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    Summary
    EudraCT Number:2008-002322-11
    Sponsor's Protocol Code Number:ARTemis
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-01-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2008-002322-11
    A.3Full title of the trial
    ARTemis : Avastin® Randomised Trial with nEo-adjuvant cheMotherapy for patients wIth early breaSt cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ARTemis : Avastin® Randomised Trial with nEo-adjuvant cheMotherapy for patients wIth early breaSt cancer
    A.3.2Name or abbreviated title of the trial where available
    ARTemis
    A.4.1Sponsor's protocol code numberARTemis
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN68502941
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01093235
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCambridge University Hospitals NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    B.Sponsor: 2
    B.1.1Name of SponsorUniversity of Cambridge
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche registration limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBevacizumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNbevacizumab
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRo 487-6646
    D.3.9.3Other descriptive namerhuMab, VEGF, anti-VEGF
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100mg/4ml to 400mg/16ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Taxotere
    D.2.1.1.2Name of the Marketing Authorisation holderAventis-Pharma S.A
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDocetaxel
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDocetaxel
    D.3.9.1CAS number 114977-28-5
    D.3.9.3Other descriptive nameantineoplastic
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20mg/1ml to 80mg/4ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HER2 negative invasive breast cancer
    E.1.1.1Medical condition in easily understood language
    Early breast cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if patients with HER2 negative early breast cancer receiving a standard regimen of neo-adjuvant chemotherapy with Avastin show better rates of complete pathological response.
    E.2.2Secondary objectives of the trial
    •Disease-Free Survival
    •Overall Survival
    •Rate of breast conservation
    •pathCR rate in breast alone
    •Safety and toxicity
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    ARTemis-SCIENCE:
    Tumour tissue samples from paraffin-embedded blocks obtained at initial diagnosis and surgery, will be collected from all patients. Analysis of tumour tissue will involve (i) tissue microarrays for immunohistochemistry (IHC) of protein gene products and in situ hybridisation analysis, and (ii) whole-genome profiling using expression and DNA microarrays.
    Blood samples will be used to discover single nucleotide polymorphisms (SNPs) as genetic / pharmacogenetic determinants of prognosis, toxicity and treatment outcome.

    OPTIONAL Quality of Life sub-study:
    All women patients will be invited to take part. Standardised measures of quality of life collected pre-chemotherapy, after 3 cycles, 6 cycles, surgery and radiotherapy, and then annually for 2 years from completion of chemotherapy.

    OPTIONAL CTCR-BR05 sub-study:
    Fresh tissue samples will also be collected from a sub-set of up to 400 patients before, during, and after neoadjuvant chemotherapy.
    Analysis of tumour tissue will involve assessment of prospective predictive high throughput molecular profiling, with candidate gene and mutational analysis.

    OPTIONAL Sequential blood samples sub-study:
    Blood samples (20mls) will be taken 5 times in a subset of patients and will be collected in order to carry out isolation of specific cells and also measurement of DNA, RNA or proteins. This information will be matched with clinical information to try to identify markers predicting patients response to chemotherapy or bevacizumab.

    OPTIONAL Samples Collection At Relapse and Follow-up (SCARF) sub-study:
    Blood samples (20mls) will be taken at each follow-up visit (up to and including year 5); and at relapse (if applicable), in order to carry out isolation of specific cells and also measurement of DNA, RNA or proteins. Tissue samples of relapsed / metatstatic site(s) (as is reasonably practical) will also be collected.
    This information will be matched with clinical information to try to identify markers predicting patients response / resistance to chemotherapy or bevacizumab.

    OPTIONAL MAN-ACT Radiology sub-study (lead site only):
    1H MRS, DWI & DCE MRI to assess and predict treatment response. 5 radiography scans at pre-treatment, before cycle 2, after cycle 3 and after cycle 6 in 20 - 30 patients. Also a 30ml blood sample is collected pre-treatment, immediately after cycle 1, before cycle 2, after cycle 3, after cycle 6 and post surgery for research into activity of Circulating Tumour Cells.
    E.3Principal inclusion criteria
    - Patients with histological diagnosis of HER2 negative invasive breast cancer.
    • UNIFOCAL TUMOUR :
    - T2 or T3 tumours (radiological size > or = 20 mm).
    - T4 tumour of any size with direct extension to (a) chest wall or (b) skin.
    OR
    Inflammatory carcinoma with tumour of any size.
    OR
    • OTHER LOCALLY ADVANCED DISEASE:
    - Involvement of large or fixed axillary lymph nodes (radiological diameter >20 mm or clinical N2) and primary breast tumour of any diameter.
    - Where no primary breast tumour was found, the presence of breast cancer in a lymph node (LN) must be histopathologically confirmed by LN biopsy
    (trucut or whole LN).
    OR
    • MULTIFOCAL TUMOURS:
    - The sum of each tumours’ maximum diameter must be > OR = 20mm (total radiological tumour size > 20mm).
    - Patients with bilateral disease are eligible to enter the trial.
    - Any hormone receptor status.
    - Patient fit to receive the trial chemotherapy regimen
    - Patient must not have clinically significant cardiac abnormalities and must not have had a previous myocardial infarction during the 6 months prior to recruitment. Cardiac function should be assessed by physical examination and by baseline measurement of LVEF.
    - Patient must have adequate bone marrow, hepatic, and renal function.*
    - ECOG performance status of 0, 1, or 2
    - No previous chemotherapy or endocrine therapy.
    - No previous diagnosis of malignancy unless: managed by surgical or radiological treatment only, and disease-free for 10 years, or previous basal cell carcinoma, cervical carcinoma in situ or ductal carcinoma in situ of the breast treated by surgery only.
    - Non-pregnant and non-lactating, with no intention of pregnancy during chemotherapy, and prepared to adopt adequate barrier contraceptive measures if there is any possibility of pregnancy (males and females).
    - No concomitant medical or psychiatric problems that might prevent completion of treatment or follow-up.
    - 18 years or older
    - Male or female
    - Written informed consent for the study.
    - Randomisation is recommended within 4 weeks of biopsy and chemotherapy should start 1 week after randomisation
    - Availability of paraffin embedded tumour blocks, from pre-chemotherapy biopsy and from surgical specimen, with corresponding slides, is required.
    - Adequate hepatic function defined as
    - AST/ALT <1.5xULN
    - Alkaline phosphatase ≤2xULN
    - Bilirubin within normal range. If AST/ALT and Alkaline phosphatase are within normal limits then isolated elevation of bilirubin to ≤3xULN and a presumptive diagnosis of Gilbert’s syndrome is permitted.
    - Adequate renal function with Creatinine ≤1.5xULN
    - Adequate bone marrow function defined as
    - Hb≥10 g/dL; WBC≥3xunits/L; platelets> 100xunits/L
    - Prothrombin time (PT) and Partial thromboplastin time (PTT/ aPTT) ≤1.5xULN.
    E.4Principal exclusion criteria
    •HER2 positive invasive breast cancer (IHC 3+ or FISH positive)
    •T0 and T1 tumours in absence of large (total tumour size >20mm) or fixed axillary nodes
    •Evidence of metastatic disease.
    •Prior diagnosis of ishaemic heart disease, cerebrovascular disease, peripheral vascular disease, arterial or venous thromboembolic disease, cardiac failure
    •Prior diagnosis of gastroduodenal ulcer, symptomatic diverticulitis, inflammatory bowel disease.
    •Bleeding diathesis.
    •On therapeutic full dose of anti-coagulants, aspirin, clopidogrel or corticosteroids
    •Uncontrolled hypertension defined by a systolic pressure >150mmHg and/or
    diastolic pressure >90mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
    •Presence of active uncontrolled infection
    •History of nephritic or nephrotic syndrome
    •Major surgical procedure or traumatic injury within 28 days prior to randomisation.
    •Any evidence of other disease which in the opinion of the investigator places the patient at high risk of treatment related complication.
    •Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent completion of treatment or follow-up.
    •Non-healing wound, or peptic ulcer, or bone fracture.
    •On LHRH-agonists for ER strongly positive disease
    E.5 End points
    E.5.1Primary end point(s)
    Complete pathological response (pathCR) rates (tumour and lymph nodes) after neoadjuvant chemotherapy defined as no residual invasive carcinoma within the breast (DCIS permitted) AND no evidence of metastatic disease within the lymph nodes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    We aim to have completed analysis of the primary endpoint within 3 years of recruitment completion.
    E.5.2Secondary end point(s)
    • Disease-Free Survival
    • Overall Survival
    • pathCR rate in breast alone
    • Radiological (ultrasound) response after 3 and after 6 cycles of chemotherapy.
    • Rate of breast conservation
    • Toxicities and safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    We aim to have completed analysis of the secondary endpoints within 3 years of recruitment completion.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    standard chemotherapy
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned67
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the intervention period of the trial will be 1 year after the last patient completes trial treatment (expected to be approximately second quarter 2013). The non-interventional observation period of the trial will continue for at least 10 years following the completion of surgery of the last patient to enter the trial (per the follow-up protocol mentioned above); projected to be 2023.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years14
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 800
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state800
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-05-20
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