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    Clinical Trial Results:
    An Open Label, Multicenter, Phase II Study of Intravenous SAR3419, an Anti-CD19 Antibody-Maytansine Conjugate, in Combination with Rituximab in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphomas

    Summary
    EudraCT number
    2011-002865-39
    Trial protocol
    SE   DE   AT  
    Global end of trial date
    22 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Mar 2016
    First version publication date
    20 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TCD12333
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01470456
    WHO universal trial number (UTN)
    U1111-1120-0315
    Other trial identifiers
    Study name : SARIT
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly, Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    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 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the objective response rate (ORR) of SAR3419 in combination with rituximab.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    France: 51
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    21
    From 65 to 84 years
    30
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 12 sites in France and Norway. A total of 85 subjects were screened between 22 November 2011 and 21 February 2013.

    Pre-assignment
    Screening details
    Of 85 screened subjects, 32 were screen failure; the screen failures were due to failure to meet the inclusion/exclusion criteria. Of 53 included subjects, 1 was not treated due to disease progression.

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

    Arms
    Arm title
    SAR3419 + Rituximab
    Arm description
    SAR3419 and Rituximab administered weekly from Weeks 1 to 4, then biweekly on Weeks 6, 8, 10, and 12. One cycle was defined as a 4-week period, except Cycle 1, which was to last 5 weeks (4 weekly administrations followed by a week's rest).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR3419
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    SAR3419 55 mg/m² infusion, administered over approximately an hour.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375 mg/m² administered over approximately 4 hours.

    Number of subjects in period 1
    SAR3419 + Rituximab
    Started
    52
    Completed
    29
    Not completed
    23
         disease progression
             23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAR3419 + Rituximab
    Reporting group description
    SAR3419 and Rituximab administered weekly from Weeks 1 to 4, then biweekly on Weeks 6, 8, 10, and 12. One cycle was defined as a 4-week period, except Cycle 1, which was to last 5 weeks (4 weekly administrations followed by a week's rest).

    Reporting group values
    SAR3419 + Rituximab Total
    Number of subjects
    52 52
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.7 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    26 26
        Male
    26 26

    End points

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    End points reporting groups
    Reporting group title
    SAR3419 + Rituximab
    Reporting group description
    SAR3419 and Rituximab administered weekly from Weeks 1 to 4, then biweekly on Weeks 6, 8, 10, and 12. One cycle was defined as a 4-week period, except Cycle 1, which was to last 5 weeks (4 weekly administrations followed by a week's rest).

    Primary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR) [1]
    End point description
    ORR was defined as the percentage of subjects achieving a complete response (CR) or partial response (PR), assessed based on International Workshop Guidelines (IWG) Cheson 2007 criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. Analysis was performed on per protocol (PP) population including all treated subjects who had an evaluable response assessment during treatment or end of treatment visit and without any important protocol deviation impacting efficacy.
    End point type
    Primary
    End point timeframe
    Baseline; end of the treatment and then every 3 months during the follow-up until progression or initiation of further anticancer therapy (24 months)
    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 data is provided as a separate attachment.
    End point values
    SAR3419 + Rituximab
    Number of subjects analysed
    45 [2]
    Units: percentage of subjects
        number (confidence interval 80%)
    31.1 (22 to 41.6)
    Attachments
    Statistical Analyses for ORR
    Notes
    [2] - 45 out of 52 subjects were eligible for the PP population.
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response was defined as the time interval from the date of first occurrence of complete response or partial response to the date of first documentation of disease progression (DP) or death due to any cause, which ever occurred first. Responses were assessed based on IWG Cheson 2007 criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. DP was defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. Duration of response was calculated using the Kaplan-Meier method. Number of subjects with duration of response ≤6 months and >6 months are provided. Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    Baseline; end of the treatment and then every 3 months during the follow-up until progression or initiation of further anticancer therapy (24 months)
    End point values
    SAR3419 + Rituximab
    Number of subjects analysed
    45 [3]
    Units: subjects
        <=6 months
    7
        >6 months
    7
    Notes
    [3] - 45 out of 52 subjects were eligible for the PP population.
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    Progression-free survival was defined as the time interval (in months) from the date of first study treatment infusion to the date of first occurrence of progression or death from any cause, whichever occurred first. DP was defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. Duration of response was calculated using the Kaplan Meier method. Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment infusion to the date of first occurrence of progression or death from any cause (24 months)
    End point values
    SAR3419 + Rituximab
    Number of subjects analysed
    45 [4]
    Units: months
        median (confidence interval 80%)
    3.9 (3.22 to 3.98)
    Notes
    [4] - 45 out of 52 subjects were eligible for the PP population.
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival was defined as the time interval (in months) from the date of first study treatment infusion to the date of death from any cause. Analysis was performed on safety population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment infusion to the date of death from any cause (24 months)
    End point values
    SAR3419 + Rituximab
    Number of subjects analysed
    52
    Units: months
        median (confidence interval 80%)
    9 (6.47 to 13.67)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Month 24) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events and death are treatment-emergent that is AEs that developed/worsened and death that occurred during the ‘on treatment period’ (from first study treatment infusion to 42 days after last study treatment infusion [i.e, last infusion of last cycle]).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    SAR3419 + Rituximab
    Reporting group description
    SAR3419 and Rituximab administered weekly from Weeks 1 to 4, then biweekly, on Weeks 6, 8, 10, and 12. One cycle was defined as a 4-week period, except Cycle 1, which was to last 5 weeks (4 weekly administrations followed by a week's rest).

    Serious adverse events
    SAR3419 + Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 52 (42.31%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    Vascular disorders
    Superior Vena Cava Syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease Progression
         subjects affected / exposed
    9 / 52 (17.31%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 7
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal Failure Acute
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ureteric Obstruction
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck Pain
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia Bacterial
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SAR3419 + Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 52 (75.00%)
    Investigations
    Weight Decreased
         subjects affected / exposed
    9 / 52 (17.31%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 52 (19.23%)
         occurrences all number
    11
    Dyspnoea
         subjects affected / exposed
    6 / 52 (11.54%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    4
    Neuropathy Peripheral
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Eye disorders
    Dry Eye
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Keratitis
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 52 (25.00%)
         occurrences all number
    13
    Oedema Peripheral
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    7 / 52 (13.46%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 52 (11.54%)
         occurrences all number
    8
    Constipation
         subjects affected / exposed
    6 / 52 (11.54%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    9 / 52 (17.31%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    11 / 52 (21.15%)
         occurrences all number
    11
    Vomiting
         subjects affected / exposed
    8 / 52 (15.38%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Back Pain
         subjects affected / exposed
    7 / 52 (13.46%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    4 / 52 (7.69%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2011
    - Pregnancy tests which were initially required at baseline and end of treatment Visit were performed at Day 1 of each cycle. - Contraception which was required to be continued during 3 months after the last treatment administration was extended until 12 months after the last treatment administration. - To provide the study name. - To correct the formulation and instruction for preparing and administrating the investigational medicinal product in the clinical trial summary and protocol.
    16 Dec 2011
    - To correct the schedule for tumor assessment in reference to response criteria Cheson 2007 applying to diffuse large B-cell lymphoma (DLBCL) being a fluorodeoxyglucose-avid (FDG-avid), aggressive lymphoma. Both computed tomography (CT) and positron emission tomography (PET) scans were performed for any subject at baseline and at the end of treatment Visit (42 days after the last treatment administration). For non-progressing subjects at the end of treatment, surveillance CT scans were performed 3 months during the follow-up period. - To remove the central reviews for both histology confirmation and disease response in this phase II Proof of Concept study. - To add the option of retrospectively using archived diagnostic biopsies in case of missing material for exploratory endpoint at study entry. - To answer the exploratory endpoint of the study, all subjects must had either a recent biopsy or a free needle aspiration (FNA) at study entry. Any effort should be done in order to obtain fresh biopsies. At the end of the study, the diagnosis biopsy might be retrospectively collected and used for the centralized analysis of the selected biomarkers defined in Hans and Choi algorithms. If necessary, a specific informed consent was to be obtained. - To revise the reporting of biological results in the safety follow-up period after further anticancer therapy was administered. - To add the pharmacokinetic (PK) parameters as an endpoint of the interim analysis on the first 20 subjects. - To clarify the stopping rules and timing of the interim analysis. - To harmonize the safety follow-up period as a 42-day period.

    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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