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    The EU Clinical Trials Register currently displays   35504   clinical trials with a EudraCT protocol, of which   5838   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2014-002249-22
    Sponsor's Protocol Code Number:D-V
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-03-23
    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 number2014-002249-22
    A.3Full title of the trial
    DETECT V/CHEVENDO: A multicenter, randomized phase III study to compare chemo- versus endocrine therapy in combination with dual HER2-targeted therapy of Herceptin® (trastuzumab) and Perjeta® (pertuzumab) plus Kisqali® (ribociclib) in patients with HER2 positive and hormone-receptor positive metastatic breast cancer.
    DETECT V/CHEVENDO: Eine multizentrische, randomisierte Phase III-Studie zum Vergleich einer Chemo- versus einer endokrinen Behandlung in Kombination mit einer dualen HER2-gerichteten Herceptin® (Trastuzumab)/ Perjeta® (Pertuzumab)-Therapie plus Kisqali® (Ribociclib) bei Patientinnen mit HER2-positivem und hormonrezeptorpositivem metastasiertem Brustkrebs.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of patients with metastatic breast cancer with cancer cells bearing a HER2-protein and a hormone-receptor protein on the surface with a chemo- in comparison to an anti-hormone therapy in combination with a dual therapy directed against the HER2.
    Behandlung von Patientinnen mit metastasierenden Brustkrebs, bei dem die Krebszellen das HER2-Protein sowie einer Hormon-Rezeptor tragen, mit einer Chemo- im Vergleich zu einer anti-Hormontherapie in Kombination mit einer dualen gegen den HER2-Rezeptor gerichteten Therapie (Herceptin® (Trastuzumab)/ Perjeta® (Pertuzumab)).
    A.3.2Name or abbreviated title of the trial where available
    DETECT V / CHEVENDO
    DETECT V / CHEVENDO
    A.4.1Sponsor's protocol code numberD-V
    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 supportRoche
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportJanssen Diagnostics LLC
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportNovartis
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportCelgene
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportEisai
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsfrauenklinik 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 number004937150058520
    B.5.5Fax number004937150058526
    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 Perjeta
    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 namePertuzumab
    D.3.2Product code Perjeta® (Pertuzumab), RO4368451
    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 INNPERTUZUMAB
    D.3.9.1CAS number 380610-27-5
    D.3.9.3Other descriptive namePERTUZUMAB
    D.3.9.4EV Substance CodeSUB16455MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 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 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 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 Herceptin®
    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 nameTrastuzumab
    D.3.4Pharmaceutical form Powder 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 INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 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 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: 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 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 nameCapecitabine
    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 INNCapecitabine
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    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 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 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 namePaclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    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 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 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.3.9.3Other descriptive nameDOCETAXEL
    D.3.9.4EV Substance CodeSUB12492MIG
    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 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 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 nameVinorelbine
    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 INNVINORELBINE
    D.3.9.1CAS number 71486-22-1
    D.3.9.4EV Substance CodeSUB00069MIG
    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 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 nameExemestane
    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 INNExemestane
    D.3.9.3Other descriptive nameEXEMESTANE
    D.3.9.4EV Substance CodeSUB07492MIG
    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 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 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 nameLetrozol
    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 INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeSUB08444MIG
    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: 9
    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 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 nameAnastrozol
    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.3.11 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: 10
    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 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 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.3.11 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: 11
    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 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 nameFulvestrant
    D.3.4Pharmaceutical form Solution for injection
    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.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    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: 12
    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 ABRAXANE®
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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.3.4Pharmaceutical form Powder 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 Yes
    D.3.11.13.1Other medicinal product typeThe IMP contains an excipient of biological origin, albumin, a non-active stabilizing agent. It is derived from human blood subject to approved donor screening and product manufacturing processes.
    D.IMP: 13
    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 Halaven®
    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 nameHalaven®
    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: 14
    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 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 nameKisqali®
    D.3.4Pharmaceutical form 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.3.9.4EV 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.IMP: 15
    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 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 nameGoserelin
    D.3.4Pharmaceutical form Implant in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGOSERELIN
    D.3.9.1CAS number 65807-02-5
    D.3.9.4EV Substance CodeSUB07962MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.6
    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: 16
    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 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 nameLeuprolide
    D.3.4Pharmaceutical form Suspension for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLEUPRORELIN
    D.3.9.1CAS number 53714-56-0
    D.3.9.3Other descriptive nameLeuprolide
    D.3.9.4EV Substance CodeSUB08449MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.75; 11.25
    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
    Patients with HER2-positive and hormone-receptor positive metastatic breast cancer
    Patienten mit HER2-positivem und hormonrezeptorpositivem, metastasierendem Brustkrebs
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic breast cancer, whose cancer cells have HER2 and hormone receptor proteins on their surface
    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
    Primary objective (before amendment)
    Assessment of safety of dual HER2-targeted ther. with Herceptin® (trastuzumab) and Perjeta® (pertuzumab) + endocrine ther. compared to dual HER2-targeted ther. with Herceptin® (trastuzumab) and Perjeta® (pertuzumab) + chemother. in patients with HER2-pos., hormone-receptor pos. metastatic breast cancer. Safety: Proportion of patients experiencing any AE (as defined by the modified AE score) during treatment period.
    New primary objective
    Assessment of tolerability of dual HER2-targeted ther. with Herceptin® and Perjeta® + Kisquali® and standard endocrine ther. compared to dual HER2-targeted ther. with Herceptin® and Perjeta® + chemother. (followed by endocrine therapy + ribociclib in combination with trastuzumab and pertuzumab as maintenance ther.) in patients with HER2-pos., hormone-receptor pos. metastatic breast cancer. Tolerability: Proportion of patients experiencing any AE as defined by the modified AE score during treatment period.
    Primärer Studienendpunkt (vor Amendment)
    Evaluation Verträglichkeit der dualen HER2-gerichteten Ther. (Trastuzumab + Pertuzumab) in Komb. mit einer endokrinen Ther. vs der dualen HER2-gerichteten Ther. in Komb. mit einer Chemother. bei Pat. mit HER2-pos., hormonrezeptorpos. metastasiertem Brustkrebs. Sicherheit/Verträglichkeit: Anteil an Pat. mit UEs (AEs) während des Behandlungszeitraums (Definition nach dem modifizierten „AE score“).
    Neuer primärer Studienendpunkt
    Vergleich der Verträglichkeit der dualen HER2-gerichteten Therapie (Trastuzumab plus Pertuzumab) in Kombination mit Ribociclib und endokriner Therapie versus der dualen HER2-gerichteten Therapie in Kombination mit einer Chemotherapie (gefolgt von einer Erhaltungstherapie mit Trastuzumab und Pertuzumab plus Ribociclib und endokrine Therapie). Sicherheit/Verträglichkeit: Anzahl an UEs (AEs) während des Behandlungszeitraums.
    E.2.2Secondary objectives of the trial
    -Tolerability (proportion of pat. with any AE as def. by the mod. AE score during treatment period) of dual HER2-targ. ther. with Herceptin®and Perjeta® + endocrine ther. compared to + chemother. for:
    --> pat. randomized before add. of ribociclib
    --> pat. randomized before or after the add. of ribociclib
    -primary anal. will be repeated as secondary explorative anal. with specific mod. AE score for the ribociclib cohort
    -quality-adjusted survival (Q-TWiST method) + comp. between both treatment arms (TA)
    -Comp. efficacy of both TA (overall resp. rate, disease cont. r., prog.-free surv., overall surv.) acc. to RECIST v1.1
    -incidence of CNS metast. (by CT or MRI according to RECIST v1.1)
    -eval. of EORTC QLQ-C30 + EORTC QLQ-BR23 questionnaires
    -presence and number of CTCs in peripheral blood + value of CTCs (therapy success)
    -endocrine responsiveness score (ERS) of CTCs + value of ERS (therapy success)
    -toxicity of both TA
    - safety of the study treatments (all grades, all events)
    -Vergleich Verträglichkeit (Anzahl UEs, mod. "AE score") duale HER2-gerichtete Ther. (Trastuzumab + Pertuzumab) + endokrine Ther. vs + Chemotherapie
    --> bei Pat. die vor Amend1 in die Studie eingeschlossen wurden
    --> bei allen in die Studie eingeschlossenen Pat.
    -Primäre Analyse für Ribociclibkohorte (mod. "AE score" beinhaltet zus. Übelkeit, Erbrechen, Durchfall und Stomatitis ab Grad 2)
    -quality-adjusted survival (Q-TWiST-Methode), Vergleich der Behandlungsarmen (BA)
    -Unterschiede der BA (Allgemeinen Ansprechrate, klin. Erfolgsrate,Progressionsfreies Überleben, Gesamtüberleben) entspr. RECIST v1.1
    -Inzidenz ZNS-Metastasen(mittels CT oder MRT nach RECIST Version 1.1)
    -Auswert. EORTC QLQ-C30 und EORTC QLQ-BR23 Fragebögen
    -Vorkommen und Anzahl der CTCs im peripheren Blut (Therapieansprechen)
    -endocrine responsiveness score ERS der CTCs(Therapieansprechen)
    -Toxizitätsanalyse und Vergleich der Toxizität beider BA
    -Sicherheit und Verträglichkeit der Studienmedikation
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Translational research
    Within the DETECT V/CHEVENDO trial, prevalence and number of CTCs in the peripheral blood will be determined parallel to tumor evaluation at baseline (i.e. before the start of treatment), 6 weeks after randomization, and after the 12-month study treatment period or at the time of progression, whatever comes first (if possible in correlation with Re-Staging, e.g. CT-Scan).
    In addition to the quantitative assessment of CTCs, the expression of the markers estrogen receptor (ER) and HER2 on isolated CTCs will be determined using the CellSearch® system (as described by Paoletti et al. 2011). Based on the level of expression for these markers and the proportion of CTCs showing such marker expression, an endocrine responsiveness score (ERS) will be calculated and its predictive value for assessing therapy efficacy will be determined. The generation of an ERS is based on the idea that high expression levels of ER are predictive of responsiveness to endocrine therapy, while high HER2- expression levels are indicative of resistance to endocrine therapy. The aim of this project is to create an ERS that allows to predict the responsiveness of patients with hormone-receptor positive and HER2-positive metastatic breast cancer to a combined endocrine and HER2-targeted therapy.
    E.3Principal inclusion criteria
    Patients will be included in the study only if they meet all the following criteria:
    -Signed, written informed consent in study participation
    -The primary tumor and/or biopsies from metastatic sites or locoregional recurrences have been confirmed as HER2-positive (FISH-positive or IHC 3+) and hormone receptor positive breast cancer by histopathology according to local testing
    -Metastatic breast cancer or locally advanced BC, which cannot be treated by surgery or radiotherapy only
    -Pre- and postmenopausal women are allowed
    -No more than two prior chemotherapies for metastatic disease
    -No more than two prior anti-HER2 therapies for metastatic disease
    -Pertuzumab retreatment is allowed if prior adjuvant /neoadjuvant pertuzumab treatment was finished 12 months before
    -At least one measurable lesion assessable using standard techniques by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)
    -Tumor evaluation according to RECIST version 1.1 has been performed within 4 weeks before randomization based on local assessment
    -Age ≥ 18 years
    -Standard 12-lead ECG values assessed by the local laboratory:
    --QTcF interval at screening < 450 msec (using Fridericia’s correction)
    --Resting heart rate 50-90 bpm
    -Left ventricular cardiac ejection fraction (LVEF) ≥ 50% at baseline (as measured by echocardiogram)
    -ECOG Score ≤ 2
    -Adequate organ function within 14 days before randomization, evidenced by the following laboratory results below:
    --absolute neutrophil count ≥ 1500 cells/μL,
    --platelet count ≥ 100000 cells/μL,
    --hemoglobin ≥ 9 g/dL,
    --ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
    --AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
    --bilirubin ≤ 1.5 × ULN (with the exception of Gilbert’s syndrome)
    --creatinine ≤ 2.0 mg/dl or 177μmol/L
    --INR ≤ 1,5
    -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
    -In case of patients of child bearing potential:
    Negative serum pregnancy test at baseline (within 7 days prior to randomization) and agreement to remain abstinent (if it is in line with the preferred and usual lifestyle) or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment.
    Patientinnen können nur eingeschlossen werden, wenn alle der folgenden Kriterien erfüllt werden:
    -Schriftliches Einverständnis zur Studienteilnahme
    -Bestimmung des HER2-Status des primären Mammakarzinoms und/oder einer Metastase mit HER2-Positivität der Gewebsproben, d.h. Immunhistochmie 3+ oder Fluoreszenz in situ Hybridisierung (FISH) positiv sowie histopathologisch bestätigter Hormonrezeptorpositivität
    -Metastasiertes Mammakarzinom, das einer Operation oder Strahlentherapie alleine nicht zugänglich ist
    -Nicht mehr als 2 vorrangegangenen Chemotherapielinien in der metastasierten Situation
    -Prä- oder postmenapausaler Status
    -Mindestens eine nach RECIST auswertbare metastatische Läsion, entsprechend den RECIST Leitlinien Version 1.1., basierend auf lokaler Beuerteilung.
    -Tumorevaluation nach RECIST Version 1.1 innerhalb von 4 Wochen vor Studienrandomisierung
    -Alter ≥ 18 Jahre
    -12-Kanal-EKG:
    --QTcF Interval bei der Einschlussvisite < 450 msec
    --Ruheherzfrequenz 50-90 s/min
    -Echokardiografischer Nachweis einer linksventrikulären Ejaktionsfraktion (LVEF) ≥ 50% zu Studienbeginn
    -ECOG Score ≤ 2
    -Adäquate Knochenmarksreserve und Organfunktion 14 Tage vor dem Zeitpunkt der Rekrutierung, durch folgende Laborparameter bestätigt:
    --Absolute Neutrophile ≥ 1500/μL
    --Thrombozyten ≥ 100000/μL,
    --Hämoglobin ≥ 9 g/dL
    --ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN bei Lebermetastasierung)
    --AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN bei Lebermetastasierung)
    --Bilirubin (gesamt) ≤ 1.5 × ULN (Ausnahme Gilbert’s Syndrom)
    --Kreatinin ≤ 2.0 mg/dl oder 177μmol/L
    --INR ≤ 1,5
    -Unauffällige Laborwerte für: Natrium, Kalium, Kalzium (Ribociclib-Therapie)
    -Bei Patientinnen im gebärfähigen Alter gilt: Negativer Schwangerschaftstest innerhalb von 7 Tagen vor Randomisierung und sichere Kontrazeption (d.h. einfache oder kombinierte nicht-hormonelle Kontrazeption mit einer Versagerquote < 1% oder komplette sexuelle Abstinenz) während der Behandlungsdauer bis einschließlich 7 Monate nach Einnahmeende der Studienmedikation.
    E.4Principal exclusion criteria
    Patients will be excluded from the study for any of the following reasons:
    -History of hypersensitivity reactions attributed to trastuzumab, pertuzumab, ribociclib or to other components of drug formulation
    -Mandatory need for cytostatic treatment at time of study entry based on clinical judgment and national/international treatment guidelines
    -Known CNS metastases
    -Any concurrent severe, uncontrolled systemic disease, social or psychiatric condition that might interfere with the planned treatment and with the patient’s adherence to the protocol
    -Progression on prior Pertuzumab therapy
    -Treatment with Pertuzumab within the last 12 months
    -Prior treatment with any mTOR- or CDK4/6-inhibitor
    -Treatment with any other investigational agents during trial
    -Known hypersensitivity to lecithin (soya) or peanuts
    -Life expectancy < 6 months
    -Patients with pre-existing grade ≥2 peripheral neuropathy are excluded from taxane-based chemotherapy
    -History of serious cardiac disease, including but not confined to:
    --history of documented heart failure or systolic dysfunction (LVEF < 50%)
    --high-risk uncontrolled arrhythmias i.e., atrial tachycardia with a heart rate ≥100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block) - angina pectoris requiring anti-anginal medication
    --clinically significant valvular heart disease
    --evidence of transmural infarction on ECG - poorly controlled hypertension (e.g., systolic >180 mm Hg or diastolic >100 mm Hg)
    --any other cardiac condition, which in the opinion of the treating physician would make this protocol unreasonably hazardous for the patient
    -Dyspnea at rest or other diseases that require continuous oxygen therapy
    -Patients with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications
    -Patients with known infection with HIV, hepatitis B virus, or hepatitis C virus
    -Male patients
    -Pregnant, lactating or women of childbearing potential without a negative pregnancy test (serum) within 7 days prior to randomization, irrespective of the method of contraception used
    -Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
    -Participation in another clinical study within the 30 days before registration
    -Legal incapacity or limited legal capacity
    Patientinnen können nicht in die Studie eingeschlossen werden, wenn einer der folgenden Punkte zutrifft:
    -Anamnestisch bekannte Überempfindlichkeit gegenüber Trastuzumab, Pertuzumab oder Ribociclib oder chemisch verwandten Bestandteilen bzw. weiteren Bestandteilen der Medikation
    -Vortherapie mit mTOR- oder CDK4/6-Inhibotoren.
    -Zwingende Indikation zur Durchführung einer Chemotherapie
    -Polyneuropathie (PNP) ≥ 2 für Taxantherapie
    -ZNS Metastasen
    -Vorliegen von Erkrankungen oder besonderen sozialen oder psychiatrischen Bedingung, die die adäquate Einschätzung oder Evaluation der Studiendaten gefährden oder die Einhaltung des Studienprotokolls stören oder nach Ansicht des behandelnden Arztes zu einer unverhältnismäßigen Gefährdung der Patientin bei Studienteilnahme führen würde
    -Progress unter Pertuzumab Therapie
    -Behandlung mit Pertuzumab innerhalb der letzten 12 Monate
    -Behandlung mit anderen Prüfsubstanzen während der Studie
    -Unverträglichkeit gegen Soyalecithin und Erdnüsse
    -Lebenserwartung < 6 Monate
    -Manifeste kardiale Vorerkrankungen, einschließlich:
    --Symptomatische Herzinsuffizenz oder LVEF < 50 %
    --Therapiebedürftige oder klinisch relevante Arrhythmien, z.B. Vorhoftachykardien mit einem Ruhepuls ≥100/min, relevante ventrikuläre Arrhythmien (ventrikuläre Tachykardie), höhergradiger AV-Block (2° AV-Block Typ 2 [Mobitz 2] oder 3° AV-Block)
    --behandlungsbedürftige Angina Pectoris
    --klinisch relevante Herzklappenerkrankungen
    --Nachweis einer transmuralen Infarzierung im EKG
    --schlecht kontrollierte art. Hypertonie (z.B. systolisch >180 mm Hg oder diastolisch >100 mm Hg)
    --jede andere kardiale Begleiterkrankung, die nach Ansicht des behandelnden Arztes zu einer unverhältnismäßigen Gefährdung der Patientin bei Studienteilnahme führen würde
    -Ruhedyspnoe oder andere Erkrankungen, die eine kontinuierliche Sauerstofftherapie erfordern
    -Schlecht eingestellter Diabetes mellitus oder Nachweis einer klinisch relevanten diabetischen Vaskulopathie
    -Bekannte HIV-, Hepatitis B- oder Hepatitis C-Erkrankung
    -Männlicher Patient
    -Schwangerschaft oder Stillzeit sowie gebärfähige Patientinnen ohne negativen Schwangerschaftstest in den letzten 7 Tagen vor Studienrandomisierung oder mit unsicheren Verhütungsmethoden
    -Medizinische oder psychologische Gegebenheiten, die das Verständnis oder die Wiedergabe der informierten Einwilligung verhindern oder die Beendigung der Studie stören.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is defined as the proportion of patients that experience any adverse events (as defined by the modified adverse event score and assessed based on NCI CTCAE Version 4.03) during the treatment period.
    The modified adverse event score includes all adverse events grade 3 or higher with the exception of neutropenia, which is only included if rated grade 4, and alopecia, rash, peripheral neuropathy and hand-foot syndrome, all of which are included if rated grade 2 or higher.
    E.5.1.1Timepoint(s) of evaluation of this end point
    every 9 weeks during treatment phase
    E.5.2Secondary end point(s)
    Secondary endpoints are
    1. Specific modified adverse event score including nausea, vomiting, diarrhea and stomatitis grade 2 (in addition to the adverse events included in the modified adverse event score as used for the primary analysis)
    2. 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
    3. Progression free survival (PFS): Time interval from randomization until progressive disease (PD) or death from any cause, whichever comes first (to be assessed by investigator)
    4. Overall response rate (ORR): Rate of complete (CR) and partial responses (PR) in patients with whom target lesions were defined
    5. Clinical benefit rate: Rate of patients who were assessed PR or CR or who had stable disease (SD) for at least 6 months
    6. Overall survival (OS): Time from randomization until death of any cause
    7. Quality of life (QoL): As assessed by evaluation of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
    8. Prevalence of CTCs at baseline and at different time points after the start of palliative treatment including the time of progression (as assessed using the CellSearch® System)
    9. Endocrine responsiveness score (ERS) of CTCs at baseline and at different time points after the start of palliative treatment including the time of progression
    (CR, PR, SD, and PD are defined according to the RECIST Version 1.1 criteria)
    E.5.2.1Timepoint(s) of evaluation of this end point
    every 9 weeks during treatment phase
    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) 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 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) Yes
    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 concerned120
    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 No
    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 years7
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 135
    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 Yes
    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 state270
    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 Decision2015-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-15
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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