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    Clinical Trial Results:
    Efficacy of first line Dexamethasone, Rituximab and Cyclophosphamide (DRC) +/- Bortezomib for patients with Waldenström's Macroglobulinemia

    Summary
    EudraCT number
    		 2013-000506-37
    Trial protocol
    		 CZ   IT   PT   SE   GR   ES  
    Global end of trial date
    17 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2025
    First version publication date
    26 Apr 2025
    Other versions
    Summary report(s)
    		 ECWM-1_Summary of Results_08.04.2025

    Trial information

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    Trial identification
    Sponsor protocol code
    ECWM-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01788020
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Ulm
    Sponsor organisation address
    Albert-Einstein-Allee 23, Ulm, Germany, 89081
    Public contact
    Prof. Dr. Christian Buske, University Hospital Ulm , +49 731 500 65800, christian.buske@uni-ulm.de
    Scientific contact
    Prof. Dr. Christian Buske, University Hospital Ulm , +49 731 500 65800, christian.buske@uni-ulm.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Apr 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate whether the addition of Bortezomib to the combination regimen Dexamethasone/Rituximab/Cyclophosphamide (B-DRC) improves PFS compared to DRC alone.
    Protection of trial subjects
    In this study safety was assessed by evaluating the following: reported adverse events, clinical laboratory test results, vital signs measurements, chest X-ray/CT, physical examination findings, monitoring of concomitant therapy. For each safety paramenter, all findings were recorded in the CRF.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    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
    Portugal: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    France: 110
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Greece: 26
    Worldwide total number of subjects
    202
    EEA total number of subjects
    202
    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)
    74
    From 65 to 84 years
    127
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient in: 28-Jan-2014 Date of early recruitment termination: 21-SEP-2018 Last patient last treatment: 17-APR-2019 Last patient completed Follow Up time: 16-APR-2024

    Pre-assignment
    Screening details
    		 Clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM and in need of treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 arm A
    Arm description
    		 induction standard arm (DRC)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg p.o., Cycle 1-6, Day 1

    Investigational medicinal product name
    Rituximab IV
    Investigational medicinal product code
    Other name
    MabThera IV
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, Cycle 1 Day 1

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m2 twice daily, Cycle 1-6, Day 1-5

    Investigational medicinal product name
    Rituximab SC
    Investigational medicinal product code
    Other name
    MabThera SC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection
    Dosage and administration details
    1400 mg absolute SC, cycle 2-6, day 1

    Arm title
    		 arm B
    Arm description
    		 induction experimental arm (DRC +B)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    1.6 mg/m2 Cycle 1-6, Day 1, 8 and 15

    Investigational medicinal product name
    Rituximab IV
    Investigational medicinal product code
    Other name
    MabThera IV
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, Cycle 1 Day 1

    Investigational medicinal product name
    Rituximab SC
    Investigational medicinal product code
    Other name
    MabThera SC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection
    Dosage and administration details
    1400 mg absolute SC, cycle 2-6, day 1

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg p.o., Cycle 1-6, Day 1

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m2 twice daily, Cycle 1-6, Day 1-5

    Number of subjects in period 1
    		arm A arm B
    Started
    100
    102
    Completed
    82
    89
    Not completed
    18
    13
         Adverse event, serious fatal
    2
    2
         Consent withdrawn by subject
    5
    5
         Screening failure
    3
    1
         missing of relevant values
    2
    -
         Progression during treatment
    2
    1
         Adverse event, non-fatal
    4
    2
         Additional malignancy during follow up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    arm A
    Reporting group description
    		 induction standard arm (DRC)

    Reporting group title
    arm B
    Reporting group description
    		 induction experimental arm (DRC +B)

    Reporting group values
    		 arm A arm B Total
    Number of subjects
    		 100 102 202
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 36 38 74
        From 65-84 years
    		 64 63 127
        85 years and over
    		 0 1 1
    Gender categorical
    Units: Subjects
        Female
    		 33 34 67
        Male
    		 67 68 135

    End points

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    End points reporting groups
    Reporting group title
    arm A
    Reporting group description
    		 induction standard arm (DRC)

    Reporting group title
    arm B
    Reporting group description
    		 induction experimental arm (DRC +B)

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population includes all patients randomized for induction regardless of study drug being received or not or other protocol violations. According to the ITT, patients from the ITT population were analysed based on assigned treatment group per induction randomization. Patients without staging during induction were excluded for the evaluation of remission rates.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    For safety analyses, patients who started treatment were evaluated according to the treatment actually received (as treated).

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    End point type
    Primary
    End point timeframe
    From date of inclusion to the following events: the date of progression and the date of death if it occurred earlier. In the absence of progression and death, PFS duration is censored at the stopping date or the date of last follow-up.
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: month
        number (not applicable)
    50.1
    60.0
    Statistical analysis title
    		 Primary analysis PFS
    Comparison groups
    arm B v arm A
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.914
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.629
         upper limit
    		 1.329

    Secondary: Remission duration (RD)

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    End point title
    		 Remission duration (RD)
    End point description
    End point type
    Secondary
    End point timeframe
    Calculated in patients with response (CR, VGPR, PR, MR) from end of induction to the date of progression, relapse or death from any cause. Patients alive without progression and relapse is censored at the latest tumor assessment date.
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: month
        number (not applicable)
    43.5
    51.1
    Statistical analysis title
    		 remission duration
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to next treatment (TNT)

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    End point title
    		 Time to next treatment (TNT)
    End point description
    End point type
    Secondary
    End point timeframe
    Time to next treatment (TNT) is defined as the time of randomization to start of new anti-cancer therapy. Patients alive without new anti-cancer therapy are censored at the latest tumor assessment date.
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: month
        number (not applicable)
    67.5
    68.8
    Statistical analysis title
    		 time to next treatment
    Comparison groups
    arm B v arm A
    Number of subjects included in analysis
    202
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Logrank
    Confidence interval

    Secondary: Cumulative incidence of first response

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    End point title
    		 Cumulative incidence of first response
    End point description
    End point type
    Secondary
    End point timeframe
    4-months cumulative incidence
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: %
        number (confidence interval 95%)
    61 (52 to 70)
    73 (64 to 81)
    Statistical analysis title
    		 cumulative incidence of first response
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    202
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Fine and gray test
    Confidence interval

    Secondary: Response rate (RR) and overall response rate (ORR) after therapy

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    End point title
    		 Response rate (RR) and overall response rate (ORR) after therapy
    End point description
    End point type
    Secondary
    End point timeframe
    four weeks after end of induction therapy
    End point values
    		 arm A arm B ITT population
    Number of subjects analysed
    90
    94
    184
    Units: %
    number (not applicable)
        Complete remission/response
    1.1
    2.1
    1.6
        Very good partial response
    8.9
    15.8
    12.4
        Partial remission
    56.7
    60.0
    58.5
        Minor response
    21.1
    15.8
    18.4
        Stable disease
    8.9
    4.2
    6.5
        Progressive disease
    3.3
    2.1
    2.7
        ORR (CR, VGPR, PR, MR)
    87.7
    93.7
    90.8
    Statistical analysis title
    		 response rate
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Best response

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    End point title
    		 Best response
    End point description
    End point type
    Secondary
    End point timeframe
    from end of induction therapy to end of follow-up
    End point values
    		 arm A arm B ITT population
    Number of subjects analysed
    90 [1]
    96 [2]
    186 [3]
    Units: %
    number (not applicable)
        Complete remission/response
    1.1
    5.2
    3.2
        Very good partial response
    21.1
    30.2
    25.8
        Partial remission
    62.3
    53.1
    57.5
        Minor response
    11.1
    7.3
    9.2
        Stable disease
    2.2
    3.1
    2.7
        Progressive disease
    2.2
    1.1
    1.6
    Notes
    [1] - 10 not assessable
    [2] - 6 not assessable
    [3] - 16 not assessable
    Statistical analysis title
    		 best response
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to treatment failure (TTF)

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    End point title
    		 Time to treatment failure (TTF)
    End point description
    End point type
    Secondary
    End point timeframe
    Time of randomization to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy. Patients alive without treatment failure are censored at the latest tumor assessment date.
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: months
        number (not applicable)
    40.5
    51.5
    Statistical analysis title
    		 Time to treatment failure (TTF)
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Logrank
    Confidence interval

    Secondary: Cumulative incidence of best response

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    End point title
    		 Cumulative incidence of best response
    End point description
    End point type
    Secondary
    End point timeframe
    12-months cumulative incidence
    End point values
    		 arm A arm B
    Number of subjects analysed
    100
    102
    Units: %
        number (confidence interval 95%)
    67 (58 to 76)
    74 (65 to 83)
    Statistical analysis title
    		 Cumulative incidence of best response
    Comparison groups
    arm A v arm B
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Fine and gray test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events will be recorded from the time the subject receives study treatment to 28 days after the last dose of treatment.
    Adverse event reporting additional description
    All subjects will be monitored for AEs during the study. Assessments may include monitoring of any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, radiological or surgical findings, physical examination findings, or other appropriate tests and procedures.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    ARM A
    Reporting group description
    		 Induction standard arm - reference therapy (Dexamethasone, Rituximab, Cyclophosphamide)

    Reporting group title
    ARM B
    Reporting group description
    		 Induction experimental arm - (Bortezomib, Dexamethasone, Rituximab, Cyclophosphamide)

    Serious adverse events
    		 ARM A ARM B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 96 (28.13%)
    14 / 99 (14.14%)
         number of deaths (all causes)
    9
    17
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Second primary malignancy
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         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 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 96 (4.17%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract inflammation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shoulder fracture
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain hypoxia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         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 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ARM A ARM B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 96 (94.79%)
    97 / 99 (97.98%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 96 (5.21%)
    4 / 99 (4.04%)
         occurrences all number
    7
    5
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 96 (5.21%)
    21 / 99 (21.21%)
         occurrences all number
    10
    31
    Headache
         subjects affected / exposed
    4 / 96 (4.17%)
    5 / 99 (5.05%)
         occurrences all number
    6
    6
    Paraesthesia
         subjects affected / exposed
    5 / 96 (5.21%)
    4 / 99 (4.04%)
         occurrences all number
    5
    5
    Dizziness
         subjects affected / exposed
    1 / 96 (1.04%)
    7 / 99 (7.07%)
         occurrences all number
    1
    7
    Neuropathy peripheral
         subjects affected / exposed
    4 / 96 (4.17%)
    5 / 99 (5.05%)
         occurrences all number
    4
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 96 (23.96%)
    21 / 99 (21.21%)
         occurrences all number
    36
    41
    Neutropenia
         subjects affected / exposed
    28 / 96 (29.17%)
    34 / 99 (34.34%)
         occurrences all number
    80
    99
    Thrombocytopenia
         subjects affected / exposed
    9 / 96 (9.38%)
    18 / 99 (18.18%)
         occurrences all number
    22
    39
    Leukopenia
         subjects affected / exposed
    6 / 96 (6.25%)
    9 / 99 (9.09%)
         occurrences all number
    22
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 96 (21.88%)
    20 / 99 (20.20%)
         occurrences all number
    29
    34
    Pyrexia
         subjects affected / exposed
    18 / 96 (18.75%)
    16 / 99 (16.16%)
         occurrences all number
    21
    21
    Chills
         subjects affected / exposed
    7 / 96 (7.29%)
    5 / 99 (5.05%)
         occurrences all number
    7
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    39 / 96 (40.63%)
    43 / 99 (43.43%)
         occurrences all number
    66
    74
    Diarrhea
         subjects affected / exposed
    8 / 96 (8.33%)
    17 / 99 (17.17%)
         occurrences all number
    8
    32
    Constipation
         subjects affected / exposed
    10 / 96 (10.42%)
    21 / 99 (21.21%)
         occurrences all number
    13
    24
    Vomiting
         subjects affected / exposed
    13 / 96 (13.54%)
    23 / 99 (23.23%)
         occurrences all number
    13
    28
    Abdominal pain
         subjects affected / exposed
    7 / 96 (7.29%)
    6 / 99 (6.06%)
         occurrences all number
    9
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 96 (5.21%)
    4 / 99 (4.04%)
         occurrences all number
    6
    5
    Dyspnoea
         subjects affected / exposed
    6 / 96 (6.25%)
    6 / 99 (6.06%)
         occurrences all number
    6
    7
    Epistaxis
         subjects affected / exposed
    5 / 96 (5.21%)
    2 / 99 (2.02%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 99 (1.01%)
         occurrences all number
    7
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 96 (7.29%)
    1 / 99 (1.01%)
         occurrences all number
    8
    1
    Back pain
         subjects affected / exposed
    7 / 96 (7.29%)
    3 / 99 (3.03%)
         occurrences all number
    7
    4
    Bone pain
         subjects affected / exposed
    6 / 96 (6.25%)
    6 / 99 (6.06%)
         occurrences all number
    9
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 96 (2.08%)
    9 / 99 (9.09%)
         occurrences all number
    4
    9
    Rash pustular
         subjects affected / exposed
    1 / 96 (1.04%)
    5 / 99 (5.05%)
         occurrences all number
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 96 (1.04%)
    5 / 99 (5.05%)
         occurrences all number
    1
    7
    Urinary tract infection
         subjects affected / exposed
    2 / 96 (2.08%)
    9 / 99 (9.09%)
         occurrences all number
    2
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 96 (2.08%)
    5 / 99 (5.05%)
         occurrences all number
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2018
    The study was conducted as planned in the protocol until 21-SEP-2018 when the recruitment was terminated early. 202 patients (instead of 384) were recruited over a period of 4 years and 8 months before the study prematurely stopped recruitment. Planned duration of recruitment was approximately 3.3 years. The early recruitment termination was due to the fact that the treatment landscape had changed tremendously through ibrutinib availability.

    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
    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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