    25 / 307 (8.14%)
         occurrences all number
    19
    30
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 146 (6.16%)
    25 / 307 (8.14%)
         occurrences all number
    15
    37
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 146 (4.79%)
    23 / 307 (7.49%)
         occurrences all number
    9
    36
    Lipase increased
         subjects affected / exposed
    4 / 146 (2.74%)
    17 / 307 (5.54%)
         occurrences all number
    11
    26
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 146 (6.16%)
    38 / 307 (12.38%)
         occurrences all number
    37
    107
    Weight decreased
         subjects affected / exposed
    4 / 146 (2.74%)
    45 / 307 (14.66%)
         occurrences all number
    5
    63
    Platelet count decreased
         subjects affected / exposed
    12 / 146 (8.22%)
    40 / 307 (13.03%)
         occurrences all number
    22
    107
    Neutrophil count decreased
         subjects affected / exposed
    34 / 146 (23.29%)
    101 / 307 (32.90%)
         occurrences all number
    73
    410
    White blood cell count decreased
         subjects affected / exposed
    16 / 146 (10.96%)
    61 / 307 (19.87%)
         occurrences all number
    51
    293
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 146 (19.18%)
    151 / 307 (49.19%)
         occurrences all number
    94
    710
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 146 (6.16%)
    42 / 307 (13.68%)
         occurrences all number
    19
    67
    Dysgeusia
         subjects affected / exposed
    1 / 146 (0.68%)
    20 / 307 (6.51%)
         occurrences all number
    1
    27
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    24 / 146 (16.44%)
    63 / 307 (20.52%)
         occurrences all number
    57
    202
    Anaemia
         subjects affected / exposed
    15 / 146 (10.27%)
    57 / 307 (18.57%)
         occurrences all number
    53
    127
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 146 (2.74%)
    21 / 307 (6.84%)
         occurrences all number
    6
    27
    Chills
         subjects affected / exposed
    7 / 146 (4.79%)
    20 / 307 (6.51%)
         occurrences all number
    10
    29
    Fatigue
         subjects affected / exposed
    10 / 146 (6.85%)
    42 / 307 (13.68%)
         occurrences all number
    15
    48
    Mucosal inflammation
         subjects affected / exposed
    2 / 146 (1.37%)
    18 / 307 (5.86%)
         occurrences all number
    2
    23
    Pyrexia
         subjects affected / exposed
    11 / 146 (7.53%)
    59 / 307 (19.22%)
         occurrences all number
    18
    88
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 146 (8.22%)
    30 / 307 (9.77%)
         occurrences all number
    14
    33
    Mouth ulceration
         subjects affected / exposed
    4 / 146 (2.74%)
    19 / 307 (6.19%)
         occurrences all number
    6
    27
    Diarrhoea
         subjects affected / exposed
    14 / 146 (9.59%)
    103 / 307 (33.55%)
         occurrences all number
    18
    229
    Nausea
         subjects affected / exposed
    17 / 146 (11.64%)
    69 / 307 (22.48%)
         occurrences all number
    25
    114
    Stomatitis
         subjects affected / exposed
    4 / 146 (2.74%)
    39 / 307 (12.70%)
         occurrences all number
    9
    53
    Vomiting
         subjects affected / exposed
    5 / 146 (3.42%)
    44 / 307 (14.33%)
         occurrences all number
    5
    61
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 146 (11.64%)
    45 / 307 (14.66%)
         occurrences all number
    28
    63
    Dyspnoea
         subjects affected / exposed
    11 / 146 (7.53%)
    17 / 307 (5.54%)
         occurrences all number
    15
    17
    Oropharyngeal pain
         subjects affected / exposed
    6 / 146 (4.11%)
    17 / 307 (5.54%)
         occurrences all number
    7
    19
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 146 (0.68%)
    17 / 307 (5.54%)
         occurrences all number
    1
    18
    Rash maculo-papular
         subjects affected / exposed
    3 / 146 (2.05%)
    19 / 307 (6.19%)
         occurrences all number
    4
    30
    Pruritus
         subjects affected / exposed
    9 / 146 (6.16%)
    30 / 307 (9.77%)
         occurrences all number
    11
    36
    Rash
         subjects affected / exposed
    10 / 146 (6.85%)
    35 / 307 (11.40%)
         occurrences all number
    13
    49
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 146 (2.74%)
    17 / 307 (5.54%)
         occurrences all number
    4
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 146 (4.79%)
    19 / 307 (6.19%)
         occurrences all number
    10
    20
    Back pain
         subjects affected / exposed
    13 / 146 (8.90%)
    17 / 307 (5.54%)
         occurrences all number
    16
    19
    Myalgia
         subjects affected / exposed
    9 / 146 (6.16%)
    8 / 307 (2.61%)
         occurrences all number
    10
    10
    Muscle spasms
         subjects affected / exposed
    2 / 146 (1.37%)
    18 / 307 (5.86%)
         occurrences all number
    2
    25
    Pain in extremity
         subjects affected / exposed
    4 / 146 (2.74%)
    17 / 307 (5.54%)
         occurrences all number
    5
    24
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 146 (6.16%)
    8 / 307 (2.61%)
         occurrences all number
    10
    8
    Bronchitis
         subjects affected / exposed
    7 / 146 (4.79%)
    17 / 307 (5.54%)
         occurrences all number
    7
    23
    Nasopharyngitis
         subjects affected / exposed
    7 / 146 (4.79%)
    27 / 307 (8.79%)
         occurrences all number
    12
    36
    Pneumonia
         subjects affected / exposed
    12 / 146 (8.22%)
    32 / 307 (10.42%)
         occurrences all number
    14
    45
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 146 (16.44%)
    55 / 307 (17.92%)
         occurrences all number
    30
    98
    Urinary tract infection
         subjects affected / exposed
    10 / 146 (6.85%)
    33 / 307 (10.75%)
         occurrences all number
    16
    58
    Oral herpes
         subjects affected / exposed
    4 / 146 (2.74%)
    17 / 307 (5.54%)
         occurrences all number
    5
    25
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    34 / 146 (23.29%)
    210 / 307 (68.40%)
         occurrences all number
    87
    912
    Hypertriglyceridaemia
         subjects affected / exposed
    6 / 146 (4.11%)
    18 / 307 (5.86%)
         occurrences all number
    20
    26
    Hyperuricaemia
         subjects affected / exposed
    8 / 146 (5.48%)
    18 / 307 (5.86%)
         occurrences all number
    17
    29
    Hypokalaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    20 / 307 (6.51%)
         occurrences all number
    2
    33
    Decreased appetite
         subjects affected / exposed
    4 / 146 (2.74%)
    23 / 307 (7.49%)
         occurrences all number
    4
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2015
    - The study target population for the efficacy analysis was changed from iNHL patients to FL patients. - The randomization ratio was changed from 1:1 to 2:1 and the stratification factors were changed. - Time to improvement in DRS-P was added as a secondary efficacy variable.
    18 Feb 2016
    - The conservative requirement for blood pressure levels during the evaluation of patient’s eligibility was removed due to feedback from the investigators and lymphoma specialists. - A requirement for prophylactic antiviral therapy to be given to patients who are positive for HBsAg or HBcAb at screening was added. - Copanlisib was added to the list of prohibited previous therapies and medications.
    28 Jul 2016
    - Guidance on dose modification of copanlisib or placebo for hematological toxicity was updated. - Following Health Authority alerts related to safety issues with Zydelig (idelalisib, a PI3K inhibitor) treatment in clinical trials, text was added to provide guidance for monitoring and prophylaxis of opportunistic infections in patients who are at risk for opportunistic infection development while on study treatment.
    02 Feb 2018
    - The total sample size was reduced from 567 patients to 450 patients and the primary efficacy analysis was revised to be performed in the FAS instead of both the FAS and FL subpopulation. - Patients considered unwilling/unfit to receive chemotherapy were bundled to differentiate them in a subgroup different from the long-term responders (i.e., progression-free and treatment-free interval of ≥12 months after completion of the last rituximab-containing treatment).
    08 Oct 2019
    - The statistical assumptions for the primary efficacy analysis of PFS were modified. The required number of PFS events was changed from 288 to 190. - The confirmatory testing strategy was modified.
    22 May 2020
    - Number of events necessary for primary completion analyses was changed to “at least 190 PFS events” to remain flexible. - Removed potential pooling of strata. In order to avoid a too low number of events, only stratification factors “iNHL histology” and “entry criterion” will be adjusted simultaneously in the statistical analyses. - Confirmatory statistical testing strategy for the US was revised and an additional confirmatory statistical testing strategy for the EU was added.

    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.
    The Overall Survival analysis is very immature due to the low number of events.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33848462
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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