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    Clinical Trial Results:
    A Randomised Stratified Multicentre Phase II Clinical Trial of Single-Agent ADI-PEG 20 (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma.

    Summary
    EudraCT number
    2006-004592-35
    Trial protocol
    GB  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Sep 2017
    First version publication date
    16 Sep 2017
    Other versions
    Summary report(s)
    ADAM Publication_Sep2016

    Trial information

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    Trial identification
    Sponsor protocol code
    6836
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01279967
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Barts Health NHS Trust
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    CECM Trials Team, Queen Mary University London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    CECM Trials Team, Queen Mary University London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk
    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
    01 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the time to disease progression between the control group receiving best supportive care and the group receiving ADI-PEG 20 and best supportive care.
    Protection of trial subjects
    The Trial Management Group consisted of an independent chairperson, the Chief Investigator, trial co-ordination team, collaborators, and the trial statistician and provided review of cumulative reports of all Serious Adverse Events (SAEs) on a minimum 6 monthly basis to identify patterns or trends of events or identify safety issues, which would not be apparent on an individual basis.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Jan 2011
    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
    United Kingdom: 68
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    29
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    From March 2, 2011 to March 21, 2013 201 patients were screened to take part in ADAM.

    Pre-assignment
    Screening details
    From March 2, 2011 to March 21, 2013 201 patients were screened to take part in ADAM. Of these 97 were found to be ASS1 negative and 70 were randomised into the trial. 2 patients were subsequently found to be ineligible so that the total number of patients randomised into the trial is 68.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ADI-PEG20 + BSC
    Arm description
    Patients randomised into this arm received a weekly intramuscular injection of ADI-PEG20 (36.8mg/m2) for up to 6 months (cycles) plus best supportive care (BSC). Patients continued to receive study treatment, with regular blood sampling, until disease progression, withdrawal of consent, or unacceptable toxic effects. ADI-PEG20–treated patients with disease control were allowed to exceed 6 cycles. Chemotherapy-naive patients were offered chemotherapy on progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegylated arginine deiminase (ADI-PEG 20)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Weekly intramuscular injection of ADI-PEG20 dose of 36.8mg/m2 (equivalent to 320IU/m2) for up to 6 months.

    Arm title
    BSC alone
    Arm description
    Best supportive care
    Arm type
    Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    ADI-PEG20 + BSC BSC alone
    Started
    44
    24
    Completed
    44
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ADI-PEG20 + BSC
    Reporting group description
    Patients randomised into this arm received a weekly intramuscular injection of ADI-PEG20 (36.8mg/m2) for up to 6 months (cycles) plus best supportive care (BSC). Patients continued to receive study treatment, with regular blood sampling, until disease progression, withdrawal of consent, or unacceptable toxic effects. ADI-PEG20–treated patients with disease control were allowed to exceed 6 cycles. Chemotherapy-naive patients were offered chemotherapy on progression.

    Reporting group title
    BSC alone
    Reporting group description
    Best supportive care

    Reporting group values
    ADI-PEG20 + BSC BSC alone Total
    Number of subjects
    44 24 68
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17 13 30
        From 65-84 years
    27 11 38
    Gender categorical
    Units: Subjects
        Female
    8 5 13
        Male
    36 19 55
    ECOG
    Units: Subjects
        PS 0
    9 7 16
        PS 1
    35 17 52
    Smoking history
    Units: Subjects
        Never smoker
    18 7 25
        Current smoker
    1 1 2
        Ex-smoker
    25 16 41
    Histological sub-type
    Units: Subjects
        Sarcomatoid
    1 1 2
        Non-sarcomatoid
    43 23 66
    Prior Chemotherapy
    Units: Subjects
        None
    17 11 28
        Platinum based
    27 13 40
    Subject analysis sets

    Subject analysis set title
    All analyses
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All eligible patients that had been randomised (excludes 2 patients who were randomised but not eligible, as ascertained after randomisation)

    Subject analysis sets values
    All analyses
    Number of subjects
    68
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    30
        From 65-84 years
    38
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    ECOG
    Units: Subjects
        PS 0
        PS 1
    Smoking history
    Units: Subjects
        Never smoker
        Current smoker
        Ex-smoker
    Histological sub-type
    Units: Subjects
        Sarcomatoid
        Non-sarcomatoid
    Prior Chemotherapy
    Units: Subjects
        None
        Platinum based

    End points

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    End points reporting groups
    Reporting group title
    ADI-PEG20 + BSC
    Reporting group description
    Patients randomised into this arm received a weekly intramuscular injection of ADI-PEG20 (36.8mg/m2) for up to 6 months (cycles) plus best supportive care (BSC). Patients continued to receive study treatment, with regular blood sampling, until disease progression, withdrawal of consent, or unacceptable toxic effects. ADI-PEG20–treated patients with disease control were allowed to exceed 6 cycles. Chemotherapy-naive patients were offered chemotherapy on progression.

    Reporting group title
    BSC alone
    Reporting group description
    Best supportive care

    Subject analysis set title
    All analyses
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All eligible patients that had been randomised (excludes 2 patients who were randomised but not eligible, as ascertained after randomisation)

    Primary: Progression free survival

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    End point title
    Progression free survival
    End point description
    End point type
    Primary
    End point timeframe
    Until end of follow up
    End point values
    ADI-PEG20 + BSC BSC alone
    Number of subjects analysed
    44
    24
    Units: Months
        median (inter-quartile range (Q1-Q3))
    3.2 (1.8 to 5.5)
    2 (1.8 to 3.6)
    Statistical analysis title
    ADI-PEG20 analyses
    Comparison groups
    ADI-PEG20 + BSC v BSC alone
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.15 [1]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.96
    Notes
    [1] - randomised phase II trial

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Until end of follow up
    End point values
    ADI-PEG20 + BSC BSC alone
    Number of subjects analysed
    44
    24
    Units: Months
        median (inter-quartile range (Q1-Q3))
    11.5 (4.2 to 22.9)
    11.1 (6.9 to 14.2)
    Statistical analysis title
    Overall survival
    Comparison groups
    ADI-PEG20 + BSC v BSC alone
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.15 [3]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.16
    Notes
    [2] - The Kaplan-Meier curves did not show proportional hazards. Therefore restricted mean survival times also provided: RMST ADI-PEG20: 15.7 months BSC: 12.1 months Difference in RMST 3.6 (95% CI -1.0 to 8.1), p=0.6 (one-sided), p=0.13 (two-sided)
    [3] - p=0.15 (2-sided) or 0.08 (one-sided)

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    Proportion of evaluable subjects who achieve a confirmed SD, CR or PR per modified RECIST guidelines for plain CT and by EORTC guidelines for PET-CT. The number and percentage of subjects falling into each response category will be descriptively tabulated. At 4 months, the best response observed by patients was stable disease (SD), there were no CR or PR.
    End point type
    Secondary
    End point timeframe
    Those with evaluable disease at 4 months
    End point values
    ADI-PEG20 + BSC BSC alone
    Number of subjects analysed
    23
    9
    Units: Percentage
    12
    2
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    Adverse events
    End point description
    Assessed from adverse event and SUSAR reporting. Based on the highest grade of toxicity (grade 1 to 4) for each patient and each event type.
    End point type
    Secondary
    End point timeframe
    Until end of follow up
    End point values
    ADI-PEG20 + BSC BSC alone
    Number of subjects analysed
    44
    24
    Units: Number of patients
    40
    14
    Attachments
    Untitled (Filename: ADAM trial - Eudract toxicity table.docx)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent date to 30 days post last dose of IMP.
    Adverse event reporting additional description
    SAEs are as defined in the regulations. Non-serious adverse events are all grades 1 to 2. The uploaded table shows grade 1-2 and grade 3-4 separately.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    ADI-PEG20 + BSC
    Reporting group description
    Patients randomised into this arm received a weekly intramuscular injection of ADI-PEG20 (36.8mg/m2) for up to 6 months (cycles) plus best supportive care (BSC). Patients continued to receive study treatment, with regular blood sampling, until disease progression, withdrawal of consent, or unacceptable toxic effects. ADI-PEG20–treated patients with disease control were allowed to exceed 6 cycles. Chemotherapy-naive patients were offered chemotherapy on progression.

    Reporting group title
    BSC alone
    Reporting group description
    Best supportive care

    Serious adverse events
    ADI-PEG20 + BSC BSC alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 44 (20.45%)
    2 / 24 (8.33%)
         number of deaths (all causes)
    35
    20
         number of deaths resulting from adverse events
    Investigations
    Neutropenia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (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
    Pleural effusion
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adult respiratory distress syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
    Additional description: Allopurinol allergy with renal impairment
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowsiness
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unwell
    Additional description: pale, clammy, BP low 70/35, chest pressure and rash
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: abdominal pain due to pericardial effusion
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Difficulty swallowing
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Rash
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpuric rash legs
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ADI-PEG20 + BSC BSC alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 44 (97.73%)
    21 / 24 (87.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Investigations
    Abnormal haematologic test result
         subjects affected / exposed
    12 / 44 (27.27%)
    2 / 24 (8.33%)
         occurrences all number
    47
    2
    Neutropenia
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Immune system disorders
    Allergic reaction and/or anaphylaxis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dizzy spell
         subjects affected / exposed
    6 / 44 (13.64%)
    0 / 24 (0.00%)
         occurrences all number
    6
    0
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    16 / 44 (36.36%)
    0 / 24 (0.00%)
         occurrences all number
    21
    0
    Chest pain and/or trouble breathing
         subjects affected / exposed
    24 / 44 (54.55%)
    8 / 24 (33.33%)
         occurrences all number
    45
    8
    Fatigue
         subjects affected / exposed
    19 / 44 (43.18%)
    6 / 24 (25.00%)
         occurrences all number
    36
    6
    Fever
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Pain
         subjects affected / exposed
    22 / 44 (50.00%)
    4 / 24 (16.67%)
         occurrences all number
    33
    5
    Swelling in limbs
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    GI events
         subjects affected / exposed
    23 / 44 (52.27%)
    6 / 24 (25.00%)
         occurrences all number
    73
    14
    Metabolism and nutrition disorders
    Abnormal biochemical test result
         subjects affected / exposed
    6 / 44 (13.64%)
    1 / 24 (4.17%)
         occurrences all number
    42
    2
    Infections and infestations
    Infection
         subjects affected / exposed
    12 / 44 (27.27%)
    3 / 24 (12.50%)
         occurrences all number
    19
    3
    Rash
         subjects affected / exposed
    17 / 44 (38.64%)
    1 / 24 (4.17%)
         occurrences all number
    24
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2010
    - Changes to primary endpoint (TTP to PFS) - Increased sample size - IMP dose adjustment in line with recent published data
    10 Nov 2010
    IMPD updates
    18 Feb 2011
    Inclusion of patients with prior platinum therapy
    19 Sep 2011
    Changes to screening timeframe
    29 Mar 2012
    Updates to IMP thawing process, clarification of registration, screening, withdrawal and follow-up processes
    18 May 2012
    Change to Sponsor name
    19 Oct 2012
    - Change of requirement to check serum uric acid levels on every day of dosing to Day 1 of each cycle - Inclusion of study schedule for patients who wish to extend treatment beyond 6 months - New Investigator Brochure

    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/27584578
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