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    Clinical Trial Results:
    Fludarabine/Rituximab combined with escalating doses of Lenalidomide followed by Rituximab/Lenalidomide in untreated chronic lymphocytic leukemia (CLL) – a dose-finding study with concomitant evaluation of safety and efficacy

    Summary
    EudraCT number
    2008-001430-27
    Trial protocol
    AT  
    Global end of trial date
    16 Jan 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jul 2016
    First version publication date
    30 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLL-5 RevliRit
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00738829
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AGMT
    Sponsor organisation address
    Gentzgasse 60/20, Vienna, Austria, 1180
    Public contact
    Daniela Wolkersdorfer, AGMT, 0043 6626404411, d.wolkersdorfer@agmt.at
    Scientific contact
    Richard Greil, AGMT, 0043 5725525801, r.greil@salk.at
    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
    16 Jan 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this dose-finding study is to determine the maximum tolerated dose of lenalidomide in combination with fludarabine/rituximab therapy.
    Protection of trial subjects
    Safety assessments were done regularly. Premedication prior to each infusion of rituximab and prophylactic anti-thrombotic therapy during study therapy was given. The study was designed to have a reduced dose fludarabine/rituximab debulking step and slow dose escalation for lenalidomide in order to minimize the risk of tumor lysis syndrome.
    Background therapy
    In this study lenalidomide was combined with a backbone of FR (taken from the FCR regimen) for an initial 6 months treatment and dose-finding phase and followed by a 6 month course of lenalidomide in combination with rituximab maintenance.
    Evidence for comparator
    Lenalidomide has been shown to be synergistic with rituximab in vitro, thus arguing for trials of a combination therapy. In mantle cell lymphoma a phase I/II trial combining lenalidomide with rituximab has shown promising results.
    Actual start date of recruitment
    30 Sep 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    19
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between 30-Sep-2008 and 29-Nov-2010 45 patients were enrolled at 7 sites in Austria.

    Pre-assignment
    Screening details
    Patients with untreated CLL with treatment indication according to NCI criteria, age 18 or older, ECOG 0-2 were enrolled.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    FLR Induction
    Arm description
    Fludarabine-rituximab backbone with escalating lenalidomide doses
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide: day 8-21 of cycle 1; day 1-21 of cycles 2-6 Starting Dose: 2,5mg Lenalidomide dose was increades via dose levels 5/10/15/20/25mg/d every 28 days in the absence of grade 3/4 infection or prolonged cytopenia (not due to bone marrow infiltration by CLL), as well as in the absence of Grade 3/4 non hematologic toxicities. In case of limiting toxicity (serious infection or limiting grade 3 to 4 toxicity other than neutropenia) treatment should be continued at last tolerated dose (1 dose level below).

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera(R)
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab q4w 375mg/m2 iv day 4 on cycle 1 500mg/m2 iv day 1 on cycles 2-6

    Number of subjects in period 1
    FLR Induction
    Started
    45
    Completed
    40
    Not completed
    5
         Lack of efficacy
             1
         Adverse event, non-fatal
             2
         Consent withdrawn by subject
             2
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    LR Maintenance
    Arm description
    Rituximab-lenalidomide maintenance
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide day 1-28 of 28 day cycles for 6 months at the maximal dose level reached individually in induction phase

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera(R)
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375mg/m2 iv 2/4/6 months after end of induction phase

    Number of subjects in period 2
    LR Maintenance
    Started
    40
    Completed
    39
    Not completed
    1
         Physician decision
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction
    Reporting group description
    -

    Reporting group values
    Induction Total
    Number of subjects
    45 45
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    66 (43 to 79) -
    Gender categorical
    Units: Subjects
        Female
    19 19
        Male
    26 26

    End points

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    End points reporting groups
    Reporting group title
    FLR Induction
    Reporting group description
    Fludarabine-rituximab backbone with escalating lenalidomide doses
    Reporting group title
    LR Maintenance
    Reporting group description
    Rituximab-lenalidomide maintenance

    Primary: Achieved lenalidomide dose at end of 6 cycles

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    End point title
    Achieved lenalidomide dose at end of 6 cycles [1]
    End point description
    Individual dose of lenalidomide achieved at cycle 6 of FLR induction treatment
    End point type
    Primary
    End point timeframe
    6 cycles of FLR induction treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is provided as this is an one armed, open label, non-comperative study.
    End point values
    FLR Induction
    Number of subjects analysed
    40
    Units: Patients
        25 mg
    15
        20 mg
    3
        15 mg
    6
        10 mg
    5
        5 mg
    5
        2,5 mg
    3
        0 mg
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All patients having received at least one dose of the study medication were followed for adverse events for 28 days after discontinuing study treatment or completion of study treatment.
    Adverse event reporting additional description
    All adverse events grade 2 or greater including all SAEs and all AEs resulting in IMP dose modifications were collected. Laboratory test value abnormalities were not reported as AEs unless there was an associated clinical condition for which the patient was given treatment or treatment altered.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    All enrolled patients
    Reporting group description
    -

    Serious adverse events
    All enrolled patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 45 (44.44%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hydrocele operation
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 45 (2.22%)
         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 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dry skin
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteremia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.4%
    Non-serious adverse events
    All enrolled patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 45 (91.11%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Thrombophlebitis
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    Hypersensitivity
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    7
    Leukopenia
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    16
    Neutropenia
         subjects affected / exposed
    28 / 45 (62.22%)
         occurrences all number
    57
    Thrombocytopenia
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Influenza like illness
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    7 / 45 (15.56%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Osteoarthritis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Herpes zoster
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Sinusitis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2009
    The amendment was concerning administrational issues as well as a safety issue: a new thrombose prophylaxis was added.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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