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    Clinical Trial Results:
    A CLINICO-PATHOLOGIC STUDY OF PRIMARY MEDIASTINAL B-CELL LYMPHOMA

    Summary
    EudraCT number
    2006-005794-22
    Trial protocol
    IT  
    Global end of trial date
    27 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Nov 2018
    First version publication date
    06 Feb 2019
    Other versions
    Summary report(s)
    IELSG26 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    IELSG26
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00944567
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Previous Protocol Number: IIL-PMDLBL
    Sponsors
    Sponsor organisation name
    International Extranodal Lymphoma Study Group
    Sponsor organisation address
    Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland, 6500
    Public contact
    Study Coordination Office, International Extranodal Lymphoma Study Group (IELSG) , 0041 91 811 90 40, ielsg@eoc.ch
    Scientific contact
    Emanuele Zucca, International Extranodal Lymphoma Study Group (IELSG), 0041 91 811 90 40, ielsg@eoc.ch
    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
    27 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the PET response rate following chemo-immunotherapy
    Protection of trial subjects
    Not Applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jun 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Italy: 112
    Worldwide total number of subjects
    125
    EEA total number of subjects
    118
    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)
    122
    From 65 to 84 years
    2
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    From 22 June 2007 to 17 Jun 2009

    Pre-assignment
    Screening details
    Patients with histopathological proven diagnosis of Primary Mediastinal Large B-Cell Lymphoma (PMBCL) of any stage, previously untreated and eligible for intensive immunochemotherapy were enrolled.

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

    Arms
    Arm title
    Enrolled patients
    Arm description
    The main aim of the study did not comprise any treatment evaluation. Patient were treated with standard immunochemotherapy (followed by consolidation radiotherapy if this was standard policy at the treating centre)
    Arm type
    Experimental

    Investigational medicinal product name
    NOT APPLICABLE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Not Applicable

    Number of subjects in period 1
    Enrolled patients
    Started
    125
    Completed
    119
    Not completed
    6
         Tumor progression
    4
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    Treated patients

    Reporting group values
    Overall Trial Total
    Number of subjects
    125 125
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    122 122
        From 65-84 years
    2 2
        85 years and over
    1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    33 (27 to 41) -
    Gender categorical
    Units: Subjects
        Female
    77 77
        Male
    48 48
    Performance Status (ECOG)
    Units: Subjects
        ECOG = 0
    61 61
        ECOG = 1
    47 47
        ECOG > 1
    17 17
    B Symptoms at presentation
    Units: Subjects
        Present
    45 45
        Absent
    80 80
    Anna Arbor Stage
    Units: Subjects
        I-II
    98 98
        III-IV
    27 27
    International Prognostic Index (IPI)
    Units: Subjects
        Low risk
    91 91
        Low-intermediate risk
    21 21
        Intermediate-high risk
    12 12
        High risk
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Enrolled patients
    Reporting group description
    The main aim of the study did not comprise any treatment evaluation. Patient were treated with standard immunochemotherapy (followed by consolidation radiotherapy if this was standard policy at the treating centre)

    Primary: Complete Metabolic Response (CMR) on PET scanning after frontline immunochemotherapy and risk stratification

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    End point title
    Complete Metabolic Response (CMR) on PET scanning after frontline immunochemotherapy and risk stratification [1]
    End point description
    The main purpose is to evaluate the role of PET as a tool to evaluate treatment results in PMBCL. It was verified if the achievement of complete metabolic response after 1st line chemotherapy is significantly associated with a better prognosis.
    End point type
    Primary
    End point timeframe
    At the completion of chemoimmunotherapy
    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: OS and PFS were estimated using the Kaplan-Meier or the life-table method as appropriate. Follow-up was calculated as the median time to censoring using a reverse Kaplan-Meier analysis. Cox regression was used for extimation of hazard ratio and its confidence interval. The exact 95%CI were calculated for incidence percentages. P-values of 0.05 or less (two sides test) were considered to indicate statistical significance. Statistical analysis was conducted using the STATA 5.0 software package.
    End point values
    Enrolled patients
    Number of subjects analysed
    115 [2]
    Units: Percentage
    number (confidence interval 95%)
        Complete Metabolic Response (CMR) on PET scanning
    47 (38 to 56)
        Overall Survival at 5 years
    95 (89 to 98)
        Progression Free Survival at 5 years
    90 (82 to 94)
    Notes
    [2] - Per-Protocol (Efficacy Evaluable) Population receiving immunotherapy
    No statistical analyses for this end point

    Primary: CMR on PET scanning defined by cutpoint

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    End point title
    CMR on PET scanning defined by cutpoint [3]
    End point description
    The main purpose is to evaluate the role of PET as a tool to evaluate treatment results in PMBCL. The cutpoint for defining the achievement of a metabolic complete response was evaluated. CMR defined by Deauville Score (DS) 2 - Mediastinal Blood Pool (MBP) and DS 3 - Liver uptake were analyzed. Complete results are shown in Figure 1
    End point type
    Primary
    End point timeframe
    At the end of chemiotherapy
    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 PET CR rate was expected to be approximately 50% in the group undergoing protocol therapy, and with a sample size of a minimum 100 patients the PET CR rate would be estimated with a standard error < 5%, and hence the 95% CI would extend from approximately 40%-60%. The PET CR rate and its 95% CI were estimated for patients who completed the planned chemotherapy
    End point values
    Enrolled patients
    Number of subjects analysed
    115 [4]
    Units: Percentage
    number (not applicable)
        DS 2 - Mediastinal Blood Pool
    47
        DS 3 - Liver uptake
    80
    Attachments
    Figure 1
    Notes
    [4] - Per-Protocol (Efficacy Evaluable) Population receiving immunotherapy
    No statistical analyses for this end point

    Post-hoc: Complete Metabolic Response (CMR) on PET scanning after consolidation radiotherapy

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    End point title
    Complete Metabolic Response (CMR) on PET scanning after consolidation radiotherapy
    End point description
    The post-radiotherapy scans were visually assessed according to the Deauville criteria with 18FDG uptake of any residual lesion scored according to the 5-point scale using Mediastinal Blood Pool and liver uptake as reference settings. The achievement of a CMR was defined, according to the Lugano Classification and the results of the previous analysis, by a completely PET-negative scan or a scan having minimal residual uptake less than/equal to the liver activity (Deauville score ≤3).
    End point type
    Post-hoc
    End point timeframe
    At least two months from the completion of involved-field radiotherapy
    End point values
    Enrolled patients
    Number of subjects analysed
    88 [5]
    Units: Percentage
        number (confidence interval 95%)
    89 (80 to 94)
    Notes
    [5] - Per-Protocol (Efficacy Evaluable) Population receiving consolidation therapy
    No statistical analyses for this end point

    Post-hoc: PET-CT Response assessment and risk stratification - 5 years Overall Survival

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    End point title
    PET-CT Response assessment and risk stratification - 5 years Overall Survival
    End point description
    Metabolic PET-metrics, particularly TLG, were evaluated to establish potential biomarkers. Correlation between the total lesion glycolysis (TLG) and Overall Survival at 5 years is reported. TLG was calculated as the product of Standardized Uptake Value (SUV) mean and Metabolic Tumor Volume (MTV). TLG was homogenously estimated in all patients during the central review of PET scans to mitigate the risks. Complete results are shown in Figure 2.
    End point type
    Post-hoc
    End point timeframe
    At baseline and 5 years after treatment start
    End point values
    Enrolled patients
    Number of subjects analysed
    103 [6]
    Units: Percentage
    number (not applicable)
        Low TLG (<cut off value)
    100
        High TLG (> cut-off value)
    80
    Attachments
    Figure 2
    Notes
    [6] - Per Protocol (Efficacy-evaluable) Population - prognostic stratification
    No statistical analyses for this end point

    Post-hoc: PET-CT Response assessment and risk stratification - Progression Free Survival (PFS)

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    End point title
    PET-CT Response assessment and risk stratification - Progression Free Survival (PFS)
    End point description
    Metabolic PET-metrics, particularly TLG, were evaluated to establish potential biomarkers. Correlation between the total lesion glycolysis (TLG) and Progression Free Survival at 5 years is reported. Complete results are shown in Figure 2.
    End point type
    Post-hoc
    End point timeframe
    At baseline and 5 years from treatment start
    End point values
    Enrolled patients
    Number of subjects analysed
    103 [7]
    Units: Percentage
    number (not applicable)
        High TLG (> cut off value)
    64
        Low TLG (< cut off value)
    99
    Attachments
    Figure 2
    Notes
    [7] - Per Protocol (Efficacy Evaluable) Population - Prognostic Stratification Analysis
    No statistical analyses for this end point

    Post-hoc: Combination of quantitative PET-CT parameters in prognostic stratification - Positive Predictive Value (PPV)

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    End point title
    Combination of quantitative PET-CT parameters in prognostic stratification - Positive Predictive Value (PPV)
    End point description
    Metabolic heterogenity is a prognostic factor and combined with TLG may allow early identification of poor prognosis patients. TLG and other clinical and imaging parameters were combined to evaluate if PPV can be improved. Complete results are shown in Table 1.
    End point type
    Post-hoc
    End point timeframe
    At baseline, after chemoimmunotherapy and 5 years after treatment start
    End point values
    Enrolled patients
    Number of subjects analysed
    100 [8]
    Units: Percentage
    number (not applicable)
        End of therapy TLG
    53
        Baseline TLG + end of therapy DS
    45
    Attachments
    Univariate Analysis
    Notes
    [8] - Per Protocol (Efficacy Evaluable) Population - combination of quantitative parameters
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From the signature of informed consent, during treatment and follow up
    Adverse event reporting additional description
    As per protocol only AEs of grade >/=3 with a suspected relationship to the study drugs and SAEs were collected
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    5.1
    Reporting groups
    Reporting group title
    Safety evaluable population
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No safety objectives were identified for this clinical-pathologic study. As per protocol, only AEs of Grade ≥3 with a suspected relationship to the study drugs and SAEs were collected. All treatments were well tolerated and no unexpected side effects were recorded. The most frequent toxicities were myelosuppression, transaminases elevation and mucositis, as expected.
    Serious adverse events
    Safety evaluable population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 125 (10.40%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    1
    Investigations
    Alanine aminotransferase increased
    Additional description: and Aspartate Aminotransferase increased
         subjects affected / exposed
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dehydration
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety evaluable population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 125 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2006
    Amendment No. 1: the main purpose of this amendment was to change the days of administration of vincristine and the dose of bleomycin (R-MACOP-B and R-VACOP-B regimes). In addition, the web link for the CTCAE was updated to version 3.0.
    28 Jan 2008
    Amendment No. 2: this amendment was implemented to align the 2 schedules of follow up reported in the protocol.
    12 Aug 2008
    Amendment No.3 : the main purpose of this amendment was the correction of a typo present in the Schedule of Events regarding the CT scan of the neck.
    24 Nov 2008
    Amendment No. 4: this amendment was implemented to correct a typo in the section 20 - Statistical Considerations (with a standard error of PET CR <5 %, the CI of 95 % extends approximatively 40%-60%).

    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.
    Not Applicable

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29720487
    http://www.ncbi.nlm.nih.gov/pubmed/28485042
    http://www.ncbi.nlm.nih.gov/pubmed/27839910
    http://www.ncbi.nlm.nih.gov/pubmed/26089397
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