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    Summary
    EudraCT Number:2013-001269-18
    Sponsor's Protocol Code Number:D-IVa/D-IVb
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-30
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-001269-18
    A.3Full title of the trial
    A multicenter phase II study in patients with HER2-negative metastatic breast cancer and persisting HER2-negative circulating tumor cells (CTCs).
    DETECT IV – Multizentrische, prospektive, offene Phase II Studie bei Patintinnen mit HER2-negativem metastasiertem Brustkrebs und persisitierenden HER2-negativen zirkulierenden Tumorzellen (CTCs).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DetectIV - Treatment of patients with advanced metastatic breast cancer and circulating blood cells devoid of Her2/neu.
    DetectIV - Behandlung von Patientinnen mit metastierendem Brustkrebs, bei denen die im zirkulierenden Tumorzellen kein Her2/neu aufweisen.
    A.3.2Name or abbreviated title of the trial where available
    DETECT - IV
    DETECT - IV
    A.4.1Sponsor's protocol code numberD-IVa/D-IVb
    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 SponsorUniversitätsklinikum Ulm (AöR)
    B.1.3.4CountryGermany
    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 supportNovartis GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportVeridex
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportEisai GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportTeva GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniverstitäsfrauenklinik Ulm
    B.5.2Functional name of contact pointStudienzentrale
    B.5.3 Address:
    B.5.3.1Street AddressPrittwitzstr. 43
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89075
    B.5.3.4CountryGermany
    B.5.4Telephone number004973150058520
    B.5.5Fax number004973150058526
    B.5.6E-mailstudienzentrale.ufk@uniklinik-ulm.de
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameAfinitor
    D.3.4Pharmaceutical form 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.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    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: 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.2.1.2Country 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 nameExemestan
    D.3.4Pharmaceutical form 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 INNExemestan
    D.3.9.3Other descriptive nameEXEMESTANE
    D.3.9.4EV Substance CodeSUB07492MIG
    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: 3
    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.2.1.2Country 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 nameFemara
    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 INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 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.2.1.2Country 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 nameArimidex
    D.3.4Pharmaceutical form 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 INNAnastrozole
    D.3.9.3Other descriptive nameANASTROZOLE
    D.3.9.4EV Substance CodeSUB05502MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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.2.1.2Country 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 nameTamoxifen
    D.3.4Pharmaceutical form 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 INNTAMOXIFEN
    D.3.9.1CAS number 10540-29-1
    D.3.9.4EV Substance CodeSUB10825MIG
    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.IMP: 6
    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 Havalen
    D.2.1.1.2Name of the Marketing Authorisation holderEisai GmbH
    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 nameHavalen
    D.3.2Product code 300558
    D.3.4Pharmaceutical form Solution for injection
    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 INNEribulin
    D.3.9.1CAS number 441045-17-6
    D.3.9.3Other descriptive nameERIBULIN MESYLATE
    D.3.9.4EV Substance CodeSUB31126
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.44
    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: 7
    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.2.1.2Country 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 nameFaslodex
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNfulvestrant
    D.3.9.1CAS number 129453-61-8
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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: 8
    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 Kisqali
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameKisqali
    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 INNRIBOCICLIB
    D.3.9.1CAS number 1211441-98-3
    D.3.9.3Other descriptive nameribociclib
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Everolimus/ribociclib cohort (D-IVa):
    Postmenopausal female patients with hormone-receptor positive, HER2-negative metastatic breast cancer with HER2-negative circulating tumor cells (CTCs) and indication for standard endocrine therapy.

    Eribulin cohort (D-IVb):
    Patients with hormone-receptor positive, HER2-negative metastatic breast cancer and indication to chemotherapy or patients with triple-negative metastatic breast cancer, both with HER2-negative circulating tumor cells (CTCs).
    E.1.1.1Medical condition in easily understood language
    Patients with HER2-negative metastatic breast cancer and persisting HER2-negative circulating tumor cells (CTCs).
    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
    Everolimus/Ribociclib cohort (DIVa)
    The primary objective is to investigate the clinical efficacy of everolimus/ribociclib (as assessed by the CTC clearance rate) in combination with endocrine therapy in postmenopausal patients with hormone-receptor positive, HER2-negative metastatic breast cancer and persisting HER2-negative circulating tumor cells (CTCs).

    Eribulin cohort (DIVb)
    The primary objective is to investigate the clinical efficacy of eribulin (as assessed by progression-free survival, PFS) both in patients with HER2-negative, hormone-receptor positive metastatic breast cancer and indication to chemotherapy and triple-negative metastatic breast cancer both with persisting HER2-negative CTCs.
    E.2.2Secondary objectives of the trial
    • Evaluation of efficacy of the study treatment as assessed by overall response rate (ORR), disease control rate (DCR), and overall survival (OS)
    • Assessment of the dynamic of CTCs by longitudinal comparisons of CTC counts before during and after treatment and evaluation of the value of different measures of CTC dynamics for prognosis and assessing therapy efficacy
    • Assessment of Quality of Life (QoL) as evaluated based on the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
    • Assessment of quality-adjusted survival (as calculated by the Q-TWiST method)
    • Assessment of toxicity, safety and tolerability of the study treatments (everolimus/ribociclib or eribulin)
    • Evaluation of compliance to study procedures
    • Evaluation of efficacy of the study treatment as assessed by progression-free survival (PFS) (Everolimus/Ribociclib cohort (DIVa))
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    TRAFO-Projects:
    Everolimus/Ribociclib cohort (DIVa):
    • Establishing of immune histochemistry and assessment of the response of phosphorylated ribosomal protein S6 (pS6) analysed in CTCs to treatment
    • Evaluation of the correlation of pS6 levels analysed in CTCs with clinical outcome (PFS)
    • Assessment of the activation of the PI3K/Akt/mTOR-pathway in CTCs (SNaPshot methodology for PI3KCA mutations)
    • Establishing and assessment of immune histochem-istry for pAKT and PTEN in CTCs
    • Establishing the analysis of estrogen-receptor 1 (ESR-1) mutations via SNaPshot methodology in CTCs
    • Expression of Epithelial Mesenchymal Transition inducing transcription factors in CTCs
    • Resistance to anoikis in CTCs
    • Expression of LKB1 in CTC
    • Molecular profiling of CTCs in breast cancer
    • Quantification of circulating microRNAs miR-125a, miR-125b, miR-18a und miR18b in the serum of breast cancer patients

    Eribulin cohort (DIVb)
    • Evaluation of efficacy of the study treatment as assessed by new metastasis-free survival (nMFS)
    • To determine the androgen receptor (AR) expression on CTCs using AR specific monoclonal antibody
    • To determine mutation status of AR by PCR amplification of AR exons followed by sequencing analysis
    • To determine PIK3CA mutations on CTC based on SNaPshot technology
    • To isolate Eribulin resistant CTCs from TNBC patients and to characterize them on the molecular level with a special focus on the correlation between EMT and their capacity to overcome anoikis.
    • To determine the predictive values of the detection of aberrant 53BP1 signals on CTCs and genetic alterations in BRCA1 in peripheral blood samples as potential biomarkers for responsiveness to therapy with Eribulin in patients with TNBC and persisting HER2-negative CTCs.
    • To assess the dynamic of 53BP1 signals on CTCs by longitudinal comparisons before, during, and after treatment, to evaluate the suitability of the different measures for assessing therapy efficacy
    E.3Principal inclusion criteria
    In general:
    1. Metastatic breast cancer, which cannot be cured by surgery or radiotherapy. The primary tumor and/or biopsies must have be confirmed as cancer by histolopathology.
    2. HER2 status (as investigated on all primary tumor tissue and/or biopsies from metastatic sites or loco regional recur-rences) must be negative. HER2-negativity is defined as (i.e.: immunohistochemistry (IHC) score 0-1+ or 2+ and fluorescent in situ hybridization (FISH) negative or just FISH negative, whichever was performed) in all tissue samples.
    3. Evidence of CTCs. At least one CTC has been detected in 7.5 ml patient blood by means of the CellSearch® Circulating Tumor Cell Kit (Veridex LLC, Raritan, USA).
    4. HER2 negativity of all detected CTCs.
    5. Adequate organ function within 7 days before date of recruitment.
    6. Written informed consent in study participation.
    7. Undergoing a re-biopsy prior to inclusion if tissue is accessible, which can be safely biopsied, is otional but desirable.
    8. Tumor evaluation has been performed within 6 weeks before date of recruitment and results are available.
    9. Patients must have at least one not previously irradiated lesion that can be evaluated according to RECIST version 1.1 (Eisenhauer 2009). Patients with measurable and non-measurable disease are eligible. Presence of clinically and/or radiologically documented disease.
    10. Age ≥ 18 years.
    11. ECOG Performance Status ≤ 2.

    Everolimus/ribociclib cohort (DIVa)
    • Indication for an endocrine therapy (Histological confirmation of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer).
    • Up to two lines of previous cytostatic treatment for MBC.
    • Any endocrine therapy in the history is allowed.
    • Cholesterol ≤ 2.0 × ULN.
    • Disease progression following prior treatment with endocrine therapy (endocrine therapy does not have to be the last therapy before inclusion in the trial).
    • Postmenopausal women. The investigator must confirm postmenopausal status
    Postmenopausal status is defined either by
    - Age ≥ 55 years and one year or more of amenorrhea
    - Age < 55 years and one year or more of amenorrhea and postmenopausal levels of FSH and LH
    - Prior hysterectomy and has postmenopausal levels of FSH and LH
    - Surgical menopause with bilateral oophorectomy
    Everolimus cohort:
    • Cholesterol ≤ 2.0 × ULN
    Ribociclib cohort:
    • Standard 12-lead ECG values assessed by the local laboratory:
    - QTcF interval at screening < 450 msec (us-ing Fridericia’s correction)
    - Resting heart rate 50-90 bpm
    • INR ≤ 1,5 (ribocilclib cohort)
    • Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplemets before the first dose of study medication:
    -Sodium
    -Potassium
    -Total calcium


    Eribulin cohort (DIVb)
    • Either hormone-receptor negative MBC or hormone-receptor positive MBC with indication for chemotherapy
    • Up to three previous chemotherapy treatment lines for metastatic disease
    • In case of patients of child bearing potential:
    - Negative pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) within 7 days prior to recruitment
    - Contraception by means of a reliable method (i.e. non-hormonal contraception, IUD, a double barrier method, vasectomy of the sexual partner, complete sexual abstinence). Patient must consent in maintaining such contraception until 3 months after completion of study treatment
    E.4Principal exclusion criteria
    In general:
    1. Treatment with other investigational agents of any type or anticancer therapy during the trial, within 2 weeks prior to the start of treatment.
    2. Adverse events due to prior anticancer therapy which are > Grade 1 (NCI CTCAE) and therapeutically relevant at time of treatment start.
    3. Known HIV infection.
    4. Current active hepatitis B or C, cliniclally relevant known liver dysfunction, e.g. known liver dysfunction according to Child Pugh Classification class B and C, or biliary disease (with exception of patients with Gilbert‘s syndrome, asymptomatic gall-stones, liver metastases or stable chronic non-viral liver disease per investigator assessment).
    5. Concurrent disease or condition that might interfere with adequate assessment or evaluation of study data, or any medical disorder that would make the patient‘s participation unreasonably hazardous.
    6. Other malignant diseases within the last 3 years (apart from carcinoma in situ of the cervix or non-melanoma skin cancer)
    7. Dementia, altered mental status, or any psychiatric or social condition which would prohibit the understanding or rendering of informed consent or which might interfere with the patient‘s adherence to the protocol.
    8. Life expectancy < 3 months.
    9. Male gender.

    Everolimus/Ribociclib cohort (DIVa)
    • Known hypersensitivity to any of the excipients of ribociclib, everolimus or any of the other given drugs.
    • Known hypersensitivity to lecithin (soya) and peanuts (ribocilib-cohort)
    • Disease or condition, which might restrain the ability to take or resorb oral medication. This includes malabsorption syndrome, requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption (for example resection of small bowel or stomach), uncontrolled inflammatory GI disease (e.g., Crohn‘s disease, ulcerative colitis) and any other diseases significantly affecting gastrointestinal function as well as inability to swallow and retain oral medication for any other reason.

    Eribulin cohort (DIVb)
    • History of hypersensitivity reactions attributed to eribulin.
    • Pre-existing neuropathy grade 3 or higher.
    • Severe Congenital long QT syndrome.
    • Pregnancy or nursing.
    E.5 End points
    E.5.1Primary end point(s)
    Everolimus/Ribociclib cohort (DIVa)
    CTC clearance rate: Proportion of patients with at least one CTC detected in 7.5 ml of peripheral blood drawn before treatment that show no evidence of CTCs in the blood after treatment (CTC prevalence as assessed using the Cell-Search® System; Veridex LLC, Raritan, USA)

    Eribulin cohort (DIVb)
    The primary endpoint is progression-free survival (PFS), defined as time interval from date of recruitment until progressive disease (PD) or death from any cause, whichever comes first (as defined by RECIST guideline version 1.1). If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    every 12 weeks
    E.5.2Secondary end point(s)
    In General:
    • Overall response rate (ORR): rate of complete (CR) and partial responses (PR) in patients in whom target lesions were defined
    • Disease control rate (DCR): rate of patients who were assessed as having a PR or a CR or who had stable disease (SD) for at least 6 months
    • Overall survival (OS), defined as the time interval from start of treatment until death due to any cause. If a patient is not known to have died, survival is censored at the date of last contact
    • Dynamic of CTC: Descriptive statistics of regular CTC counts
    • Level of compliance to the study protocol
    • The assessment of safety will be based mainly on the frequency of adverse events. Other safety data (e.g. laboratory values, vital signs, and special tests) will be considered as appropriate
    • Quality of life (QoL) as assessed by evaluation of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
    • Quality-adjusted survival (as assessed by the Q-TWiST method), with the utility scores for the different health states being prospectively determined in the clinical trial subjects based on the EORTC QOL C30 questionnaire

    Everolimus/Ribociclib cohort (DIVa)
    • Progression-free survival (PFS), defined as time interval from date of recruitment until progressive disease (PD) or death from any cause, whichever comes first (as defined by RECIST guideline version 1.1).
    • Dynamic of CTCs: changes in CTC counts from baseline numbers (start of treatment) to the time of first radiological tumor evaluation after about 12 weeks, and every 12 weeks thereafter until progression
    • Levels of pS6 at baseline, at first radiological tumor assessment after about 12 weeks, and at the time of progression
    • Change in the activation of the PI3K/Akt/mTOR-pathway in CTCs as assessed by longitudinal comparisons (at baseline, after 12 weeks, at time of progression)
    • Estrogen-receptor 1 (ESR-1) mutations in CTCs at baseline, after 12 weeks and at time of progression

    Eribulin cohort (DIVb)
    • Dynamic of CTCs: changes in CTC counts from baseline numbers (start of treatment) to first (6 weeks) and second (12 weeks) control visit as well as the time of progression or end of treatment.
    • New metastasis-free survival (nMFS), defined as time from recruitment to death or progression due to appearance of a new metastasis, whichever comes first. If a patient has not had an event, nMFS is censored at the date of last adequate tumor assessment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    every 6 weeks
    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 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 No
    E.8.1.1Randomised No
    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 No
    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 concerned100
    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
    LPLV (last patient last visit)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    E.8.9.1In the Member State concerned months6
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state300
    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)
    patients will be returned to normal clinical treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-17
    P. End of Trial
    P.End of Trial StatusCompleted
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