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    Clinical Trial Results:
    Lenalidomide in conjunction with methotrexate, leucovorin, cytarabine and rituximab for the treatment of relapsed or refractory CD20-positive aggressive lymphomas: an open-label, multicenter phase I/II trial

    Summary
    EudraCT number
    		 2012-001891-13
    Trial protocol
    		 DE  
    Global end of trial date
    20 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2022
    First version publication date
    06 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LeMLAR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01788189
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Essen
    Sponsor organisation address
    Hufelandstrasse 55, Essen, Germany, 45147
    Public contact
    Prof. Dr. Ulrich Dührsen, University Hospital Essen, 0049 2102847374, ulrich.duehrsen@uk-essen.de
    Scientific contact
    Prof. Dr. Ulrich Dührsen, University Hospital Essen, 0049 2102847374, ulrich.duehrsen@uk-essen.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
    20 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1: Evaluation of the feasibility, safety and dose-limiting toxicity of the LeMLAR regimen Phase 2: Evaluation of the efficacy of the LeMLAR regimen at the maximum tolerated dose
    Protection of trial subjects
    Documentation of adverse events according to CTCAE version 3.0
    Background therapy
    		 -
    Evidence for comparator
    		 Phase 2: The objective response rate of patients with relapsed or refractory diffuse large B-cell lymphoma to lenalidomide alone had been reported to be 20% (J Clin Oncol 26: 4952-4957, 2008). The phase II part of the LeMLAR trial tested the hypothesis that the objective response rate will be increased to ≥40% by combining lenalidomide with MLAR at the maximum tolerated dose (p<0.05, power=0.4).
    Actual start date of recruitment
    18 Dec 2012
    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
    Germany: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    16
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients ≥18 years with relapsed or refractory CD20-positive aggressive B cell lymphoma (excluding mantle cell lymphoma and central nervous system involvement) lacking other treatment options were eligible. Exclusion criteria included inadequate organ function and uncontrolled infection. First patient in: 25/01/2013 Last patient in: 23/05/2018

    Pre-assignment
    Screening details
    		 Details specified in the inclusion and exclusion criteria (publication of the LeMLAR trial, Blood Cancer J 11: 95, 2021).

    Period 1
    Period 1 title
    Phase 1 and 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1. Dose level 3-1
    Arm description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 1
    Arm type
    		 Phase 1 Level 3-1

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg, day 1-21 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg four times per day, day 2, 9 and 16 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each 28-day cycle, maximum 6 cycles

    Arm title
    		 2. Dose level 3-2
    Arm description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 2
    Arm type
    		 Phase 1 Level 3-2

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg, day 1-21 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg four times per day, day 2, 9 and 16 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each 28-day cycle, maximum 6 cycles

    Arm title
    		 3. Dose level 2-2
    Arm description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 2
    Arm type
    		 Phase 1 Level 2-2

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg, day 1-21 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg four times per day, day 2, 9 and 16 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each 28-day cycle, maximum 6 cycles

    Arm title
    		 4. Dose level 2-3
    Arm description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 3
    Arm type
    		 Phase 1 Level 2-3

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg, day 1-21 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg four times per day, day 2, 9 and 16 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    225 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each 28-day cycle, maximum 6 cycles

    Arm title
    		 Phase 2 at MTD level (2-2)
    Arm description
    		 Treatment at MTD level and comparison with published results for lenalidomide monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg, day 1-21 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg four times per day, day 2, 9 and 16 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m2, day 1, 8 and 15 of each 28-day cycle, maximum 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each 28-day cycle, maximum 6 cycles

    Number of subjects in period 1
    		1. Dose level 3-1 2. Dose level 3-2 3. Dose level 2-2 4. Dose level 2-3 Phase 2 at MTD level (2-2)
    Started
    4
    4
    8
    6
    12
    Completed
    4
    4
    8
    6
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1. Dose level 3-1
    Reporting group description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 1

    Reporting group title
    2. Dose level 3-2
    Reporting group description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 2

    Reporting group title
    3. Dose level 2-2
    Reporting group description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 2

    Reporting group title
    4. Dose level 2-3
    Reporting group description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 3

    Reporting group title
    Phase 2 at MTD level (2-2)
    Reporting group description
    		 Treatment at MTD level and comparison with published results for lenalidomide monotherapy

    Reporting group values
    		 1. Dose level 3-1 2. Dose level 3-2 3. Dose level 2-2 4. Dose level 2-3 Phase 2 at MTD level (2-2) Total
    Number of subjects
    		 4 4 8 6 12 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 2 4 3 7 16
        From 65-84 years
    		 4 2 4 3 5 18
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 72 (70 to 74) 68 (56 to 80) 68 (56 to 80) 64 (49 to 72) 61 (40 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 2 1 7 15
        Male
    		 0 3 6 5 5 19

    End points

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    End points reporting groups
    Reporting group title
    1. Dose level 3-1
    Reporting group description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 1

    Reporting group title
    2. Dose level 3-2
    Reporting group description
    		 Lenalidomide 25 mg, methotrexate and cytarabine dose level 2

    Reporting group title
    3. Dose level 2-2
    Reporting group description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 2

    Reporting group title
    4. Dose level 2-3
    Reporting group description
    		 Lenalidomide 20 mg, methotrexate and cytarabine dose level 3

    Reporting group title
    Phase 2 at MTD level (2-2)
    Reporting group description
    		 Treatment at MTD level and comparison with published results for lenalidomide monotherapy

    Primary: Dose-limiting toxicity

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    End point title
    		 Dose-limiting toxicity [1] [2]
    End point description
    Treatment tolerance was assumed if none of three or only one of six patients experienced dose limiting toxicity (DLT). Definition of DLT: Neutrophils <0.5 /nl, platelets <25 /nl, creatinine clearance <60 ml/min, bilirubine ≥3 mg/dl, serum AST or ALT ≥6× ULN, or mucositis grade ≥3 on day 8 (plus a maximum of 3 extra days), day 15 (plus ≤6 days), or day 29 (plus ≤7 days). Failure to reach these thresholds at the indicated time-points prevented timely administration of methotrexate and cytarabine. Adverse events requiring dose reduction in cycle 1 or 2, receipt of <21 lenalidomide doses per cycle, cycle length >35 days, and any adverse event preventing continuation according to the protocol were also rated as DLT. Patients without DLT terminating treatment in cycle 1 or 2 prematurely due to disease progression were replaced by new patients. They were rated as not evaluable. The maximum tolerated dose (MTD) was the dose level immediately below the level where DLT occurred.
    End point type
    Primary
    End point timeframe
    Phase 1, first two treatment cycles (56-70 days from first treatment day)
    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: The first four arms represent groups of patients treated at escalating dose levels and are not meant to be compared by standard statistical methods. Dose escalation followed the 3+3 design whereby dose-limiting toxicity (DLT) was defined as an occurrence of toxicity in ≥1 of 3 or ≥2 of 6 patients treated at a given dose level. The maximum tolerated dose (2-2) was the level immediately below the level at which DLT occurred (2-3).
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The first four arms represent groups of patients treated at escalating dose levels and are not meant to be compared by standard statistical methods. Dose escalation followed the 3+3 design whereby dose-limiting toxicity (DLT) was defined as an occurrence of toxicity in ≥1 of 3 or ≥2 of 6 patients treated at a given dose level. The maximum tolerated dose (2-2) was the level immediately below the level at which DLT occurred (2-3).
    End point values
    		 1. Dose level 3-1 2. Dose level 3-2 3. Dose level 2-2 4. Dose level 2-3
    Number of subjects analysed
    4
    4
    8
    6
    Units: Patients
        No DLT
    3
    1
    5
    4
        DLT
    0
    2
    1
    2
        Not evaluable
    1
    1
    2
    0
    No statistical analyses for this end point

    Primary: Objective response rate

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    End point title
    		 Objective response rate [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    End of treatment (4 weeks after the last LeMLAR cycle)
    Notes
    [3] - 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: The study aimed at including 20 patients treated at the maximum tolerated dose (MTD = level 2-2). These were 8 patients from phase 1 and 12 patients additionally recruited in phase 2. These groups were not meant to be compared with each other, but to be combined to describe the objective response rate (ORR). The hypothesis of the phase 2 part was that the published ORR of lenalidomide monotherapy (20%) would be increased to ≥40% by combining lenalidomide with MLAR. This was confirmed (ORR=55%).
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study aimed at including 20 patients treated at the maximum tolerated dose (MTD = level 2-2). These were 8 patients from phase 1 and 12 patients additionally recruited in phase 2. These groups were not meant to be compared with each other, but to be combined to describe the objective response rate (ORR). The hypothesis of the phase 2 part was that the published ORR of lenalidomide monotherapy (20%) would be increased to ≥40% by combining lenalidomide with MLAR. This was confirmed (ORR=55%).
    End point values
    		 3. Dose level 2-2 Phase 2 at MTD level (2-2)
    Number of subjects analysed
    8
    12
    Units: Patients
        Objective response
    3
    8
        No objective response
    3
    4
        Not evaluable
    2
    0
    No statistical analyses for this end point

    Secondary: Complete remission rate

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    End point title
    		 Complete remission rate [5]
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (4 weeks after the last LeMLAR cycle)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study aimed at including 20 patients treated at the maximum tolerated dose (MTD = level 2-2). These were 8 patients from the phase 1 part and 12 patients additionally recruited in the phase 2 part. These groups were not meant to be compared with each other, but to be combined to describe the complete remission rate.
    End point values
    		 3. Dose level 2-2 Phase 2 at MTD level (2-2)
    Number of subjects analysed
    8
    12
    Units: Patients
        Complete remission
    1
    4
        Partial remission
    2
    4
        Stable disease
    2
    1
        Progressive disease
    1
    3
        Not evaluable
    2
    0
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response [6]
    End point description
    This analysis includes patients from Phase 1, Arm 3 (dose level 2-2) and Phase 2 at MTD level (2-2) combined
    End point type
    Secondary
    End point timeframe
    From achievement of an objective response to progression or last follow-up
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study aimed at including 20 patients treated at the maximum tolerated dose (MTD = level 2-2). These were 8 patients from phase 1 and 12 patients additionally recruited in phase 2. These groups were not meant to be compared with each other, but to be combined to describe the duration of response. This was compared to other therapies in similar patient groups (see LeMLAR publication, Blood Cancer J 11:95, 2021)
    End point values
    		 3. Dose level 2-2 Phase 2 at MTD level (2-2)
    Number of subjects analysed
    3
    12
    Units: Months
        median (full range (min-max))
    19 (1 to 32)
    19 (1 to 32)
    Attachments
    		 Duration of response to LeMLAR
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the consent form for trial participation to 4 weeks after the last treatment cycle Only for overall deaths: From signing the consent form to death or last follow-up (median follow-up: 31 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    		 -

    Reporting group title
    Phase 2
    Reporting group description
    		 -

    Serious adverse events
    		 Phase 1 Phase 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 22 (63.64%)
    6 / 12 (50.00%)
         number of deaths (all causes)
    22
    7
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Thromboembolism
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Worsening of general condition
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter-related infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (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 / 22 (9.09%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinuria
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infection
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (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
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1 Phase 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 22 (77.27%)
    6 / 12 (50.00%)
    Blood and lymphatic system disorders
    Anemia, grade 3 or 4
         subjects affected / exposed
    4 / 22 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    4
    3
    Leukopenia, grade 3 or 4
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Neutropenia, grade 3 or 4
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    2
    2
    Thrombocytopenia, grade 3 or 4
         subjects affected / exposed
    4 / 22 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    4
    3
    Gastrointestinal disorders
    Diarrhea, grade 3 or 4
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Infections and infestations
    Infection, grade 3 to 4
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2014
    Deescalation of lenalidomide dose from 25 mg to 20 mg and from 20 mg to 15 mg, if chemotherapy dose level 1 cannot be escalated at a lenalidomide dose of 25 mg or 20 mg, respectively

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34001867
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