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    Summary
    EudraCT Number:2014-004909-33
    Sponsor's Protocol Code Number:LCTU122
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2015-07-27
    Trial 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 number2014-004909-33
    A.3Full title of the trial
    Thrombin Inhibition Preoperatively in Early Breast Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Thrombin Inhibition Preoperatively in Early Breast Cancer
    A.3.2Name or abbreviated title of the trial where available
    TIP
    A.4.1Sponsor's protocol code numberLCTU122
    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 SponsorManchester University 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 supportNIHR Clinical Scientist Award
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCancer Research UK Liverpool Cancer Trials Unit
    B.5.2Functional name of contact pointGreg Gibson
    B.5.3 Address:
    B.5.3.1Street AddressBlock C, Waterhouse Building, 1-3 Brownlow St
    B.5.3.2Town/ cityLiverpool
    B.5.3.3Post codeL69 3GL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01517955289
    B.5.5Fax number01517948250
    B.5.6E-mailgreg.gibson@liverpool.ac.uk
    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 No
    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 nameRivaroxaban 20mg
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRivaroxaban 20mg
    D.3.9.1CAS number 366789-02-8
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Breast Cancer
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Percentage reduction in tumour Ki67 expression in post Rivaroxaban tumour core biopsies compared to pre Rivaroxaban tumour core biopsies
    E.2.2Secondary objectives of the trial
    In pre-treatment compared to post treatment samples, and in between group analysis (no Rivaroxaban vs 10mg Rivaroxaban vs 20mg Rivaroxaban) :

    In post Rivaroxaban compared to pre- Rivaroxaban patient samples:
    • Reduction in tumour tissue expression of TF, TAT and PAR 1 and other procoagulant and stromal activation markers
    • Reduction in tumour tissue expression of CD31 and other angiogenic markers
    • Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL and other apoptotic cell death / survival markers
    • Reduction in Circulating Tumour Cells (CTCs)
    • Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI)
    • Reduction in plasma d-dimer, TF and TAT and other clotting / cancer activity related markers
    • Alterations in proteomics, correlating to tumour response

    All changes in tumour and systemic levels of markers will be analysed as a percentage (pre-post/pre x 100) and an absolute (pre-post) change from baseline.
    Correlation of cancer effects
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Provision of written informed consent.

    World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks

    Patients must be able to swallow and retain oral medication

    Female patients, age over 18, with histological confirmation of ER negative invasive breast carcinoma

    AJCC Stage 1 - 3 with primary tumour in the breast amenable to biopsies

    Scheduled to have definitive breast surgery 11 or more days after study entry

    Tumour size ≥10mm (large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy (free-hand or under ultrasound guidance as per local protocols).

    As judged by the site's Principal Investigator, no evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.

    Full blood count, renal and liver biochemistry (within 10% of laboratory normal limits)

    EGFR above 50.
    E.4Principal exclusion criteria
    Tumour size <10mm

    Prior treatment for breast or other cancer (excluding non-melanoma skin cancer)

    Concurrent anticoagulant therapy (excluding antiplatelet therapy such as aspirin or clopidogrel)

    Concurrent treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors), dronedarone and strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort

    Major surgery within 4 weeks before the first dose of study treatment.

    Conditions associated with an increased risk of bleeding:
    a. Major surgery or trauma within the previous month
    b. Hemorrhagic disorder or bleeding diathesis
    c. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra‐articular bleeding
    d. Gastrointestinal hemorrhage within the past year
    e. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days
    f. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm
    g. Need for anticoagulant treatment of disorders other than atrial fibrillation
    h. Fibrinolytic agents within 48 hours of study entry
    i. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg

    Participation in another interventional trial
    E.5 End points
    E.5.1Primary end point(s)
    Percentage reduction in tumour Ki67 expression in post Rivaroxaban tumour core biopsies compared to pre Rivaroxaban tumour core biopsies
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint will be evaluated following the recruitment of the last patient
    E.5.2Secondary end point(s)
    In patients receiving preoperative Rivaroxaban, to determine (in post treatment compared to pre-treatment patient samples) if:
    • Mammosphere Forming Efficiency (MFE) of cultured patient tumour tissue is inhibited
    • Tumour tissue demonstrates a reduction in expression of thrombin pathway related markers [Tissue Factor (TF), thrombin-antithrombin (TAT) and Protease Activated Receptor (PAR 1)]
    • Tumour tissue demonstrates an increase in the apoptotic markers, cleaved Caspase 3 expression and TUNEL
    • Tumour demonstrates an increase in the cell cycle inhibitor p27
    • Tumour tissue demonstrates a reduction in the angiogenic marker CD31
    • Circulating tumour cell (CTC) numbers decrease
    • Circulating free DNA (cfDNA) is increased and cfDNA Integrity (cfDI) is decreased
    • Plasma d-dimer, TF and TAT decrease
    • Identification of proteomic biomarkers of response

    To determine if there is a dose-response to Rivaroxaban in the above measures

    All the above markers will be compared in pre-treatment compared to post-treatment samples, and in post treatment Rivaroxaban compared to placebo arms. In addition, the Rivaroxaban subgroup (divided 1:1 to 20mg once daily [od] or 10mg Rivaroxaban od) will have within-group assessment of dose response using the above markers.
    Changes in markers of proliferation (Ki67 and p27), apoptosis (cleaved Caspase 3, TUNEL), angiogenesis (CD31), cfDNA, cfDI, proteomics and changes in MFE and CTC numbers will be correlated to tumour and systemic thrombin pathway activation (tissue TF, TAT, PAR1 and plasma d-dimer, TF and TAT respectively).
    To determine if Ki67 score on Tissue MicroArray (TMA) constructs correlation with whole section Ki67 score.
    To determine if Ki67 score on TMA constructs determined manually correlates with automated Ki67 score
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoint will be evaluated following the recruitment of the last patient
    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 No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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
    No treatment (standard care is surgery)
    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 concerned6
    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 trial is when the database is locked. As the follow up time of each patient is relatively short, adequate time will be needed to ensure that the trial data is cleaned sufficiently for analysis.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 No
    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 state81
    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)
    If the trial is stopped, patients will be treated and followed up according to local practice.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Greater Manchester NIHR CRN
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-13
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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