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    Clinical Trial Results:
    Avastin Randomised Trial with neo-adjuvant chemotherapy for patients with early HER2- negative breast cancer

    Summary
    EudraCT number
    2008-002322-11
    Trial protocol
    GB  
    Global end of trial date
    19 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jul 2016
    First version publication date
    31 Jul 2015
    Other versions
    Summary report(s)
    Artemis Article
    Artemis SupplementaryAppendix

    Trial information

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    Trial identification
    Sponsor protocol code
    ARTemis
    Additional study identifiers
    ISRCTN number
    ISRCTN68502941
    US NCT number
    NCT01093235
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
    Sponsor organisation address
    R&D, Box 277, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Louise Grybowicz , Cambridge University Hospitals NHS Foundation Trust, +44 1223 348447, louise.grybowicz@addenbrookes.nhs.uk
    Scientific contact
    Dr. Helena Earl, University of Cambridge , hme22@cam.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
    16 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A phase III, randomised trial to determine whether the addition to neo-adjuvant chemotherapy (3 cycles of docetaxel followed by 3 cycles of 5-fluorouracil, epirubicin and cyclophosphamide) of 4 cycles of an anti-angiogenic agent bevacizumab given concurrently with the chemotherapy is more effective than standard chemotherapy alone in terms of short-term and long-term outcome in patients presenting with high risk HER2-negative early breast cancer.
    Protection of trial subjects
    Protocol design: Prevention of AEs included cardiac monitoring (LVEF and BP) mandated before, during and after treatment; G-CSF strongly recommended for use alongside treatment; schedule of chemotherapy reversed to be less cardiotoxic and more efficacious; mandatory treatment washout period before surgery; early interim safety analysis of toxicities on first 200 patients; various exclusion criteria, screening, and on-treatment investigations conducted to ascertain and maintain knowledge of patients' fitness to receive the treatment; on-study toxicity management guidelines; and continuous monitoring and dissemination of the safety data for the treatments used throughout the trial, and of the patients themselves.
    Background therapy
    5-Fluorouracil 500mg/m2, Epirubicin 100mg/m2 and Cyclophosphamide 500mg/m2: every 3 weeks for 3 cycles.
    Evidence for comparator
    -
    Actual start date of recruitment
    07 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 800
    Worldwide total number of subjects
    800
    EEA total number of subjects
    800
    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)
    758
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were approached, consented, and recruited at hospital oncology clinics for recently-diagnosed, HER-2 negative, early (non-metastatic) breast cancer. Recruitment period was from May 2009 to Jan 2013.

    Pre-assignment
    Screening details
    HER2, ER, FBC, biochem, BP, Pregnancy, Urine, Coagulation, LVEF, Staging inflammatory/LN+ Exclusions: Cardiac-related or Thromboembolic disease, Inflammatory GI disease, Bleeding diathesis, Nephritic/nephrotic syndrome, Infection, Major surgery/trauma, Non-healing wound/fracture, Anticoagulants, LHRH-agonists, Other chemo/bio agent or malignancy.

    Pre-assignment period milestones
    Number of subjects started
    800
    Number of subjects completed
    800

    Period 1
    Period 1 title
    Primary endpoint analysis (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 B
    Arm description
    Research
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab (Avastin)
    Investigational medicinal product code
    Bev
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/kg; IV infusion every 3 weeks, for 4 cycles.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    D
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100mg/m2, every 3 weeks for 3 cycles.

    Arm title
    Arm A
    Arm description
    Standard treatment
    Arm type
    Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    D
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100mg/m2, every 3 weeks for 3 cycles.

    Number of subjects in period 1
    Arm B Arm A
    Started
    399
    401
    Completed
    388
    393
    Not completed
    11
    8
         Physician decision
    1
    1
         'disease progression '
    3
    -
         Consent withdrawn by subject
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm B
    Reporting group description
    Research

    Reporting group title
    Arm A
    Reporting group description
    Standard treatment

    Reporting group values
    Arm B Arm A Total
    Number of subjects
    399 401 800
    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)
    377 381 758
        From 65-84 years
    22 20 42
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    399 401 800
        Male
    0 0 0
    ER status
    Units: Subjects
        ER negative
    122 126 248
        ER weakly positive
    37 38 75
        ER strongly positive
    240 237 477
    Tumour Size
    Units: Subjects
        <=50mm
    317 318 635
        >50mm
    82 83 165
    Clinical involvement of axillary nodes
    Units: Subjects
        No
    190 193 383
        Yes
    209 208 417
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomised patients.

    Subject analysis sets values
    ITT
    Number of subjects
    800
    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)
    758
        From 65-84 years
    42
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    800
        Male
    0
    ER status
    Units: Subjects
        ER negative
    248
        ER weakly positive
    75
        ER strongly positive
    477
    Tumour Size
    Units: Subjects
        <=50mm
    635
        >50mm
    165
    Clinical involvement of axillary nodes
    Units: Subjects
        No
    383
        Yes
    417

    End points

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    End points reporting groups
    Reporting group title
    Arm B
    Reporting group description
    Research

    Reporting group title
    Arm A
    Reporting group description
    Standard treatment

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomised patients.

    Primary: Complete pathological response (pathCR) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.

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    End point title
    Complete pathological response (pathCR) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.
    End point description
    No residual invasive carcinoma within the breast (DCIS permitted) AND no evidence of metastatic disease within the lymph nodes {Pinder, 2007 #86}
    End point type
    Primary
    End point timeframe
    Period of assessment: 02July2013 - 11Mar2014
    End point values
    Arm B Arm A
    Number of subjects analysed
    388
    393
    Units: pathological complete response (pCR)
        Yes
    87
    66
        No
    301
    327
    Statistical analysis title
    Complete pathological response (pathCR) rates.
    Statistical analysis description
    No residual invasive carcinoma within the breast (DCIS permitted) AND no evidence of metastatic disease within the lymph nodes {Pinder, 2007 #86}
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    781
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    2.26
    Notes
    [1] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors."

    Secondary: pCR and Minimal Residual Disease (MRD)

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    End point title
    pCR and Minimal Residual Disease (MRD)
    End point description
    Complete pathological response (pathCR) and Minimal Residual Disease (MRD) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.
    End point type
    Secondary
    End point timeframe
    Period of assessment: 02July2013 - 11Mar2014
    End point values
    Arm B Arm A
    Number of subjects analysed
    388
    394
    Units: subjects
        Yes
    138
    114
        No
    250
    280
    Statistical analysis title
    pCR and Minimal Residual Disease (MRD)
    Statistical analysis description
    Complete pathological response (pathCR) and Minimal Residual Disease (MRD) rates (tumour and lymph nodes) after neo-adjuvant chemotherapy.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    782
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.03 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    1.98
    Notes
    [2] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors."
    Statistical analysis title
    pCR in breast only
    Statistical analysis description
    pCR in all breast tumours
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    2.24
    Notes
    [3] - "Multivariate logistic regression provided p values for the treatment effect after adjustment for stratification factors."

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation of the first trial patient, to 6 weeks after the final infusion of the final patient (or longer if considered related to treatment or protocol).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    All patients randomised into the trial

    Serious adverse events
    All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    362 / 800 (45.25%)
         number of deaths (all causes)
    90
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thrombosis / Thrombus / Embolism [10043607]
         subjects affected / exposed
    9 / 800 (1.13%)
         occurrences causally related to treatment / all
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever) [10020751]
         subjects affected / exposed
    36 / 800 (4.50%)
         occurrences causally related to treatment / all
    38 / 38
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutrophils [10029366]
    Additional description: Low neutrophils
         subjects affected / exposed
    55 / 800 (6.88%)
         occurrences causally related to treatment / all
    40 / 64
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever [10016558]
    Additional description: In the absence of neutropenia
         subjects affected / exposed
    36 / 800 (4.50%)
         occurrences causally related to treatment / all
    27 / 39
         deaths causally related to treatment / all
    0 / 0
    Pain: Other [90004082]
         subjects affected / exposed
    21 / 800 (2.63%)
         occurrences causally related to treatment / all
    15 / 21
         deaths causally related to treatment / all
    0 / 0
    Other
    Additional description: All other events <10% of patients reported
         subjects affected / exposed
    92 / 800 (11.50%)
         occurrences causally related to treatment / all
    64 / 99
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea [10012727]
         subjects affected / exposed
    18 / 800 (2.25%)
         occurrences causally related to treatment / all
    13 / 18
         deaths causally related to treatment / all
    0 / 0
    Vomiting [10047700]
         subjects affected / exposed
    12 / 800 (1.50%)
         occurrences causally related to treatment / all
    5 / 12
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Febrile neutropenia [10016288]
         subjects affected / exposed
    171 / 800 (21.38%)
         occurrences causally related to treatment / all
    152 / 185
         deaths causally related to treatment / all
    0 / 0
    Infection: Other [10021789]
    Additional description: All types
         subjects affected / exposed
    83 / 800 (10.38%)
         occurrences causally related to treatment / all
    66 / 88
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    800 / 800 (100.00%)
    Cardiac disorders
    Hypertension (10020772)
         subjects affected / exposed
    89 / 800 (11.13%)
         occurrences all number
    174
    Blood and lymphatic system disorders
    Neutropenia (10029366)
    Additional description: Any grade
         subjects affected / exposed
    353 / 800 (44.13%)
         occurrences all number
    527
    Nervous system disorders
    Peripheral neuropathy (10034620)
    Additional description: Any grade
         subjects affected / exposed
    403 / 800 (50.38%)
         occurrences all number
    977
    General disorders and administration site conditions
    Fatigue (10016256)
         subjects affected / exposed
    720 / 800 (90.00%)
         occurrences all number
    2978
    Other
    Additional description: All other events reported
         subjects affected / exposed
    731 / 800 (91.38%)
         occurrences all number
    7051
    Gastrointestinal disorders
    Constipation (10010774)
    Additional description: Any grade
         subjects affected / exposed
    478 / 800 (59.75%)
         occurrences all number
    1150
    Diarrhoea (10012727)
    Additional description: Any grade
         subjects affected / exposed
    430 / 800 (53.75%)
         occurrences all number
    852
    Nausea (10028813)
         subjects affected / exposed
    613 / 800 (76.63%)
         occurrences all number
    1634
    Vomiting (10047700)
         subjects affected / exposed
    283 / 800 (35.38%)
         occurrences all number
    489
    Skin and subcutaneous tissue disorders
    Alopecia (10001760)
    Additional description: Any grade
         subjects affected / exposed
    719 / 800 (89.88%)
         occurrences all number
    3495
    Metabolism and nutrition disorders
    Proteinuria (10037020)
    Additional description: Any grade
         subjects affected / exposed
    65 / 800 (8.13%)
         occurrences all number
    100
    Infections and infestations
    Infection (10021789)
    Additional description: Any grade
         subjects affected / exposed
    361 / 800 (45.13%)
         occurrences all number
    596

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2009
    Administrative changes & clarifications to Protocol & Patient Information Sheets; addition of screening tests and time limits to pre-randomisation tests; long-term follow-up increased to 10 years.
    22 Jun 2010
    New reference safety information (Summary of Product Characteristics) for IMP docetaxel
    18 Oct 2010
    Change of distributor of IMP Bevacizumab - outsourced by the manufacturer.
    27 Sep 2011
    Administrative changes & clarifications to Protocol & Patient Information Sheets; addition of eligibility criteria; interim saftey analysis complete, requirement to report specific AEs lifted.
    29 Oct 2013
    Addition of a translational sample collection sub-study; clarification of primary endpoint; clarification of definition of end of trial.

    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/25975632
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