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    Clinical Trial Results:
    A phase II multicenter open-label study of MabThera (Rituximab) addition to regularly prescribed chemotherapy in patients with untreated Mantle Cell Lymphoma

    Summary
    EudraCT number
    2009-011433-27
    Trial protocol
    RO  
    Global end of trial date
    19 Aug 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ML22489
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01144403
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, 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
    19 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine Overall Response Rate (ORR) (expressed as complete response [CR] and partial response [PR]) in Mantle Cell Lymphoma (MCL) subjects treated with MabThera plus chemotherapy. The percentage of subjects who achieve CR/ unconfirmed complete (CRu) or PR while on rituximab induction therapy will be assessed.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    7
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total 8 subjects were enrolled from Romania.

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

    Arms
    Arm title
    Rituximab
    Arm description
    Rituximab, 375 milligram per metre square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera, Rituxan
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375 mg/m^2 was administered intravenously, Day 1 of each 28-day cycle, up to 8 cycles.

    Number of subjects in period 1
    Rituximab
    Started
    8
    Completed
    3
    Not completed
    5
         Death
    1
         Adverse Event
    1
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    Rituximab, 375 milligram per metre square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles.

    Reporting group values
    Rituximab Total
    Number of subjects
    8 8
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.5 ± 7.964 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    Rituximab, 375 milligram per metre square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles.

    Primary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR) [1]
    End point description
    Overall Response Rate (ORR) was determined by tumor response according to International Workshop Group to Standardize Response Criteria for mantle cell lymphoma (MCL) criteria from confirmed evaluations of both target, radiographically evaluated, and non-target lesions. A responder is defined as a subject experiencing either a complete (CR)/ unconfirmed complete (Cru), or partial response (PR) by these criteria. As per criteria; CR = disappearance of all evidence of disease; CRu = the sum of the product of the diameters (SPD) of multiple nodes decreased by at least 75%; PR = regression of measurable disease and no new sites. Efficacy population included all the subjects who had received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 50 months (approximately)
    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: Only descriptive data was planned to be reported.
    End point values
    Rituximab
    Number of subjects analysed
    8
    Units: percentage of subjects
        number (not applicable)
    87.5
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is defined as time from date of enrollment to the date of death, regardless of the cause of death. Efficacy population included all the subjects who had received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of enrollment until death due to any cause (up to 50 months [approximately])
    End point values
    Rituximab
    Number of subjects analysed
    8
    Units: days
        median (confidence interval 95%)
    927 (0 to 2204.066)
    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 is defined as the interval between the day of enrollment and the first documentation of progressive disease or death. Progression of disease is defined as at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Efficacy population included all the subjects who had received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of enrollment until death due to any cause (up to 50 months [approximately])
    End point values
    Rituximab
    Number of subjects analysed
    8
    Units: days
        median (confidence interval 95%)
    653 (537.058 to 768.942)
    No statistical analyses for this end point

    Secondary: Number of Subject With Adverse Event (AE)

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    End point title
    Number of Subject With Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment. Safety population included all the subjects who had received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 50 months (approximately)
    End point values
    Rituximab
    Number of subjects analysed
    8
    Units: subjects
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 50 months
    Adverse event reporting additional description
    Safety population included all the subjects who had received at least one dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    Rituximab, 375 milligram per metre square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles.

    Serious adverse events
    Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Toxicity
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    Vascular disorders
    Ascending Aorta Dilatation
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Drug Eruption
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Cardiac disorders
    Supraventricular arrhythmia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    5
    Leucopenia
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    7
    Neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    ß2-microglobuline ↗
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    C-reactive protein
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Tracheitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Respiratory Virosis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nervous system disorders
    Vertiginous syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastric Pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatitis Ag HBS+
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis Eczematous
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Herpes
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Oral Candidiasis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2010
    Added 6 new sites and 6 new investigators to the study.
    06 Jun 2011
    Protocol version 2.0/14.09.2010

    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.
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. The study was prematurely terminated with 8 subjects enrolled, all of them were included into the statistical analyses.
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