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    Clinical Trial Results:
    A SECOND-LINE, SINGLE ARM, PHASE II CLINICAL STUDY WITH TREMELIMUMAB, A FULLY HUMANIZED ANTI-CTLA-4 MONOCLONAL ANTIBODY, AS MONOTHERAPY IN PATIENTS WITH UNRESECTABLE MALIGNANT MESOTHELIOMA

    Summary
    EudraCT number
    		 2012-002762-12
    Trial protocol
    		 IT  
    Global end of trial date
    20 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2021
    First version publication date
    15 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MESOT-TREM-2012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01655888
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Azienda Ospedaliera Universitaria Senese
    Sponsor organisation address
    Viale Bracci 14, Siena, Italy, 53100
    Public contact
    UOC Immunoterapia Oncologica, Azienda Ospedaliera Universitaria Senese, l.calabro@ao-siena.toscana.it
    Scientific contact
    UOC Immunoterapia Oncologica, Azienda Ospedaliera Universitaria Senese, l.calabro@ao-siena.toscana.it
    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
    26 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the rate of objective clinical complete response (CR) or partial response (PR)
    Protection of trial subjects
    nothing
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jul 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
    Italy: 29
    Worldwide total number of subjects
    29
    EEA total number of subjects
    29
    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)
    12
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between July 30, 2012, and July 15, 2013, we enrolled 29 patients, Enrollment ended on 15/july/2013

    Pre-assignment
    Screening details
    		 Eligible patient were: advanced mesothelioma (pleural or peritoneal) in progression disease after one platinum-based chemotherapy regimen. Patient without Brain Metastasis or aoutoimmune disease and ECOG between 0 and 2 Need to have measurable disease per modified RECIST

    Period 1
    Period 1 title
    advance mesothelioma (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    single arm

    Arms
    Arm title
    		 tremelimumab arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg every 28 days

    Number of subjects in period 1
    		tremelimumab arm
    Started
    29
    Completed
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    tremelimumab arm
    Reporting group description
    		 -

    Reporting group values
    		 tremelimumab arm Total
    Number of subjects
    		 29 29
    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)
    		 12 12
        From 65-84 years
    		 17 17
        85 years and over
    		 0 0
    Age continuous
    Age at the start of treatment
    Units: years
        median (full range (min-max))
    		 65 (42 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 20 20
    Subject analysis sets

    Subject analysis set title
    primary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients were considered for the primary endpoint: immune related response All patients were also considered for secondary endpoint: immune related disease control; immune related PSF; OS; toxicity

    Subject analysis sets values
    		 primary analysis
    Number of subjects
    29
    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)
    12
        From 65-84 years
    17
        85 years and over
    0
    Age continuous
    Age at the start of treatment
    Units: years
        median (full range (min-max))
    65 (42 to 78)
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    tremelimumab arm
    Reporting group description
    		 -

    Subject analysis set title
    primary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients were considered for the primary endpoint: immune related response All patients were also considered for secondary endpoint: immune related disease control; immune related PSF; OS; toxicity

    Primary: Objective tumor response

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    End point title
    		 Objective tumor response
    End point description
    End point type
    Primary
    End point timeframe
    To estimate objective responce rate (proportion of patients with best response of CR+PR) defined as the total number of patients with CR, PR, , divided by the the total number of treated patients
    End point values
    		 tremelimumab arm primary analysis
    Number of subjects analysed
    29
    29
    Units: number
    29
    29
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The proportion of patients with immune related response was calculated as a ratio between the number of CR or PR and the number of patients included. Immune-related progression-free survival, overall survival, and survival rates at specified timepoints with two-sided 95% CIs based on normal approximation were estimated with the Kaplan-Meier method. Median values of circulating cells were taken as the cutoff to divide patient in two subgroups.
    Comparison groups
    tremelimumab arm v primary analysis
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Based on 95% confidence interval
    Parameter type
    		 Based on 95% confidence interval
    Point estimate
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 31.7
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Assuming a response rate of 5% or lower (null hypothesis) of no therapeutic interest (ie, a response rate below which the treatment would be deemed inactive) and a target response rate of 17% (alternative hypothesis) to consider the study drug clinically active, an α error of 0·05, we calculated that a total of 29 evaluable patients would have 70% power to detect an effect. On this basis, at least four immune-related objective responses would need to be detected to consider the drug active.
    [2] - The Simon's two stage design was used.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the sign of ICF to 90 days from the last study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    immune-related toxicity
    Reporting group description
    		 -

    Serious adverse events
    		 immune-related toxicity
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
         number of deaths (all causes)
    23
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    diarrhea
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 immune-related toxicity
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    General disorders and administration site conditions
    fever
         subjects affected / exposed
    12 / 29 (41.38%)
         occurrences all number
    29
    Gastrointestinal disorders
    gastrointestinal toxicity
         subjects affected / exposed
    21 / 29 (72.41%)
         occurrences all number
    29
    Hepatobiliary disorders
    liver toxicities
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    29
    Skin and subcutaneous tissue disorders
    dermatological toxicities
         subjects affected / exposed
    17 / 29 (58.62%)
         occurrences all number
    29
    Musculoskeletal and connective tissue disorders
    general pain toxcities
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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