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    Clinical Trial Results:
    An Open Label Non-Randomized Phase 2 Study Evaluating SAR3419, an Anti-CD19 Antibody – Maytansine Conjugate, Administered as Single Agent by Intravenous Infusion to Patients With Relapsed or Refractory CD19+ Diffuse Large B Cell Lymphoma

    Summary
    EudraCT number
    2011-003657-26
    Trial protocol
    CZ   BE   ES   IT   GB  
    Global end of trial date
    10 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARD10248
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01472887
    WHO universal trial number (UTN)
    U1111-1115-3349
    Other trial identifiers
    Study Name: STARLYTE
    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
    25 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the objective response rate (ORR) produced by SAR3419 in subjects with CD19+ diffuse large B-cell lymphoma (DLBCL) after failure of at least 1 prior line of standard therapy.
    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
    19 Jan 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
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    61
    EEA total number of subjects
    48
    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)
    17
    From 65 to 84 years
    42
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 28 sites in 9 countries between 19 January 2012 and 10 October 2016. A total of 79 subjects were screened in the study, out of which 18 were screen failures and 61 were enrolled and treated in the study.

    Pre-assignment
    Screening details
    Subjects enrolled in the study to evaluate the efficacy and safety of SAR3419 in adult subjects with CD19+ DLBCL with relapsed or refractory disease after failure of at least 1 prior line of standard therapy.

    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
    Arm description
    SAR3419 55 mg/m^2 once weekly for 4 weeks, followed by 1 week rest, and thereafter, every 2 weeks until disease progression (DP), unacceptable toxicity, or any other reason for treatment discontinuation.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR3419
    Investigational medicinal product code
    Other name
    Coltuximab ravtansine
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    SAR3419 administered at initial infusion rate of 1 mL/min for 30 minutes and then increased progressively by 0.5 mL/min increments at 15-minute intervals up to 3 mL/min.

    Number of subjects in period 1
    SAR3419
    Started
    61
    Completed
    0
    Not completed
    61
         Other than specified
             3
         Adverse event
             9
         Disease progression
             49

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAR3419
    Reporting group description
    SAR3419 55 mg/m^2 once weekly for 4 weeks, followed by 1 week rest, and thereafter, every 2 weeks until disease progression (DP), unacceptable toxicity, or any other reason for treatment discontinuation.

    Reporting group values
    SAR3419 Total
    Number of subjects
    61 61
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.1 ± 11.3 -
    Gender categorical
    Units: Subjects
        Female
    30 30
        Male
    31 31

    End points

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    End points reporting groups
    Reporting group title
    SAR3419
    Reporting group description
    SAR3419 55 mg/m^2 once weekly for 4 weeks, followed by 1 week rest, and thereafter, every 2 weeks until disease progression (DP), unacceptable toxicity, or any other reason for treatment discontinuation.

    Primary: Percentage of Subjects with Objective Response (OR)

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    End point title
    Percentage of Subjects with Objective Response (OR) [1]
    End point description
    OR reported as percentage of subjects achieving complete response (CR) or partial response (PR) relative to total number of subjects in per protocol (PP) population. As per Revised Response Criteria for Malignant Lymphoma, CR:Disappearance of all evidence of disease (nodal masses: [18F] Fluorodeoxyglucose[FDG]-avid or Positron emission tomography[PET] positive before therapy;Variably FDG-avid or if PET negative,regression to normal size; spleen/liver: not palpable,nodules disappeared; bone marrow infiltration cleared on repeat biopsy or negative immunohistochemistry) and PR: Regression of measurable disease, no new sites (≥50% decrease in sum of product of diameters of up to 6 largest dominant nodes or masses; no increase in size of other nodes, liver or spleen). PP population: all subjects who received at least 1 dose of study drug with no protocol deviation impacting efficacy at study entry & had an evaluable response assessment during treatment period or at end of treatment (EOT).
    End point type
    Primary
    End point timeframe
    Baseline, every 12 weeks up to DP, or any other reason for treatment discontinuation (upto 95.14 weeks )
    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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    SAR3419
    Number of subjects analysed
    41
    Units: percentage of subjects
        number (confidence interval 90%)
    43.9 (30.6 to 57.9)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    Duration of response (DOR)
    End point description
    Duration of tumor response was defined as the time interval from the date of the first occurrence of CR or PR to the date of the first documentation of disease progression or death due to any reason, whichever occurred first. In the absence of DP or death or further anticancer therapy at the time of the data cut-off date, duration of response was censored to the earliest date of the last evaluable response assessment without evidence of progression and data cut-off date. Analysis was performed on PP population using Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline, every 12 weeks up to DP, or any other reason for treatment discontinuation (maximum duration: 166 weeks)
    End point values
    SAR3419
    Number of subjects analysed
    41
    Units: months
        median (full range (min-max))
    4.6 (0 to 40)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    Progression-free survival was defined as the time interval from the date of the first study treatment infusion to the date of the first occurrence of progression or death (from any reason), whichever occurred first. In the absence of DP, death or further anticancer therapy at the time of the data cut-off date, the PFS was censored to the earliest date between the date of last evaluable response assessment without evidence of progression and the time of the data cut-off date. Analysis was performed on PP population using Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline, every 12 weeks up to DP, or any other reason for treatment discontinuation (maximum duration: 166 weeks)
    End point values
    SAR3419
    Number of subjects analysed
    41
    Units: months
        median (confidence interval 90%)
    4.4 (3.02 to 5.95)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Overall survival was defined as the time interval from the date of the first study treatment infusion to the date of death (due to any reason). Analysis was performed using Kaplan-Meier method. Analysis was performed on safety population that included all-treated population who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, every 12 weeks up to death or study cut-off, whichever came first (maximum duration: 166 weeks)
    End point values
    SAR3419
    Number of subjects analysed
    61
    Units: months
        median (confidence interval 90%)
    9.2 (6.57 to 12.22)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (maximum duration: 166 weeks) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment emergent that is AEs that developed/worsened and deaths that occurred during 'on treatment period’ (time from first study treatment infusion to last study treatment infusion + 42 days). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    SAR3419
    Reporting group description
    SAR3419 55 mg/m^2 once weekly for 4 weeks, followed by 1 week rest, and thereafter, every 2 weeks until DP, unacceptable toxicity, or any other reason for treatment discontinuation.

    Serious adverse events
    SAR3419
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 61 (44.26%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    1 / 61 (1.64%)
         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
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease Progression
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 5
    Injury, poisoning and procedural complications
    Humerus Fracture
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Pulmonary Oedema
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Spinal Cord Compression
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute Hepatic Failure
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SAR3419
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 61 (81.97%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Cough
         subjects affected / exposed
    12 / 61 (19.67%)
         occurrences all number
    13
    Oropharyngeal Pain
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 61 (18.03%)
         occurrences all number
    13
    Oedema Peripheral
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Asthenia
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    11 / 61 (18.03%)
         occurrences all number
    16
    Vomiting
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    13 / 61 (21.31%)
         occurrences all number
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    7
    Back Pain
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Pain In Extremity
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 61 (6.56%)
         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
    30 Mar 2012
    Following amendments were made: • Changed the schedule for tumor assessment; • Corrected the schedule for tumor assessment along the treatment period mixing response criteria Cheson 1999 and Cheson 2007 applying to Diffuse large B-cell lymphoma (DLBCL) being a FDG-avid, aggressive lymphoma; • Changed to the biomarkers analysis; • Changed the inclusion/exclusion criteria; • Provided the study name as STARLYTE; • Clarified the stopping rules and timing of the interim analysis; • Changed the investigational medicinal product administration: Corrected the formulation and instruction for preparing and administering the IMP; • Updated the safety follow-up period as a 42-day period; • Corrected minor inconsistencies/typos throughout the protocol.
    25 May 2012
    • Changes in inclusion/exclusion criteria; • Changed the primary objective as: to evaluate the objective response rate (ORR) of SAR3419 in subjects with CD19+ DLBCL after failure of at least one prior line of standard therapy; • Changed the study design as: This is an open label, uncontrolled Phase 2 evaluation of the efficacy and safety of SAR3419 as single agent in subjects with CD19+DLBCL after failure of at least one prior line of standard therapy, • Updated the study rationale.
    12 Nov 2012
    • Replaced 1 working day with within 24 hours in SAE reporting timelines, • Changed minor inconsistencies/typos throughout the protocol.
    19 Jul 2013
    • Changed the concomitant medication with study treatment; • Changed the IP preparation; • Clarification on related AE/SAEs occurring during FU period or ongoing at the EOT visit.
    22 Jan 2014
    Updated the management of specific adverse reactions (management of potential specific toxicities).

    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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