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    Summary
    EudraCT Number:2013-002403-34
    Sponsor's Protocol Code Number:009175QM
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-03-31
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2013-002403-34
    A.3Full title of the trial
    A Randomized Phase II Study of Fulvestrant in Combination with the dual mTOR Inhibitor AZD2014 or Everolimus or Fulvestrant alone in Estrogen Receptor-Positive Advanced or Metastatic Breast Cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized Phase II study comparing treatment combinatons of Fulvestrant and AZD2014, Fulvestrant and Everolimus or Fulvestrant alone for patients with advanced or metastatic breast cancer.
    A.3.2Name or abbreviated title of the trial where available
    MANTA
    A.4.1Sponsor's protocol code number009175QM
    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 SponsorQueen Mary, University of London
    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 supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCovance Clinical and Periapproval Services Limited, organizační složka
    B.5.2Functional name of contact pointMonika Kocourkova
    B.5.3 Address:
    B.5.3.1Street AddressBusiness Centrum Zálesí, building A2, Pod Višňovkou 1661/31
    B.5.3.2Town/ cityPraha 4 Krč
    B.5.3.3Post code140 00
    B.5.3.4CountryCzech Republic
    B.5.4Telephone number00420702 019 121
    B.5.6E-mailmonika.kocourkova@covance.com
    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 nameAZD2014
    D.3.2Product code AZD2014
    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 INNAZD2014
    D.3.9.2Current sponsor codeAZD2014
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 2
    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.2.1.2Country which granted the Marketing AuthorisationHungary
    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 nameEverolimus
    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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 3
    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 nameAZD2014
    D.3.2Product code AZD2014
    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 INNAZD2014
    D.3.9.2Current sponsor codeAZD2014
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 4
    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 nameAZD2014
    D.3.2Product code AZD2014
    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 INNAZD2014
    D.3.9.2Current sponsor codeAZD2014
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 5
    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.2.1.2Country which granted the Marketing AuthorisationHungary
    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 nameEverolimus
    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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Estrogen receptor-positive advanced or metastatic 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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Determine whether dual inhibition of mTORC 1 and mTORC2 with AZD2014 will increase the anti-tumour activity of endocrine treatment with fulvestrant in ER-positive advanced or metastatic breast cancer.
    • Determine whether inhibition of both mTORC 1 and mTORC2 using AZD2014 will have superior anti-tumour activity compared to inhibition of mTORC1 alone with everolimus, when combined with fulvestrant
    • Evaluate the efficacy and safety of an intermittent schedule of AZD2014 relative to continuous daily dosing of AZD2014
    • Explore whether additional efficacy is likely to be present in a subgroup with PI3K-pathway activation for whom it is hypothesised that there will be greater sensitivity to mTOR inhibitors
    • Characterize the patient population who might benefit from fulvestrant plus AZD2014 to identify potential predictors of sensitivity
    E.2.2Secondary objectives of the trial
    - Estimate the clinical benefit, assess the clinical activity (measured by repsonse rate per RECIST 1.1), clinical benefit rate, duration of clinical benefit and duration of response and establish the safety and tolerability and overall survival benefit of the Fulvestrant + AZD2014 continuous and intermittent schedule relative to each other and Fulvestrant + Everolimus and Fulvestrant alone.
    - Investigate the effects of fulvestrant +/- AZD2014 or everolimus on bone-turnover biomarkers
    - Compare the differences in patient reported outcomes as measured by the Functional Assessment of Cancer Therapy-General (FACT-G) scale together with the Breast-Anti-A and Endocrine Symptom (FACTAnti-A-ES) subscales
    - Investigate the pharmacokinetics of AZD2014 in breast cancer patients co-administered with fulvestrant
    - Determine the minimum plasma concentration at steady state in breast cancer patients of fulvestrant alone and when administered in combination with AZD2014 or everolimus
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient must meet all of the following inclusion criteria to be enrolled in the study:
    1. Written informed consent prior to admission to this study
    2. Women, age ≥18 years
    3. Histologically confirmed breast cancer
    4. Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible).
    5. Patients must have:
    a. at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
    b. lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
    6. Radiological or clinical evidence of recurrence or progression
    7. ER-positive disease, defined as tumour cells being positive for ER with ≥ 1% of tumour cells positive for ER on IHC or IHC score (Allred) of ≥ 3
    8. HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
    9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing
    10. Postmenopausal women. Women will be considered postmenopausal if they meet one of the following criteria:
    a. Age >= 50 years and 1 year or more of amenorrhea
    b. Age < 50 years and 1 year or more of amenorrhea, with an estradiol assay < 20pg/mL
    c. Age < 50 with prior hysterectomy but intact ovaries with an estradiol assay < 20pg/mL
    d. Status after bilateral oophorectomy (>= 28 days prior to first study treatment)
    Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
    11. Disease refractory to aromatase inhibitors (AI), defined as
    a. Disease recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, anastrozole, or exemestane.
    b. Progression while on, or within one month of end of letrozole, anastrozole or exemastane treatment for locally advanced or metastatic Breast Cancer.
    Note: Any number of lines of hormonal therapy before or after AI therapy is allowed.
    Note: Letrozole, anastrozole or exemestane do not have to be the last treatment prior to randomisation.
    12. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation
    a. ANC >= 1500 cells/µl, haemoglobin >= 9g/dl, and platelet count >= 100000/µl.
    b. Serum Creatinine < 1.5 times ULN or > 1.5 times ULN concurrent with creatinine clearance ≥ 50ml/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.
    c. Bilirubin level < 1.5 x ULN if no demonstrable liver metastases or < 3 times ULN in the presence of liver metastases.
    d. AST or ALT < 2.5 x ULN.
    e. International normalized ratio (INR) < 1.5 and activated partial thromboplastin time (aPTT) < 1.5 x ULN; for patients requiring therapeutic anticoagulation therapy, a stable INR ≤ 2.5 x ULN is required to mitigate potential bleeding.
    f. No clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium.
    g. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved.
    13. ECOG performance status 0-2
    14. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, bilateral oopheroctemy, bilateral tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year)
    E.4Principal exclusion criteria
    1. Presence of life-threatening metastatic visceral disease.
    2. More than one line of prior chemotherapy for metastatic breast cancer.
    3. Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other anticancer agents or any investigational agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites), radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4 weeks of starting study treatment, or strontium-90 (or other radiopharmaceuticals) within the past 3 months or major surgery within 4 weeks prior to entry into the study.
    4. Prior treatment with fulvestrant or everolimus.
    5. Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.
    6. Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomisation are allowed.
    7. Current refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the study medication.
    8. Clinically significant pulmonary dysfunction.
    9. Significant cardiovascular disease.
    10. QTc prolongation defined as a QTc interval >470 msecs or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min).
    11. Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age).
    12. Clinically significant abnormalities of glucose metabolism.
    13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within the specified wash-out periods before the first dose of study treatment.
    14. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolizing enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1) and BCRP within the appropriate wash-out period before the first dose of study treatment.
    15. Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before receiving study drug.
    16. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
    17. History of hypersensitivity to active or inactive excipients of AZD2014 or everolimus or drugs with a similar chemical structure or class to AZD2014 or everlimus.
    18. History of hypersensitivity to active or inactive excipients of fulvestrant and/or castor oil.
    19. Patients presenting with anaemia symptoms (anaemia classed as haemoglobin < 90 g/L).
    20. Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy (last dose ≤ 7 days prior to randomisation).
    21. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
    22. Detained persons or prisoners.
    23. Pregnant or nursing women (including no breast feeding from two weeks before the first dose of study medication, till 8 weeks after the last dose of study medication).
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure for this study is progression-free survival.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression-free survival (PFS), defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first..
    E.5.2Secondary end point(s)
    The secondary outcome measures for this study are:
    1. Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.
    2. Objective response, defined as a complete or partial response, based on investigator and IRF assessment using RECIST 1.1
    3. Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1; tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions
    4. Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks, based on investigator and IRF assessment using RECIST 1.1)
    5. Overall survival, defined as the time from date of randomisation to the date of death due to any cause
    6. Duration of response, defined as the time from first documentation of complete or partial response to disease progression based on investigator and IRF assessment using RECIST 1.1
    7. Duration of clinical benefit, defined as the time from randomisation to disease progression based on investigator and IRF assessment using RECIST1.1 in patients with CB
    8. Percentage change in serum of serum beta C-terminal cross-linking telopeptide of Type I collagen (βCTx) and N-terminal propeptide of Type I procollagen (PINP) from screening/baseline to each time that samples are collected.
    9. Patient reported outcomes, as assessed by the Functional Assessment of Cancer Therapy-General (FACT-G) scale together with the Breast-Anti-A and Endocrine Symptom (Anti-A-ES) subscales.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy 1. Assessed at the end of the study by an independent review facility (IRF). 2. Assessed at the end of patient treatment (Investigator) and at the end of the study (IRF). 3. Assessed at week 16 and at the end of the trial. 4. Assessed at ≥24 weeks (investigator) and at the end of the study (IRF). 5. Assessed on patient death. 6&7. Assessed at disease progression (investigator) and at the end of the study (IRF). 8. Assessed at when the last patient has given their last sample for analysis. 9. Assessed when the last patient has submitted their last FACT questionnaire. Safety Assessed at all study visits and analysed at the end of the study. Pharmacokinetics Analysed when final patient submits last sample. Exploratory When final patients submits last sample.
    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 Yes
    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 Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA84
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Georgia
    Korea, Republic of
    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
    For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 2001/20/EC, the study is deemed to have ended 30 days after the last patient receives the last dose of the investigational medicinal product (IMP). For all other purposes, the study end date is deemed to be the date of last data capture.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days14
    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: 197
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 119
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 258
    F.4.2.2In the whole clinical trial 316
    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)
    when the study is closed by the Sponsor. At the end of the study, the study doctors will discuss treatment options with the participants and ensure their on-going care.
    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 Decision2015-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-18
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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