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    Clinical Trial Results:
    A phase II, randomized, multi-center study, assessing value of adding RAD 001 to Trastuzumab as preoperative therapy of HER-2 positive primary breast cancer amenable to surgery.

    Summary
    EudraCT number
    2007-004098-24
    Trial protocol
    FR  
    Global end of trial date
    31 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2021
    First version publication date
    04 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEP 04/0606
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00674414
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT RAHMOUNE, UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT RAHMOUNE, UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    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
    20 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the added efficacy obtained by the association of Trastuzumab with RAD001 as preoperative therapy of primary HER-2 positive breast cancer as shown by increased clinical tumor response rate.
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was performed in compliance with the principles laid down in the declaration of Helsinki, good Clinical Practice and European regulation.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Jul 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    62
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Date of first inclusion: 07 July 2008; Date of last inclusion: February 15th 2012; Date last patient out : March 2015

    Pre-assignment
    Screening details
    Main selection criteria are : Female patients (≥ 18 years old), with Histologically-confirmed diagnosis of invasive breast cancer, previously untreated (patients who have been treated for cancer of the controlateral breast cancer can be included if there is at least a 5 year time interval from last systemic treatment and randomization

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A (Reference therapy)
    Arm description
    Trastuzumab is administered once a week for 6 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Dose: Loading dose 4 mg/kg then 2 mg/kg Trastuzumab was administered once a week for 6 weeks.

    Arm title
    Arm B: experimental
    Arm description
    Trastuzumab was administered once a week for 6 weeks RAD001 was administered once daily for 6 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Dose: Loading dose 4 mg/kg then 2 mg/kg Trastuzumab was administered once a week for 6 weeks.

    Investigational medicinal product name
    RAD001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg/day. Two x 5 mg tablets started at D1 and taken once daily, in the morning, during 6 weeks.

    Number of subjects in period 1
    Arm A (Reference therapy) Arm B: experimental
    Started
    41
    41
    Completed
    39
    40
    Not completed
    2
    1
         Disease progression
    1
    -
         Not treated
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Reference therapy)
    Reporting group description
    Trastuzumab is administered once a week for 6 weeks.

    Reporting group title
    Arm B: experimental
    Reporting group description
    Trastuzumab was administered once a week for 6 weeks RAD001 was administered once daily for 6 weeks

    Reporting group values
    Arm A (Reference therapy) Arm B: experimental Total
    Number of subjects
    41 41 82
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    31 29 60
        From 65-84 years
    10 12 22
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    41 41 82
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Reference therapy)
    Reporting group description
    Trastuzumab is administered once a week for 6 weeks.

    Reporting group title
    Arm B: experimental
    Reporting group description
    Trastuzumab was administered once a week for 6 weeks RAD001 was administered once daily for 6 weeks

    Primary: Primary efficacy endpoint

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    End point title
    Primary efficacy endpoint
    End point description
    End point type
    Primary
    End point timeframe
    After 6 week of treatment
    End point values
    Arm A (Reference therapy) Arm B: experimental
    Number of subjects analysed
    38
    39
    Units: Number of complete or partial response
    14
    18
    Statistical analysis title
    EFFICACY RESULTS
    Comparison groups
    Arm A (Reference therapy) v Arm B: experimental
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 5
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall the study
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    -

    Reporting group title
    Arm B
    Reporting group description
    -

    Serious adverse events
    Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 41 (7.32%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Immune system disorders
    Hypersensitivity reaction
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    MUCOSITIS ORAL
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abscess breast
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    41 / 41 (100.00%)
    Investigations
    blood sugar abnormal
         subjects affected / exposed
    9 / 41 (21.95%)
    12 / 41 (29.27%)
         occurrences all number
    9
    12
    Cardiac disorders
    Ejection fraction decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Arrhythmia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 41 (9.76%)
         occurrences all number
    1
    4
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    6 / 41 (14.63%)
    19 / 41 (46.34%)
         occurrences all number
    6
    19
    leukocytes
         subjects affected / exposed
    4 / 41 (9.76%)
    10 / 41 (24.39%)
         occurrences all number
    4
    10
    Neutropenia
         subjects affected / exposed
    2 / 41 (4.88%)
    12 / 41 (29.27%)
         occurrences all number
    2
    12
    Platelet count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    16 / 41 (39.02%)
         occurrences all number
    0
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 41 (21.95%)
    17 / 41 (41.46%)
         occurrences all number
    9
    17
    Sensory disturbance
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    11 / 41 (26.83%)
    5 / 41 (12.20%)
         occurrences all number
    11
    5
    Asthenia
         subjects affected / exposed
    16 / 41 (39.02%)
    26 / 41 (63.41%)
         occurrences all number
    16
    26
    fever
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Chills
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    Infection
         subjects affected / exposed
    2 / 41 (4.88%)
    5 / 41 (12.20%)
         occurrences all number
    2
    5
    Infusion related reaction
         subjects affected / exposed
    6 / 41 (14.63%)
    1 / 41 (2.44%)
         occurrences all number
    6
    1
    retention water
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 41 (12.20%)
         occurrences all number
    4
    5
    Diarrhoea
         subjects affected / exposed
    6 / 41 (14.63%)
    12 / 41 (29.27%)
         occurrences all number
    6
    12
    Abdominal pain
         subjects affected / exposed
    5 / 41 (12.20%)
    4 / 41 (9.76%)
         occurrences all number
    5
    4
    Dyspepsia
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Stomatitis
         subjects affected / exposed
    2 / 41 (4.88%)
    33 / 41 (80.49%)
         occurrences all number
    2
    33
    Nausea
         subjects affected / exposed
    6 / 41 (14.63%)
    13 / 41 (31.71%)
         occurrences all number
    6
    13
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 41 (9.76%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 41 (9.76%)
    23 / 41 (56.10%)
         occurrences all number
    4
    23
    Dry skin
         subjects affected / exposed
    2 / 41 (4.88%)
    6 / 41 (14.63%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Bone pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 41 (9.76%)
         occurrences all number
    3
    4
    Metabolism and nutrition disorders
    Transaminases increased
         subjects affected / exposed
    11 / 41 (26.83%)
    17 / 41 (41.46%)
         occurrences all number
    11
    17
    Lipids abnormal
         subjects affected / exposed
    5 / 41 (12.20%)
    10 / 41 (24.39%)
         occurrences all number
    5
    10
    alkaline phosphatase
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 41 (7.32%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2009
    Investigators list updated
    19 Jun 2009
    Modification of some inclusion and non inclusion criteria Precision concerning the randomization procedure Precision concerning the interval between surgery and RAD001 intake Precision concerning surgery and adjuvant treatments Precision concerning HER2 status confirmation and biological material Precision concerning exams at baseline and during treatment
    13 May 2011
    Precision concerning inclusion and exclusion criteria Precision conserning the pharmacokinetic study of RAD001 Modification of study duration Modification of PIS/IC
    09 Feb 2012
    Name of the sponsor was modified (from FNCLCC to Unicancer)

    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.
    82 patients (41 in each arm) were randomized and analyzed for the primary objective. Initially 120 patients planned concerning adverse events the "Occurrences all number" is not known, the number of patients is noted in this field.
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