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    Clinical Trial Results:
    Multicentre, Non-Randomised, Open-Label Phase II Study to Evaluate the Efficacy and Safety of Induction Treatment With Rituximab, Fludarabine, Cyclophosphamide, Followed by Rituximab Maintenance Therapy (R-Fc-Rm) in the First Lline Treatment of Chronic Lymphocytic Leukaemia

    Summary
    EudraCT number
    2007-002733-36
    Trial protocol
    ES  
    Global end of trial date
    20 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    31 May 2017
    First version publication date
    31 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML21135
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00545714
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This single arm study assessed the efficacy and safety of rituximab in combination with fludarabine and cyclophosphamide, followed by rituximab maintenance therapy, as first line treatment of participants with chronic lymphocytic leukemia (CLL).
    Protection of trial subjects
    Investigators ensured that this study was conducted in full compliance with the principles of the last version of the Declaration of Helsinki and with the law and regulations of the country where the research was conducted, whichever provided greater protection to the study participants. The study fully complied with the principles stated in the “Good Clinical Practice Standards” of the International Council for Harmonisation (ICH) Tripartite Guideline (January 1997) and with all local regulations on clinical trials (Directive 2001/20/EC of the European Union and RD 223/2004).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Nov 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    46 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    69
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Of the 86 participants treated, demographic data were available for only 84 participants, and therefore, the 2 remaining participants have been counted under 'Adults (18-64 years)' in the preceding table.

    Pre-assignment
    Screening details
    A total of 86 participants were enrolled in 29 centers in Spain in this two-phase study (Induction Phase and Maintenance Phase).

    Period 1
    Period 1 title
    Induction Phase (6 Months)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Rituximab + Fludarabine + Cyclophosphamide
    Arm description
    Participants received rituximab 375 milligrams per square meter (mg/m^2) as intravenous (IV) infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a partial response (PR) or complete response (CR) and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 375 mg/m^2 on Day 0 of Cycle 1 and 500 mg/m^2 on Day 1 of Cycles 2-6 (cycle length = 28 days) as IV infusion during the Induction Phase. Participants with PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of induction phase.

    Number of subjects in period 1
    Rituximab + Fludarabine + Cyclophosphamide
    Started
    86
    Safety Population
    86
    Intent-to-Treat (ITT) Population
    84
    Completed
    74
    Not completed
    12
         Disease Progression
    1
         Physician decision
    3
         Eligibility Criteria Violation
    2
         Unacceptable Toxicity
    6
    Period 2
    Period 2 title
    Maintenance Phase (36 Months)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Rituximab + Fludarabine + Cyclophosphamide
    Arm description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of cycle 1, and 500 mg/m^2 as IV infusion on Day 1 of cycles 2-6 (1 cycle = 28 days); fludarabine 25 mg/m^2 on Days 1 to 3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1 to 3 of each cycle during the induction phase. Participants with a partial or complete response (and appropriate neutrophil conditions) received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of induction phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 375 mg/m^2 on Day 0 of Cycle 1 and 500 mg/m^2 on Day 1 of Cycles 2-6 (cycle length = 28 days) as IV infusion during the Induction Phase. Participants with PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of induction phase.

    Number of subjects in period 2
    Rituximab + Fludarabine + Cyclophosphamide
    Started
    74
    Completed
    42
    Not completed
    32
         Death
    2
         Disease Progression
    9
         Protocol deviation
    1
         Withdrawal by Subject
    3
         Physician decision
    1
         Unacceptable Toxicity
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction Phase (6 Months)
    Reporting group description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.

    Reporting group values
    Induction Phase (6 Months) Total
    Number of subjects
    86
    Age Categorical
    Units: Subjects
    Age Continuous
    Age data were available for 84 out of 86 participants.
    Units: years
        arithmetic mean (standard deviation)
    57.92 ± 7.87 -
    Gender Categorical
    Units: Subjects
        Female
    27 27
        Male
    57 57
        Missing
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Rituximab + Fludarabine + Cyclophosphamide
    Reporting group description
    Participants received rituximab 375 milligrams per square meter (mg/m^2) as intravenous (IV) infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a partial response (PR) or complete response (CR) and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
    Reporting group title
    Rituximab + Fludarabine + Cyclophosphamide
    Reporting group description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of cycle 1, and 500 mg/m^2 as IV infusion on Day 1 of cycles 2-6 (1 cycle = 28 days); fludarabine 25 mg/m^2 on Days 1 to 3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1 to 3 of each cycle during the induction phase. Participants with a partial or complete response (and appropriate neutrophil conditions) received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of induction phase.

    Subject analysis set title
    Rituximab + Fludarabine + Cyclophosphamide
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.

    Subject analysis set title
    Rituximab + Fludarabine + Cyclophosphamide
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.

    Primary: Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen

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    End point title
    Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen [1]
    End point description
    CR was defined as no adenopathies (ADPs) and visceromegalies (VSMs) in physical examination (PE); no general symptoms (Sx); lymphocytes (Lymph) in peripheral blood less than (<) 4000 per cubic millimeter (mm^3); normalization of peripheral blood parameters: neutrophils (Neut) greater than (>) 1500/mm^3, platelets (Plt) >100,000/mm^3, hemoglobin (Hb) >11 grams per deciliter (g/dL) without transfusion; normocellular bone marrow (BM) with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. ITT Population included participants who received at least one dose of study drug and met inclusion/exclusion criteria.
    End point type
    Primary
    End point timeframe
    Month 9
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential analysis was performed. Only descriptive summaries were planned.
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84
    Units: Percentage of Participants
        number (confidence interval 95%)
    95.2 (88.25 to 98.69)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry

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    End point title
    Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry
    End point description
    CR was defined as no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR was defined as decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase (IP): at 6 months; during Maintenance Phase (MP): at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up (FU): at Follow-Up Months 6, 12, 18, 24, 30, 36
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [2]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP: CR (n= 84)
    75
        Post-IP: PR (n= 84)
    13.1
        MP (9 Cycles): CR (n= 47)
    89.4
        MP (9 Cycles): PR (n= 47)
    6.4
        MP (12 Cycles): CR (n= 33)
    87.9
        MP (12 Cycles): PR (n= 33)
    6.1
        MP (15 Cycles): CR (n= 22)
    90.9
        MP (15 Cycles): PR (n= 22)
    4.5
        MP (18 Cycles): CR (n= 59)
    88.1
        MP (18 Cycles): PR (n= 59)
    8.5
        6 Months FU: CR (n= 12)
    83.3
        6 Months FU: PR (n= 12)
    0
        12 Months FU: CR (n= 36)
    94.4
        12 Months FU: PR (n= 36)
    0
        18 Months FU: CR (n= 2)
    100
        18 Months FU: PR (n= 2)
    0
        24 Months FU: CR (n= 29)
    93.1
        24 Months FU: PR (n= 29)
    0
        30 Months FU: CR (n= 2)
    100
        30 Months FU: PR (n= 2)
    0
        36 Months FU: CR (n= 31)
    100
        36 Months FU: PR (n= 31)
    0
    Notes
    [2] - Here, 'n' signifies participants who were evaluable for indicated category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Response of CR or PR Among Participants with Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry

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    End point title
    Percentage of Participants With Clinical Response of CR or PR Among Participants with Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry
    End point description
    CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR: decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. Negative MRD: Lymph <0.01% of all white blood cells (WBCs) in blood or BM after two consecutive measurements. Analysis performed only in blood during Maintenance Phase and Follow-Up.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 36
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    60 [3]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP: Blood MRD Negative (n= 60)
    100
        Post-IP: BM MRD Negative (n= 37)
    100
        MP (9 Cycles): Blood MRD Negative (n= 33)
    100
        MP (12 Cycles): Blood MRD Negative (n= 22)
    100
        MP (15 Cycles): Blood MRD Negative (n= 16)
    100
        MP (18 Cycles): Blood MRD Negative (n= 40)
    100
        6 Months FU: Blood MRD Negative (n= 4)
    100
        12 Months FU: Blood MRD Negative (n= 24)
    100
        18 Months FU: Blood MRD Negative (n= 1)
    100
        24 Months FollowFU: Blood MRD Negative (n= 19)
    100
        36 Months FU: Blood MRD Negative (n= 22)
    100
    Notes
    [3] - ITT Population. Those with negative MRD evaluable, where 'n' signifies those evaluable for category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi)

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    End point title
    Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi)
    End point description
    Participants with CRi were those who met all CR criteria (including BM examinations) but had persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to chronic lymphocytic leukemia (CLL) but related to drug toxicity. CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline up to progressive disease (PD) or death due to any cause, whichever occurred first (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84
    Units: Percentage of Participants
        number (not applicable)
    7.1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as time from treatment start to death of the participant. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered. OS was estimated using Kaplan-Meier (KM) methodology. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline up to death due to any cause (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [4]
    Units: Years
        median (confidence interval 95%)
    7.51 (7.5 to 99999)
    Notes
    [4] - 99999 = upper limit not estimable due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS was defined as time from start of study treatment to PD or death, whichever occurred first. For other participants, last follow-up available was taken as last control. If participant did not complete study, date of last visit available was considered. PFS was estimated using KM methodology. PD was defined as new ADPs (1.5 centimeters [cm]), hepato-/splenomegaly (HSM), Richter syndrome (RS), or other infiltrated organs; greater than or equal to (>/=) 50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [5]
    Units: Years
        median (confidence interval 95%)
    6.96 (5.72 to 99999)
    Notes
    [5] - 99999 = upper limit not estimable due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    Percentage of Participants Who Died
    End point description
    Safety Population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to death due to any cause (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    86
    Units: Percentage of Participants
        number (not applicable)
    23.2
    No statistical analyses for this end point

    Secondary: Treatment-Free Survival (TFS)

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    End point title
    Treatment-Free Survival (TFS)
    End point description
    TFS was defined time from start of study treatment until participant received new chemotherapy/immunotherapy because of PD and to reduce the disease with palliative or curative intent. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. ITT Population. Only those who received new chemotherapy/immunotherapy, as per definitions for TFS, were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    27
    Units: Years
        median (confidence interval 95%)
    4.13 (2.98 to 4.87)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    DOR: time from CR/PR to MRD/PD. PD: new ADP (1.5 cm), HSM, RS, other infiltrated organs or >/=50% increase size in those with PR; blood Lymph increase >/=50% with B Lymph >/=5000/mm^3; cytopenia due to CLL. Progression of (nonautoimmune) cytopenia: 2-g/dL decrease basal Hb, Hb <10 g/dL, >/=50% decrease basal Plt or <100,000/mm^3 at >/=3 months post-treatment was PD if clonal CLL cell infiltration on BM biopsy. CR: no ADP/VSM in PE; no general Sx; blood Lymph <4000/mm^3; Neut >1500/mm^3; Plt >100,000/mm^3; Hb >11 g/dL (no transfusion); normocellular BM with <30% Lymph; BM aspirate/biopsy with no lymphoid nodule infiltration. PR: >50% decrease blood Lymph; >50% decrease in total sum up to 6 ADPs or baseline ADP of LD, no new/enlargement of prior ADP; >50% decrease VSM; Neut >1500/mm^3 or >50% increase; Plt >100,000/mm^3 or >50% increase; Hb >11.0 g/dL or >50% increase (no transfusion). All CR criteria but persistent anemia or thrombocytopenia was PR. MRD: Lymph >0.01% of blood/BM WBCs.
    End point type
    Secondary
    End point timeframe
    From first CR or PR up to detectable MRD or disease occurrence/PD, whichever occurred first (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    80 [6]
    Units: Years
        median (confidence interval 95%)
    99999 (99999 to 99999)
    Notes
    [6] - ITT Population. Those with CR/PR were evaluable. 99999 = not estimable due to high number censored.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood

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    End point title
    Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood
    End point description
    Percentages of participants with CD38 expression by >/=30% of CLL cells during the Induction Phase, Maintenance Phase, and Follow-Up were reported. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [7]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP (n= 84)
    47.6
        MP (9 Cycles) (n= 47)
    44.4
        MP (12 Cycles) (n= 33)
    45.5
        MP (15 Cycles) (n= 22)
    47.6
        MP (18 Cycles) (n= 59)
    47.4
        6 Months FU (n= 12)
    66.7
        12 Months FU (n= 36)
    45.7
        18 Months FU (n= 2)
    100
        24 Months FU (n= 29)
    41.4
        30 Months FU (n= 2)
    50
        36 Months FU (n= 31)
    35.5
    Notes
    [7] - Here, 'n' signifies participants who were evaluable for indicated category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Genetic Abnormalities

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    End point title
    Percentage of Participants With Genetic Abnormalities
    End point description
    Percentages of participants with genetic abnormalities (deletion 6q, deletion 11q22-q23, deletion p53, trisomy 12, and deletion 13q14) in the course of the disease during the Induction Phase and Maintenance Phase were reported. ITT Population. Designation of 'MP (xC)' refers to number of cycles in Maintenance Phase.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [8]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP: Deletion 6q (n=84)
    3.6
        Post-IP: Deletion 11q22-q23 (n=84)
    26.2
        Post-IP: Deletion p53 (n= 84)
    4.8
        Post-IP: Trisomy 12 (n= 84)
    15.5
        Post-IP: Deletion 13q14 (n= 84)
    50
        MP (9C): Deletion 6q (n= 47)
    4.3
        MP (9C): Deletion 11q22-q23 (n=47)
    25.5
        MP (9C): Deletion p53 (n=47)
    0
        MP (9C): Trisomy 12 (n= 47)
    17
        MP (9C): Deletion 13q14 (n=47)
    55.3
        MP (12C): Deletion 6q (n=33)
    3
        MP (12C): Deletion 11q22-q23 (n=33)
    21.2
        MP (12C): Deletion p53 (n=33)
    0
        MP (12C): Trisomy 12 (n=33)
    21.2
        MP (12C): Deletion 13q14 (n=33)
    51.5
        MP (15C): Deletion 6q (n=22)
    4.5
        MP (15C): Deletion 11q22-q23 (n=22)
    31.8
        MP (15C): Deletion p53 (n=22)
    0
        MP (15C): Trisomy 12 (n=22)
    18.2
        MP (15C): Deletion 13q14 (n=22)
    59.1
        MP (18C): Deletion 6q (n=59)
    3.4
        MP (18C): Deletion 11q22-q23 (n=59)
    23.7
        MP (18C): Deletion p53 (n=59)
    0
        MP (18C): Trisomy 12 (n=59)
    18.6
        MP (18C): Deletion 13q14 (n=59)
    49.2
    Notes
    [8] - Here, 'n' signifies participants who were evaluable for indicated category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression

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    End point title
    Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression
    End point description
    Percentages of participants with positive and negative ZAP-70 expression during the Induction Phase, Maintenance Phase, and Follow-Up were reported. Positive ZAP-70 was defined as ZAP-70 expression by >/=20% of CLL cells. Negative ZAP-70 was defined as ZAP-70 expression by <20% of CLL cells. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [9]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP: Positive (n= 84)
    57.3
        Post-IP: Negative (n= 84)
    42.7
        MP (9 Cycles): Positive (n=47)
    57.5
        MP (9 Cycles): Negative (n=47)
    42.5
        MP (12 Cycles): Positive (n=33)
    62.1
        MP (12 Cycles): Negative (n=33)
    37.9
        MP (15 Cycles): Positive (n=22)
    57.1
        MP (15 Cycles): Negative (n=22)
    42.9
        MP (18 Cycles): Positive (n=59)
    54.9
        MP (18 Cycles): Negative (n=59)
    45.1
        6 Months FU: Positive (n=12)
    63.6
        6 Months FU: Negative (n=12)
    36.4
        12 Months FU: Positive (n=36)
    60
        12 Months FU: Negative (n=36)
    40
        18 Months FU: Positive (n=2)
    100
        18 Months FU: Negative (n=2)
    0
        24 Months FU: Positive (n=29)
    59.3
        24 Months FU: Negative (n=29)
    40.7
        30 Months FU: Positive (n=2)
    100
        30 Months FU: Negative (n=2)
    0
        36 Months FU: Positive (n=31)
    57.1
        36 Months FU: Negative (n=31)
    42.9
    Notes
    [9] - Here, 'n' signifies participants who were evaluable for indicated category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement

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    End point title
    Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement
    End point description
    Percentages of participants with IgH rearrangement during the Induction Phase, Maintenance Phase, and Follow-Up were reported. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84 [10]
    Units: Percentage of Participants
    number (not applicable)
        Post-IP (n= 84)
    36.2
        MP (9 Cycles) (n= 47)
    37.1
        MP (12 Cycles) (n= 33)
    20
        MP (15 Cycles) (n= 22)
    29.4
        MP (18 Cycles) (n= 59)
    33.3
        6 Months FU (n= 12)
    100
        12 Months FU (n= 36)
    37.9
        18 Months FU (n= 2)
    50
        24 Months FU (n= 29)
    33.3
        30 Months FU (n= 2)
    0
        36 Months FU (n= 31)
    45.8
    Notes
    [10] - Here, 'n' signifies participants who were evaluable for indicated category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PD or Death

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    End point title
    Percentage of Participants With PD or Death
    End point description
    PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)
    End point values
    Rituximab + Fludarabine + Cyclophosphamide
    Number of subjects analysed
    84
    Units: Percentage of Participants
        number (not applicable)
    39.29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of Follow-Up (up to 92 months)
    Adverse event reporting additional description
    Safety Population included all participants who received at least one dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Rituximab + Fludarabine + Cyclophosphamide
    Reporting group description
    Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle; and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the induction phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.

    Serious adverse events
    Rituximab + Fludarabine + Cyclophosphamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 86 (40.70%)
         number of deaths (all causes)
    20
         number of deaths resulting from adverse events
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Vertebroplasty
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 86 (6.98%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 86 (9.30%)
         occurrences causally related to treatment / all
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malabsorption
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pancreatitis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic mass
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 86 (8.14%)
         occurrences causally related to treatment / all
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rituximab + Fludarabine + Cyclophosphamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 86 (95.35%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 86 (8.14%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    52 / 86 (60.47%)
         occurrences all number
    203
    Leukopenia
         subjects affected / exposed
    15 / 86 (17.44%)
         occurrences all number
    35
    Lymphopenia
         subjects affected / exposed
    24 / 86 (27.91%)
         occurrences all number
    71
    Thrombocytopenia
         subjects affected / exposed
    18 / 86 (20.93%)
         occurrences all number
    27
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 86 (16.28%)
         occurrences all number
    23
    Pyrexia
         subjects affected / exposed
    31 / 86 (36.05%)
         occurrences all number
    46
    Chills
         subjects affected / exposed
    6 / 86 (6.98%)
         occurrences all number
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 86 (6.98%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    16 / 86 (18.60%)
         occurrences all number
    23
    Nausea
         subjects affected / exposed
    26 / 86 (30.23%)
         occurrences all number
    50
    Vomiting
         subjects affected / exposed
    15 / 86 (17.44%)
         occurrences all number
    29
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 86 (5.81%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 86 (5.81%)
         occurrences all number
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    27 / 86 (31.40%)
         occurrences all number
    47
    Pneumonia
         subjects affected / exposed
    7 / 86 (8.14%)
         occurrences all number
    9
    Respiratory tract infection
         subjects affected / exposed
    14 / 86 (16.28%)
         occurrences all number
    25
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 86 (8.14%)
         occurrences all number
    8
    Urinary tract infection
         subjects affected / exposed
    8 / 86 (9.30%)
         occurrences all number
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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